Aging in the Dog: Presentation at the Fetch Kansas City Conference

Aging in the Dog:
Foundations of Canine Geriatric Medicine

What is aging?
How we define aging depends on our goals and our frame of reference. From the biomedical perspective of the veterinary clinician, the important elements are:

  • The passage of time
  • Deleterious physiologic and functional changes at the molecular, cellular, tissue, and organismal levels
  • A progressive increase in the risk of the three Ds
    • Disability
    • Disease
    • Death

As dogs age, they lose robustness (the ability to maintain a state of baseline or optimal physiologic function in the face of external stressors) and resilience (the ability to return to this state following perturbations caused by such stressors).1 This leads to frailty and the development of many age-associated diseases which seem superficially unrelated but which are actually all consequences of the same underlying mechanisms of aging. 

Is aging a disease?
Because aging is a universal phenomenon, at least in mammals, and because historically there have been no effective interventions to slow or stop the aging process per se, only treatments to mitigate the clinical consequences, aging is widely seen as natural, inevitable, and immutable. However, decades of foundational research in laboratory model species, and more limited recent studies in humans and companion dogs, suggest that the core mechanisms of aging can be altered in a way that may prevent the health consequences of aging.2,3 Much debate has focused on the semantic issue of whether or not something natural and ubiquitous but also responsible for illness and death should be labeled a disease.4 There is not yet any consensus resolution to this debate.

A pragmatic approach that avoids this semantic debate is to view aging is the most important modifiable risk factor for disease in companion dogs. This is a familiar concept to veterinarians. Obesity, for example, is a risk factor for multiple specific diseases which increases the overall risk of mortality.5 Focusing on reducing this risk by targeting obesity, rather than waiting for the clinical consequences to develop and then managing each independently is a well-established practice in preventative medicine.

Age-associated changes are responsible for most of the health problems of adult dogs, and there are plausible hypotheses suggesting therapies that could directly target aging and so prevent these problems. The focus of geroscience (the study of the fundamental mechanisms of aging) is to identify these targets and therapies so the field of geriatrics (the clinical management of the aged) can move away from the reactive practice of treating the clinical consequences of aging as they arise and towards a preventative approach of delaying and preventing these consequences by modifying the fundamental processes of aging. 

Why do dogs age?
It is sometimes supposed that because evolution selects against deleterious traits, the fact that most animals develop disability and disease with age is a paradox. Shouldn’t we have evolved for eternal good health, since this seems obviously more “fit” than getting old and frail?6

One possible explanation for this apparent paradox is that genes and phenotypes which promote reproductive success early in life can cause health problems later in life but still be favored by natural selection.7  Intensive parental investment, for example, may improve reproductive success while simultaneously diminishing the parents reserves and capacity to maintain their own health. Genes favoring such investment would likely outcompete genes favoring parental neglect even if the latter strategy led to longer healthspan and lifespan. 

Dogs are also arguably more a product of artificial than natural selection, and many aspects of their aging reflect this. Large and giant-breed dogs, for example, have much shorter lives than smaller breeds, and this is closely tied to genetic differences associated with growth and adult size.8–10

How do dogs age?
The cellular and molecular processes associated with aging, and the tissue dysfunction and ultimate health problems that result from these processes, are complex and multifactorial. Research in laboratory species, and in humans and our canine companions, has elucidated many of these mechanisms, and our understanding of them is growing rapidly.1,11–13 Figure 1 illustrated just a few nodes in the complex web of aging.

Figure 1. The web of tissue aging—a partial illustration of the interactions between key tissue-aging mechanisms. GH = Growth hormone. IGF-1 = Insulin-like growth factor-1. From McKenzie (2022)1.

Despite the complexity of aging, it is ultimately just biology, a collection of physiologic processes that can be understood and manipulated like any other.  There is a vibrant field of canine geroscience research investigating the processes of aging and potential targets for intervention to extend healthspan and lifespan.

When is a dog “old”?
The old canard that every year in a dog’s life is equivalent to seven years for a human is a misleading oversimplification. Dogs age more rapidly than humans at the beginning and end of their life cycles, but the overall lifespan trajectory is quite similar.14 Large and small dogs often age quite differently as well, so the designation of geriatric status may be appropriate much earlier for some breeds than others. In terms of chronological age, or simply the time a dog has been alive, one has to consider size, breed, and individual characteristics. For practical purposes, this approximation is at least useful for triggering more intensive monitoring and investigation of clinical complaints, but it is merely a very rough guide to when we might call a dog “old:”

  • Small  (under 20 lbs) > 12 years
  • Medium (20-50 lbs) > 10 years
  • Large (over 50 lbs) > 8 years

More important than chronological age, however, is biological age, defined as the degree to which aging has impacted the robustness, resilience, and state of health and function in an individual as measured by physical, functional, and biomarker assessment.1 We do not yet have reliable tools for measuring biological age, but many are being developed and tested, and ultimately this will be a much more accurate way to predict the age-associated risk of the three Ds (disability, disease, and death) than chronological age.

What can we do about canine aging?
The ideal response to the burden of aging on the health and wellbeing of dogs and their caregivers is to target the core mechanisms of aging and extend lifespan by preventing the entire array of age-associated diseases and clinical problems. Figure 2 illustrates the goal of extending both lifespan (the time alive) and healthspan (the time without significant age-associated health problems). 

a)

b)

Figure 2. Lifespan trajectories in the dog. a) standard trajectory showing gains and declines in robustness and resilience throughout the lifecycle from birth to death. b) trajectory showing the results of therapies targeting core aging mechanisms and resulting in extended lifespan and healthspan and morbidity compressed into a smaller window of time prior to death

Until we have validated therapies to accomplish this, however, we can best serve our canine patients by encouraging lifestyle habits that are known to delay age-associated disease and mortality:

  • Prevent obesity15
  • Encourage regular physical activity16
  • Encourage consistent, evidence-based veterinary care17

A systematic approach to the geriatric canine patient
Once age-associated health problems do develop, we can best care for our patients with systematic, rational, evidence-based assessment and management. There are many tools that allow us to evaluate pain, impaired mobility, frailty, and other manifestations of canine aging, and these are not yet widely and consistently used. Many of the most common age-associated diseases, such as chronic kidney disease, cardiac disease, and many types of neoplasia, have been the focus of extensive research, and there are often clinical practice guidelines and other evidence-based tools to help support high-quality therapeutic management of these conditions.18–20 And finally, despite some significant limitations, the emerging discipline of hospice and palliative care is an important element in caring for those patients most severely affected by aging.21

A systematic approach to geriatric medicine encourages proactive identification of disease and clinical problems and using the bets available evidence to guide diagnostic and treatment interventions. Too often, clinical signs of frailty and disease are dismissed as “just slowing down” or “normal aging” rather than appropriately assessed, monitored, and managed. In the future, proactive and systematic detection of such signs will be a critical element in the determination of biological age and the decision to employ therapies targeting aging directly.

References

1.        McKenzie BA, Chen FL, Gruen ME, Olby NJ. Canine Geriatric Syndrome: A Framework for Advancing Research in Veterinary Geroscience. Front Vet Sci. 2022;0:462. doi:10.3389/FVETS.2022.853743

2.        Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E. From discoveries in ageing research to therapeutics for healthy ageing. Nat 2019 5717764. 2019;571(7764):183-192. doi:10.1038/s41586-019-1365-2

3.        Lawler DF, Evans RH, Larson BT, Spitznagel EL, Ellersieck MR, Kealy RD. Influence of lifetime food restriction on causes, time, and predictors of death in dogs. J Am Vet Med Assoc. 2005;226(2):225-231. doi:10.2460/javma.2005.226.225

4.        McKenzie BA. Is Aging a Disease? DVM360. 2022;53(3):25.

5.        Salt C, Morris PJ, Wilson D, Lund EM, German AJ. Association between life span and body condition in neutered client-owned dogs. J Vet Intern Med. 2019;33(1):89-99. doi:10.1111/JVIM.15367

6.        Johnson AA, Shokhirev MN, Shoshitaishvili B. Revamping the evolutionary theories of aging. Ageing Res Rev. 2019;55:100947. doi:10.1016/J.ARR.2019.100947

7.        Austad SN, Hoffman JM. Is antagonistic pleiotropy ubiquitous in aging biology? Evol Med Public Heal. 2018;2018(1):287-294. doi:10.1093/EMPH/EOY033

8.        Rimbault M, Beale HC, Schoenebeck JJ, et al. Derived variants at six genes explain nearly half of size reduction in dog breeds. Genome Res. 2013;23(12):1985-1995. doi:10.1101/gr.157339.113

9.        Plassais J, Rimbault M, Williams FJ, Davis BW, Schoenebeck JJ, Ostrander EA. Analysis of large versus small dogs reveals three genes on the canine X chromosome associated with body weight, muscling and back fat thickness. Clark LA, ed. PLOS Genet. 2017;13(3):e1006661. doi:10.1371/journal.pgen.1006661

10.      Kraus C, Pavard S, Promislow DEL. The size-life span trade-off decomposed: Why large dogs die young. Am Nat. 2013;181(4):492-505. doi:10.1086/669665

11.      López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217. doi:10.1016/j.cell.2013.05.039

12.      Sándor S, Kubinyi E. Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging. Front Genet. 2019;10:948. doi:10.3389/fgene.2019.00948

13.      McKenzie BA. Comparative veterinary geroscience: mechanism of molecular, cellular, and tissue aging in humans, laboratory animal models, and companion dogs and cats. Am J Vet Res. 2022;83(6). doi:10.2460/AJVR.22.02.0027

14.      Wang T, Ma J, Hogan AN, et al. Quantitative Translation of Dog-to-Human Aging by Conserved Remodeling of the DNA Methylome. Cell Syst. 2020;11(2):176-185.e6. doi:10.1016/j.cels.2020.06.006

15.      Salt C, Morris PJ, Wilson D, Lund EM, German AJ. Association between life span and body condition in neutered client-owned dogs. J Vet Intern Med. 2019;33(1):89-99. doi:10.1111/JVIM.15367

16.      McKenzie BA. What does the evidence say about feline fitness and dog aerobics? Vet Pract News. Published online January 2022:25-26.

