Intensive feeding in the ICU kills patients

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Since publishing our clinical brief on illness anorexia (Alcock and Legrand 2014), described in the last entry on this blog, a recent trial examined whether giving intensive nutrition to critically ill patients with lung injury helps survival. Based on what we have proposed in EMPH and also the idea of immune brinksmanship, we would predict that intensive feeding would be harmful.

Braunschweig and colleagues (2015) studied whether intensive nutrition (attempting to replace most calorie and nutrient needs) improves survival in ICU patients with acute lung injury compared to standard nutrition, in which patients receive less. These patients are intubated and cannot eat, so physicians and nutritionists make feeding decisions for them. Nutritionists can calculate how many calories the body needs, and many advocate for full replacement. However, because gut motility is often impaired in critical illness, most patients receive less than calculated needs in current practice.

The  bottom line: This study was terminated early for increased deaths in the intensive feeding group. Trying to normalize calorie replacement kills critically patients with ALI.

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Illness Anorexia

Screen Shot 2015-04-16 at 5.46.01 AM

As we discussed in the last post, illness is accompanied by a dramatic decrease in eating, but also an increase in carbohydrate secretion in the gut. These events point towards a coordinated adaptive response to infection and illness that might improve survival when sick. So, should we give our patients less nutrition in the hospital when they are critically ill?

The idea of permissive underfeeding in critical illness was proposed by Zaloga and Roberts (1994). They hypothesized that maximizing nutrition “may adversely affect the host response to injury, especially when given in excess of energy and protein needs.” Supporting the view that calorie restriction during illness is protective, Huang et al 2012 showed that patients with higher illness severity had longer stays in the ICU when feeding was initiated early versus late. In an observational trial, Arabi and colleagues reported that giving higher calories to patients in the ICU was associated with worse outcomes in the ICU (2010). Similar results were found by Krishnan et al. 2003, In a randomized controlled trials, Arabi and colleagues (2011) underfeeding (60%) vs. normal (100%) replacement of calorie needs resulted in improved survival in ICU patients, in keeping with an adaptive function of illness anorexia.

Ed Legrand and I recently summarized why illness anorexia may be an evolved adpative response, and its clinical implications in Evolution Medicine and Public Health, available here.

Starve a fever

Screen Shot 2015-04-14 at 4.01.28 AMA study by Pickard and colleagues in Nature showed that exposure to lipopolysaccharide, LPS, causes anorexia. This component of sickness behavior is well known, and LPS administration is a commonly used model for illness anorexia. The figure below shows a dramatic decrease in energy intake after receiving LPS:

Both solid bars (Fut2+) and open bar (Fut 2-) had markedly decreased food intake after LPS.

In an new an important finding these authors also showed that LPS makes the host secrete carbohydrates on the intestinal epithelium. This effect depended on production of fucosylated oligosaccharides, the gene for which is FUT2. FUT2 positive mice produce these carbohydrates rapidly after stress from LPS with the consequence of directly feeding gut commensal microbiota.

Thus, LPS is an agonist for N-fucosylation and has the effect of diverting a nutrient source to commensal bacteria. N-fucosylation benefits the host in this instance by feeding beneficial barrier bacteria.  Selection may have favored this mutualism because commensal bacteria help prevent invasion by gut pathogens.

In other words sickness makes you eat less, but you may continue to feed your gut microbes. Exposure to LPS induces “sugaring” of intestinal epithelial cells with fucosylated oligosaccharides, as seen in the fluorescence image below:

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So indeed our bodies do starve a fever (LPS is a well known pyrogen), but we feed our commensals. (Now by we I mean mammals.) This was a mouse study, and humans differ in at least one important respect. Some humans lack functional Fut2, preventing the ability to secrete fucosylated oligosaccharides. Fut2 negative humans are at higher risk of inflammatory bowel disease and neonatal sepsis. Not surprisingly Fut2 in humans shows evidence of ongoing natural selection.

The consequence of FUT2 in humans was covered in detail in a previous post on this blog. Read on.

Related: Faecal microbiota composition in adults is associated with the FUT2 gene determining the secretor status.

And: Innate Susceptibility to Norovirus Infections Influenced by FUT2 Genotype in a United States Pediatric Population.

Nutrients with intrinsic anti-pathogen activity are healthy

The gut microbiome is the most important force driving the evolution of dietary inflammation.

Humans have coevolved with commensal organisms and pathogens since our distant ancestors became multicellular. Today, our bodies are a habitat for a multitude of microbes and viruses, the majority of which inhabit the gut, making up a community known as the microbiome. It turns out that these microbes number as many as 100 trillion, and the sum of their genes outnumber human genes by a ratio of more than ten to one. Thus, for as long as humans and our predecessors have been eating, we have shared the food we eat with the bacteria in our guts.

Nutrients have Jekyll and Hyde characteristics on the microbiome, and are sometimes helpful and sometimes harmful. Those nutrients that enhance the barrier function of the gut and prevent pathogen colonization and growth have evolved a signaling function that is thrifty, reducing the costs of an immune defense. Nutrients that impair the barrier function of the gut and increase the risk of pathogen colonization and invasion have the opposite effects. Melissa Franklin and Chris Kuzawa and I compiled evidence from studies showing that inflammatory signaling by nutrients compensates for the effects they have on the gut microbiome.

