New FDA 483: Euthanasia drug found in canned dog food, misc. facility findings, and questions for FDA

fda-483-footerI would be remiss in the goal of this blog if I didn’t do some digging into the form 483 that was just released by FDA this week following a recall for canned dog food containing Pentobarbital. For information on the products recalled and company involved check out the FDA recalls page and search for the issue. As usual I’ll refrain from writing company and product names on this blog when there isn’t any pending civil or criminal action associated with an event. But that information is readily available for anyone by clicking through the links or performing a simple search.

The 483 is short, just two pages. What the goal of this post will be is to go over each of the observations and try to provide additional information that isn’t included in the document to hopefully provide a complete picture.

All FDA observations began with the heading clarifying which portion of the law (FDCA) the firm violated:

The following observations were found to be adulterated [sic] under the Federal Food, Drug, and Cosmetic Act: A food shall be deemed to be adulterated if it bears or contains any added poisonous or added deleterious substance that is unsafe within the meaning of section 402.

This wouldn’t be FF&F if I didn’t pause here for some definitions. Adulterated is a condition of food by which it cannot be sold in commerce. It includes both reasons of safety as this case demonstrates, but it could also be forms of “economic adulteration”, where something claims to be what it isn’t or has otherwise been robbed of characteristics that the consumer would expect. Like if I were to sell you caviar but it was actually flavored gelatin balls or something.

Poisonous or added deleterious substance is a substance that when added to food “may render it injurious to health; but in case the substance is not an added substance such food shall not be considered adulterated under this clause if the quantity of such substance in such food does not ordinarily render it injurious to health.” (emphasis mine)

FDA says two things there. First, don’t add anything poisonous to food (Protip). Second, if the food happens to contain something poisonous naturally, you need to make sure it occurs at a level where it isn’t toxic. This is the often cited”dose makes poison” principal. An example would be that I can’t sell food into which I accidentally spilled some cyanide (whoops) no matter how much or little it was, but I can sell fruits that may have trace amounts of cyanide precursors in the seeds, because it’s not expected to cause an issue in both the actual dose of the seeds and the expectation that people will avoid them when eating. This clarification is actually pretty critical as we try to make sense of past FDA guidance in this case and why the food was adulterated.

So, how did these dog food products cause themselves to be adulterated?

Your low-acid canned dog food product…was found by chemical analysis to contain the barbiturate drug pentobarbital.

By Harbin (Own work) [Public domain], via Wikimedia Commons
By Harbin (Own work) [Public domain], via Wikimedia Commons
Pentobarbital is a sedative that in the form sodium pentobarbital is used as a euthanasia drug. This recall/483 event was initiated when 5 dogs became sick and one subsequently died. Several new updates have occurred since then and I encourage you to follow the story on a site like food safety news.

Here’s the thing about this finding, it’s annoying that the 483 made no mention of the dose that was recovered. This is important because FDA did a study on pentobarbital in dog food in 2002. In that study, the samples (not randomized/representative, convenience samples selected for likely positives) tested positive for the presence of pentobarbital in more or less than 50% of the samples. However, in the same study FDA made a determination of dose that caused adverse effects:

Based on the data from this study, CVM scientists were able to determine that the no-observable-effect level – which is the highest dose at which no effects of treatment were found – for pentobarbital was 50 micrograms of pentobarbital per day

Dogs would have to consume 5-10 micrograms of pentobarbitol per Kg body weight to hit that dose. The highest value FDA found in their samples was 32ppb (32 micrograms per Kg of food). This means that 7 Kg (15.4 lb) dog would need to eat between 35-70 micrograms to reach the minimum dose, which would have been a little over 1Kg of the highest testing food. Pet food isn’t very dense (canned pet food is denser but contains more water that dilutes other ingredients) and 2.2 lbs of it is a lot of food for a 7Kg dog. Therefore FDA concluded:

the results of the assessment led CVM to conclude that it is highly unlikely a dog consuming dry dog food will experience any adverse effects from exposures to the low levels of pentobarbital found in CVM’s dog food surveys

Which means that FDA concluded that the mere presence of pentobarbital does not make the product adulterated because “the quantity of such substance in such food does not ordinarily render it injurious to health” per the FDA study.

Now, because there is report of adverse events and an Oregon State College of Veterinary Medicine report out there showing that the levels in this food were high enough to cause an effect, this food is clearly adulterated. But it seems like FDA should have included a note about the concentration of the drug found in the food in this 483 to clarify why it was legally adulterated, given the past study.

