Chinese whispers ... the Blaylock myth

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Chinese whispers ... the Blaylock myth

Postby toxinologist » Sun Feb 24, 2013 8:04 am

Hi all,

I don't get the time to visit SAReptiles very often these days, but as I was working on researching a paper I am writing I came across some publications that reminded me of a conversation I had with a couple of people about why they believed tourniquets were the only option for managing Dendroaspis envenoming.
They had been particularly emphatic that Dr Roger Blaylock had said that mamba venoms are absorbed via the bloodstream, and not via the lymphatic system, and that this evidence proved the need the tourniquets after mamba bites.

Well today as I was reading Dr Blaylock's 1994 editorial titled Pressure immobilisation for snakebite in southern Africa remains speculative., in the South African Medical Journal [SAMJ. 1994. 84(12): 826-827.], in which he argued against the concept of using pressure immobilisation bandages for first aid treatment of most southern African snakebites, I came across the section where he states "Christensen showed that southern African elapid polypeptide toxins are absorbed rapidly into the bloodstream as shown in the subcutaneous LD50 dose's being only 10-20% higher than the intravenous LD50 dose in mice." and it occurred to me that here at last was proof in writing that what my two friends had said about Blaylock's assertion may actually be true, so I took a quick look at the reference list, and armed with the Christensen citation he had given, went hunting through the SAMJ online archive to see exactly what evidence Christensen had presented to prove this apparent dichotomy which had established that southern African elapid venom polypeptides travel via a different route to the venom polypeptides of elapid snakes elsewhere in the world.

Christensen's paper, The treatment of snakebite., was published in the SAMJ in October 1969 [SAMJ. 1969. 43: 1253-1258], and what was suprising however is that this paper contained absolutely no primary scientific evidence whatsoever demonstrating that southern African elapid polypeptide toxins are absorbed rapidly into the bloodstream! Blaylock appears to have been rather dis-ingenious!

What Christensen's paper actually says is "The lethal toxins in elapid venoms are polypeptides with little or no local action, but, being rapidly absorbed into the blood stream, they may exert their neurotoxic action soon after a bite. Consequently, the subcutaneous median lethal dose (LD50) of elapid venoms for mice is only about 10-20% larger than the intravenous LD50. As a reference to this statement, Christensen very ironically cited the well-known 1941 study by Drs Barnes and Trueta titled Absorption of bacteria, toxins and snake venoms from the tissues., which appeared in the esteemed journal, The Lancet [The Lancet. 1941. 1: 623-626.], so it was to that paper I turned next.

Those who have not read the Barnes & Trueta paper might wonder why I say that Christensen's citation of this work was ironic. Well to understand, remind yourselves that Blaylock in 1994 was geographically precise in stating that "Christensen showed that southern African elapid polypeptide toxins are absorbed rapidly into the bloodstream as shown in the subcutaneous LD50 dose's being only 10-20% higher than the intravenous LD50 dose in mice.", and yet Christensen said nothing of the sort, stating specifically that "The lethal toxins in elapid venoms are polypeptides with little or no local action, but, being rapidly absorbed into the blood stream... with no geographic qualification whatsoever. Remember also that Blaylock's 1994 statement was made in the context of rejecting an Australian method of snakebite first aid (PIB) by seeking to imply that southern African elapid venoms are absorbed via a different route to those of elapids elsewhere. And I might add that after Dr Struan Sutherland wrote to the SAMJ rejecting Blaylock's editorial in 1995 [SAMJ. 1995. 85: 1039-1040.] Blaylock actually went a step further in trying to make this point [SAMJ. 1995. 85: 1040-1041]. Again citing as his evidence the 1969 Christensen paper, he stated that "...dendroapsis venom is absorbed directly into the bloodstream and not via lymphatics." Nowhere in Christensen's paper is there any statement to the effect that Dendroaspis venom specifically is absorbed into the bloodstream. What was Blaylock playing at? Was he really so determined to have the last word against his rival Sutherland, that he made it up? Christensen's paper certainly doesn't say what he claims it does. Now getting back to irony ... the elapid venoms used in the Barnes and Trueta (1941) experiments were none other than Australian black tiger snake venom (Notechis ater) and Indian spectacled cobra (Naja naja) venom!! No southern African elapid venoms were tested and so no proof whatsoever exists in this paper trail to support any of Blaylock's statements in the 1994 and 1995 SAMJ publications, and the only evidence at the end of the trail of publications actually refers to non-African venoms!! Blaylock really should have checked Christensen's paper more carefully, and it's cited papers as well!!