17.      Urfer SR, Wang M, Yang M, Lund EM, Lefebvre SL. Risk Factors Associated with Lifespan in Pet Dogs Evaluated in Primary Care Veterinary Hospitals. J Am Anim Hosp Assoc. 2019;55(3):130-137. doi:10.5326/JAAHA-MS-6763

18.      (IRIS) IRIS. Treatment Recommendations for CKD in Dogs.; 2019.

19.      Keene BW, Atkins CE, Bonagura JD, et al. ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. J Vet Intern Med. 2019;33(3):1127-1140. doi:10.1111/jvim.15488

20.      Biller B, Patel M, Smith D, Bryan C. 2016 AAHA Oncology Guidelines for Dogs and Cats*. J Am Anim Hosp Assoc. 2016;52:181-204. doi:10.5326/JAAHA-MS-6570

21.      Bishop G, Cooney K, Cox S, et al. 2016 AAHA/IAAHPC End-of-Life Care Guidelines. J Am Anim Hosp Assoc. 2016;52(6):341-356. doi:10.5326/JAAHA-MS-6637)

Posted in Aging Science, Presentations, Lectures, Publications & Interviews | 1 Comment

Canine Aging and Health Posts from Loyal

As part of my work as Director of Veterinary Medicine for Loyal, a company studying therapies to extend lifespan and delay or prevent age-associated disease in dogs, I am writing regular blog posts. Many of these concern canine aging, though there are some addressing general canine health and biology as well. This is partly responsible for the reduced frequency of my SkeptVet posts, but since many of these may be of interest to followers of this blog as well, I am collecting these posts here just as I did for my VPN column.

As always, feedback is welcome, and if you have subjects you would like to hear more about, let me know!

Should you zoom call your dog?
There are now lots of devices that let us call our dogs and say “Hi!” when we aren’t at home. But are these really for our dogs, or just for us? (February, 2022)

Healthspan: the healthy prime of life
Lifespan is the amount of time lived. Healthspan is the time lived with vigor and good health. Which do you think is more important? (February, 2022)

Obesity and epigenetics
One of the most important health problems in veterinary medicine today is the epidemic of obesity in our pets. (April, 2022)

Signs of senior years: looking old, feeling old, and acting old
Do you ever wonder how your dog might look, feel, or act as they advance in age? Understanding aging gives us the potential to prevent or mitigate a wide range of age-related health problems in dogs. (August, 2022)

New in dog health: Sniffing out this month’s discoveries in science
Do dogs “see” with their noses? Can my dog feel guilt? Can dogs catch monkeypox from their owners? Find out in this month’s review on canine science research. (August, 2022)

Dog enrichment activities: Healthy brains and happy dogs
Exercise and enrichment activities can help you protect your dog against the effects of brain aging. (August, 2022)

Why do big dogs have unusually short lifespans compared to small dogs?
Dogs come in an astounding range of shapes and sizes. Explore how genetic differences impact age and how Loyal is working on extending the life and health of large dogs. (September, 2022)

Posted in Loyal Blog Posts | 2 Comments

Raw Diets and Allergies-SkeptVet and DogRisk Exchange Letters in the Journal of Veterinary Internal Medicine

In March of this year, I wrote a post discussing the limitations and misleading conclusions of a research study in the Journal of Veterinary Internal Medicine (JVIM) which claimed that feeding puppies a raw diet could reduce the risk of allergies later in life. This article was produced by the DogRisk research group, which has consistently supported raw diets in scientific publications and through other platforms, including the bogus documentary The Truth about Pet Cancer. My main concerns with the article were:

  • The potential for ideological and funding bias
  • The reliance on a convenience sample of online owner surveys as the main source of data
  • The inconsistency of many of the findings with the underlying hypotheses and conclusions

Because such an article in such a prestigious journal is likely to create the false impression of strong evidence in favor of feeding a raw diet, I felt it was worthwhile to submit a letter to the editor of JVIM detailing my concerns about the report. I was joined in this by Dr. Jennifer Larson, a board-certified veterinary nutrition specialist. 

The process of getting this letter printed in the journal was surprisingly prolonged and difficult. The letter was initially submitted in January, and has finally appeared today, seven months later, which is an unusually long time. The main problem appears to have been concerns on the part of the JVIM legal team that the journal might be sued over my characterization of one of the funders, Dr. Joseph Mercola. Regular readers will know that Dr. Mercola, and the leader of the veterinary side of his website, Dr. Karen Becker, are stalwart promoters of pseudoscience and alternative medicine. Dr. Mercola has been warned and sanctioned several times by the FDA and the FTC for illegal medical claims, but it was quite a struggle to get JVIM to accept this factual information as part of the letter. 

Despite this, and the compulsory insertion of much excessive qualifying language, the letter has finally appeared in the journal. Though it repeats much of what I wrote in my blog post, I will reproduce the full content here:

The report Puppyhood diet as a factor in the development of owner-reported allergy/atopy skin signs in adult dogs in Finland, which appeared in the September/October issue of the Journal of Veterinary Internal Medicine (JVIM), suggests that “puppyhood exposure to raw animal-based foods,” “human meal leftovers” and other “real foods” might have a protective influence against canine atopic dermatitis (CAD) while “heat-processed foods” might increase later occurrence of CAD. We are concerned that the results of this study likely represent residual bias in data collection and analysis rather than the actual influence of specific dietary components on the risk of CAD.

Common recognized sources of bias in research studies include a priori beliefs on the part of researchers, recall and selection bias in survey respondents,1 funding bias,2 and a large number of researcher degrees of freedom in the design, conduct, and analysis of the study.3All of these are present in this study.

Dr. Hielm-Björkman and the Dog Risk research group have expressed strong beliefs about the health benefits of raw diets and the dangers of conventional commercial pet foods in previous research reports and popular media.45

The main source of data in this study is an online survey available only in Finnish. Previous publications regarding validation of this data source have identified low response rates to validation questions and important proportions of duplicate, automated, and discordant responses.67 Asking owners to remember in detail what they fed their puppy between 2 and 8 months of age and then trying to associate that with health outcomes years later is, in our view, a questionable strategy. Self-reporting of diet and health information are unreliable in humans, and we believe that it is unlikely to be more reliable among dog owners.1 Dog owners consistently misperceive even straightforward measures such as body condition score despite formal training in this assessment, so their assessment of signs of CAD is, in our view, likely to be equally unreliable.8 The survey responses are expressions of the perceptions and beliefs of the owners who participated, not necessarily the true nutritional and environmental exposures nor health outcomes experienced by the dogs.

Dr. Hielm-Björkman has previously cited funding bias as a problem in the study of raw diets, stating that raw foods are “not really researched in universities. Most universities get sponsored by these big billion-dollar companies, and you don’t really want to step on their toes, I guess.”5 In light of the recognized problem of funding bias it could be relevant that disclosed funding sources for this research include companies selling raw pet foods.

The authors also report accepting funding from Dr. Joseph Mercola. Dr. Mercola’s organization advocates for raw pet diets and argues against conventional pet foods on its web site.911 We believe that he is also a consistent promoter of unapproved medical practices and medical product claims, as evidenced by multiple warning letters from the Food and Drug Administration and a lawsuit by the Federal Trade Commission related to therapeutic claims that violate the U.S. Food, Drug, and Cosmetic Act.1216 Such an affiliation is at least as relevant to assessing potential bias as accepting funding from an organization with a commercial interest in raw or conventional pet foods. Bias in scientific research is as likely to arise from ideological as financial factors.

We believe that the results of the analysis and how they are reported also suggest the influence of bias. Many comparisons are listed only in supplemental materials, and those reported in the main article tend to be those which support the authors’ hypotheses. This creates the appearance of consistency when, in fact, the associations identified are often inconsistent and do not logically support the claims in the conclusions. For example, why would raw tripe and organ meats be protective against CAD but raw red meat, eggs, and poultry not be? If cooking is the key risk factor, why would cook vegetables be protective and raw vegetables would not or why would both cooked and raw eggs be protective while neither cooked nor raw poultry is associated with the likelihood of CAD? If exposure to bacteria is the main variable, why is eating dirt, sticks or carcasses protective but eating clay and grass is not and drinking from puddles is actually associated with increased risk? If excessive processing is the issue, why was there no association with eating processed meats or canned foods and only a marginal association with dry food when it was the only food offered?

Dogs with CAD were reportedly more likely to be eating no raw food at all than controls, and dogs without CAD were more likely to be fed 20% or 90% raw, but there were no statistically significant differences at any other ratio of the 2 foods. Similarly, allergic dogs were more likely to be fed 80% dry than controls, but there was no significant difference in CAD risk if they were fed more than 80% dry. Control dogs were more likely to be fed 50% or less than 10% dry, but there was no difference at intermediate ratios. It is easier to see cherry picking and researcher degrees of freedom than a consistent dose-response in these results.

While the authors do acknowledge the potential for recall bias and misclassification, and they do state that their findings cannot prove causal relationships, the overall message of the paper is that uncooked foods and human meal leftovers likely have health benefits, and this is inconsistent with the methodological limitations and potential for residual bias of this study.

Given the importance of CAD, in terms of both prevalence and the negative impacts on pet and owner quality of life, we agree that identification of protective factors is warranted. However, considering the significant risks of illnesses and death that have been consistently associated with the feeding of raw animal products, rigorous and well-designed research methodology, objectivity, and full reporting of results are needed to explore if any benefits exist for this practice, and certainly are required before this practice can be confidently recommended.

CONFLICT OF INTEREST DECLARATION
Jennifer Larsen declares the following conflicts:

Investigator in clinical trials and other research partly or fully sponsored by Royal Canin, Nature’s Variety Instinct, and Nestle Purina PetCare.

Develops educational materials for Mark Morris Institute and HealthyPet magazine.

Serves as advisory group consultant for Elanco Animal Health.

Participates in continuing education events, as a speaker & as an attendee, sponsored/organized by Royal Canin, Nestle Purina PetCare, Nature’s Variety Instinct, and Hill’s Pet Nutrition.

A resident of the Nutrition Service received funds through the Hill’s Pet Nutrition Resident Clinical Study Grants program.

The Veterinary Medical Teaching Hospital at the University of California, Davis receives funds from Nestlé Purina PetCare to partially support a nutrition technician.

Brennen McKenzie declares no conflict of interest.

