Category Archives: Level 4

Level 4

Finding your way around the human metabole

Comment

Wound care gets very interesting if you move away from casual observations or intervention comparisons. This has become easier the last decade, especially the “omic-type” diagnostic tools allow for analysis of large and complex systems. This enables us to move away from the trial and error type of research and look in depth into the wound. In general wound care articles mention genes or proteins.  Since genes and proteins are a major part of processes regulation in the body it makes sense to unravel the way they operate in regenerating tissue.  Freely quoting Goethe: All living things are connected if you do not see the connection you have not looked good enough. So we should be able to connect the dots, amongst others by reading literature or doing research. The knowledge in literature is fragmented. Luckily there are tools available to explore the context of the information:  The site reactome shows how the processes at a basic level are organised and thus allows us to connect at least some of the dots. The plug in ferret  provides depth and backround to the articles in pubmed etc. Both are tools for our endeavour to understand the incoherence of current wound care research.

http://www.reactome.org/

http://www.ferret.ai/

Level 4

The question

Comment

There is one question wound care specialists typically do not ask. If Winter and Hinman proved the use of cling film speeds up wound healing by 40%, why are there hardly any studies repeating the phenomenon in a clinical setting and do meta-analyses invariably deliver hardly any or no effect.  It seems to me the gap between Winter (animal research, evidence level C), Hinman (evidence level B) +40% and meta-analyses  (evidence level A1) +/- 0% requires an explanation. To me it is a logical question for a logical problem: the gap is too large, we cannot find 40% and 0% outcome at the same time. So who sheds some light on the logic behind the phenomenon?

General, Level 4

Epic failure: Hyperbaric oxygen therapy for treating chronic wounds

Comment

The Cochrane published the review Hyperbaric oxygen therapy for treating chronic wounds (original article)

Here are the results:

  • For diabetes-related foot ulcers, we found that HBOT seemed to improve the chance of healing in the short term (up to six weeks), but not with longer term follow-up. HBOT may reduce the number of major amputations in people with diabetes who have chronic foot ulcers.
  • For chronic wounds caused by a disease to the veins of the leg, we found that HBOT may reduce the size of wounds.
  • For chronic wounds caused by lack of blood supply through the arteries or chronic pressure ulcers, we found no evidence to confirm or refute any effects of HBOT.

These results are to be expected. Not because HBOT is not working, but because researchers lack critical information, simply because it is not available. The Cochrane results are inevitable and reproducible non-conclusive but Cochrane is not to blame. Let’s explain two of the many logical errors causing the failure of wound care research.

It starts with the inclusion criteria. If your inclusion criterion is “a non-healing wound”, you are lost from the start. (the real list is below) There are many reasons wounds do not heal. They can, for example, be patient related, wound related, mechanical or metabolic. (Levels 1,2,3 and 4 which are usually independent of each other)

The first notion regarding chronic wound is that wat caused it, is not necessarily preventing it from closing. Yet we place them all on a pile, sorted by cause of the wound (logical error 1) and then investigate if intervention x is functional. So you are testing in the blind, which is very different from double-blind. That is a gross neglect of reality.

Therefore, if you are lucky,  you will discover how many non-healing wounds accidentally fit your solution (logical error 2). This is very different from finding how effective your intervention is. In today’s setup, it is therefore almost impossible to discover how effective your intervention is. Because we lack markers and/or knowledge to diagnose and characterize the cause of not healing. Therefore, we have no choice but to pile wounds together. It is a pity we do not recognize this beforehand. If you cannot select the wounds which are lacking the solution you provide, the chances of success are next to 0. (logical error 1+2)

And now the real issue: it would be very interesting to figure out which wounds respond. And why and how they respond. This will enable us to recognise this the next time before we apply an expensive treatment. Or in other words, the non-responders are more interesting than the responders. Sadly research is acting in exact the opposite way.

It starts with the inclusion criteria. If your inclusion criterion is “a non-healing wound”, you are lost from the start. (the real list is below) There are many reasons wounds do not heal. They can be patient related, wound related, mechanical or metabolic. (Levels 1,2,3 and 4 which are usually independent of each other)

 

And now the real issue: it would be very interesting to figure out which wounds respond. And why and how they respond. This will enable us to recognise this the next time before we apply an expensive treatment.

