A recent paper, published in the New England Journal of Medicine asked the question: does treating elevated blood sugar in children with critical illness help or hurt? We have asked the same question – regarding adult patients – previously on this blog.

To get you up to speed I will reprint part of that earlier entry:

“In 2001, a paper by van den Berghe and colleagues was published in the New England Journal of Medicine. It described a trial of intensive blood sugar control in critically ill patients and reported improved survival with intensive glucose treatment using insulin.

This study led to a substantial increase in aggressive hyperglycemia treatment known as “tight glycemic control” in the intensive care unit.

In 2009, another paper refuted the results of the first. The NICE SUGAR study enrolled 6000 critically ill patients, randomizing 3000 of them to tight glycemic control. The key result:

Mortality was higher (27.5% v. 24.9%) in the intensive insulin treatment arm.”

Now, in medicine, 2009 was something like a million years ago, and you might be forgiven for thinking that the NICE SUGAR study would be the final word on the subject. However, leaving high blood sugar alone – permissive hyperglycemia – is a heretical concept, and one that has not died easily.  So, in my hospital, blood sugars are normalized, though perhaps not as aggressively as in the pre- NICE SUGAR era.

To be sure, the NICE SUGAR study did not involve children. A subsequent study examined children after cardiac surgery – and did not show a benefit for normalization of blood sugar in that pediatric population. But non-surgical pediatric patients had not been studied. To the authors of the current study, that necessitated doing a randomized controlled trial of aggressive insulin treatment of hyperglycemia in sick kids.

Researchers enrolled 713 critically ill children and randomly assigned them to a lower target blood sugar group who received more insulin (doing more something) and higher target group who received less insulin (doing more nothing). The main outcome measure was ICU-free days – i.e. time not in the ICU up to day 28.  This outcome was similar in both groups.  Mortality was also similar.

But, this study was stopped early, because the interim analysis determined a low likelihood of benefit from giving more insulin and a high risk of harm. Indeed, in the enrolled group, children receiving more insulin had “higher rates of health care–associated infections” (12 of 349 patients [3.4%] vs. 4 of 349 [1.1%], P= 0.04) in the group receiving less insulin. Not surprisingly, trying to aggressively normalize blood sugar resulted in higher rates of severe hypoglycemia (a blood glucose level below 40 mg/dl. (18 patients [5.2%] vs. 7 [2.0%], P = 0.03).

It is very unlikely that further pediatric trials on aggressive treatment of hyperglycemia will be performed. Why? Because we cannot make a case for equipoise, the state of scientific uncertainty between two possible treatments – that would make it ethical to undertake a similar trial. This is especially so for a study of kids: children are a vulnerable population unable to provide informed consent for themselves.

There are two points to made about these results, one clinical and one theoretical. Clinically, I will expect that ill children especially will not undergo aggressive insulin therapy for high blood sugars in the hospital. At least I hope so. There comes a time when antiquated ideas in medicine need to die. That time is now.

The second point is a reappraisal of the role of hyperglycemia in critical illness. It is my view that hyperglycemia is an adaptation that confers a survival benefit on average – making patients better able to meet the challenge of their critical illness. That view is supported by the recent NEJM study and the previous NICE SUGAR study.

Evolutionary medicine is useful as far as it leads to distinct and better outcomes than conventional, non-evolutionary, approaches in medicine. In the case of normalizing high blood sugars in critical illness, evolutionary medicine can help doctors identify adaptation where previously they saw only pathology. This evolutionary perspective will help save the lives of children by speeding the adoption of better, less aggressive treatments, now strongly supported by the best quality evidence.

