Refeeding syndrome

• Refeeding syndrome is a constellation of biochemical abnormalities which occurs when normal intake is resumed after a period of starvation.
• Its characteristic features are low levels of phosphate, potassium, magnesium and sodium.
• Its major complications include cardiac arrhythmias, heart failure, muscle weakness, rhabdomyolysis, seizures and an altered sensorium.
• The major risk factors are calorie malnutrition of any cause, alcohol or drug use, low BMI (18-16) and starvation for 5-10 days.

Refeeding syndrome is a lifethreatening bouquet of electrolyte abnormalities which results from the sudden reacquaintance of a starving individual with some food. Because intensivists refeed malnourished patients so frequently, the college examiners have a distinct fascination with this syndrome, and it appears frequently among the past papers. Usually, the trainees are expected to identify the syndrome from the characteristic combination of low electrolyte values (potassium, phosphate, sodium and magnesium are all decreased). Then, they are usually asked about the complications of these abnormalities, or which groups are at greatest risk of this syndrome.

In summary:

Examples of previous SAQs on this topic include the following:

• Question 23 from the first paper of 2020 (pathophysiology)
• Question 14 from the second paper of 2016 (mechanism of pathophysiology)
• Question 26.1 from the first paper of 2013 (characteristic features: name four)
• Question 19 from the second paper of 2009 ( four characteristic features and five complications)
• Question 28 from the second paper of 2007 (clinical and biochmical features of refeeding syndrome)
• Question 19 from the first paper of 2005 (biochemical abnormalities and their management)

For an excellent overview of the pathophysiology and manifestations of refeeding syndrome, one may wish to explore the 2004 article by Kraft et al. This work may act as the sole resource for a revising candidate. It was the source fo most of what follows, unless otherwise specified. Of particular interest was Table 2, "Identification of patients at risk for refeeding syndrome" as well as historical notes in the introduction. Another valuable resource is a recent article by Crook et al (2014), which offers a more detailed  overview of the problem and its management. If one is able to get access to the full text of the article, one is encouraged to do so, but it is not available as free full text as far as I am aware. The time-poor exam candidate would be well advised to stop reading now, and to instead go to the LITFL page on refeeding syndrome which offers a lossless compression of the same information.

A definition of refeeding syndrome

Kraft and colleagues quote the original study which described refeeding syndrome, conducted by Keys et al (1944). This was "a detailed report on the Minnesota starvation-rehabilitation experiment (1944-1946)", a massive 1300 page treatise describing the experience of Keys and his coworkers in managing semistarvation in a series of eight male conscientious objectors to World War II. The men voluntarily reduced their nutritional intake and continue for six months. Upon replenishment of nutrition, some of the subjects developed heart failure, which may be attributed to their hypophosphataemia.

As far as formal definitions go, the literature does not offer one. Keys et al did not define the syndrome per se, even though they are widely credited with having coined the term. Since the 1950s, definitions have ranged widely, but have been unhelpfully vague and full of fluff. "A syndrome consisting of metabolic disturbances that occur as a result of reinstitution of nutrition to patients who are starved or severely malnourished"; "a metabolic complication that occurs when nutritional support is given to severely malnourished patients". Even in the glorious 7th edition of  Oh's Manual, refeeding syndrome is mentioned only once and only briefly, on page 967 ("Nutrition and Specific Diseases") as something that "may occur when normal intake is resumed after a period of starvation". No definition follows, beyond a description of the biochemical abnormalities.

The lack of definition is lamented by Crook et al (2014). The author reports that the syndrome exists as a spectrum, consisting of two entities with blurry overlapping margins:

• "Florid" refeeding syndrome, with clinical manifestations of electrolyte disturbance (eg. heart failure due to low phosphate levels)
• "Subclinical" refeeding syndrome, with biochemical evidence of electrolyte derangement which is dealt with so swiftly by ICU staff that no clinical manifestations ever have a chance of developing.

Unfortunately, no definitions exist even for the clinical features (they are all non-specific) and so we remain without a solid definition. Which is fine. Practically speaking, the definitions only matter for the purposes of research. The pragmatic intensivist scoffs at such wankery. The patient whose potassium and phosphate levels drop with the reintroduction of nutrition has refeeding syndrome. They need electrolyte replacement. It is not rocket science.