As is usual and appropriate, the authors had an opportunity to provide a response to the letter. The response didn’t really contain any meaningful rebuttal of the concerns we expressed, merely a series of assertions that they weren’t valid, relevant, or important. Here is the full content of the authors’ rebuttal:

We read Drs McKenzie and Larsen letter with interest, and we thank the Editor for the opportunity to discuss the scientific questions through this forum.

Dr McKenzie (skeptvet1) and Larsen in their letter to the editor indicate that the DogRisk research group has a priori notions about the benefits of raw feeding. We want to point out that we only have three veterinarians and only three dog owners in our research group of eight, only two feeding raw, and that we take pride in discarding our hypotheses every time we prove them wrong. Regarding raw food we have time after time, through published articles and 10 university student theses in Finnish, seen that there are health benefits when owners use a raw diet for their dogs, compared to a dry. We acknowledge the variety of raw and dry dog diets available and therefore we also know that the reasons behind the health benefits are hard to estimate. We have analyzed gene-expression2 and metabolomics3 in a raw-dry diet-intervention study. We look at processing, the absence of heat, macronutrient profile (proteins, fats, and carbohydrates, content and origin), bacterial load, among other factors. We now work with 10 hypotheses of why the raw food diet repeatedly comes up as healthier in our studies. In a world where our dogs suffer increasingly from noncommunicable diseases that are similar to those of humans (atopy, allergies, IBD, diabetes, certain cancers and similar) we can also make veterinary medicine relevant for human medicine by reporting what we see in dogs, that share most of the other environmental factors with us, their human owners. To this end, diet is an excellent variable to investigate, as dog owners tend to keep their dogs on the same diets for extended periods of time, sometimes a whole lifetime. Also, because of diets being so homogenous, owners do not tend to forget or misrepresent it, as they might do about their own diet. These are our motivators, not proving a preconceived hypothesis.

The second issue that Dr McKenzie and Larsen were concerned about was survey problems. All relevant concerns are mentioned in the limitations part of the article, as they themselves point out. In contrast to what was said in the letter, we want to point out that our research is, and has been in all our papers, completely transparent. We always mention the reasons for omitting cases: for example, robot answers, dogs not reported to eat enough to stay alive, too young controls as they still could develop the disease etc. As expected from an academic research group, our survey is validated,4 including the dependent variable of this paper (allergy/atopy). We are of the same opinion with the authors of the letter that owners misperceive especially body condition score; our data show that only 13% of owners have reported that their dogs are overweight (12%) or obese (1%). But we also know that they are good at perceiving the clinical signs their dogs have: itching, ear, eye or skin infections, anal gland problems, teeth and gum problems etc., as those are the reasons that they contact their veterinarians for appointments. The owners in our survey also had the possibility to tick other skin related disorders (eg, hot spots, demodicosis, seborrhea etc.) than allergy/atopy. And as they did not, there are not so many other diagnoses than allergy/atopy they could have had, as flea allergic dermatitis is not a common entity in Finland.

Further, the authors of the letter to the editor addressed an issue we again take pride in, analysis of the data. We totally disagree with the notion of “cherry picking” data and instead again want to highlight that by putting all results in either the main article or supplemental material for other researchers to see, we can best forward this area of research. Regarding selection bias, when using backward stepwise regression, the computer starts with all variables and excludes the ones with the lowest coefficient of determination. The result is a computer-generated final model, including the significant variables. Only the machine chooses, not humans so no bias is even possible. It is common practice to discuss the significant results and trends while the pre-analyses are put into the supplemental data (S1-2). Figure 2A,B in our article show that there are more non-atopic dogs than atopic dogs when the dogs have been eating more than 10% raw food and on the contrary, more atopic dogs, when they have been eating more than 80% of their diets as dry. Not all 10% intervals will show significance between the two diets as there will not be enough cases at all intervals and it is also normal that some of 20 intervals (here one; eating 60% dry) will be out of line, for the same reason. That it is so consistent, is remarkable.

At the start of our response, we mentioned some of our hypotheses for why raw diets come up as healthy, but that we lack an answer to the “why?”. The authors to the letter also had many “If-why?” questions. At this time, we do not have the answers, but we hope that we will be able to answer them within a couple of years.

Another issue raised was funding bias. Also here, we have been completely transparent as can be seen in our long list of funders. We have been able to attract funding, for example, from state funding bodies, foundations, private people and companies by crowdfunding, raw food companies etc. and we are equally thankful to all. However, the big traditional dry feed companies have not been interested in funding our research, despite enquires. On our website, we disclose and thank all our sponsors (Moomin trolls and all) while letter author McKenzie instead has paid advertisements from Hills’ and Mars, for example, featuring the same Royal Canin advertisement on atopy diets both as “sponsored content” and in his “education center,” on his Veterinary Practice News homepage.5 Dr JA Larsen discloses her close co-operation with Mars, Hills’ and Nestle’ Purina in the Conflict of Interest section in all of her published articles.

Finally, we would like to point out that we have no “raw food agenda” but if we find that the “raw” is of value, we feel that we have an ethical obligation to the community to report it. We will therefore now recommend that people who feed dry food supplement the diet with at least 20% raw. If the health benefits come from beneficial bacteria, we will recommend that they should be added to the dry food, etc. Also, contrary to the letter authors’ comments, we have and will continue to report on raw feeding not being dangerous for neither dogs nor family. In our risk-analysis study, we found only three verified cases of food pathogen transmission from raw dog food to humans in 16?475 households feeding raw and in 98?353 pet years at risk.6 This study has been replicated with similar results.7 As a university-based independent research group, we are driven by a concern for the growing disease load in our dogs. We hope our research will benefit both canine and human health and therefore we report everything we find, as we find it.

Here is how I view these responses:

  • “We only have three veterinarians and only three dog owners in our research group of eight, only two feeding raw”

    If I interpret this correctly that all eight members of the group own dogs and only two of them feed raw, I would say that is interesting, but not really relevant to the issue of whether the group in general has a bias in favor of raw diets that influences their work. Our personal practices don’t always perfectly mirror our beliefs.
  • The next point they make is that their studies have consistently found benefits to feeding raw and that they have numerous hypotheses for why, though they cannot yet claim a specific reason for these benefits. Again, the fact that their work consistently finds what they believe and expect to find doesn’t say much about whether those beliefs, of the evidence they have generated, are correct. It would be much more convincing if other research groups with other perspectives and agendas found the same results. 

    It is always the case in science that when much of the evidence for a claim comes from a single source, that is a reason to be skeptical of that evidence, and there is no reason not to apply that principle to the subject of raw diets or the DogRisk group.
  • The group next acknowledges the limitations of an owner survey as a data source while simultaneously claiming that the particular evidence and conclusions they have drawn from such a survey are correct. This is just an assertion of belief, not evidence that the limitations Dr. Larson and I raised are not influencing the findings.
  • They then respond to our pointing out the inconsistency of the findings and the emphasis only on those that support their claims while those that do not are relegated to the supplemental material. This response is, again, just to assert that there is nothing about these findings or reporting that is problematic or should undermine confidence in their conclusions. That is for readers of the article to decide, but simply responding to the identification of a potential problem by saying “that’s not a problem” isn’t a very compelling argument.

    In particular, they acknowledged that they cannot explain some of the inconsistencies we pointed out in the findings, but they don’t see these inconsistencies as a reason to question their underlying conclusions about the benefits of raw diets. That response certainly has all the hallmarks of cognitive dissonance.

  • With regard to the issue of funding bias, the authors respond by arguing that it isn’t a problem since they disclose their funding sources and then move on to the tu quoque fallacywhich is the strategy of arguing that if someone else has a potential financial conflict of interest, that negates the potential significance of their own. 

    Apart from being irrelevant, this claim fails with regard to my own supposed financial interests. Since I receive no funding of any kind from the pet food industry, the only way they could make a claim of funding bias was by pointing out that the Veterinary Practice News puts ads for pet food on some of the pages where they print my column on evidence-based medicine. 

    I not only have no influence on advertisers the magazine works with and receive no income from ad in the magazine, I am actually unaware of what ads appear in the magazine since I rarely even read my own columns once they have been published. How this could possibly influence my positions on raw diets is unclear, so this is a bit of a desperate tactic.

References from Original Letter

1.         Ravelli MN, Schoeller DA. Traditional Self-Reported Dietary Instruments Are Prone to Inaccuracies and New Approaches Are Needed. Front Nutr. 2020;7:90. doi:10.3389/fnut.2020.00090

2.         Resnik DB, Elliott KC. Taking financial relationships into account when assessing research. Account Res. 2013;20(3):184-205. doi:10.1080/08989621.2013.788383

3.         Simmons JP, Nelson LD, Simonsohn U. False-positive psychology: undisclosed flexibility in data collection and analysis allows presenting anything as significant. Psychol Sci. 2011;22(11):1359-1366. doi:10.1177/0956797611417632

4.         Fredriksson-Ahomaa M, Heikkilä T, Pernu N, Kovanen S, Hielm-Björkman A, Kivistö R. Raw Meat-Based Diets in Dogs and Cats. Vet Sci. 2017;4(4):33. doi:10.3390/vetsci4030033

5.         Habib R, Becker K. The Dog Cancer Series: Rethinking the Cancer Epidemic Vol. 1- Chapter 4 (Transcript).; 2018:73.

6.         Hemida M, Vuori KA, Salin S, Moore R, Anturaniemi J, Hielm-Björkman A. Identification of modifiable pre- and postnatal dietary and environmental exposures associated with owner-reported canine atopic dermatitis in Finland using a web-based questionnaire. PLoS One. 2020;15(5):e0225675. doi:10.1371/journal.pone.0225675

7.         Roine J, Uusitalo L, Hielm-Björkman A. Validating and reliability testing the descriptive data and three different disease diagnoses of the internet-based DOGRISK questionnaire. BMC Vet Res. 2016;12(1):30. doi:10.1186/s12917-016-0658-z

8.         Eastland-Jones RC, German AJ, Holden SL, Biourge V, Pickavance LC. Owner misperception of canine body condition persists despite use of a body condition score chart. J Nutr Sci. 2014;3:e45. doi:10.1017/jns.2014.25

Posted in Nutrition | 4 Comments

Facebook Live Interview on Canine Aging with Dr. Hannah Capon of Canine Arthritis Management

Posted in Aging Science, Presentations, Lectures, Publications & Interviews | 2 Comments

Book Review- Age Later by Dr. Nir Barzilai

Dr. Nir Barzilai is a well-known researcher and advocate for longevity studies. He is an MD and the founder or driving force behind many geroscience institutes and initiatives. In 2020, he also became one of a growing number of scientific figures in the aging biology field who have written popular books on the subject for the general public.