Now for the findings not related to the chemistry analysis and recall:

Condensate dripped throughout your processing facility from the building…including condensate dripping directly into open cans of the in-process low-acid canned dog food product…and also into multiple open totes of raw meats including beef intended for your canned dog food product

steam-hood
Example: steam hood over my stove that I apparently need to clean…gross.

Condensate is found wherever foods are heated and cooled, and FDA has been addressing it more and more. Condensate was noted in the Blue Bell 483’s as well. The logic is that while steam or vapor may be clean, once it collects on a surface like the ceiling or whatever else, it can carry bacteria from these “non product contact” areas back onto your food. Think of it this way, would you lick the underside of the steam hood/vent above the stove if you hadn’t just cleaned it? Now imagine that the steam from your stroganoff was condensing on the underside of the hood and dripping back into it, carrying all that old grease and dust. Yum.

The floors throughout your processing facility are pitted, cracked, and otherwise damaged causing pooled water in areas where food is exposed including where open cans of…dog food are staged

pitted-concrete
Source: my patio.

Uncleanable floors = environmental pathogens. While they didn’t go on a “swab-a-thon” in this facility (yet), uncleanable floors are essentially considered harborage points for things like Listeria and Salmonella. In any other business than food, pitted floors aren’t normally an issue, which makes it a common finding in plants holding themselves to a manufacturing efficiency standard rather than a “food grade” standard.

Additional sanitary conditions observed…include peeling paint and mold on walls throughout the processing facility including in areas where food is exposed, a live fly-like insect in the …hand-packing area during processing, and an open sanitary sewer within approximately 25 feet of two food storage trailers and one food processing trailer at the rear exterior of the facility.

Really just shows a lack of preventative maintenance and facility investement when there wasn’t a clear ROI. This particular company has been in business for a long time in the same location, so it’s possible they themselves put that old coat of paint in years ago to spiff it up and make it look nice and be good for food. These kinds of things are expensive preventative maintenance tasks (mold removal, repainting) because it causes downtime as well as the expense of the repair. Typically FDA will show discretion depending on risk to product (e.g. if you only have closed containers in a room with old paint), but the inspectors here probably determined that this was facility neglect and should be noted. Same thing happens in restaurants and retail establishments where facilities have aged but there’s been no spiffing up.

You lack operating refrigerated storage facilities or other means of controlling the temperature exposure of raw meats during thawing, storage, and processing.

Ding, ding, ding! We have a winner, here’s where we demonstrate the true lack of food safety commitment/appreciation at this facility. The last findings all relate to proper temperature control:

…raw beef and other meats in various stages of thawing were stored in ambient temperature inside your processing facility and also at abmient temperature inside three trailers…the exterior ambient temperatures were below freezing…there was frozen ice containing a blood-like substance across the floors of the three trailers and also on the ground…

Open cans of beef were staged on a pallet at ambient temperature during the hand packing process [from the start of operations until 2:00 PM]

So here’s what the deal is with food safety here. This product is going to be retorted, which means that as a low-acid product, it’s going to be cooked until it’s commercially sterile.

So, in theory, it doesn’t matter if your raw meat doesn’t stay refrigerated, since you’ll kill anything that might grow on it! Heck, you can pack it in a dirty facility with dirty tools if you wanted to…

That was sarcasm.

Processors who think like this fail to understand how cooking and kill steps work, and don’t have respect for your food at all stages of production.

FDA expects the thermal process for low-acid foods to provide a minimum of a 5 or 7-log reduction for spores and pertinent pathogens. What this means is that the process should destroy a minimum 99.999% of spores/bacteria in the product, or alternatively, it would sterilize meat that contained 10,000 spores/gram (bacteria are easier to kill than spores, and would have a much higher log reduction with the same process).

This would work for most “raw” products used in this process. However, if you don’t refrigerate or otherwise control raw meat to keep it out of the danger zone of 40-140ºF, bacteria will start to grow. And with the average piece of beef trim having anywhere from 100 to 100,000 bacteria/gram, if these bacteria are allowed to multiply to the ten-millions from lack of refrigeration suddenly that 5-log reduction doesn’t work anymore!

99.999% of 10,000,000=100

While 100 un-killed spores may not seem like much, one of them could be C. botulinum, and with a shelf life of years in a can of dog food, it only has time to grow.