Patient groups at risk of refeeding syndrome

Historical Features Associated with Refeeding Syndrome

Associated patient features Unintentional weight loss, 10-15% of body mass Prolonged fasting (more than 5-10 days) Chronic infection Chronic inflammattion, eg. inflammatory bowel disease Hypercatabolic state Chronic poor nutrition in the presence of a normal gut, eg. associated with poverty or homelessness Malabsorption, eg. coelicac disease or short gut syndromes Low-birth-weight and premature birth

Associated conditions Anorexia nervosa Chronic alcoholism Malignancy HIV/AIDS Diabetic hyperosmolar states Chronic pancreatitis Elderly patients Bariatric surgical patients Hyperemesis gravidarum

In short, it is anybody who is chronically malnourished for any reason. More precise criteria for recognising at-risk patients does exist. A 2013 prospective cohort by Rio et al  observed the patterns of refeeding syndrome in adults commenced on artificial nutrition support. (it is interesting that Rio et al also did not feel compelled to define this disease entity in order to measure it). The authors came up with the following series of criteria to recognise patients at risk of refeeding syndrome:

Risk Factors for Refeeding Syndrome

One of the following: BMI < 16 Unintentional body weight loss >15% in the preceding 3 to 6 months Minimal or no significant nutritional intake for > 10 days Low concentrations of plasma potassium, phosphate, or magnesium before feeding

OR two of the following: BMI < 18.5 Unintentional body weight loss >10%  in the preceding 3 to 6 months Minimal or no significant nutritional intake for > 5 days History of alcohol or drug abuse

  Mechanism of refeeding syndrome

The seventh edition of Oh's Manual (page 967) offers the following  short description of refeeding pathophysiology:

" With  the  restoration  of  glucose  as  a  substrate,  insulin levels  rise  and  cause  cellular  uptake  of  these ions. Depletion of adenosine triphosphate (ATP) and 2,3-diphosphoglyceric  acid  (2,3-DPG)  results  in tissue hypoxia and failure of cellular energy metabolism. This may manifest as cardiac and respiratory failure, with paraesthesiae and seizures also reported. Thiamine deficiency may also play a part. "

This is probably satisfactory for a workmanlike understanding of this disease process. Crook et al (2014) offer a more detailed discussion. In short, the problem lies with the abrupt conversion of body fuel use from a catabolic starvation state to a normal anabolic state. Whereas during starvation fat catabolism was the chief source of energy (requiring no transmembrane electrolyte shifts), carbohydrate metabolism requires an intracellular migration of electrolytes (predominantly phosphate, which is required to trap glucose inside the cells). Thus, the insulin surge associated with the reintroduction of carbohydrate metabolism results in a sudden and massive intracellular movement of electrolytes. All the clinical features of refeeding syndrome are the result of extracellular electrolyte depletion, and the failure of normal concentration gradients. For instance, the most massive consumer of phosphate during refeeding is going to be the skeletal muscle (as there is so much of it); after the hungry quadriceps has eaten all the phosphate, there will be little left for the myocardium, and this will result in the heart failure of hypophosphataemia.

Intracellular phosphate depletion

If an insulin surge is responsible for the hypophosphataemia, why do patients receiving regular insulin not regularly develop refeeding syndrome? The entire hospital population would have low phosphate, one might think. Well, there is an answer. The intracellular phosphate stores of starving patients are depleted, and in the state of starvation extracellular phosphate levels remain deceptively normal while intracellular phosphate is whittled away. Prior to writing his awesome 2014 article, M.A Crook et al (2001) co-authored a review of refeeding syndrome from a physiological standpoint. In it, the explanation for total body phosphate depletion is offered.

In short:

• Exogenous sources of phosphate are inadequate to supplement the daily phosphate requirements
• Intracellular phosphate stores are used to synthesise ATP (using protein and fat as fuel)
• Homeostatic mechanisms maintain serum concentrations of these ions at the expense of intracellular stores

Biochemical abnormalities associated with refeeding syndrome

There is a list of electrolyte abnormalities which the college has expected its candidates to regurgitate:

• Hypokalemia
• Hypophosphatemia
• Hypomagnesaemia

These each have their consequences, as will be discussed below. As a result of such total electrolyte failure, a series of organ system complications can be observed, and the college is particularly fond of asking about them.

