Response to “The Importance of Clinically Relevant Research When Making Comparisons”

Response to “The Importance of Clinically Relevant Research When Making Comparisons” We thank you for the opportunity to respond to this Letter to the Editor entitled “The Importance of Clinically Relevant Research When Making Comparisons”1 which attempts to critique our recent publication “Hypochlorous Acid vs Povidone-Iodine Containing Irrigants: Which Antiseptic is More Effective for Breast Implant Pocket Irrigation?”2 We wholeheartedly agree with the title of this letter and believe strongly that clinically relevant data should guide clinicians in making the best choices for their patients. For surgical antisepsis, the use of a range of validated in vitro assays should be then backed up by comparative clinical trials before claims of efficacy are made. Unfortunately, at first glance, it appears that Fisher et al are trying their best to discredit our methods and to the indiscriminate reader, their accusation is that we simply dumped a bunch of proteins and did an irrelevant assay. Nothing could be further from the truth. Let us look in detail at the points raised in this letter. It is brave of these authors to criticize a validated in vitro assay as recommended by our regulator, the Therapeutic Goods Administration (TGA). The addition of 5% serum as biological soil is outlined in the Therapeutic Goods Act (1989) Therapeutic Goods Order No. 54—Standard for Disinfectants and Sterilants.3 This protein soil test is a standard that is required of every disinfectant and antiseptic prior to approval for clinical usage in Australia. The Table 1 in the Schedule 1: the TGA Disinfectant Test of Therapeutic Goods Order No. 54 suggests serum (Test option D) as biological soil for antiseptic testing. In section 3.2 for preparing the inoculum, the manual states “add 8 mL of the diluted test organism to 2 mL sheep serum” which will contain 20% serum. In section 6 of the testing procedure, the manual states “add 3 mL of diluted disinfectant to 1 mL of prepared culture organisms.” The final solution is thus a 5% sheep serum as biological soil according to TGA standard, which is exactly what we utilized in our testing. There also appear to be some serious errors in their calculations. They have calculated that the protein content of 5 µL of bovine calf serum (BCS) was 0.00325g and have criticized this as too high. The actual protein content of BCS we added as biological soil (Sigma, Catalog No. 12133C) is 5.8 to 7.1 g/dL (grams per deciliter),4 where 1 dL = 100 mL and 1 mL = 1,000 µL. For our experiment, we added 5 µL of BCS which would give us 5.8 to 7.1 g × 5 × 0.01 × 0.001 = 0.00029g to 0.000355g. This is actually 10-fold lower than what Fisher et al have reported and so we ask them to reconsider their accusation that the protein levels were too high. In fact, if you then compare this protein load to an estimate of residual blood in the implant pocket, they have made a further miscalculation. The BCS contains 5.8 to 7.1 g/dL protein content.4 There is similar protein content in human blood and also sheep serum. The normal total protein range in human blood is between 6 and 8.3 (g/dL).5 The total protein level in healthy sheep serum is 7.1 ± 0.045 g/dL.6 Using 100 mL of PhaseOne (0.025% HOCL) as breast implant pocket irrigants, 5% BCS from our experiment in 100 mL PhaseOne should be equivalent to 5 mL of blood and serum left in surgical pocket, not 60 mL of blood and serum left, as they claim in their response. A residual amount of 5 mL of blood in the implant pocket does simulate the clinical scenario and is the basis of the validation of the TGA Standard for Disinfectants and Sterilants. On the contrary, clinical claims of efficacy in the absence of valid protein testing are misleading and most likely will result in substandard disinfection. Furthermore, a 5 mL blood contamination level is most likely an underestimate of the protein load as it does not take into account residual serum, protein, and fluid from the breast tissue, any residual bacteria from breast parenchyma and skin. The TGA test thus represents a very low protein stress and for HOCL to fail at this load raises serious doubts as to its clinical effectiveness. The authors further mention a further study of clinical effectiveness and analysis of protein content of fluid within surgical pocket for revision surgery and claim that HOCL had “over 250 times the amount required for clinical effectiveness.” We would like to see a reference and methods for this estimate as none were cited. Our