Take this home: every cook or “kill” step in food processing has a log-reduction value. So while you can technically cook spoiled meat until all the bacteria are dead, you have no way of knowing (without testing) that your standard procedure of cook until 165ºf will work if the number of bacteria are 100 fold higher than what the cook was intended for.

If you still think you can throw away your refrigerator and just cook everything through, I recommend purchasing an autoclave to really sock-it-to-em. Don’t think what comes out will be very tasty though. Oh, and general autoclave parameters will give you a 12-log reduction. Happy cooking.

While this is a significant finding, it isn’t related to the issue causing the current recall (and subsequent enforcement). The issue with the product had to do with pentobarbital in the food, which is a supplier sourcing issue (pentobarbital didn’t make it’s way in at the plant unless it was a malicious act). This plant has had a poor history with supplier approval (sourcing duck that wasn’t actually duck for example), and also has a history of being ignored by the FDA based on inspection history.

What this warning letter serves to do is show that FDA is doing it’s job (or backtracking to do so) enforcing all the regs at this plant regardless of the specifics of the current problem. But I have a lingering problem with this timeline:

12/31/17: Dogs become sick after eating the implicated food.

1/3/17: Oregon State University receives the samples for autopsy and analysis, report indicates FDA was informed.

1/10/17: FDA shows up at the plant to perform inspection that led to the facility 483 findings

1/17/17: Michigan State University confirms Pentobarbital contamination

2/1-2/2/17: FDA continues inspection according to the 483, no new findings noted from the later dates

2/3/17: Recall initiated, presumably this was a result of the meeting with FDA from the previous two days where they informed them of the results and helped identify the scope of the recall and “recommended” a “voluntary” recall.

2/8/17: FDA continues inspection according to the 483, no new findings noted from later dates.

2/17/17: FDA releases their own independent press release through CVM updates

This facility had multiple problems in 2011 and 2012 that led to FDA action, and FDA had last interacted with them (according to the inspections database, which does not include contracted inspections through the state) on 2/28/13.

Did FDA inspect a facility, find problems, and then decide not to go back for 4 years? And from this timeline above, did they only go back to this facility because they had a potential poisoning related to it on file?

Thorough and rapid response to a crisis FDA, good job! But shouldn’t you have been inspecting a known problem facility to prevent problems like this from happening?

After all, in 2011, you said this:

The FDA Food Safety Modernization Act (FSMA), signed into law by President Obama on Jan. 4, enables FDA to better protect public health by strengthening the food safety system. It enables FDA to focus more on preventing food safety problems rather than relying primarily on reacting to problems after they occur.

We can’t say whether increased visits from FDA (which should have been every 3 years at minimum) would have prevented this from happening. But it certainly couldn’t have hurt.

Banned antibiotics in feather meal – A discussion with an author of the study

Following my recent post where I examined an article from Johns Hopkins that found multiple contaminants in commercial feather meal (including fluoroquinolones, a class of antibiotics that have been banned from use in poultry since 2005), I was honored to be contacted by one of the Authors, Dr. David Love. Dr. Love offered to continue the discussion with me, and was happy to answer my questions regarding the study, the media frenzy it has inspired, and some of the goals of the research conducted at the Center for a Livable Future. I immediately jumped at the chance, and was able to speak with him on the phone earlier this week.

As those who read the post last week have seen, my primary concern with the study was not to do with it’s results or conclusion, but in how the press release was worded. He didn’t feel that it was as misrepresentative as I initially interpreted it, and we quickly moved on discussing just why this article was picked up so quickly.

“I’m not sure how much more clear it could be, we specifically said feather meal, and the title of the study says ‘feather meal, a previously unrecognized route for reentry into the food supply’…I think on the whole we were careful, I don’t think we can come out of this paper with twelve samples and make sweeping generalizations, it’s important to point out that our big recommendation of the study in the last line was that more research should be done…It’s really at the intersection of the media and what they’re interested in, the consumer and what their interests are, and then our story as the authors. Consumers are so interested in what’s going on with their food. We say we did a study on chicken, there’s energy there, and if that’s what they want to talk about, it tells me that we need more transparency in packaging, labeling, and more consumer education. “

I agree, everyone is interested in what they eat, and he makes a great point that we shouldn’t ignore that interest as scientists or producers as it reflects consumer demand. Another point I wanted clarification on was the statement that self-regulation and our current FDA guidelines aren’t sufficient to keep contaminants out of food.