Organ System Complications of Refeeding Syndrome

Cardiovascular: Heart failure (overload) due to atrophy Hypotension and shock Cardiac arrhythmia Gastrointestinal LFT derangement due to acute fatty liver Diarrhoea due to intestinal atrophy Delayed gastric emptying Arrhythmias Renal Acute tubular necrosis Respiratory Respiratory muscle weakness Prolonged ventilator weaning

Haematological Haemolysis Poor platelet function Musculoskeletal Muscle weakness Tetany Rhabdomyolysis due to low phosphate or low potassium Neurological Seizures Coma Delirium Wernicke's encephalopathy Immunological Phagocyte dysfunction Increased susceptibility to sepsis

Hypophosphataemia

This complication occurs within 48 hours of re-commencement of carbohydrate nutrition. Phosphate plays numerous roles in the human body, which one day some sadistic viva may expect you to list:

• Main intracellular buffer
• Major structural component of bone, phospholipids and nucleoproteins
• Essential co-factor of ATP synthesis
• Mandatory member of the oxidative phosphorylation pathway, a role which begins with the phosphorylation of glucose
• Chemotaxis
• Phagocytosis
• Platelet aggregation
• Buffering of acid in urine

The risk of hypophosphataemia seems to depend on the severity and chronicity of undernutrition, rather than the volume of refeeding energy intake. Whitelaw et al (2010)  managed to stuff anorexic girls full of 2200 kcal/day without any clinically significant hypophosphataemia (though depressingly low numbers were generated, circa 0.40-0.50 mmol/L, which would prompt rapid knee-jerk phosphate replacement in any Australian ICU).  In a 2013 retrospective review by Agostino et al the aggressive reintroduction of food to anorexic patients failed to kill any of them with hypophosphataemic heart failure, but instead resulted in an improved mean rate of weight gain and a reduced hospital stay.

This brings into question the standard paradigm of ICU treatment for at risk patients, which is to start feeding at laughably small volumes (ridiculous prescriptions of 10ml/hr of TPN come to mind).  However, it is important to recognise several important caveats:

1. Anorexic teenagers are not representative of the critically ill ICU population
2. Mean weight gain is not a parameter of any interest to the intensivist
3. The same clinically insignificant hypophosphataemia in the anorexic teen may become clinically significant in a patient with multiorgan system failure and borderline cardiac function.
4. Hypophosphataemia may not be the most important parameter in patient-centered outcomes from refeeding syndrome (eg. mortality or ventilator-free days)

Perhaps we are correct in being so cautious? In the face of commonly cited concerns, Suzuki et al (2013) reported retrospectively on a critically ill cohort where phosphate values as low as 0.20 mmol/L were not associated with an increased mortality when other variables were corrected for, echoing the results of the anorexia studies (but these guys were not refeeding syndrome patients - it was a retrospective audit of all-comers with low phosphate).

More data has recently become available from the local citadel of clinical trials, where Doig et al (December 2015) performed a randomised multicentre single-blind clinical trial in 13 ICUs around Australia,  enrolling 339 patients at risk of refeeding syndrome. I have no access to the full text, but it appears that the old way of doing things is associated with some benefit, even in terms of "hard outcomes". The group whose caloric intake was restricted had improved 60-day survival (91%) when compared to the group receiving a normal feeding regimen (78%). Sure, the composite outcome did not reach statistical significance, but the trend is encouraging.

Hypokalemia

Hypokalemia in refeeding syndrome is the consequence of insulin release. One does not need to emphasise to the expected audience the importance of maintaining a healthy respect for normal serum potassium values. In the CICM Fellowship one should not expect to have to regurgitate a rote-learned list of the physiological roles of potassium. Clinical features of hypokalemia may include the following:

• Arrhythmias
• Seizures
• Hepatic encephalopathy
• Ileus
• ATN
• Rhabdomyolysis
• Metabolic alkalosis

Hypomagnesaemia

Magnesium is another essential cation which is mainly intracellular, and its disappearance from the serum tends to suggest that a "clinically significant" refeeding syndrome is impending. For one, magnesium is a cofactor of numerous enzymes, and practically no molecular manipulation involving ATP can occur without it. Practically speaking, the following clinical features may be expected of the desperately hypomagnesaemic patient:

• Arrhythmias
• Seizures
• Tetany
• Confusion and ataxia
• Tremor
• Paraesthesia and weakness
• Poor response to potassium replacement (if also hypokalemic)
• Hypocalcemia (as magnesium is required for optimal action of parathyroid hormone)

Other adverse effects of refeeding

Crook et al (2014) mentions a host of associated problems, without exploring them in any great detail, or conforming whether these are associated findings or properly the manifestations of refeeding syndrome. These are discussed below without any great enthusiasm, and with little attention to detail.

Thiamine deficiency

The otherwise lucid article by Crook et al (2014) cannot seem to make up its mind whether thiamine deficiency is caused by refeeding syndrome, or whether it is merely associated with malnutrition (and therefore frequently discovered alongside refeeding syndrome). Certainly, the thiamine-deficient person will develop Wernicke's encephalopathy in response to carbohydrate replenishment. Regardless of whether or not they are being refed, these people are also likely to have cardiac failure and lactic acidosis. From the published literature, it is unclear whether thiamine depletion occurs when the carbohydrates are reintroduced. It seems unlikely, because it is a cofactor in the reactions, and is not expended. Rather, the increased need for thiamine as a cofactor may unearth a deficiency which was not clinically apparent until the starvation ended. In any case, most modern authors (eg. Martinez et al, 2015) recommend thiamine supplementation for patients at risk of refeeding syndrome.