science backed analysis is that the 5% BCS protein soil test most likely sits at a level below the actual level of protein and blood contamination. We note that these authors have also previously published on the effectiveness of HOCL against Ralstonia spp.7 In this study, they compared PhaseOne solution (0.025% hypochlorous acid) with 0.35% v/v Betadine, which appears to be a much lower concentration of povidone iodine than is used in clinical practice. Clinical and laboratory studies8 have validated at least 50% v/v Betadine (5% povidone), not 0.35% v/v Betadine. It would be of use to reanalyze the comparative assay using both 5% and 10% povidone as this would be a more meaningful clinically relevant bench study. The authors found that HOCL was effective against a wide range of pathogens in vitro. Our testing also confirmed that hypochlorous acid solution is very effective against bacteria in the absence of a protein challenge.2 This effectiveness was completely neutralized with the presence of clinically relevant protein content. Presence of proteins can act as neutralizers, absorbing the oxidizing capacity of hypochlorous acid, and thus protect bacteria against its direct attack. Incidentally, HOCL also loses antibacterial activity with any significant dilution. This is another major weakness of HOCL compared to current proven breast pocket irrigations. At this stage, PhaseOne only has regulatory approval as a mechanical wound irrigant—similar to saline. There are no proven regulatory claims for its efficacy in clinical antisepsis and until such time as there are some data to support this, it would be premature to claim that it is superior to proven, available, and clinically effective pocket irrigation solutions. Good scientists will take the time to ensure that their calculations and understanding of the scientific method is accurate before jumping to false accusations and erroneous conclusions. Whilst these errors may be simply an oversight, one must also be mindful that the authors of both the letter and previous publication are both owners and/or employees of the company that stands to profit from sale of PhaseOne. It would be better for the evaluation of this product to be undertaken by independent academic institutions using known and accepted standards of antiseptic testing as backed by regulatory authorities. Moreover, any clinical claims of efficacy against capsular contracture and/or reduced biofilm load should wait until such time as evidence from prospective comparative clinical trials emerges. The availability of a good, effective, and clinically proven solution (ie, >5% povidone iodine) should, in the meantime, remain the gold standard for breast implant pocket irrigation. Disclosures The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. Funding The authors received no financial support for the research, authorship, and publication of this article. REFERENCES 1. Fisher J, Brindle CT, Porter S. The importance of clinically relevant research when making comparisons. Aesthet Surg J . 2018; 38( 4): N76- N78. 2. Hu H, Sleiman J, Johani K, Vickery K. Hypochlorous acid versus povidone-iodine containing irrigants: which antiseptic is more effective for breast implant pocket irrigation? Aesthet Surg J . 2017. doi: 10.1093/asj/sjx213. 3. Therapeutic Goods Order No. 54 — Standard for Disinfectants and Sterilants TGA. Therapeutic Goods Act 1989 . https://www.legislation.gov.au/Details/F2009C00327. Accessed January 9, 2018. 4. Bovine Calf Serum Product Information . https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma/Product_Information_Sheet/p12133.pdf. Accessed January 9, 2018. 5. Total protein range in total protein test . https://www.healthline.com/health/total-protein#results. Accessed January 9, 2018. 6. Esmaeilnejad B, Tavassoli M, Asri-Rezaei S, Dalir-Naghadeh B, Pourseyed SH. Evaluation of serum total protein concentration and protein fractions in sheep naturally infected with Babesia ovis. Comp Clin Path . 2014; 23( 1): 151- 155. Google Scholar CrossRef Search ADS   7. Brindle CT, Porter S, Bijlani Ket al.   Preliminary results of the use of a stabilized hypochlorous acid solution in the management of ralstonia pickettii biofilm on silicone breast implants. Aesthet Surg J . 2017. doi: 10.1093/asj/sjx229. 8. Deva AK, Adams WPJr, Vickery K. The role of bacterial biofilms in device-associated infection. Plast Reconstr Surg . 2013; 132( 5): 1319- 1328. Google Scholar CrossRef Search ADS PubMed  © 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Aesthetic Surgery Journal Oxford University Press