As to the experiments conducted by Barnes & Trueta, they demonstrated that Notechis ater venom injected into the legs of rabbits whose lymphatic transport vessels had been occluded or severed survived longer than control rabbits with intact lymphatic transport, but found that there was no difference in survival between control and test rabbits injected with Naja naja venom. Likewise while they found that immobilisation of rabbits injected with Notechis ater venom led to prolonged survival, the same was not true of rabbits immobilised and then injected with Naja naja venom. One of the fundamental problems with the Barnes & Trueta work however is their simplistic concept of venom molecular weight. They considered that Notechis ater venom had a MW of ~20 kDa and that Naja naja venom was only 2.5-4.0 kDa in size, when the reality is that both venoms are actually complex mixtures of many different toxins ranging in size from a few kDa to several hundred kDa. Hence their conclusions, which were that Naja naja venom (which they not had significant local effects) appeared to be absorbed into the bloodstream because lymphatic occlusion and body immobilisation failed to prevent death, whereas Notechis ater venom (which cause inconsequential local effects) must travel via the lymphatics because lymphatic occlusion and body immobilisation prolonged survival, really cannot be accepted in the light of what we know about these venoms today. The view that Naja naja venom appeared to be absorbed into the bloodstream simply holds little merit as the sole explanation for the observed outcomes, given the complexity of that venom as we now understand it, and only a series of more carefully designed and executed experiments would be likely to resolve this question further.

Certainly there was no basis for Blaylock to use this data to extrapolate his 1994 and 1995 statements about southern African elapid snakes (and specifically mambas) possessing toxins that are absorbed directly into the bloodstream, and it is well past time that this myth perpetrated by Blaylock during an acrimonious exchange between two men known for their egotistical determination to have the last word, be recognised for being nothing more than a case of Chinese whispers of the literary kind ...

To my two friends, who will no doubt read this sooner or later ... I'm sorry to kick sand on firmly held beliefs, but I believe we must question what people tell us, and we have to avoid falling into the trap of simply accepting what experts tell us, simply because of who they are. Blaylock and Sutherland's tussle in the SAMJ back in 1994 and 1995 is a great illustration of this, and neither are blameless for letting their egos and their belief in their own doctrines to ride roughshod over the truth and over impartial, unbiased scientific query. Sutherland took great delight in claiming that Blaylock's citation of a handful of clinical case reports showing PIB to be of limited value were "...quite inadequate for this purpose." - pure hypocrisy from a man who delighted in pointing to isolated clinical anecdotes from Australia as absolute proof that is invention of PIB was the only effective first aid for snakebite, making him no better than Blaylock for twisting facts to suit his agenda.

So what of first aid for snakebite? ... That's a whole other discussion, perhaps to be debated in depth at a later date. Certainly the truth is that the jury is still out right now, and that a clear answer will only come about though rigorous, unbiased investigation using cleverly designed experiments and adequate numbers to prove theories beyond doubt.

Cheers


David Williams
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Re: Chinese whispers ... the Blaylock myth

Postby Bushviper » Sun Feb 24, 2013 9:54 am

David would you have a problem if we used a tourniquet and a Pressure Immobilization Bandage on both mamba bites and Cape cobra bites if the hospital is not far and these are applied correctly? That is what I use as a training guideline especially if the tourniquet is a BP cuff and the bandage has been applied correctly.

Even just the use of a PIB cannot do any harm in the event of a neurotoxic elapid envenomation especially if it calms the patient and there is minimal soft tissue swelling as in most cases.

What would you suggest we use as a standard for FIRST AID in the event of a neurotoxic elapid bite?
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Re: Chinese whispers ... the Blaylock myth

Postby Warren Klein » Sun Feb 24, 2013 10:10 am

Very interesting read David. I remember back in 2006 how Blaylock personally told me over the phone that PIB were of no use in the case of Dendroaspis bites as their venom is absorbed via the blood stream and not the lymphatic system.