Trace element depletion

Crook quotes Korbonits et al (2007) as confirming that copper and selenium levels in starved patients decrease during refeeding. Korbonits and colleagues studied sixteen volunteers fasting for 44 days, and found that "serum zinc was elevated on admission [to treat refeeding] but rapidly returned to normal during refeeding" and that "serum copper and selenium were within the normal ranges after the fast". That is not exactly the same as saying that they were depleted by refeeding. Still, venerated authors (among them LITFL) recommend for the replacement of trace elements as a part of their strategy to manage refeeding syndrome.

Hypernatremia

If the patient is being fed a diet heavy with protein, hypernatremia associated with hypertonic dehydration may occur. This is a well known complication (Gault et al, 1968) and was mainly associated with older style nasogastric supplement formulae, which tended to the hyperosmolar end of the spectrum (some authors report 1000mOsm/L as being routine). The increased excretion of urea due to increased protein content tends to result in obligate water loss and hypovolemia, which in turn stimulates sodium retention by the stereotypical aldosterone-driven response. Voila, hypernatremia. However this is not a feature of refeeding, and even a well-nourished individual would develop some degree of this, particularly with TPN.

Hyponatremia

If the patient is being fed a carbohydrate-rich diet, hyponatremia may develop as a consequence. For an analogous mechanism, one may wish to consider beer potomania. In either case, a sodium-poor watery substance is being consumed to an excess. Hyponatremia develops because the carbohydrates are metabolised into water and CO₂, and the excess water remains. The problem may be worse with "renal-specific" dietary formulae, which tend to be protein-poor and intentionally low on sodium. Again, this is an issue which affects all patients, not only particularly malnourished ones, and so cannot be said to be a part of "refeeding syndrome proper".

Evidence-based strategies for management refeeding syndrome

If one were to look for a locally relevant up-to-date guideline for this, one could do worse than the Sydney Children's Hospital Practice Guideline from 2013. It is freely available online, whether owing to their generosity or some sort of firewall failure. Page title metadescription comes up as "PLEASE TYPE POLICY TITLE HERE", which suggests the latter.  In any case, we profit as a society. Their recommendations have been blended with LITFL, Crook et al (2014), Kraft et al (2004) and various others.

In summary:

• Prevention
  • Recognition of at-risk patients is important for prevention of sequelae
  • Introduce the feeds slowly (Doig et al, 2015)
    • 10kcal/kg/day (NICE) which is about 37% of predicted energy requirements
    • 50% of predicted requirements (SCH)
    • SCH recommend to increase in increments of 10% of total requirements, every 24 hours
  • Ensure the replacement of thiamine, multivitamins and trace elements
  • Proactively replace phosphate potassium and magnesium
• Management:
  • Arterial line for regular blood sampling and haemodynamic monitoring
  • Central line for replacement of electrolytes with concentrated solutions
  • One CVC lumen to be kept unused for TPN if needed
  • IDC for monitoring urine output
  • Aggressive replacement of electrolytes as dictated by biochemistry
  • If possible, incorporation of proactive electrolyte replacement into TPN
• Monitoring:
  • Ensure careful monitoring of electrolytes during the first 2 weeks of refeeding
  • Regular weight measurements
  • Strict fluid balance chart

The precise rate of "careful" replacement is uncertain. The abovequoted Doig et al paper (2015) has demonstrated a survival benefit associated with a conservative calorie-reduced refeeding protocol, but precisely how much one can safely restrict (or how much one can safely supplement) remains debatable. The recent Sydney Children's Hospital Practice Guidelines suggest to start with 50% of the expected goal rate. The NICE guidelines from 2006 recommend to start at 10kcal/kg/day, which is 40% of the expected goal rate (25kcal/kg/day to use the common shortcut). A paper by Jacob Frølich (2016) reports the case of a young woman with a BMI of 7.8. "To our knowledge, this level of extreme malnutrition has not previously been reported" gloat the authors. This patient was refed using the NICE guidelines (10kcal/kg/day, 50% of energy derived from carbohydrate, 15% from protein, and 35% from fat). The authors' data reports normal potassium and phosphate levels throughout the process, with only reactive oral supplements being used. In summary, it is perhaps best to err on the side of caution, and to start slow.