“From the looks of the latest FDA Guidance there’s a lot of strong language, but no teeth in the language. I think for the draft guidance for 213 we’re hopeful, as there will be a larger role for veterinarians in prescribing antibiotics. As for self regulation, I would be more willing to support it if there was more transparency. Many other countries go out of their way to report use, and we in the U.S. have trouble dividing up which antibiotics are used for growth promotion, prophylaxis, and therapy. It would be hard to go about but if we could get that, and reduce or cut growth promotion uses, we would be able to actually measure progress on how we’re reducing antibiotic use in animals.”

He made a very strong point, and following publishing my post last week I came upon  a commentary published by the authors discussing the issue created by unintentional overuse of antibiotics in feed. The article actually provided many of the citations supporting their arguments that I mockingly asked for last week, and I encourage anyone interested to check out the data behind the conclusions. In wrapping up our discussion, I asked where the authors planned to go next with follow-up research.

“A lot of people want to know. Well we found this stuff in feathers, now lets look at meat, at the consumer level with what you buy at the grocery store.”

A logical next step, and one that I’m sure will have even more interest than the findings from feather meal.

Out of our discussion, I discovered a different perspective of the research that I believe was reflected in the discussion, but was completely missed by the media and myself. While the source of the contaminants is obviously a big question, that wasn’t the purpose of the study. The authors were examining feather meal as a route to antibiotic introduction that could have implications in terms of creation of AB-resistant bacteria. Regardless of how it got there (like through contaminated groundwater, as I suggested), a small percentage of chicken producers use it as a feed supplement, thus introducing fluoroquinolones into our food supply through a previously unknown method, and thus not subject to withdrawal times that prevent meat contamination. Further exploration of this research goal will probably concern testing the meat of chickens being fed feather meal for the presence of fluoroquinolones, and seeing if they do allow a sufficient amount to reenter the food supply that may warrant a withdrawal period.

In reflecting on my first post on the subject, I believe that my own response to the press release provided an excellent example of the point I was making. As this case and my interpretation of it reveal, it’s extremely easy to think that your statements were clear and representative of the science at the time, but under outside scrutiny can still be misinterpreted whether in a press release or a blog post. I’m sure I’ll remember this article when I get to publish my first paper, and take a good, hard look at the press release before approving it.

 

 

I want to sincerely thank Dr. David Love for taking the time to speak with me about his research, food safety, and agriculture research in general. I greatly enjoyed our discussion and hope that I get to work with him again. Quotes used in this post are transcribed from my notes I took during our discussion, and are used with his prior review and permission.

If you are still interested in this topic I encourage you to read all you can about it, there’s no end to the depth of the science and social issues involved. I’ve linked to the original article several times, but you can also read the supplementary material here that includes some of the anecdotal evidence in support of the presence of some of the contaminants. You can also read the National Chicken Council’s response to the NY times opinion piece that first made this research so popular. Finally, here’s some research from Chile correlating concentrations of enrofloxacin (a fluoroquinolone)  in feathers with withdrawal times in chickens treated with the drug.

Additional government resources on AB-resistant bacteria statistics and USDA residue testing: FDA NARMS report and USDA Redbook.

Please feel free to leave comments on how you feel about the research, the media presentation, and my own interpretation! I know for a fact all you people from ResearchBlogging.org have opinions, I read them all the time!
ResearchBlogging.org

Love, D., Davis, M., Bassett, A., Gunther, A., & Nachman, K. (2010). Dose Imprecision and Resistance: Free-Choice Medicated Feeds in Industrial Food Animal Production in the United States Environmental Health Perspectives, 119 (3), 279-283 DOI: 10.1289/ehp.1002625

Love, D., Halden, R., Davis, M., & Nachman, K. (2012). Feather Meal: A Previously Unrecognized Route for Reentry into the Food Supply of Multiple Pharmaceuticals and Personal Care Products (PPCPs) Environmental Science & Technology, 46 (7), 3795-3802 DOI: 10.1021/es203970e

San Martín B, Cornejo J, Iragüen D, Hidalgo H, & Anadón A (2007). Depletion study of enrofloxacin and its metabolite ciprofloxacin in edible tissues and feathers of white leghorn hens by liquid chromatography coupled with tandem mass spectrometry. Journal of food protection, 70 (8), 1952-7 PMID: 17803156

Newsworthy: Banned antibiotics found in feather meal at Johns Hopkins – How did they get there, and why does your press release contain different conclusions?