Logo, company name

Description automatically generated

Among the aging science books I have reviewed so far, this one is the most casual and conversational. It conveys the impression that the reader is sitting in a living room as a relaxed but enthusiastic Dr. Barzilai shares anecdotes, recollections, and opinions over a few glasses of wine. This approach has both advantages and disadvantages. 

The material is easy to read and not overly technical or full of scientific jargon. It is also very loosely organized, even a bit rambling at times, and it is heavy on anecdotes and opinions and light on evidence and critical assessment. One could easily come away with the impression that every idea, every hypothesis about aging is exceptionally promising and that radical transformation of human lifespan and healthspan is just around the corner. Unfortunately, that is probably not the most accurate picture of the field, and it glosses over the complexity of aging biology and the scientific challenges of significant lifespan extension. 

Dr. Barzilai does talk quite a bit about the political and financial challenges, going so far as to say “the only thing standing between [a world of healthy, productive elderly people] and the one we have is money.” Much of the book is about commercial ventures he has been involved in that hope to turn promising scientific hypotheses into readily available therapies and products at warp speed; much faster than the painstaking, laborious processes of non-profit scientific investigation and regulatory approval. Again, the reader gets a very clear impression (accurate or not) of Dr. Barzilai’s personality and views on the best way to move forward with geroscience. Though he is a well-respected scientist who has made significant contributions to aging biology, he seems a bit impatient with the speed of progress and inclined to suggest the market could do a better, or at least faster, job of capitalizing on the scientific possibilities with sufficient funding and less conservative regulatory constraints.

The book shares many anecdotes about the human experience of aging, and this fits well with one of the central stories, which is Dr. Barzilai’s work with centenarians attempting to uncover the secrets to their exceptional longevity and health. The predominant message coming from this work appears to be the importance of genetic factors in protecting some individuals against aging and age-related disease. This may disappoint some readers looking for tips to improve their own health and lifespan, but Dr. Barzilai also provides plenty of these. Despite the appropriate caveats about not blindly following his example, he shares with his friend Dr. David Sinclair a willingness to try out new treatments on himself long before the scientific evidence and the drug approval system endorse doing so, and he shares many of these in this book.

In several of these reviews, I have talked about the tricky balance of skeptical optimism. As researchers in a relatively new and rapidly changing field, we must be sufficiently hopeful and open-minded to take up and test new ideas, even with relatively little to go on at first. However, such enthusiasm can easily carry us beyond the boundaries of rigorous science and good sense if we don’t balance it with appropriate skepticism. Particularly when writing for a non-science audience, it is easy to convey the false impression that big problems are easy or on the verge of being solved or that we already have good reason to put treatments into use that, in reality, we have not yet proven are effective or safe. Striking the perfect balance, to sustain excitement and energy without giving in to wishful thinking, is a difficult and ongoing challenge in the field.

Dr. Barzilai leans a bit too far to the side of enthusiasm over skepticism for my taste. He lists many approaches as “promising” even when the evidence or scientific rationale for these is pretty weak. Reasonable advice about exercise and diet are mixed in with questionable ideas about supplements and fasting, and even some pretty fanciful stuff about the benefits of pseudoscience like reflexology or the claim that prayer can lengthen telomeres. In the long list of ideas put forward in the book, little meaningful distinction is made between science, speculation, and fantasy, and that has significant potential to create a misleading picture for many readers.

Overall, Dr. Barzilai’s book is an engaging, relaxed, and relatively personal look at the aging biology field. It skims the surface broadly with limited scientific depth and it leaves a positive, rosy picture of the state of the field. While Age Later may not be the most scientifically detailed or critical assessment of the field, it is easy to see why Dr. Barzilai has been so successful at organizing and leading geroscience research efforts and finding funding for his endeavors. These activities require the kind of exuberance and optimism that comes across quite clearly in his book. 

Posted in Aging Science, Book Reviews | 2 Comments

Managing Sepsis: A Rational Approach & the Vitamin C Controversy

Introduction
Sepsis is currently defined as a life-threatening organ dysfunction secondary to a dysregulated physiologic response to infection. There are widely used, evidence-based guidelines for diagnosis and management of sepsis in human medicine,1but there is no single guideline or consensus statement on sepsis management in veterinary medicine. The guidelines most veterinarians follow, and those which we use at my hospital, are derived from expert opinion and the adaptation of human sepsis protocols employed at several academic veterinary institutions

Management of sepsis is a great example of the challenge of practicing evidence-based medicine in an evidence-poor environment. Extrapolation from evidence in humans and reasoning from physiologic first principles are rational and necessary strategies, but of course they sometimes lead to practices which turn out to be ineffective or even counterproductive in veterinary patients. Such approaches should always be viewed as a starting point, a provisional strategy pending the development of better evidence in clinical studies of the target patient population.

Human medicine, though often blessed with much higher quality evidence that we can typically expect, still finds itself mired in controversies over questionable practices that become widespread despite limited or poor-quality evidence and which later turn out to have been ineffective. A condition such as sepsis, which is acutely life-threatening and for which no universal, highly-effective therapy is yet available, is fertile ground for such disputed approaches. These often spill over into veterinary medicine when we adopt new practices in human patient care, and it is important for us to keep an eye on the evolution of ideas and evidence regarding such practices. In the case of sepsis, for example, the use of Vitamin C, alone or in combination with steroids and other vitamins, is an example of a controversial practice that has been ported into our patient care protocols to some extent based on limited, and controversial, early evidence and which we may now want to rethink.

Diagnosis of Sepsis
Confirming sepsis and identifying a source of infection can be challenging. However, the emphasis in sepsis management is now on early initiation of therapy since this has been associated with lower mortality in human patients, so diagnostic criteria have been developed to favor rapid diagnosis and therapy. Based on the definition of sepsis given above, a tentative diagnosis of sepsis should be made whenever there is a known or suspected infection and evidence of organ dysfunction or a systemic inflammatory response. Suspicion of infection should be based on history and physical examination findings. Suggested criteria for identifying organ dysfunction and an inflammatory response in dogs and cats, adapted from those used in humans, include:

Therapy
The emphasis on early intervention for sepsis has led to the development of treatment and monitoring “bundles,” that is sets of tests and treatments to be implemented universally when sepsis is suspected. There are no validated guidelines or consensus statements to define sepsis bundles in veterinary patients, however many institutions use treatment protocols adapted from those recommended for humans. The priorities for sepsis treatment are:

  1. Early institution of antibiotic therapy2
  2. Hemodynamic stabilization
  3. Identification and control of the source of infection
  4. Supportive care and recovery

Immediate Therapy for Sepsis

Following a tentative diagnosis of sepsis, recommended immediate care should include:

  1. Culture samples- Samples for culture should be obtained before antibiotic administration if this does not delay the use of antibiotics more than 45 minutes. Samples should be specific to the site of infection if this has been identified and can be accessed. If the site is unknown or inaccessible, blood cultures and urine cultures can be taken. Both aerobic and anaerobic cultures should be run.
  2. Antibiotics- A de-escalation approach is currently favored in the treatment of human sepsis patients. This involves early initiation of broad-spectrum antibiotic therapy and then a reduction in antibiotic coverage as soon as possible as indicated by culture results. Recommended duration of antibiotic therapy for humans is 7-10 days unless the source of infection cannot be definitively controlled

    There are no evidence-based guidelines for antibiotic use in veterinary sepsis patients. Ideally, antibiotic selection should be based on culture results, local population susceptibility patterns, and the history and condition of the individual patient. Common empiric protocols used in veterinary sepsis patients include:
  • Ampicillin/Unasyn + Amikacin
  • Ampicillin/Unasyn + Enrofloxacin
  • Cefazolin + Cefotaxime
  • Cefoxitin 
  • Clindamycin + Enrofloxacin 
  • Lactate Measurement- Lactate is an important biomarker for sepsis management. Values > 2.5 mmol/L should be interpreted as an indicator of inadequate perfusion.
  1. Fluid therapy- Crystalloids are the initial fluid of choice, and aggressive fluid therapy (e.g. boluses of 20-30mL/kg over 15 minutes) should be initiated for patients with evidence of hypotension (e.g. MAP< 65mmHg) or poor perfusion (e.g. lactate > 4.0 mmol/L or consistent physical exam findings) unless there is a clear contraindication (e.g. primary cardiac disease, evidence of overhydration). Fluid therapy should be titrated to endpoints, including:
  2. Normalization of heart rate
  3. Normalization of respiratory rate
  4. Normalization of blood pressure (MAP> 65mmHg, systolic > 100mmHg)
  5. Normalization of lactate (< 2.0mmol/L)
  6. Normalization of mentation
  7. Normalization of urine output (UOP> 1mL/kg/hr)

Hetastarch is not recommended in human sepsis patients due to some evidence of increased mortality and risk for acute kidney injury. It is unclear the extent to which this applies to veterinary patients,3 however many experts recommend avoiding synthetic colloids if possible. Canine albumin is preferred as a colloid, though it is often unavailable or unaffordable. 

Additional Therapy

  1. Continued hemodynamic stabilization- If the targets for fluid therapy (blood pressure, lactate, etc.) are not met with initial crystalloid treatment, vasopressors should be started early because hypotension in sepsis is often due to decreased peripheral vasomotor tone. Based on guidelines for humans and limited evidence in veterinary patients, the following are common recommendations for use of vasopressors in sepsis patients:

Warning! Some vasopressors can cause ischemic necrosis due to extreme vasoconstriction. They should ideally be given through a central line, and clients should be advised of this possible complication.