There are certain themes that I return to, and the smoke detector principle is one of them. I wrote an Op-Ed piece for the Evolution and Medicine Review last year. An excerpt:

“Randolph Nesse coined the term smoke detector principle to explain why some people display an exaggerated response to threats, perceived and real, resulting in anxiety disorders and panic. He writes “False alarms are to be expected” because of uncertainty about the nature of a threat. That alarming noise behind you that triggers an involuntary intake of breath and a racing heart might simply be a harmless falling branch, or a charging grizzly bear. The overreaction to the falling branch evolved because hair-trigger reactions protect us from the far greater cost of being eaten alive.”

I applied the smoke detector principle to the Toll-like Receptor TLR4 that alerts the body to the threat of invasive bacterial infection.

Function (or dysfunction) of the Toll like receptor TLR4

Read the complete article at the Evolution and Medicine Review here

Image from The Atlantic – click for content

I cannot recommend this recent Atlantic piece by David Epstein more strongly. It absolutely captures the problem of overtreatment and the pressures that fuel this source of medical waste and patient harm. Plus, it does a great job of explaining the number needed to treat and the number needed to harm. Read the original article here.

The audio version is here, for those who prefer to listen instead of read (I did both):

Mark your calendars. This August 18th-21st will be the third annual meeting of the International Society for Evolution Medicine and Public Health. The first two meetings were amazing and fun. This summer’s event promises to be that and more.

For more information click here

Important: November 15th is the deadline for abstract submissions. If you have not yet, please submit right away!

See you in Groningen, Netherlands, this summer!

I recently did a brief Q & A with Eirik Garnas who writes at the blog Darwinian-Medicine.com

Here is the interview:

1. Who are you? What’s your profession and educational background?

I am an emergency physician and professor of emergency medicine at the University of New Mexico Health Sciences Center, and I am an adjunct professor in the UNM Biology Department, where I teach a course on evolutionary medicine. I have a background in evolutionary ecology, with a master’s degree in neurobiology and behavior from Cornell University. I received my MD from UCLA in 1997 and did my residency in emergency medicine at UNM.

2. How did you get interested in Darwinian/evolutionary medicine and the human microbiome?

My original plan was to become an evolutionary biologist. I changed gears during graduate school after I heard a talk by Paul Ewald, the author of the book “The Evolution of Infectious Disease.” He explained why microbes like Vibrio cholerae (the one that causes cholera) have evolved to be deadly pathogens, untamed despite a long coevolutionary history with humans. I found his argument very convincing and I was excited to study evolutionary questions that apply to human health and disease. Soon after, I decided to go to medical school hoping to contribute to the emerging scientific field known as evolutionary medicine, or Darwinian medicine.

3. What’s the main focus of your research?

My research uses evolutionary principles to understand cooperation and conflict in the human gut microbiome, specifically in relation to diet, stress and sleep. One of the things I am interested in is the effect of workplace stress on gut bacteria, and how that affects on-the-job eating, especially during night shifts.  It is known that overnight shift work causes weight gain, obesity, and mood disturbances. My current research is exploring whether there is a link between those outcomes and the microbiota. 

4. 2014, you published an excellent review paper entitled Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms in the journal Can you briefly summarize what that article is about?

We proposed in that paper that unhealthy food preferences, cravings and aversions may serve the evolutionary interests of our gut microbes. One possibility is that microbes hijack our nervous systems with neurotransmitters and appetite peptides that mimic our own. If so, our food choices may be less an issue of willpower, and more the result of our gut bacteria. Many examples exist of microbes manipulating the behavior of host organisms, and we hypothesized that microbes influence eating behavior, in part by rewarding us for eating the foods upon which they depend, and by making us feel bad if we do not provide a constant supply of growth-limiting nutrients. In other words, the problems of overeating, obesity and diabetes may lie less in our genes or our brains, and more in the composition of our guts.

Continue reading →

Start on Tuesday!

Here’s what to expect:

Be sure to click on the link that describes the grading rubric and has a template that you can (or not) use.

Do’s and Don’ts

Here is what I will be looking for: While I am listening to your presentation, I am waiting for the evolutionary hypothesis and evidence that you understand how to consider diseases in terms of evolution and natural selection. So make sure that evolution appears early in your presentation

Make eye contact with the audience.