An article recently published in Environmental Science and Technology details a study conducted at Johns Hopkins where when examining samples of commercially available feather meal (used as a protein supplement feed or fertilizer) they found trace amounts of fluoroquinolones, a class of antibiotics that have been banned for use in animal feed for 6 years. This is an interesting find, and definitely warrants further research before any broad sweeping conclusions can be made. You know…unless you publish a press release condemning the entire industry for breaking the law and trying to kill us all (question, if all the chicken consumers are dead, how does that lead to higher profits?).

The article itself is very well done. The authors collected samples of feather meal from several states and Canada and tested them for various pharmaceuticals. They also autoclaved the samples to see how the heating processes involved in creation of the product affected degradation/digestion of any of the compounds, and exposed E. Coli cultures to the meal to see if the presence of one or more of the compounds was enough to select for antibiotic resistant populations (they were).

The researchers examined each of the compounds of interest and proposed mechanisms for their presence. Some of them are used at various levels legally within the industry, and the presence of many others (such as caffeine) can be explained by their introduction through various feedstuffs (such as coffee pulp and green tea powder) (Love et al., 2012).

Obviously of most interest to the researchers were the levels of fluoroquinolones, and they hesitantly proposed possible mechanisms for their introduction into feather meal.

“Fluoroquinolones (enrofloxacin, norofloxacin, or ofloxacin) were detected in 6 of 10 U.S. samples, which was not expected because fluoroquinolone use in U.S. poultry production has been banned since 2005. These findings may suggest that the ban is not being adequately enforced or that other pathways, for example, through use of commodity feed products from livestock industries not covered by the ban, may inadvertently contaminate poultry feed with fluoroquinolones…To better interpret our findings, corroborating evidence in the form of antimicrobial usage practices and dosing amounts would be needed.” (Love et al., 2012)

Clearly we’re not ruling out the possibility of these antibiotics being fed, but there is no cause and effect relationship here. They also make note that feather’s contain antibiotics in higher concentrations than meat or other tissues, even after legally defined withdrawal times to remove them from edible tissue. The conclusions here are justly cautious, and place no blame or accusations upon the industry.

The other interesting find was that the feather meal tested would select for antibiotic resistant strains of E. Coli when exposed to cultures. However, this was only testable with autoclaved samples of the meal. And did we mention that the only samples tested here were sourced from China (who according to the article use many more antibiotics than we do in poultry production)?

“These initial results suggest, but cannot prove, that the inhibiting substance may be an antibiotic/bacteriostatic. Autoclaving may have attenuated the quantity and bioavailability of antimicrobial drugs originally present.” (Love et al., 2012)

Again, a cautious observation and hardly conclusive. Comparisons were made from standard cultures exposed to low levels of relevant antibiotics to see if the same strains were removed, but this data cannot be correctly compared as the feather meal was not controlled enough to isolate those compounds. The authors finish their discussion with an appreciation for the novel information they found and an invitation for others to verify, replicate, and build upon their results.

“We have previously described risks related to administration of medicated feed to food animals, which may promote selection for antimicrobial resistance. The presence of antimicrobials in feather meal, as determined in this study, is a previously unrecognized source of these drugs in animal feed. Because this is the first study of PPCPs in feather meal, we invite independent verification of our results by others. More work is needed to determine whether the detected levels of PPCPs in feather meal have an impact on the quality of food animal products and the safety of consumers.” (Love et al., 2012)

And there we have it, an exciting new study that presents a lot of questions to be used for follow-up research. So we’ll publish it and make sure to put out a press release so that not only those keeping up with the journals can read and understand what we’re currently researching.

Well…it seems like the authors like to be scientific when submitting journal articles, but prefer big headlines and sensationalizing when trying to popularize their research. In their official press release, these researchers quickly turn from cautious scientists to industry whistleblowers.

“The discovery of certain antibiotics in feather meal strongly suggests the continued use of these drugs, despite the ban put in place in 2005 by the FDA…The public health community has long been frustrated with the unwillingness of FDA to effectively address what antibiotics are fed to food animals.” – David Love, PhD

Comments from Keeve Nachman, PhD, show a level of conviction that I had no idea he possessed in the original article.