I was led to believe that this specifically applied to Dendroaspis and did not include other African elapids and this information had an effect on the snake bite 1st aid protocol I was developing at the time. Blaylock could very well be correct regarding the mode of absorption of Dendroaspis venom via the blood stream but if you say his information was cited from research conducted using Australian and Asian elapid species this does throw his theory into question. Are you aware of any current research that has been conducted with African species regarding the mode of absorption of their venom?
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Re: Chinese whispers ... the Blaylock myth

Postby toxinologist » Sun Feb 24, 2013 11:38 am

Arno - I think it really isn't possible at this point to favour any one method's possible benefits over the other, but at the same time, the disadvantages of tourniquets far outweigh the disadvantages of PIB. I think I've said before that what I would like to see are a series of carefully designed "real-life" experiments using either radio-labeling or fluorescent labels and real snake venoms in an animal model (preferably primate, but given the ethical issues, it might have to be a 'lesser animal' rather than a hominid). Basically label all the venom components, inject them peripherally into subcutaneous tissue and monitor time it takes for systemic bio-distribution to occur with and without a range of different interventions, in the hope of establishing the best single intervention or combination of interventions. There are actually a number of studies which suggest that proteins of different sizes are taken up by the body in different ways - with small molecular weight proteins being absorbed by the capillary beds, and larger ones tending to enter the lymphatics. This would mean that nearly all venoms contain toxins that transit via different routes, since the range of kDa sizes goes from 3-4 kDa right up to 250-300+ kDa, and it explains very simply why we see different venom effects occurring at different times, depending on the transit time to the tissue target site. If it were me personally, given the lack of current evidence, I would mostly likely opt for a very firmly applied PIB (in the 65-70 mmHg range) and then get horizontal in a hurry, since venous return pressure when prone is a lot lower than when standing or sitting, and this would likely mean that the PIB would not just occlude the lymphatic vessels, but most of the shallow capillary beds in the limb as well. Failing that (e.g.: if I didn't have a bandage) I would go for a broad (15 cm) pressure band around the thigh or biceps, again, at 65-70 mmHg. A narrow tourniquet would be my last option.
HH - I am not aware of any current research in this field, but I would very strongly recommend it to anyone with the necessary skills and equipment. We really just do not know, although my gut suspicion is that small molecular weight alpha-NTX such as are found in many elapid venoms right around the world, i.e.: Notechis, Dendroaspis, Oxyuranus, Bungarus some Naja, etc.) are ideal candidates for capillary absorption given most are in the 6-9 kDa range. I really would love someone to prove it, and as I say above - find a way to slow it right down.
Cheers

David
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Re: Chinese whispers ... the Blaylock myth

Postby Warren Klein » Sun Feb 24, 2013 11:50 am

It's a shame we can’t' get any convicted murderers and rapists out of our jails to be used as venom test subjects and spare the animals.
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Re: Chinese whispers ... the Blaylock myth

Postby WW » Sun Feb 24, 2013 5:20 pm

Struan Sutherland actually did test his PI method on "Naja naja" (i.e., some unidentifiable Asian cobra....) venom and found it to be effective, albeit with a small sample size (of one monkey each for test and control). While not exactly a large and rigorous study, it does suggest that these small 6-9 kDa toxins (three-finger toxins, the main killers after cobra and mamba bites) are absorbed through the lymphatics and/or are susceptible to being immobilised with a pressure bandage.
http://www.avru.org/archives/sutherland/image-viewer/SUTH00086/1

There is certainly zero reason for believing that African elapid toxins should behave any differently.
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Re: Chinese whispers ... the Blaylock myth

Postby toxinologist » Sun Feb 24, 2013 6:00 pm

Equally, as I explained to Arno, there is strong evidence from lymphatic transport experts that show fairly convincingly that small molecular weight proteins are taken up rapidly by capillary beds rather than lymph vessels, and that they can very quickly be transit to the systemic circulation, whereas larger proteins tend to be absorbed into the lymph vessels and take a somewhat slower path to the rest of the body. 3FTX are certainly in the size range that is believed to take the capillary vessel drainage route. What Sutherland neglected to mention in most of his papers is that at the sort of pressures recommended (40-70 mmHg), a well applied PIB will not just occlude the lymphatic vessels, but also the capillary beds of the skin and subcutaneous tissues as well. In a supine patient, the venous pressure is typically 10-25 mmHg (standing it can reach 90 mmHg), so even a modest pressure of 25-30 mmHg can act as a venous tourniquet, and certainly the application of 50-70 mmHg of bandage pressure is more than adequate to obstruct both tissue fluid transport and venous return. Hence it is feasible that different toxins may take different routes into the systemic circulation, and that some may opt for capillary uptake and venous drainage, leading to more rapid onset of clinical signs of envenoming in patients without adequate sequestration (e.g.: very firm PIB). We know from training experience that most people do not apply PIB at the correct pressure without significant training, and the reality is that inadequate pressure results in incomplete or even absent delay of venom transit from the periphery. Someone needs to do the right experiments and assemble the evidence one way or another ...
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Re: Chinese whispers ... the Blaylock myth