  • Norepinephrine- 0.1-0.5mcg/kg/min Start low and titrate upwards in 0.1mcg/kg/min increments every 5-10 min until BP targets are reached (e.g. MAP>65mmHg) or 2-3mcg/kg/min is reached.
  • Vasopressin is often recommended as a second-line pressor or to reduce the dose of norepinephrine in humans, but it is often unavailable to veterinary patients due to cost.
    • Epinephrine-  0.05- 1mcg/kg/min. This can be added to norepinephrine if needed and titrated upwards every 5-10 min until BP targets are reached.
    • Dopamine- This drug has historically been the pressor of choice in veterinary patients, but recent practice has shifted to norepinephrine based largely on extrapolation from research in human sepsis patients. 
    • Dobutamine- This is primarily an inotrope and is only recommended if there is evidence of poor contractility because it decreases vascular tone and can decrease BP

It is important to identify all physiologic abnormalities that can be treated in patients with sepsis and septic shock. These may include:

  1. Electrolytes
  2. Blood Glucose
  3. Lactate
  4. PCV/TP/albumin
  5. Coagulation- PT/PTT/platelet counts 
  6. Blood Pressure
  7. Vital signs- HR, RR, body temperature, pulse quality, mm color, CRT
  8. SPO2
  9. ECG
  10. Pain Score and mental status- Analgesia should be provided if there is  evidence of pain. NSAIDs should be avoided if there is hemodynamic instability or evidence of GI or renal impairments.
  11. Urine output and renal values
  12. Body weight- this is a key measure for assessing fluid balance

    Other Therapies
  • Gastroprotectants- (e.g. pantoprazole) 
    These can be considered if there is evidence of gastrointestinal lesions or symptoms
  • Anti-emetics- (e.g. maropitant, ondansetron) 
    These can be considered if there is evidence of nausea or vomiting.
  • Promotility drugs- (e.g. metoclopramide, low-dose erythromycin) These can be considered if there is evidence of GI hypomotility or ileus.
  • Blood products- 
    There is significant controversy and uncertainty regarding the use of blood products in septic patients. Strict arbitrary cutoff values for use of blood products are now discouraged in human patients due to growing evidence of harm related to transfusion. There are no clear guidelines for veterinary patients.
  • Treatment of Anemia- 
    Most critical patients become anemic at some point. Anemia should be treated when associated with significant clinical symptoms (e.g. hypoxia, tachypnea/tachycardia), ongoing losses of red blood cells, or anticipated losses associated with surgical source control procedures.. Though strict cutoffs are discouraged, a Hb of 7.0g/dL is often used as a guideline for when to transfuse in human sepsis patients.
  • Treatment of Thrombocytopenia- 
    Platelet-rich plasma is given to humans when there is clinical evidence of bleeding (e.g. petechiae, ecchymoses, epistaxis), when a surgical procedure is planned and platelet count is < 50k/mm3, or prophylactically when platelet count is <10k/mm3.
  • Treatmwnt of Coagulopathy- It is not recommended to give fresh-frozen plasma (FFP) to correct clotting times in the absence of active bleeding. If PT/PTT are elevated and there is bleeding or a surgical procedure is planned, FFP may be beneficial.

Vitamin C
Though this is, at best, an ancillary therapy to consider in patients with sepsis, without the acknowledged critical importance of many others and not necessarily widely used in veterinary patients, I want to focus a bit on it because it illustrates the challenges of an evidence-based approach to a complex medical problem. 

In human medicine, as in the veterinary field, practices may be adopted based on early evidence that is both encouraging and extremely limited. Unlike veterinary medicine, however, follow-up studies are much more common and robust, and better evidence that shows the true state of affairs is often available within a few years. Unfortunately, in our profession we are more likely to adopt a practice based on a single small study and then employ it widely for a long time before subsequent studies either confirm the benefits or show them to be illusory. Vitamin C for sepsis is a cautionary tale that should encourage us to try harder to confirm our initial assessment of new therapies.

In 2017, a study of 94 human patients with sepsis was published comparing patient given standard treatment and those also given Vitamin C, thiamine, and low-dose hydrocortisone (called HAT therapy).4 This was a small by the standards of human medicine, though larger than many equally influential veterinary trials, but it appeared to show dramatic benefits. Mortality was 8.5% in the experimental group and 40.4% in the control group, and there were apparent benefits in terms of other standardized measures of disease severity.

This study had a dramatic impact in the human critical care field, with reverberations in veterinary medicine. Debate and additional research began immediately in human medicine. In the veterinary profession, there was buzz about this new treatment at conferences5 and online, and some veterinarians began adding it to their management of sepsis cases.6 It is unclear how widespread this practice became in veterinary circles, but the published research on Vitamin C in critically ill veterinary patients is pretty sparse, and there are not prospective randomized clinical trials specifically comparing HAT to standard care in veterinary sepsis cases.5–7

In contrast, the five years since the publication of the original HAT study has seen a flurry of research in humans, and there are now more than a dozen systematic reviews and meta-analyses evaluating studies in thousands of sepsis patients.4,8–17 Unfortunately, the majority of these have failed to confirm the dramatic results from the original study. Most have found no reduction in mortality from adding HAT to standard care. Some have shown modest improvement in some assessments of disease severity, but many have found no statistically significant nor clinically meaningful effect at all. 

This is about as clear an example of the Decline Effect as one could ask for. Dramatic effects seen in initial studies of a new therapy get smaller and smaller as subsequent studies attempt to replicate the results until the literature settles on a far less dramatic reality, which surprisingly often turns out to be no effect at all. The explanations for this involve both intentional and, most of the time, unconscious bias on the part of enthusiastic researchers studying a new idea, as well as the limitations of small, often poorly controlled research studies in unrepresentative patient populations. This phenomenon is the main reason we should avoid enthusiastically embracing new therapies before appropriate replication of such initial studies has been done.

In the case of HAT, the controversy has grown more dramatic than usual. The primary author of the original study, Dr. Paul Marik, vehemently stands by his results despite all the failed attempts to replicate them. A recent letter to the editorof the journal in which this study was published has alleged that analysis of the results and statistics reported in the original paper is not only suggestive of data fabrication but clear proof of misconduct. An investigation by the journal is likely, especially in light of a very similar controversy involving the same investigator.

Dr. Marik has also published a study purportedly showing a different novel approach with equally dramatic benefits in COVID-19 patients. This paper has recently been retracted due to evidence of data manipulation. The author has also been reprimanded by the Virginia Medical Board for misconduct, resigned his academic position, and become involved in a lawsuit with his hospital over the use of ivermectin as a COVID-19 therapy. Like HAT, the approach Dr. Marik advocates for COVID-19 appeared promising in his early studies, but the elements of it have so far failed to show benefits in subsequent research.18,19 Dr. Marik illustrates starkly how hard the habit of excessive enthusiasm for new therapies based on preliminary evidence is to break.

Bottom Line
Sepsis is a serious and complex problem with numerous possible treatment approaches and mixed, often disappointing results. An evidence-based approach involves attention to the limited and weak evidence available in veterinary patients and judicious extrapolation from the more robust, but still imperfect, evidence available in humans. 

The use of Vitamin C, alone or in combination, in sepsis patients has evolved from an exciting and promising new idea to an example of failed promise, and of the dangers of unconscious bias, if not outright scientific fraud. The lesson we should draw from this is not merely that use of Vitamin C in veterinary sepsis patients is probably not warranted, but that we should proportion our acceptance of and confidence in new therapies to the strength of the evidence for them. For veterinarians, this often means a perpetual state of using treatments in which we can have very little confidence, but this is still preferable to enthusiastic commitment to practices which later prove ineffective or even dangerous for our patients.

References

1.        Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. doi:10.1097/CCM.0000000000005337

2.        Abelson AL, Buckley GJ, Rozanski EA. Positive impact of an emergency department protocol on time to antimicrobial administration in dogs with septic peritonitis. J Vet Emerg Crit Care. 2013;23(5):n/a-n/a. doi:10.1111/vec.12092

3.        Glover PA, Rudloff E, Kirby R. Hydroxyethyl starch: a review of pharmacokinetics, pharmacodynamics, current products, and potential clinical risks, benefits, and use. J Vet Emerg Crit Care (San Antonio). 2014;24(6):642-661. doi:10.1111/vec.12208

4.        Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229-1238. doi:10.1016/j.chest.2016.11.036

5.        Silverstein D. Treating Sepsis with Vitamins? The Risks, Benefits, and Evidence. In: International Veterinary Emergency and Critical Care Symposium. Washington, D.C.; 2019.

6.        Taylor SD. Oranges for Horses? Exploring Vitamin C in the Fight against Equine Sepsis. Purdue Equine Heal Updat. 2019;21(2):5.

7.        Gordon DS, Rudinsky AJ, Guillaumin J, Parker VJ, Creighton KJ. Vitamin C in Health and Disease: A Companion Animal Focus. Top Companion Anim Med. 2020;39:100432. doi:10.1016/j.tcam.2020.100432

8.        Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock. JAMA. 2020;323(5):423. doi:10.1001/jama.2019.22176

9.        Anderson MJ, Ibrahim AS, Cooper BR, Woolcock AD, Moore GE, Taylor SD. Effects of administration of ascorbic acid and low-dose hydrocortisone after infusion of sublethal doses of lipopolysaccharide to horses. J Vet Intern Med. 2020;34(6):2710-2718. doi:10.1111/jvim.15896

10.      Lee YR, Vo K, Varughese JT. Benefits of combination therapy of hydrocortisone, ascorbic acid and thiamine in sepsis and septic shock: A systematic review. Nutr Health. 2022;28(1):77-93. doi:10.1177/02601060211018371

11.      Wu T, Hu C, Huang W, Xu Q, Hu B, Li J. Effect of Combined Hydrocortisone, Ascorbic Acid and Thiamine for Patients with Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Shock. 2021;56(6):880-889. doi:10.1097/SHK.0000000000001781

12.      Assouline B, Faivre A, Verissimo T, et al. Thiamine, Ascorbic Acid, and Hydrocortisone As a Metabolic Resuscitation Cocktail in Sepsis: A Meta-Analysis of Randomized Controlled Trials With Trial Sequential Analysis. Crit Care Med. 2021;49(12):2112-2120. doi:10.1097/CCM.0000000000005262

13.      Patel JJ, Ortiz-Reyes A, Dhaliwal R, et al. IV Vitamin C in Critically Ill Patients: A Systematic Review and Meta-Analysis. Crit Care Med. 2022;50(3):e304-e312. doi:10.1097/CCM.0000000000005320