If you need help: harmjsmit@gmail.com

 

Inclusion criteria varied in these trials. Doctor 1992 included any person with diabetes with a chronic foot lesion (time not specified); Faglia 1996a included people with diabetes and Wagner grade 2, 3 or 4 lesions (Wagner 1987); Lin 2001 and Kessler 2003 people with “early diabetic feet”, Wagner grades 0, 1 or 2, while Duzgun 2008; Abidia 2003 and Londahl 2010 included people with diabetes whose lesions had been present for more than four weeks, six weeks and three months respectively. In addition, Londahl 2010
required evidence of good standard wound care in a specialist clinic setting for a minimum of two months. Exclusion criteria generally followed from the specific inclusions detailed above, but Abidia 2003 also specifically excluded participants for whom vascular surgical procedures were planned and Kessler 2003 excluded all patients with transcutaneous oxygen tensions of < 30 mmHg. Ma 2013 included patients with diagnosed diabetes, at least one fullthickness wound below the ankle (Wagner grades III or less) for > 3 month, standard care for > 2 month, TcPO2 > 30 mmHg. Khandelwal 2013 included patients with a diabetic foot ulcer of at least 8 weeks duration, patients with only stage III and IV diabetic foot ulcer and the absence of vascular insufficiency.

Level 2, Level 4

Microbiome; the shepherd and the flock

Comment

Many bacteria in the wound are unknown to us. This is why they call it dark matter in the article below. We know it is there but cannot see it. The entire system in a wound bed is called the microbiome, it may be compared to a city in its diversity and complexity. We are now beginning to understand what this means to wound healing. In a healthy subject, the microbiome may well be part of the normal wound healing process whereas in a compromised wound it may have a very different role.

One reason for looking into this is pure curiosity. Another may be to discover new bacteria and new ways bacteria and human cells live together in the wound. The last and more intriguing reason is S aureus and P. aeruginosa may be just the flock while we still have to find the shepherd. Like P. gingivalis is a shepherd in gingivitis. In the article of Hajishengallis it is described that a les abundant microbe is actually controlling the mouth microbiome like a shepherd controls a flock. Metagenomic research may bring us something, if only if S.aureus and P.aeruginosa are flock or shepherd. Hopefully, it will unravel the systems in the wound which may be more important that the individual cells. (meaning the system describes roles to be fulfilled and which organism actually fulfills it is less important.) Anyway, let us hope we are abele to discern between detrimental microbes and microbes which have a more positive role in wound healing.

In the end, this type of research will allow us to decide when and how to remove the microbiome or when it makes sense to take a more probiotic approach.

  1. http://www.nature.com/news/mining-the-microbial-dark-matter-1.17774
  2. Hajishengallis, G. Lamont, R. J. Breaking bad: Manipulation of the host response by Porphyromonas gingivalis.  Eur. J. Immunol. 44.2.1521-4141  http://dx.doi.org/10.1002/eji.201344202
  3. http://www.nature.com/nrmicro/posters/metagenomics/posters.pdf
  4. https://microbewiki.kenyon.edu/index.php/Pseudomonas_aeruginosa_infection
  5. http://www.nature.com/nrmicro/posters/pseudomonas/posters.pdf
Level 3, Level 4

Refuelling cells

Comment

Elegant article on delivering intracellular ATP in a “level 3” animal model.  It’s like refuelling the tank.  Due to the ischaemia the cells may have been somewhat starved for energy. External energy in the form of ATP in lipid vehicles, which apparently reaches inside the cell, leads to faster wound healing. Not all cells respond similarly, granulation tissue responds with a kind of hyper granulation. Apparently it is more sensible to the ATP or just receiving more because it is at the surface of the wound bed. They have looked in depth at the energy  metabolism in the cell and thoudn bed. A refreshing approach to non-healing wounds where these days reseach focusses on inflammation and infection. What would happen if we combine this level 4 metabolic approach, to a proteomic/metobolomic shotgun analysis.  Until then, as the authors cite a 1943 study: “Howes tested the healing effects of various drugs and concluded that: 1) epithelialization begins after a latent period of 3–6 days, during which the underlying connective tissue is hardly regenerated at all; 2) a suitable granulating base is necessary for epithelialization to begin; and 3) the requirement for frequent dressing changes prolongs the latent period due to tearing away of the regenerating cells”. It appears wound care is still in the previous century.

Howard JD, Sarojini H, Wan R, Chien S. Rapid Granulation Tissue Regeneration by Intracellular ATP Delivery-A Comparison with Regranex. Yamamoto M, ed.PLoS ONE. 2014;9(3):e91787. doi:10.1371/journal.pone.0091787. /  http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091787
E L Howes. The rate and nature of epithelization in wounds with loss of substance SGO 1943 Vol 76 (738-745)

Level 4

Bacteria and phagocytosis

Comment

The dynamic host-microbe interaction keeps getting better.