“In recent years, we’ve seen the rate of fluoroquinolone resistance slow, but not drop…With such a ban, you would expect a decline in resistance to these drugs. The continued use of fluoroquinolones and unintended antibiotic contamination of poultry feed may help explain why high rates of fluoroquinolone-resistant Campylobacter continue to be found on commercial poultry meat products over half a decade after the ban.” (I guess we know for sure they’re still being used in the US, I must have missed that citation in your introduction)

“A high enough concentration was found in one of the samples to select for bacteria that are resistant to drugs important to treat infections in humans” (Note: the concentration comment is true, however, your study stated that there was not controlled enough testing to prove that any specific compound present caused the bacterial selection)

“We strongly believe that the FDA should monitor what drugs are going into animal feed…Based on what we’ve learned, I’m concerned that the new FDA guidance documents, which call for voluntary action from industry, will be ineffectual. By looking into feather meal, and uncovering a drug banned nearly 6 years ago, we have very little confidence that the food animal production industry can be left to regulate itself.”

Wow, this press release from the actual authors of the article must be legit, after all, they wrote it, and they wouldn’t write/act completely differently so as to both dangle a carrot to the media and still get their research published in a peer-reviewed journal right?

I knew the Colonel was lying to me. Source: kfc.com

Well, the press release did its job, and Nachman can be found interviewing left and right about how he was “floored” by the result, and how that the more he learns, “the more [he is] drawn to Organic”. There’s a severe lack of integrity here, and the misrepresentation of your data and analysis to cater to anti-big-Ag sentiments is irresponsible and unethical.

So, future scientific corespondents for the Daily Mail aside, what are some other proposed mechanisms for the presence of these banned antibiotics? After all, I’m suggesting that they aren’t being fed routinely as the authors apparently really believe. Let me rephrase that, I’m not ignoring multiple unproven mechanisms for the purpose of shock science.

I spoke with James Hermes PhD, a professor and Poultry Science Extension Specialist here at Oregon State University, about the article. He had obviously heard of it and shared with me some discussions he had had with his colleagues. Their proposed mechanism for the introduction of the pharmaceuticals was through groundwater.

“Feather meal is boiled at the rendering plant, it’s processed with a lot of water, so anything in the groundwater can end up in the meal…Just recently near [Corvallis] they did some testing and found nearly everything we use at home. For years they told us to flush our excess medications…It’s always been there, we’ve just only recently been able to look at such small concentrations 1 parts per billion, trillion, or even possibly quadrillion.” – James Hermes, PhD

So in addition to whatever chickens could be exposed to via drinking the water and concentrating pollutants in their feathers, additional water and pollutants are introduced during the rendering of the product. He encouraged me to find some research showing that ground water contains any and all of the things discovered in the feather meal, and I found it.

So is this a possible mechanism for the introduction of these contaminants? I suggest the authors of the study follow their own advice in the article and explore this mechanism. Perhaps see if the levels of the pharmaceuticals change in the feathers both prior to and after rendering/boiling, explore if they are present in organically produced feather meal, and find out if there are still large concentrations of fluoroquinolones in the groundwater of the areas processing feather meal. And hey, if they want to keep on trucking with scare tactics, I think finding this stuff in the water supply will be much more frightening to the public given that we can’t buy organic water (don’t start).

Finally, in evaluating consumer exposure to the present antibiotics in feather meal, we should keep in mind the steps necessary in the shortest route to the consumer. First, there have to be high concentrations of antibiotics in feather meal; second, that feather meal must be fed to an animal used for food, third; those antibiotics must be retained and remain active until slaughter of that animal at a high enough concentration; fourth, they have to survive gastric juices and be absorbed into the small intestine of the person eating the meat/milk. Nevermind that along the way, the authors of the relevant study note that at any point the vector for the antibiotics is heated most of them will degrade.

Obviously, if the feather meal is used as fertilizer instead of a by product feed, then there are a few more steps that need to take place to get those pollutants onto the plate.

Now if you’ll excuse me, I need to finish this compelling article on how those fat cats selling nautral almond extract are trying to murder me .

 

ResearchBlogging.org
D.C. Love, R.U. Halden, M.F. Davis, & K.E. Nachman (2012). Feather Meal: A Previously Unrecognized Route for Reentry into the Food Supply of Multiple Pharmaceuticals and Personal Care Products (PPCPs) Environmental Science and Technology, 46, 3795-3802

Kolpin, D., Furlong, E., Meyer, M., Thurman, E., Zaugg, S., Barber, L., & Buxton, H. (2002). Pharmaceuticals, Hormones, and Other Organic Wastewater Contaminants in U.S. Streams, 1999−2000: A National Reconnaissance Environmental Science & Technology, 36 (6), 1202-1211 DOI: 10.1021/es011055j

 

 

Update: following this post I had a chance to talk with one of the Authors of the article, read about our discussion here.