14.      Fujii T, Salanti G, Belletti A, et al. Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis. Intensive Care Med. 2022;48(1):16. doi:10.1007/S00134-021-06558-0

15.      Ge Z, Huang J, Liu Y, et al. Thiamine combined with vitamin C in sepsis or septic shock: a systematic review and meta-analysis. Eur J Emerg Med. 2021;28(3):189-195. doi:10.1097/MEJ.0000000000000812

16.      Scholz SS, Borgstedt R, Ebeling N, Menzel LC, Jansen G, Rehberg S. Mortality in septic patients treated with vitamin C: a systematic meta-analysis. Crit Care. 2021;25(1):17. doi:10.1186/s13054-020-03438-9

17.      Somagutta MKR, Pormento MKL, Khan MA, et al. The Efficacy of vitamin C, thiamine, and corticosteroid therapy in adult sepsis patients: a systematic review and meta-analysis. Acute Crit care. 2021;36(3):185-200. doi:10.4266/acc.2021.00108

18.      Popp M, Stegemann M, Metzendorf M-I, et al. Ivermectin for preventing and treating COVID?19. Cochrane Database Syst Rev. 2021;(7). doi:10.1002/14651858.CD015017.PUB2

19.      Lim SCL, Hor CP, Tay KH, et al. Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities. JAMA Intern Med. 2022;182(4):426. doi:10.1001/jamainternmed.2022.0189

Posted in Science-Based Veterinary Medicine | 2 Comments

Recent Canine Aging Science Articles

If my posts have seemed few and far between lately, one of many reasons is I have been busily typing away producing some scientific publications in my new focus area- canine aging science. My collaborators and I have produced several recent papers which I hope will be of some interest to some of you. Since not all are readily available outside of academia, I will post them here. Enjoy!

McKenzie, BA. Chen, FL. Gruen, ME. Olby, NJ. Canine Geriatric Syndrome: A Framework for Advancing Research in Veterinary Geroscience . Front Vet Sci. 9:853743. April, 2022.

Abstract
Biological aging is the single most important risk factor for disease, disability, and ultimately death in geriatric dogs. The effects of aging in companion dogs also impose significant financial and psychological burdens on their human caregivers. The underlying physiologic processes of canine aging may be occult, or early signs of aging may be ignored because of the misconception that biological aging is natural and therefore inevitable. The ability to detect, quantify, and mitigate the deleterious processes of canine aging would greatly enhance veterinary preventative medicine and animal welfare. In this paper we propose a new conceptual framework for aging in dogs, the Canine Geriatric Syndrome (CGS). CGS consists of the multiple, interrelated physical, functional, behavioral, and metabolic changes that characterize canine aging as well as the resulting clinical manifestations, including frailty, diminished quality of life, and age-associated disease. We also identify potential key components of a CGS assessment tool, a clinical instrument that would enable veterinarians to diagnose CGS and would facilitate the development and testing of interventions to prolong healthspan and lifespan in dogs by directly targeting the biological mechanisms of aging. There are many gaps in our knowledge of the mechanisms and phenotype of aging in dogs that must be bridged before a CGS assessment tool can be deployed. The conceptual framework of CGS should facilitate identifying these gaps and should stimulate research to better characterize the processes and effects of aging in dogs and to identify themost promising preventative strategies to target these.

McKenzie, BA. Comparative Veterinary Geroscience: Mechanism of molecular, cellular, and tissue aging in humans, laboratory animal models, and companion dogs and cats. Amer J Vet Res. 2022;83(6:). https://doi.org/10.2460/ajvr.22.02.0027. 

Abstract
Aging is the single most important cause of disease, disability, and death in companion animal species. Contrary to the common view of aging as mysterious and inevitable, it is more usefully understood as a set of complex but comprehensible and modifiable biological processes that are highly conserved across species. The purpose of this Currents in One Health manuscript is to describe key mechanisms of aging at the cellular and molecular level and the manifestations of these in the tissues of the musculoskeletal system, adipose, and the brain. The characteristics of these processes as identified in common laboratory animal models and in humans will be described and compared with the much more limited information available concerning aging in dogs and cats. This will highlight important targets for future research in these species. The consistent patterns across species in the hallmarks of aging and their manifestations at the level of tissues, organ systems, and individual animals signify potential targets for interventions to mitigate the negative health impacts of aging and extend both life span and health span (the period of life free of significant disease or disability). Further research to elucidate aging mechanisms in companion dogs and cats will eventually support development, testing, and implementation of clinical therapies to prevent and ameliorate age-related dysfunction, disease, and death.

McKenzie, BA. Lacroix-Fralish, ML. Chen, F. The phenotype of aging in the dog: How aging impacts the health and wellbeing of dogs and their caregivers. J Amer Vet Med Assoc. 2022;260(9):963-970. 

Abstract
Aging is the single most important cause of disease, disability, and death in adult dogs. Contrary to the common view of aging as a mysterious and inevitable natural event, it is more usefully understood as a set of complex but comprehensible biological processes that are highly conserved across species. Although the phenotypic expression of these processes is variable, there are consistent patterns both within and between species. The purpose of this feature is to describe the patterns currently recognized in the physical and behavioral manifestations of aging in the dog and how these impact the health and welfare of companion dogs and their human caregivers. Important gaps in our knowledge of the canine aging phenotype will be identified, and current research efforts to better characterize aging in the dog will be discussed. This will help set the context for future efforts to develop clinical assessments and treatments to mitigate the negative impact of aging on dogs and humans.

Posted in Aging Science | 6 Comments

Are Vegan Diets Healthier for Dogs & Cats?

Introduction
Given the media frenzy the article has kicked off, it is unlikely very many people are unaware of a recent study reported in the journal PLOS One that claims to show vegan diets are healthier for dogs and cats than diets containing meat. 

Knight A, Huang E, Rai N, Brown H. Vegan versus meat-based dog food: Guardian-reported indicators of health. PLoS One. 2022 Apr 13;17(4):e0265662.

Dramatic headlines have appeared in many major news sources proclaiming that vegan diets are “linked to better health” or “are healthier and safer” than conventional diets. Getting beyond the headlines, one may even read that this study demonstrates raw diets to be healthier than conventional foods, though that is less emphasized in both the original article and the media coverage.

I’ve written about vegan diets for dogs before, and indeed this article cites my column on the subject, though only to dismiss my claim that vegan diets “should not be recommended” as “without evidence.” This is not entirely accurate, since my article did cite the limited evidence available, and I did not actually recommend against vegan diets for dogs, though I did conclude they were a bad choice for cats. My actual claims were:

There is no evidence vegetarian diets have health benefits for dogs and cats, and no real reason to believe they should, based on the physiology and nutritional requirements of these species.

Dogs are omnivores that are able to eat both plant and animal foods, and in theory, they should be able to thrive on vegetarian or vegan diets. However, these diets must be carefully formulated, and many commercial vegetarian dog foods do not appear to be nutritionally adequate. There is also little reliable research evidence showing dogs can remain healthy when fed only a vegan diet. Given the unexpected health problems seen with theoretically adequate grain-free diets, we should be cautious about the potential risks of vegetarian formulations for dogs until there is better and more evidence showing their long-term health effects.

Cats are clearly obligate carnivores with nutritional requirements that are unlikely to be effectively met by vegan diets. Such diets offer only risks and no benefits for cats and should be avoided.

In any case, I am sympathetic to many of the potential environmental and health benefits of plant-based diets, and I have been a vegetarian, though not a vegan, for almost 20 years  (technically, an ovo/lacto/pescatarian, though realistically I don’t like fish and so eat very little of it). However, the evidence for benefits of plant-based diets for dogs and cats is far weaker than that for humans, which is itself often nuanced and not always conclusive. And I believe in following the evidence wherever it leads, even when it doesn’t support my personal beliefs or practices.

So, does this paper change the game in terms of showing real health benefits to raw and/or vegan diets? Spoiler, but not really! Let’s look at the actual findings a bit closer.

The Study- Results
The study reported the following statistically significant differences between “conventional,” raw, and vegan diets (leaving aside the fuzzy definitions of these, the ubiquitous feeding of unidentified treats to all pets, and the lack of clarity about how strictly feeding practices corresponded to each category).

  • Dogs fed raw and vegan diets were less likely to have had multiple veterinary visits in the year observed.
  • Dogs fed raw and vegan diets were less likely to have been given medications
  • Dogs fed raw and vegan diets were less likely to have been transitioned onto a therapeutic diet
  • Dogs fed raw and vegan diets were less likely to have an owner-reported veterinary assessment of poor health status
  • Dogs fed raw and vegan diets were less likely to have an owner reported assessment of poor health
  • Dogs fed raw and vegan diets were less likely to be reported to be “unwell,” and when unwell dogs on raw diets had fewer reported disorders than dogs on conventional diets.
  • There were differences in the occurrence of specific health conditions between diet groups as illustrated in this figure and table:
  • Dogs fed raw and vegan diets were less likely to have had multiple veterinary visits in the year observed.
  • Dogs fed raw and vegan diets were less likely to have been given medications
  • Dogs fed raw and vegan diets were less likely to have been transitioned onto a therapeutic diet
  • Dogs fed raw and vegan diets were less likely to have an owner-reported veterinary assessment of poor health status
  • Dogs fed raw and vegan diets were less likely to have an owner reported assessment of poor health
  • Dogs fed raw and vegan diets were less likely to be reported to be “unwell,” and when unwell dogs on raw diets had fewer reported disorders than dogs on conventional diets.
  • There were differences in the occurrence of specific health conditions between diet groups as illustrated in this figure and table:

All-in-all, these results would seem to be pretty bad news for conventional diets (whatever that means) and pretty good news for feeders of raw and vegan diets. Anyone reading this, however, can probably sense the “but” coming, so let’s get into the caveats.

The Study-Limitations
The biggest limitation (and boy is it a big one!) is that all the data were collected from online surveys of pet owners. Everything from the diet fed to the health status and even the reported veterinary assessment of health all relied entirely on the responses of pet owners who found the survey online and took the trouble to complete it. None of the facts, not the feeding practices nor the health of the pets, were verified objectively in any way. Right from the start, then, that makes this a study of what some small subset of pet owners believe about their pets’ diet and health, not about the actual feeding and health of these animals.