Postby WW » Sun Feb 24, 2013 6:24 pm

toxinologist wrote:Equally, as I explained to Arno, there is strong evidence from lymphatic transport experts that show fairly convincingly that small molecular weight proteins are taken up rapidly by capillary beds rather than lymph vessels, and that they can very quickly be transit to the systemic circulation, whereas larger proteins tend to be absorbed into the lymph vessels and take a somewhat slower path to the rest of the body. 3FTX are certainly in the size range that is believed to take the capillary vessel drainage route. What Sutherland neglected to mention in most of his papers is that at the sort of pressures recommended (40-70 mmHg), a well applied PIB will not just occlude the lymphatic vessels, but also the capillary beds of the skin and subcutaneous tissues as well. In a supine patient, the venous pressure is typically 10-25 mmHg (standing it can reach 90 mmHg), so even a modest pressure of 25-30 mmHg can act as a venous tourniquet, and certainly the application of 50-70 mmHg of bandage pressure is more than adequate to obstruct both tissue fluid transport and venous return. Hence it is feasible that different toxins may take different routes into the systemic circulation, and that some may opt for capillary uptake and venous drainage, leading to more rapid onset of clinical signs of envenoming in patients without adequate sequestration (e.g.: very firm PIB). We know from training experience that most people do not apply PIB at the correct pressure without significant training, and the reality is that inadequate pressure results in incomplete or even absent delay of venom transit from the periphery.


OK, I did not word that accurately - my main point was simply that there is no reason to believe that African elapid venoms would act differently from others that the method was tried on, whether as a result of capillary or lymphatic occlusion. That said, long delays in the appearance of symptoms are not unusual even in untreated 3FTx neurotoxic bites, so there are no hard and fast rules there either.

Someone needs to do the right experiments and assemble the evidence one way or another ...


That aptly describes ~99% of the snake bite first aid literature. There can't be many fields of medicine (or at least I hope not.....) where so much hot air has been produced on the basis of so little hard evidence.
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Re: Chinese whispers ... the Blaylock myth

Postby Bushviper » Sun Feb 24, 2013 6:34 pm

David how do you know when the PIB has been applied correctly and with the right amount of pressure in the 65-70 mmHg range? Is there some indicator we can use in the field?
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Re: Chinese whispers ... the Blaylock myth

Postby toxinologist » Mon Feb 25, 2013 1:35 am

Arno: the easiest way is to train people to use it with the aid of an aneroid BP cuff ... remove the outer part of the cuff leaving just the rubber inflation bag and the tubing (one end going to the gauge and the other to the inflation bulb). Place the rubber bag on the limb (flat on the anterior lower leg, or on the forearm) that will be bandaged and then apply PIB over the entire limb leaving the rubber bag encased under it. When done, pump one good puff of air from the inflation bulb into the cuff bag, and read off the pressure on the gauge... with practice people soon learn how much bandage stretch is needed to get in the right pressure range. In theory this setup could actually be used under the bandage in a snakebite victim and used to monitor the pressure during transport to hospital, but it adds another element to the technique that invites potential errors, not to mention additional cost and complexity. We use it simply for training.
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Re: Chinese whispers ... the Blaylock myth

Postby Bushviper » Mon Feb 25, 2013 10:54 am

Thanks. One further question now surfaces. What potential errors does this invite? I train a number of medical personnel as well so the cost and complexity of using a BP cuff is not a problem.
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Re: Chinese whispers ... the Blaylock myth

Postby toxinologist » Mon Feb 25, 2013 4:07 pm

We have found that using this method to train rural village people results in 80% skill retention (against the parameters for correct application) 1 year after the initial training, with periodic refresher training. What needs to be realised that you simply cannot learn how to get it right in one session. Like all skills, it requires repetition, positive reinforcement and practice.
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Re: Chinese whispers ... the Blaylock myth

Postby swazi » Tue Feb 26, 2013 1:20 pm

Love all you clever people!
Using a pressure bandage might be the most effective first-aid technique but it’s still not a viable option for most people in the rural areas.
Swazi
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Re: Chinese whispers ... the Blaylock myth

Postby Bushviper » Tue Feb 26, 2013 1:40 pm

Thea most of your patients dont even own bandages. You also have far too many spitter bites which will be a nightmare if this is all they remember.

What is sad is Swaziland is such a small country you would think they could get to any decent hospital in less than two hours. Reality is not so.
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