Urine protein profiles in cats with cystitis are indicative of increased epithelial damage

Cystocentesis - Image from University of Minnesota CVM

Cats and urinary problems go paw in paw, from the obstruction emergency in males, to common urolithiasis. As a cat owner, it is always important to search for a medical problem before blaming behavioral issues for “accidents” in the house. There’s a whole world of disease out there that can manifest itself as litter box trouble. This article in JAVMA discusses the protein analysis of both healthy cats and those with idiopathic cystitis, urolithiasis, or a UTI.

I’ve actually been thinking about performing a similar study now that I’m at a veterinary clinic with digital records, but do not have the control or finances to have as specific inclusion criteria as this study did (each patient that met inclusion criteria had urine cultures, bladder biopsy, and additional lab work to identify components of the urine performed). The results from this simple small study (n=60) are interpreted well and not only identify a protein present in urine correlated with idiopathic cystitis, but propose a mechanism for it’s presence. Clearly simple, specific, and thorough analysis of blood/urine chemistry have been paying off well for identifying these indicators.

The protein of interest the study found was fibronectin, a protein that plays a role in creating the extracellular matrix and adhesion, and is found in abundance around all cells. This adhesion role implies that fibronectin is crucial within epithelial tissues such as those lining the bladder and urinary tract. What’s interesting is that according to the article, while fibronectin plays large roles in wound healing, blood clot formation, and tumor invasion (Lemberger Et Al., 2011), it was not found in the same high concentrations in any of the cats in the study with conditions other than idiopathic cystitis. One would expect with any inflammation or blood present there would be the same abundance of this protein, but that was not the case. The authors proposed the mechanism that, with chronic idiopathic cystitis, there is significant fibrosis in the urinary tract which damages the epithelial walls. This damage is corrected by increased expression of the fibronectin gene so that the tight junctions between epithelial cells in the cell matrix can be repaired. Thus, with an abundance of fibronectin available to repair chronic damage in the urinary tract, some of it is released and flushed out with urine.

Further study is obviously needed with a larger sample size and more variability in cases, but if the authors’ prediction is correct, fibronectin could be an indicator of epithelial damage in other areas of the body as well. I’m not sure how exactly to go about identifying localized damage, but I am interested in the role that fibronectin could play in anticipating chronic renal failure in cats, as urine chemistry will often not yield an obvious diagnosis until loss of renal function is severe.
ResearchBlogging.orgLemberger SI, Deeg CA, Hauck SM, Amann B, Hirmer S, Hartmann K, & Dorsch R (2011). Comparison of urine protein profiles in cats without urinary tract disease and cats with idiopathic cystitis, bacterial urinary tract infection, or urolithiasis. American journal of veterinary research, 72 (10), 1407-15 PMID: 21962285

Newsworthy: Veterinarians Find Infections Faster by Monitoring Nt-pCNP

"Stinger", a dog with sepsis from a bite wound. Image from Valley Center Veterinary Clinic, Valley Center, CA.

N-terminal portion of pro C-type natriuretic peptide. Try to say that one three times fast. ScienceDaily has a cool article detailing a couple new studies showing that this peptide (Nt-pCNP) could be a solid indicator of sepsis as opposed to a generalized inflammatory response. It could potentially be added to current serum chemistry analysis, or packaged as an ELISA snap for quick, in-house diagnostics for pertinent cases.

Overuse of antibiotics has been a long term problem that is being well addressed in human medicine, however they are used much more broadly and liberally in animals due to their non-prescription access (especially in large animal work), and their use as a diagnostic tool for patients who can’t speak and often can’t afford thorough diagnostics. A veterinarian who’s client is unwilling to pay for a culture will often send broad spectrum antibiotics home anyway as a less expensive option in the hopes that they will take care of the problem.

I was unable to find a chemistry profile of Nt-pCNP, but the journal article itself talks a bit about C-type natriuretic peptide. CNP is produced by vascular endothelial cells and immune system macrophages. It “inhibits microbial growth and modifies pathogenicity of microorganisms” (DeClue, 2011). The problem with looking for just CNP as an indicator of sepsis is that it has a very short half life, and tends to degrade even faster in removed serum. Therefore, the researchers decided to use Nt-pCNP as their target molecule.  Nt-pCNP is created in a 1:1 ratio with CNP as a byproduct, and is much more durable and long-lived in both the bloodstream and collected serum.