Since 2012 even more evidence suggests that the immune effects of nutrients matches their influence on the microbiome. Lucky for us, some of the foods that kill pathogens and pathobionts and promote beneficial microbes are some of the tastiest: coffee, chocolate, many fruits and the healthy fats found in the Mediterranean diet.

Results of a recent study on the effects of chocolate matched our predictions exactly: decreased immune investment with nutrients that inhibit pathogens and promote protective species. Less IgA production accompanied beneficial changes in microbiome production with cacao feeding.

Cacao reduced fecal IgA

Cacao reduced fecal IgA

Closed circles represent the control diet, triangles and open circle are cacao/polyphenol diets.

From the paper: “In general, cocoa diets inhibited the growth of Staphylococcus, Streptococcus, and Clostridium histolyticum/C. perfringens (belonging to the Firmicutes phylum) produced by age.”

Our 2012 paper, Nutrient signaling: evolutionary origins of the immune-modulating effects of dietary fat. is available in this previous post.

Reference: Massot-Cladera, Malen, et al. Impact of cocoa polyphenol extracts on the immune system and microbiota in two strains of young rats. British Journal of Nutrition 112.12 (2014): 1944-1954.

Do as much nothing as possible

Never more timely from Samuel Shem’s 1978 classic, the House of God, Fat Man’s Rule #13:

The delivery of good medical care is to do as much nothing as possible

As we have covered on this site, many examples of aggressive treatments aimed at fixing abnormal results have proved useless or harmful.  Doing as much nothing as possible might be the prudent thing to do in many cases. Now, evidence suggests the same is true for cardiac drugs frequently given during codes.

Is epinephrine useless after cardiac arrest?

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In a recent study, giving epinephrine during cardiac arrest resuscitation increased the risk of death. Medications for cardiac arrest have surprisingly little evidence (e.g. virtually none) to support their use, despite the most recent ACLS guidelines that recommend them.

Read: Time for AHA to Revisit Epinephrine in Cardiac Arrest

The rest of the rules (1-12) from House of God are a little questionable. Check them out on the Life in the Fast Lane blog.

Electric light disrupts human gene expression

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Light exposure enables night shift work, but also has body wide effects on circadian gene expression. This gene-environment mismatch contributes to cancer, depression, and cardiovascular disease.  The harmful effects of artificial light were explored in Stevens and Zhu in this month’s Philisophical Transactions B. 

From the abstract:

“Over the past 3 billion years, an endogenous circadian rhythmicity has developed in almost all life forms in which daily oscillations in physiology occur. This allows for anticipation of sunrise and sunset. This physiological rhythmicity is kept at precisely 24 h by the daily cycle of sunlight and dark. However, since the introduction of electric lighting, there has been inadequate light during the day inside buildings for a robust resetting of the human endogenous circadian rhythmicity, and too much light at night for a true dark to be detected; this results in circadian disruption and alters sleep/wake cycle, core body temperature, hormone regulation and release, and patterns of gene expression throughout the body. The question is the extent to which circadian disruption compromises human health, and can account for a portion of the modern pandemics of breast and prostate cancers, obesity, diabetes and depression. As societies modernize (i.e. electrify) these conditions increase in prevalence. There are a number of promising leads on putative mechanisms, and epidemiological findings supporting an aetiologic role for electric lighting in disease causation. These include melatonin suppression, circadian gene expression, and connection of circadian rhythmicity to metabolism in part affected by haem iron intake and distribution.”

The article is here: Electric light, particularly at night, disrupts human circadian rhythmicity: is that a problem?

From ACEP News: Combat Sleep Disorders after Night Shifts

Transmissible cancers found in clams

In cancer, clonal cells evolve ways to escape restraints on growth and motility. These evolved traits favor the fitness of the clones (in the short term anyway) usually to the detriment of the organism that gave rise to the neoplasm. However, cancer lineages are usually dead ends, so that adaptations that allow neoplasia are not passed on from generation to generation. New cancers have to start from scratch, evolving de novo mechanisms to evade controls on growth and reproduction in each lineage. At the same time, anti-cancer adaptations have evolved in multicellular organisms that control and remove proto-neoplastic cells. Multi-generational selection thus permits ongoing evolution of adaptations against outlaw cells, keeping cancer at bay, at least most of the time.

What happens when cancer lineages don’t die with their host? Those cancers would not require de novo mutations to escape control. One might suppose that a cancer that can jump from host to host would evolve to be a formidable parasite with efficient means of evading host control. In a recent study published in Cell, a transmissible leukemia found in clams seems to support this view. Transmissible cancer in clams joins only two other contagious cancers, the facial tumors of Tasmanian devils and a venereal cancer of dogs.  In these unfortunate cases, the cancers is apparently passed from generation to generation. These cancers do not have the handicap of starting from scratch in carcinogenic evolution. They behave more like pathogens, in a never ending evolutionary arms race with the host organism.

In soft shell clams found in the Northeastern US and Canada, a leukemic cancer is genetically identical and widespread, suggesting it has evolved a parasite-like capacity for infection and transmission. Click on the image for the Cell paper by Metzger et al, Horizontal Transmission of Clonal Cancer Cells Causes Leukemia in Soft-Shell Clams:

Metzger et al. 2105

Metzger et al. 2015

Read also: What cancer in clams might tell us about cancer in humans from Washington Post