It is not difficult to find reasons to be concerned that these responses may not reflect reality, or even the opinions of other groups of pet owners. The respondents were overwhelmingly female (92%) and European (86%), which is a pretty narrow population to survey. They were, of course, also in a socioeconomic class inclined to participate in online pet health surveys, which is also not representative of many other pet owners.

More concerning, 22% of the population of owners were themselves vegan. This is a group likely to have strong beliefs and biases about plant-based vs meat-based nutrition and health, so it would be, frankly, shocking if they did not report that plant-based diets were healthier than other diets. 13% of these owners fed their pets vegan diets and 33% fed raw meat, indicating nearly half fed unconventional diets not usually recommended by veterinarians or veterinary nutrition specialists. Such a group is clearly a population biased in favor of the kind of outcomes reported in this study, and given the study only shows us the opinions of owners, not actual objective data about health and diet, the outcomes are simply a fancy way of reporting what people in this group think. 

Other studies in other populations have reported lower rates of veganism (5.8%) and of feeding vegan diets to pets (1-3%), which emphasizes that this study surveys a very specific, narrow group of owners. A review of previous owner surveys also shows more nuanced and variable feeding practices reported in these studies, again suggesting this paper may not be applicable outside of the specific population included in the survey.

In terms of potential sources of bias beyond the survey population, it is worth pointing out that the lead author is a consistent advocate for plant-based diets, for humans and pets, on environmental and ethical grounds. The study was also funded by a plant-based diet advocacy group. As I have discussed in detail in previous articles on conflict of interest, these facts do not indicate the research is fraudulent or inaccurate, nor are they a justification for ignoring the claims, arguments, and evidence provided in this paper. They are, however, a reason to consider carefully the potential for uncontrolled unconscious bias in the design, conduct, analysis, and reporting of the study. Given that the study itself was essentially a survey of subjective opinions, methods to control such bias are minimal, so the results have to be viewed in that context.

The authors, to their credit, do acknowledge some of these limitations. They call out the fact that, for example, fewer reported veterinary visits in dogs fed raw diets may be due to the fact that feeders of raw diets are often skeptical of conventional veterinary medicine and less likely to seek care rather than to any actual difference in health status. The same logic, of course, applies to the frequency of vet visits for dogs fed vegan diets, and to the reported use of medicine and therapeutic diets by owners who have a clear preference for unconventional health practices to begin with.

Conclusions
So what does this study mean? Overall, it means that the particular population of pet owners surveyed believes that feeding raw and plant-based diets are associated with better health in their pets. They also believe that their veterinarians think their pets are healthier (though whether these vets actually believe this is unknown). And these owners report less use of veterinary medical services, though whether this means their pets are healthier or simply that they try harder to avoid taking their pets to the vet is also unknown.

Like previous studies relying on owner surveys and both conducted and funded by folks with strong a priori opinions about diet and health, this is a useful insight into such beliefs. It is not compelling or probative evidence for actual health effects of different feeding strategies. Sadly, the media coverage of the paper rarely recognizes or emphasizes this.

As the authors themselves suggest, though with little evident enthusiasm, controlled studies with objective measures of outcome and more defined and verified feeding practices are required to draw any meaningful, actionable conclusions about the healthiest feeding strategy for our pets. I am neither for nor against vegan diets for dogs, and I am even open to reversing my objection to feeding vegan to cats or raw diets to cats or dogs if strong evidence is generated that these are safe or beneficial practices. However, regardless of the difficulties in funding and conducting the necessary research, we are not justified in making confident claims about the health impact of raw, vegan, or conventional diets without it.

Posted in Nutrition | 8 Comments

Do Dogs Like Music? (Evidence Update)

Over the roughly 13 years I have been writing this blog, I have covered quite a few different topics, though with all I have maintained the central theme of evaluating claims about pet health from a science-based perspective. Part of this perspective is keeping track of the changing evidence as new research results become available. This can be tough as the number of topics, and the volume of evidence, grows over such a long period. 

Today, I am returning briefly to a topic I previously covered in 2015 and twice in 2017 (A and B). As often proves to be the case, my conclusions have remained relatively unchanged, though this is one area in which I began with, and have maintained, some cautious optimism.

2015
While it is very likely some kinds of music can be beneficial to our pets and veterinary patients under some circumstances, the devil is, as usual, in the details, and we don’t know much about the details yet. It is reasonable to experiment with music in veterinary environments, especially with more quiet, instrumental genres, but we must try to develop objective measures of the effect to be sure we are not imply wasting our effort or, even worse, actually adding stress for our patients.

2017- January
On balance, then, I think it is possible that music might have some benefits for dogs in stressful circumstances, such as boarding kennels, hospitals, and shelters, but this is by no means clearly proven. The risk is also likely quite low, so there is probably little harm in using quiet music for this purpose so long as it is not substituted for other, more comprehensive approaches to reducing stress and anxiety.

2017- July
The existing evidence is weak and inconsistent, so no clear conclusion can be drawn. In this study, there was no sign of any effect of classical music or the same music digitally altered with the goal of reducing stress in dogs. The question remains open, and definitive claims for or against the potential effects of music in this situation are not justified.

My reason for revisiting the topic now is that I have run across a systematic review looking at al the available evidence up through 2019.

Lindig AM, McGreevy PD, Crean AJ. Musical Dogs: A Review of the Influence of Auditory Enrichment on Canine Health and BehaviorAnimals. 2020; 10(1):127. 

Systematic reviews are incredibly useful as they provide a comprehensive evaluation of the available scientific literature with an explicit focus on evaluating the strengths and weaknesses of the available evidence. They are never, of course, completely without bias, and they can often be frustrating since they rarely allow definitive conclusions or a high level of confidence in a particular interpretation of the evidence. But having such a review gives us a reasonable chance of getting a good overview of the subject and the evidence.

The conclusions of this review track pretty well with my own assessments in the past:

Interest in the use of music therapy as a behavioral enrichment tool in veterinary medicine is growing. Indeed, an industry has formed around the development of ‘dog music’, which has been purposely designed to relax dogs. Despite enthusiastic uptake of the idea, there is little empirical evidence supporting the design of such tools… As a general observation, animals appear less stressed or anxious when exposed to classical music than to control conditions. [This review] also acknowledges that this field is relatively under-researched, and more rigorous studies must be conducted before species-specific recommendations can be made. Such studies must reflect individuals’ and species’ preferences for different genres and songs, taking care to avoid habituation.

The best we can say about the value of music for dogs is that a few studies have shown short-term changes in behavior and some physiologic measurements that suggest quiet genres of music, such as classical, may have a calming effect on some dogs in some circumstances. Sounds specifically designed for dogs don’t’ seem to have any more effect than classical music. These short-term effects may wane with repeated exposure to the same music. And there is virtually no research on the long-term effects of music exposure, the potential health effects, and the importance of breed and individual differences or preferences.

Posted in General | 5 Comments

Does eating a Raw Diet as a Puppy Reduce later Allergy Risk?

I have written many times about the controversial subject of raw diets for dogs. The bottom line, based on existing evidence, is there are no proven health benefits to these diets and several well-documented risks, including infectious disease and nutritional inadequacy.1

Proponents of these diets offer varied theoretical arguments for why they should be healthier than commercial cooked foods. Many are simply fallacious claims about what is “natural” or “ancestral.” However, there are some plausible, but unproven hypotheses, about the potential negative health impacts of conventional diets or the possible health benefits of feeding uncooked meat.

Concerns about Maillard reaction products (MRPs) in cooked foods, for example, are reasonable given the potential carcinogenicity of some of these compounds at some amounts in some species. However, it is far from evident these compounds actually do cause harm in the form and amount found in cooked dog foods, and research has identified potential benefits as well as risks to their consumption, so the assumption that cooked foods must be unhealthy because they contain MRPs is unreasonable.2

Similarly, the hypothesis that exposure to microorganisms during development can reduce the subsequent risk of allergies and other immune-system diseases is plausible, and there is some supportive evidence, though there is also evidence against this “hygiene hypothesis.”3-6 However, this does not justify the assertion that exposure to such organisms through eating raw meat, dirt, or other substances, has more benefits than risks.

A recent paper published in the Journal of Veterinary Internal Medicine (JVIM) purports to support claims for health benefits from raw diets.7 

Hemida MBM, Salin S, Vuori KA, et al. Puppyhood diet as a factor in the development of owner?reported allergy/atopy skin signs in adult dogs in Finland. J Vet Intern Med. 2021;35(5):2374-2383.

The authors suggest exposure to raw diets in puppies may reduce the risk of later development of canine atopic dermatitis (CAD), and exposure to conventional commercial diets may increase CAD occurrence in adulthood. There are, however, numerous limitations and red flags associated with this study, and it is not strong evidence.

The authors of the paper have a long history of promoting raw diets and various alternative therapies, and they have a clear bias on the subject.8-16 Of course, researchers often have confident beliefs, rather than tentative hypotheses, when they design and conduct scientific studies. It is well-established that “researcher degrees of freedom,” the amount of leeway investigators have in designing studies and in collecting and analyzing data, is associated with the likelihood of false-positive results.17

Given researchers with clear a priori beliefs about raw diets designed the survey, defined the variables of interest, and had total freedom to create and conduct the regression analysis, the results likely reflect the beliefs of the researchers more than the underlying reality of nature.

One example of the clear bias behind this study is in the terminology chosen for different diet categories. They divide foods into “non-processed meats/ingredients” and “ultra-processed carbohydrate-rich foods.” These are artificial categories reflecting the ideological bias of the researchers, not the reality of the kinds of foods dogs are actually fed.

“Non-processed” is meaningless unless the dogs are eating whole prey and plants they find for themselves. Likewise, the term “ultra-processed” is also an inappropriate extrapolation of terms used to describe human snack foods, which are not meaningfully similar to commercial pet foods. The label is a value judgment that implies a negative health impact not actually proven to exist.

Commercial canned and dry foods are also not accurately described as “carbohydrate-rich.” The carbohydrate content of commercial dry diets varies dramatically, as does the type of carbohydrate (from simple sugars to complex fibers). The nutritional value and potential health effects of commercial diets will vary greatly based on these differences, and lumping them all together in this artificial category is not a sound scientific approach.