The results of the study support the hypothesis  that CNP is a good indicator of sepsis, however like anything else, it’s not ideal. CNP was shown to be a poor indicator of sepsis when the infection was peritoneal. This includes gastrointestinal perforations or other possible infections found within the peritoneum (the authors mention that using peritoneal fluid as opposed to serum from a distal point may yield better sensitivity). Taking these false negatives into account, the test had a 65.5% sensitivity, for all other origins of sepsis in the study, sensitivity was 92%. Unfortunately, there appears to be a large potential for ambiguous negatives when peritoneal infection is suspected, but it’s always important to remember to educate clients that medicine is rarely black and white. It’s nice that House is able to identify exactly what’s wrong with each of his patients every week, but most of the time, we’re just going to give them supportive care based on the most likely result. Some of the limitations of the study that the authors mentioned were the small sample size and uncontrolled natures of the ailments that may have influenced the blood chemistry (samples taken from bacterial vs. viral infections, condition as of admission, underlying secondary infection or ailment, etc.).

In the case of this test and many other lab tests, positives are very definitive and help us out, while negatives are ambiguous. This is true whether it’s a heartworm test, fine needle aspirate, fecal flotation, radiology, or any number of other diagnostic tests. Every one is a tool, and hopefully looking at Nt-pCNP levels will give us another way to confirm sepsis while our cultures are growing at the lab, or perhaps offering another faster or less expensive option that the situation necessitates.
This post was chosen as an Editor's Selection for ResearchBlogging.org
DeClue AE, Osterbur K, Bigio A, & Sharp CR (2011). Evaluation of serum NT-pCNP as a diagnostic and prognostic biomarker for sepsis in dogs. Journal of veterinary internal medicine / American College of Veterinary Internal Medicine, 25 (3), 453-9 PMID: 21457321

Article Review: Effects of intravenous administration of Lactated Ringer’s solution on hematologic, serum biochemical, rheological, hemodynamic, and renal measurements in healthy isoflurane-anesthetized dogs

Well, it’s about time I mentioned an article I didn’t particularly enjoy on here. It’s not like I think it’s a waste of paper, it’s an important topic, but it does nothing creative and does little to contribute to the understanding of the subject. The article looks at the effects of different rates of Lactated Ringers Solution administered while under isoflurane anesthesia. It uses healthy animals, discusses well documented effects in humans, and just reinforces common practice.

Lactated Ringers is the most frequently prescribed fluid for maintenance of homeostasis in surgery and pretty much any other health stress event. I know when any patient wasn’t feeling well from any situation at my clinic, we always administered LRS either through a catheter or subcutaneously for outpatients, the dosage based on weight and severity of condition. We know how to use it, and it’s gotten a proven history of effectiveness in both humans and animals. The article justifies itself by saying that fluid therapy in dogs is largely based on human evidence, and that the formulas we use to determine rates have not been thoroughly investigated. Yet throughout the article they repeatedly compare their results to similar studies, and make no conclusions that aren’t already accepted in human and animal medicine. Additionally, the gaps in the literature they identify can’t even be answered using the methods and results of this study, so you can’t use them to justify its existence.

So the big conclusions they determined were that providing LRS increased plasma volume and cardiac output, didn’t increase urine production, and appears to leave the blood volume and remain in extracellular space. These are important points, but they were accepted unanimously without the presence of this study. Further, if their goal was to confirm these assumptions, their results are pretty much irrelevant with a sample size of only 8 animals, all in perfect health, similar size (26-41 lbs isn’t a lot of variance in the world of dogs), and undergoing no medical stress other than common anesthesia and mechanical ventilation.

My impression after finishing the paper was that the people at QTest labs (associated with Ohio State University College of Veterinary Medicine) needed a study to do, needed to get a grant proposal ready, and did enough research on the subject to sell this trial. It’s well written and the authors do a great job of placing their results in context of the literature, mostly because it all agrees. But it can’t hide the fact that it does nothing revolutionary other than providing history on the subject, and giving an excellent account of the methods used in the study. With such great, specific, and controlled procedures, this facility could be solidifying other theories that have conflicting data, if they’d use a sample size large enough.  I’m sure that they don’t always do milk run trials such as this one, and I look forward to seeing their name again in future articles.

ResearchBlogging.orgWilliam W. Muir III, Anusak Kijtawornrat, Yukie Ueyama, Steven V. Radecki, & Robert L. Hamlin (2011). Effects of intravenous administration of lactated Ringer’s solution on hematologic, serum biochemical, rheological, hemodynamic, and renal measurements in healthy isoflurane-anesthetized dogs JAVMA, 239 (5), 630-637