Response to “The Importance of Clinically Relevant Research When Making Comparisons”

Loading next page...
 
/lp/ou_press/response-to-the-importance-of-clinically-relevant-research-when-making-Xiz4WJkIco
Publisher
Oxford University Press
Copyright
© 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com
ISSN
1090-820X
eISSN
1527-330X
D.O.I.
10.1093/asj/sjy015
Publisher site
See Article on Publisher Site

Abstract

We thank you for the opportunity to respond to this Letter to the Editor entitled “The Importance of Clinically Relevant Research When Making Comparisons”1 which attempts to critique our recent publication “Hypochlorous Acid vs Povidone-Iodine Containing Irrigants: Which Antiseptic is More Effective for Breast Implant Pocket Irrigation?”2 We wholeheartedly agree with the title of this letter and believe strongly that clinically relevant data should guide clinicians in making the best choices for their patients. For surgical antisepsis, the use of a range of validated in vitro assays should be then backed up by comparative clinical trials before claims of efficacy are made. Unfortunately, at first glance, it appears that Fisher et al are trying their best to discredit our methods and to the indiscriminate reader, their accusation is that we simply dumped a bunch of proteins and did an irrelevant assay. Nothing could be further from the truth. Let us look in detail at the points raised in this letter. It is brave of these authors to criticize a validated in vitro assay as recommended by our regulator, the Therapeutic Goods Administration (TGA). The addition of 5% serum as biological soil is outlined in the Therapeutic Goods Act (1989) Therapeutic Goods Order No. 54—Standard for Disinfectants and Sterilants.3 This protein soil test is a standard that is required of every disinfectant and antiseptic prior to approval for clinical usage in Australia. The Table 1 in the Schedule 1: the TGA Disinfectant Test of Therapeutic Goods Order No. 54 suggests serum (Test option D) as biological soil for antiseptic testing. In section 3.2 for preparing the inoculum, the manual states “add 8 mL of the diluted test organism to 2 mL sheep serum” which will contain 20% serum. In section 6 of the testing procedure, the manual states “add 3 mL of diluted disinfectant to 1 mL of prepared culture organisms.” The final solution is thus a 5% sheep serum as biological soil according to TGA standard, which is exactly what we utilized in our testing. There also appear to be some serious errors in their calculations. They have calculated that the protein content of 5 µL of bovine calf serum (BCS) was 0.00325g and have criticized this as too high. The actual protein content of BCS we added as biological soil (Sigma, Catalog No. 12133C) is 5.8 to 7.1 g/dL (grams per deciliter),4 where 1 dL = 100 mL and 1 mL = 1,000 µL. For our experiment, we added 5 µL of BCS which would give us 5.8 to 7.1 g × 5 × 0.01 × 0.001 = 0.00029g to 0.000355g. This is actually 10-fold lower than what Fisher et al have reported and so we ask them to reconsider their accusation that the protein levels were too high. In fact, if you then compare this protein load to an estimate of residual blood in the implant pocket, they have made a further miscalculation. The BCS contains 5.8 to 7.1 g/dL protein content.4 There is similar protein content in human blood and also sheep serum. The normal total protein range in human blood is between 6 and 8.3 (g/dL).5 The total protein level in healthy sheep serum is 7.1 ± 0.045 g/dL.6 Using 100 mL of PhaseOne (0.025% HOCL) as breast implant pocket irrigants, 5% BCS from our experiment in 100 mL PhaseOne should be equivalent to 5 mL of blood and serum left in surgical pocket, not 60 mL of blood and serum left, as they claim in their response. A residual amount of 5 mL of blood in the implant pocket does simulate the clinical scenario and is the basis of the validation of the TGA Standard for Disinfectants and Sterilants. On the contrary, clinical claims of efficacy in the absence of valid protein testing are misleading and most likely will result in substandard disinfection. Furthermore, a 5 mL blood contamination level is most likely an underestimate of the protein load as it does not take into account residual serum, protein, and fluid from the breast tissue, any residual bacteria from breast parenchyma and skin. The TGA test thus represents a very low protein stress and for HOCL to fail at this load raises serious doubts as to its clinical effectiveness. The authors further mention a further study of clinical effectiveness and analysis of protein content of fluid within surgical pocket for revision surgery and claim that HOCL had “over 250 times the amount required for clinical effectiveness.” We