Another potential influence on this study is funding bias. It is, again, well-established that funding sources can influence the outcomes of research, which is why disclosure of funding sources is required by scientific journals.18 In a web documentary called The Dog Cancer Series, one of the authors of this study herself cites funding bias as a factor in the literature concerning raw diets:

“[Raw food is] not really researched in universities. Most universities get sponsored by these big billion-dollar companies, and you don’t really want to step on their toes, I guess. But, I think that’s not really ethical,” says Dr. Anna Hielm-Bjorkman.19

It is relevant, then, to point out this study received financial support from raw diet manufacturers, as well as Dr. Joseph Mercola, an infamous proponent of alternative medicine and anti-vaccine activist repeatedly warned by the Food and Drug Administration (FDA) for promoting COVID-19 misinformation and selling unproven treatments.20,21 Given the potential for ideological and funding bias in this research project, the lack of rigorous controls for possible bias in this study is concerning.

The main source of data is an online survey available only in Finnish. This is a very narrow sample population, and it is unlikely to be representative of the views or practices of dog owners generally.

More importantly, the responses are simply expressions of the perceptions and beliefs of the owners who participated, not necessarily the nutritional and environmental exposures nor health outcomes actually experienced by the dogs. Self-reporting of diet and health information has been shown to be unreliable in humans, and it is unlikely to be more reliable among dog owners.22,23

Previous reports evaluating this source of data do not inspire confidence.2,15 The researchers validated responses by emailing respondents and looking for consistency in their answers to selected questions. In a previous study, only about 30 percent of the respondents replied to these emails, and almost 13 percent of responses to this survey tool were discarded as “robot” answers. Also, 26 percent of respondents provided inconsistent or discordant answers regarding diet and CAD symptoms.15

The current study reports 4.2 percent of answers were discarded as duplicates or robot responses, but provides no information on discordant responses. The report does indicate, however, 31 percent of the responses were discarded because an analysis of the foods reported indicated significant underfeeding.7

It seems more likely owners were misremembering their feeding practices rather than 30 percent of owners were dramatically underfeeding their dogs.

Asking owners to remember in great detail what they fed their puppy between two to eight months of age, and then trying to associate this with health outcomes years later, is a questionable strategy. With no direct or objective verification, it seems very likely the dietary and health information reported in this survey is unreliable.

The associations discovered during statistical analysis support this interpretation because they are often inconsistent and make no obvious sense in terms of the authors’ hypothesis that raw foods are protective against CAD. For example, why would raw tripe and organ meats be protective, but raw red meat, eggs, and poultry would not be?

If cooking is the main risk factor, why would cooked vegetables be protective and raw vegetables would not? Why would both cooked and raw eggs be protective while neither cooked nor raw poultry is associated with the likelihood of CAD? If exposure to bacteria is the main variable, why is eating dirt, sticks, or carcasses protective, but eating clay and grass is not, and drinking from puddles is actually associated with increased risk?

If excessive processing is the issue, why was there no association with eating processed meats or canned foods, and only a marginal association with dry food when it was the only food offered?

Additionally, the paper reports associations between the proportion of various foods fed and adult CAD risk that are hard to explain.

Dogs with CAD were more likely to be eating no raw food at all than controls, and dogs without CAD were more likely to be fed 20 percent or 90 percent raw, but there were no differences at any other ratio of the two foods. Similarly, allergic dogs were more likely to be fed 80 percent dry than controls, but there was no significant difference if they were fed more than 80 percent dry.

Control dogs were more likely to be fed 50 percent or less than 10 percent dry, but there was no difference at intermediate ratios. It is easier to see cherry picking and researcher degrees of freedom than a consistent dose-response in these results.

Identifying causal associations between nutrition and health outcomes is inherently difficult. Available feeding strategies involve many differences in nutrient form and content other than the narrow aspects we may choose to focus on, such as cooked versus raw.

It is worth conducting research to investigate such relationships, but strong evidence will always be scarce and difficult to produce. However, productive research efforts must involve meaningful attempts to control for bias and to obtain fundamentally reliable data, even when conclusions may always have to be tentative.

The authors of this study continue to publish papers suggesting health benefits to raw diets and risks to conventional diets based on a single online survey tool and a convenience sample of Finnish-speaking dog owners. This is never going to be a solid data set upon which useful conclusions can be based, and the research produced from it are more likely to be an expression of the beliefs and perceptions of the respondents and the researchers, rather than a sound representation of the complex relationships between nutrition and health.

Brennen McKenzie, MA, MSc, VMD, cVMA, discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists’ opinions do not necessarily reflect those of Veterinary Practice News.

References

  1. McKenzie B. Debating Raw Diets. Vet Pract News. January 2019:30-31. https://www.veterinarypracticenews.com/debating-raw-diets-january-2019/.
  2. Roine J, Uusitalo L, Hielm-Björkman A. Validating and reliability testing the descriptive data and three different disease diagnoses of the internet-based DOGRISK questionnaire. BMC Vet Res. 2016;12(1):30. doi:10.1186/s12917-016-0658-z
  3. Brooks C, Pearce N, Douwes J. The hygiene hypothesis in allergy and asthma. Curr Opin Allergy Clin Immunol. 2013;13(1):70-77. doi:10.1097/ACI.0b013e32835ad0d2
  4. Kemp A, Björkstén B. Immune deviation and the hygiene hypothesis: A review of the epidemiological evidence. Pediatr Allergy Immunol. 2003;14(2):74-80. doi:10.1034/j.1399-3038.2003.00017.x
  5. Tizard IR, Jones SW. The Microbiota Regulates Immunity and Immunologic Diseases in Dogs and Cats. Vet Clin North Am Small Anim Pract. 2018;48(2):307-322. doi:10.1016/j.cvsm.2017.10.008
  6. Lynch S V, Wood RA, Boushey H, et al. Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children. J Allergy Clin Immunol. 2014;134(3):593-601.e12. doi:10.1016/j.jaci.2014.04.018
  7. Hemida MBM, Salin S, Vuori KA, et al. Puppyhood diet as a factor in the development of owner?reported allergy/atopy skin signs in adult dogs in Finland. J Vet Intern Med. 2021;35(5):2374-2383. doi:10.1111/jvim.16211
  8. Hielm-Björkman A, Reunanen V, Meri P, Tulamo R-M. Panax Ginseng in combination with brewers’ yeast (Gerivet) as a stimulant for geriatric dogs: a controlled-randomized blinded study. J Vet Pharmacol Ther. 2007;30(4):295-304. doi:10.1111/j.1365-2885.2007.00876.x
  9. Teixeira LR, Luna SPL, Matsubara LM, et al. Owner assessment of chronic pain intensity and results of gait analysis of dogs with hip dysplasia treated with acupuncture. J Am Vet Med Assoc. 2016;249(9):1031-1039. doi:10.2460/javma.249.9.1031
  10. Hielm-Björkman A, Tulamo R-M, Salonen H, Raekallio M. Evaluating complementary therapies for canine osteoarthritis–Part II: a homeopathic combination preparation (Zeel). Evid Based Complement Alternat Med. 2009;6(4):465-471. doi:10.1093/ecam/nem143
  11. Rosendahl S, Anturaniemi J, Vuori KA, Moore R, Hemida M, Hielm-Björkman A. Diet and dog characteristics affect major and trace elements in hair and blood of healthy dogs. Vet Res Commun. November 2021. doi:10.1007/s11259-021-09854-8
  12. Hakanen E, Lehtimäki J, Salmela E, et al. Urban environment predisposes dogs and their owners to allergic symptoms. Sci Rep. 2018;8(1):1585. doi:10.1038/s41598-018-19953-3
  13. Anturaniemi J, Barrouin-Melo SM, Zaldivar-López S, Sinkko H, Hielm-Björkman A. Owners’ perception of acquiring infections through raw pet food: a comprehensive internet-based survey. Vet Rec. 2019;185(21):658. doi:10.1136/vr.105122
  14. Fredriksson-Ahomaa M, Heikkilä T, Pernu N, Kovanen S, Hielm-Björkman A, Kivistö R. Raw Meat-Based Diets in Dogs and Cats. Vet Sci. 2017;4(3). doi:10.3390/vetsci4030033
  15. Hemida M, Vuori KA, Salin S, Moore R, Anturaniemi J, Hielm-Björkman A. Identification of modifiable pre- and postnatal dietary and environmental exposures associated with owner-reported canine atopic dermatitis in Finland using a web-based questionnaire. PLoS One. 2020;15(5):e0225675. doi:10.1371/journal.pone.0225675
  16. Hemida MBM, Salin S, Vuori KA, et al. Puppyhood diet as a factor in the development of owner?reported allergy/atopy skin signs in adult dogs in Finland. J Vet Intern Med. 2021;35(5):2374-2383. doi:10.1111/jvim.16211
  17. Simmons JP, Nelson LD, Simonsohn U. False-positive psychology: undisclosed flexibility in data collection and analysis allows presenting anything as significant. Psychol Sci. 2011;22(11):1359-1366. doi:10.1177/0956797611417632
  18. Resnik DB, Elliott KC. Taking financial relationships into account when assessing research. Account Res. 2013;20(3):184-205. doi:10.1080/08989621.2013.788383
  19. Habib R, Becker K. The Dog Cancer Series: Rethinking the Cancer Epidemic Vol. 1- Chapter 4 (Transcript).; 2018:73.
  20. Satija N, Sun L. A major funder of the anti-vaccine movement has made millions selling natural health products. Washington Post. December 20, 2019.
  21. Science A for. FDA warns Mercola: Stop selling fake COVID remedies and cures.
  22. Fadnes LT, Taube A, Tylleskär T. How to identify information bias due to self-reporting in epidemiological research. Internet J Epidemiol. 2009;70(2). http://www.ispub.com/journal/the_internet_journal_of_epidemiology/volume_7_number_2_25/article_printable/how-to-identify-information-bias-due-to-self-reporting-in-epidemiological-research.html. Accessed December 23, 2021.
  23.  Ravelli MN, Schoeller DA. Traditional Self-Reported Dietary Instruments Are Prone to Inaccuracies and New Approaches Are Needed. Front Nutr. 2020;7:90. doi:10.3389/fnut.2020.00090
Posted in Nutrition | 4 Comments