You just think; once a bacterium has been eaten by a macrophage it is the end!  Well it may be, but it may be not.

Apparently some bacteria benefit from being phagocytosed.  Pseudomonas aeruginosa and E.coli have some genes which allow them to metabolise lysosome fluid. Are they hitchhiking on a macrophage to get to places they normally would not come? It will be a matter of time before we describe a similar process for S. aureus, they already behave suspicious. And how does that make you feel about wound healing and the microbiome?

Bacterial itaconate degradation promotes pathogenicity.
Sasikaran J, Ziemski M, Zadora PK, Fleig A, Berg IA.
Nat Chem Biol. 2014 May;10(5):371-7. doi: 10.1038/nchembio.1482. Epub 2014 Mar 23.
Kicking Out Pathogens in Exosomes.
Sergeeva OA1, van der Goot FG2.Cell. 2 015 Jun 4;161(6):1241-2. doi: 10.1016/j.cell.2015.05.040.
https://en.wikipedia.org/wiki/Red_Queen_hypothesis

Level 4

Reverse evidence

Comment

Since 1962 we all know that wounds without a scab heal 40% faster compared to wounds with a scab. This has been tested on two pigs (Winter, Nature 1962) and seven inmates (Hinman, Nature1963). This means, since 1962, we all are convinced that a for instance diabetic wound on an 83-year-old will heal up to 40% faster, only if you apply a moist environment.

Reversibly you may also try to answer the question how much slower wounds would heal if you would use of moist gauze, which have to be changed up to 3 times a day. Almost 50 years after Winter some people have tried to answer this question (Ubbink DT et al, Arch Surg 2008). What appears was that moist wound healing was not better but actually worse than a conventional gauze treatment. But there was one remark, these findings apply only for wounds with an acute etiology (and in a hospital setting).

Ehh well yess…. what type of wounds were investigated in the Winter and Hinman papers?

But fair is fair, one study should not make a difference, scientific principles dictate a finding should be repeated several times in order to be accepted.

This is why we have organisations which examine the evidence. One of those organisation is the Cochrane foundation which has as purpose to help medical professionals in their decisions. The method they use is to ruthlessly examine all research papers against the highest standards. <http://www.cochrane.org/about-us>. And nothing is easier than to go to their website and read what they have to tell about wound care.

If I cite them randomly: negative pressure therapy, there is not enough evidence. (And it is not only Cochraine but also for instance Vig S et al, J. of Tissue Viability 2011), Alginate; there is no evidence that alginate is better than any other addressing, foams; conclusion is the same, no evidence. The only exception appears to be hydrogel were the conclusion is that hydrogel is have some evidence to be more effective compared to other dressings. Silver dressings, no evidence etc. After a quick glance I counted 105 studies with almost 10,000 patients which actually met the Cochrane criteria.

Cochrane provides one, real unnerving outcome, no one is able to prove or repeat the 40% faster promise from the original articles more than 50 years. Apparently it is not possible to design a study or do a study which is meeting current scientific criteria and show a 40% faster healing.

So we start reducing our expectations. Perhaps we are asking too much my looking for a 40% faster healing, so let’s settle for 20%, 10% or even 5%. That appears fair to me.

But even that is not possible, the most positive statement in these studies is “there is some proof”, which is quite different from 5% faster healing. Apparently it is not possible for any current wound care dressing to prove in a well-designed study it actually makes sense to use.

Now what, it appears we have a problem.

We are not able to prove how much a wound benefits from using a moist dressing. The next step would be to reverse the question, does it actually work? The answer to this question is very easy to answer, because there are plenty studies, meeting the highest scientific standards providing the answer, the Cochrane collection from above. The significant answer meeting the highest standards is: a moist environment does not lead to faster wound healing.

And this finally leads us to the heart of the problem. We have a Mexican standoff between 2 pigs, seven inmates and 285 clinical patients. I don’t believe that the Winter and Hinman articles were wrong. It doesn’t take rocket science to understand why a scab might be hindering wound healing progress. But I also don’t believe that the Cochrane findings have to be dismissed because they don’t fit our view on today’s wound care. It does mean we have a gap in our knowledge. The gap can be summarised as we are not able to explain why Cochrane and Winter are both right.

Interesting is that all stakeholders in wound care should be aware of this gap since there have been no repeating studies which proof the moist paradigm in different circumstances.

For some reason we have chosen to ignore this issue for the last 50 years which sadly also lead to 50 years of “less useful” research which papers invariably end with the conclusion “more research is needed”.

To me it appears we have some work to do.

To paraphrase: if not me, who… if not now, when.