would like to see a reference and methods for this estimate as none were cited. Our science backed analysis is that the 5% BCS protein soil test most likely sits at a level below the actual level of protein and blood contamination. We note that these authors have also previously published on the effectiveness of HOCL against Ralstonia spp.7 In this study, they compared PhaseOne solution (0.025% hypochlorous acid) with 0.35% v/v Betadine, which appears to be a much lower concentration of povidone iodine than is used in clinical practice. Clinical and laboratory studies8 have validated at least 50% v/v Betadine (5% povidone), not 0.35% v/v Betadine. It would be of use to reanalyze the comparative assay using both 5% and 10% povidone as this would be a more meaningful clinically relevant bench study. The authors found that HOCL was effective against a wide range of pathogens in vitro. Our testing also confirmed that hypochlorous acid solution is very effective against bacteria in the absence of a protein challenge.2 This effectiveness was completely neutralized with the presence of clinically relevant protein content. Presence of proteins can act as neutralizers, absorbing the oxidizing capacity of hypochlorous acid, and thus protect bacteria against its direct attack. Incidentally, HOCL also loses antibacterial activity with any significant dilution. This is another major weakness of HOCL compared to current proven breast pocket irrigations. At this stage, PhaseOne only has regulatory approval as a mechanical wound irrigant—similar to saline. There are no proven regulatory claims for its efficacy in clinical antisepsis and until such time as there are some data to support this, it would be premature to claim that it is superior to proven, available, and clinically effective pocket irrigation solutions. Good scientists will take the time to ensure that their calculations and understanding of the scientific method is accurate before jumping to false accusations and erroneous conclusions. Whilst these errors may be simply an oversight, one must also be mindful that the authors of both the letter and previous publication are both owners and/or employees of the company that stands to profit from sale of PhaseOne. It would be better for the evaluation of this product to be undertaken by independent academic institutions using known and accepted standards of antiseptic testing as backed by regulatory authorities. Moreover, any clinical claims of efficacy against capsular contracture and/or reduced biofilm load should wait until such time as evidence from prospective comparative clinical trials emerges. The availability of a good, effective, and clinically proven solution (ie, >5% povidone iodine) should, in the meantime, remain the gold standard for breast implant pocket irrigation. Disclosures The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. Funding The authors received no financial support for the research, authorship, and publication of this article. REFERENCES 1. Fisher J, Brindle CT, Porter S. The importance of clinically relevant research when making comparisons. Aesthet Surg J . 2018; 38( 4): N76- N78. 2. Hu H, Sleiman J, Johani K, Vickery K. Hypochlorous acid versus povidone-iodine containing irrigants: which antiseptic is more effective for breast implant pocket irrigation? Aesthet Surg J . 2017. doi: 10.1093/asj/sjx213. 3. Therapeutic Goods Order No. 54 — Standard for Disinfectants and Sterilants TGA. Therapeutic Goods Act 1989 . https://www.legislation.gov.au/Details/F2009C00327. Accessed January 9, 2018. 4. Bovine Calf Serum Product Information . https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma/Product_Information_Sheet/p12133.pdf. Accessed January 9, 2018. 5. Total protein range in total protein test . https://www.healthline.com/health/total-protein#results. Accessed January 9, 2018. 6. Esmaeilnejad B, Tavassoli M, Asri-Rezaei S, Dalir-Naghadeh B, Pourseyed SH. Evaluation of serum total protein concentration and protein fractions in sheep naturally infected with Babesia ovis. Comp Clin Path . 2014; 23( 1): 151- 155. Google Scholar CrossRef Search ADS   7. Brindle CT, Porter S, Bijlani Ket al.   Preliminary results of the use of a stabilized hypochlorous acid solution in the management of ralstonia pickettii biofilm on silicone breast implants. Aesthet Surg J . 2017. doi: 10.1093/asj/sjx229. 8. Deva AK, Adams WPJr, Vickery K. The role of bacterial biofilms in device-associated infection. Plast Reconstr Surg . 2013; 132( 5): 1319- 1328. Google Scholar CrossRef Search ADS PubMed  © 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com

Journal

Aesthetic Surgery JournalOxford University Press

Published: Apr 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off