Practice your presentation, it will be better.

Time your presentation at home. Aim for 12 – 15 minutes.

Things to avoid:

Some previous students have started their presentations with a lot of detail about proximate causes and leave their discussion of an evolutionary hypothesis until the last slide or two. That is not good.

Avoid too much text on your slides.

Make sure you don’t have too many slides!

Good luck!

Developmental programming is thought to be a source of many adult diseases, including obesity, diabetes, and cardiovascular disease. The notion that early life experiences, including nutrient transfer from the mother in utero, can shape the risk of later adult diseases is known as the Developmental Origins of Disease.

This relationship first came to light when Barker documented a curious association between birth weight and adult cardiac events in British men. Babies born small had a higher risk of chronic inflammatory diseases as adults. These small babies have been described as adopting a “thrifty phenotype.” That is, nutrient deprivation as a fetus is thought to have shaped the developmental trajectory in these individuals. This shift results in reduced expenditure on muscle and increased energy storage as fat. These developmental adjustments would be “thrifty” because muscle has much greater metabolic fuel demands than does fat. In addition, these small babies are also known to differ in the composition of their adipose tissues: they store fat primarily as visceral fat.  Visceral fat is the “unhealthy” abdominal fat which predisposes to diabetes and atherosclerosis. However, visceral fat has the advantage of being readily mobilized in the setting of stress or infection. The combination of metabolic thriftiness, reduced outlays devoted to costly muscle tissue, and increased ability to mobilize energy during times of stress is posited to promote survival. In terms of human development, the thrifty phenotype also preserves priority energy access for key organs, such as the brain.  For an expanded treatment of these concepts, see Kuzawa et al: Developmental Origins of Adult Function and Health: Evolutionary Hypotheses (below).

As a corollary to these arguments, it has been suggested that fetal nutrient provisioning provides a signal to the developing organism about the future state of the environment it will be born into. If conditions are good, reflected by increased maternal transfer of resources to the developing fetus, the baby will be born large. If these cues are an accurate signal of plentiful nutrition in childhood and later life, babies born large may develop as more muscular, larger, and with less stored fat, even though this strategy may be riskier in times of famine or epidemic disease.  By contrast, small babies, reflecting poor maternal nutrient provisioning in utero, may portend a resource-scarce environment during childhood and early adulthood. These infants might have an advantage if they develop a thrify phenotype that promotes a robust response to environmental stress.   The key is whether in utero conditions can predict a future state. If so, these fetal physiological adjustments, favoring a thrifty phenotype, will be adaptive in later life.

Recently, the Predictive Adaptive Response (PAR), which provides the underpinnings of the adaptive nature of the thrifty phenotype, has come under criticism. The main argument against the PAR is that fetal nutrient scarcity is a poor predictor of later scarcity. Even if a mother is pregnant in a time of famine, it does not mean that 20 years later, their adult offspring will be more likely to experience famine than a baby born to a mother who did not experience food shortage. As a result the thrifty phenotype is as likely to be maladaptive in adulthood than adaptive.

However, the fetus does have access to other cues which might be better predictors of a future state.

These are microbial cues, because infants inherit their microbiota from their mothers. Because microbiota transfer is a key determinant of the composition of the gut microbiota, with durable effects, it follows that microbiota transfer constitutes an intergenerational transfer of signals that can affect development.

Readings:

1) Kuzawa et al: Developmental Origins of Adult Function and Health: Evolutionary Hypotheses Annu Rev Anthropol 2009 

2) Gluckman Effect of in Utero and Early Life Conditions on Adult Health and Disease

3) Saben Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations Cell Reports 2016

Extra 1): Muller birth mode and the neonatal intestinal microbiome

Extra 2) Of the bugs that shape us: maternal obesity, the gut microbiome, and long-term disease risk