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Copyright © by ESPEN LLL Programme 2014
Nutritional Support in
Intensive Care Unit (ICU) Patients Topic 18
Module 18.1
How to Maintain Homeostasis by Nutrition Care in the ICU
Michael. J. Hiesmayr
Division of Cardiothoracic & Vascular Anesthesia and Intensive Care
Währingergürtel 18-20
Medical University Vienna
Austria
Learning objectives
Understand the metabolic & endocrinological consequences of underfeeding
Determine target for energy supply
Methods to determine energy consumption
Determine or estimate target for protein supply
Identify patients at risk for the refeeding syndrome
Learn key features of the refeeding syndrome
Learn how to prevent the refeeding syndrome
Content
1. Introduction
2. Amount of protein needed
3. Amount of nutrients needed
4. Excessive nutrient intake
4.1 The lung and ventilation
4.2 The heart and circulation
4.3 Endocrine system
4.4 General signs and symptoms
5. Insufficient nutrient intake
6. Composition of the diet
7. Organs & nutrition
7.1 Brain
7.2 Cardiovascular system
7.3 Lung
7.4 Abdomen
7.5 Kidney function
7.6 Haematological system
7.7 Endocrine system/metabolic equilibrium
8. Refeeding syndrome
8.1 Pathophysiology
8.2 Clinical symptoms
8.2.1 Fluid equilibrium
8.2.2 Glucose and lipid metabolism
8.2.3 Thiamine deficiency
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8.2.4 Hypophosphataemia
8.2.5 Hypomagnesaemia
8.2.6 Hypokalaemia
8.3 Treatment and prevention
9. References
1. Introduction
Nutrition Care is considered to be a basic and mandatory (essential) element of modern
intensive care treatment. Recommendations and guidelines exist from several
professional organizations: ASPEN, Canadian Critical Care Group and ESPEN. Their focus
is on the indication for EN vs PN, amount of nutrient to be given, composition of all-in-
one mixtures, and specific nutrients such as glutamine. No guidelines give any practical
advice on how to maintain homeostasis during nutrition care or clinical problem solving in
case of problems. Several large nutrition trials (1-5) have questioned some
recommendations and are now integrated into this educational material.
Nutrition Care in the ICU has several challenges because the usual control mechanisms
such as hunger, thirst may be missing during critical illness. On the one hand the control
of the intake is under external control and on the other hand nutrients may have a
complex interaction with various organ systems. A further challenge is that acute illness
triggers an internal production of nutrients, usually called catabolism, that does not
immediately stop when external nutrients are given. This “catabolic response” to injury is
an essential mechanism to survive periods of missing intake. The availability of certain
nutrients impairs essential repair mechanisms such as autophagy, an internal mechanism
to sequester injured organelles in autophagosomes (6). These four factors indicate that
an integrative view is essential.
The patient groups at highest risk for complications associated with nutrition care are
obviously those at the extremes of body size, nutrient intake and actual disease:
Table 1
- BMI very low or very high
- Higher age
- Prolonged starvation
- High level of organ support in the ICU
- Severe physiological impairment
The common denominator of all these conditions is an altered body composition. Most
conditions are associated with a decrease in lean body mass. This decrease may not be
easily apparent because still maintained body fat is hiding the decrease in lean body
mass. Various methods such as body impedance assessment (BIA), ultrasound, CT and
MRI scans, but also functional measurements of muscle function, are used in specialist
centres. Sarcopenia research has addressed this issue extensively (7).
The challenge of nutrition science and care is to define to margins: the minimal
requirement for macro- and micronutrients necessary for recovery from acute illness and
the maximum tolerable margin. A new concept is that minimal requirements and
maximum tolerable concentrations vary during the course of an acute illness.
This concept is shown for health and disease in Fig. 1a and b. During health a minimum
of glucose (G) is needed for glucose dependent tissues such as the central nervous
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system, suprarenal glands, erythrocytes. If glucose supply from intake is not sufficient
gluconeogenesis from protein (red arrow) can prevent a shortage. If glucose is available
above needs and glycogen stores are full, storage into (yellow arrow) fat (F) occurs. High
levels of amino acids (AA) are either oxidized and excreted or enter gluconeogenesis and
are stored as fat. Saturated (yellow bar) and unsaturated (green bar) fat are necessary
in different amounts as energy sources but also to build e.g. cell membranes, hormones,
etc. During acute illness needs change and endogenous mobilisation of macronutrients
combines with external supply of nutrients. Thus the danger limit and the minimum may
be changed. Recent research has shown that early large provision of nutrients is
associated with storage of fat even in organs such as muscle where storage usually does
not occur (8). Any level of nutrients below the minimum will induce an increased
catabolic response mostly of the muscle.
Fig. 1 Margins for macronutrients between minimum and danger zone
Energy expenditure remains relatively stable during the early phase of starvation and is
only decreased by roughly 10% after 3 weeks of starvation. Energy expenditure is mostly
determined by a few organs that have a high energy demand such as brain, liver,
intestine, heart and kidney that represent 5% of body mass and 66% of energy
expenditure. Only the brain maintains its weight during severe starvation. Thus the
functional capacity of vital organs (especially heart, kidney, intestine) is decreased
because structural protein has been lost during starvation. Individuals with a regularly
decreased lean body mass such as the elderly have a decrease in energy expenditure,
which is about 1% per year above the age of 60 years. Of course these general estimates
need to be adapted if functional status is different from the age group. In addition to
these basic rules related to lean body mass, synthesis of acute phase proteins by the
liver, faster turn-over of immune cells, uncontrolled muscle activity in delirium and repair
of injured tissues modify energy expenditure.
Protein handling follows another basic structure. Protein turnover is not similar to energy
expenditure. The brain has a low protein turnover but a high energy expenditure, the
kidney a relatively lower energy expenditure but a higher protein turnover. During health
protein balance is equilibrated. Proteolysis of 300 g/day is balanced by protein synthesis
(Fig. 2).
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Fig. 2 Protein handling in stable humans
The largest contribution (100g/day) to proteolysis comes from muscle that has a daily
turnover rate of 2%, in contrast to the liver that contributes about half (50g/day) with a
turnover rate of 25%. The largest turnover rate is in the intestine (Fig. 3). This turn-over
of protein decreases at higher age and is related to less efficient repair mechanisms and
accumulation of less functional organelles. In a quite general sense this is the process of
ageing.
During acute illness there is a net deficit in protein despite an increased whole body
protein synthesis because there is an increase in breakdown that is relatively higher. The
major site of protein synthesis in acute illness is the liver and the major site of
breakdown is the muscle. The take-up of amino acids from the pool of free amino acids
by the liver serves the generation of acute phase proteins and gluconeogenesis. There
appears to be a priority of organs according to the needs of acute illness.
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Fig. 3 Protein turnover in % for individual organs
2. Amount of Protein Needed
In principle the amount of protein needed should be sufficient to cover usual protein
turn-over plus the additional needs related to the increased protein synthesis in the liver
and in injured tissues. The usual recommendations are that a supply of 1-1.5 g.kg-1.day-1
is sufficient. Protein breakdown associated with starvation needs several days before a
decrease occurs. This is the point where ketogenesis increases and ketones partially
replace glucose as preferred fuel. There is an additional breakdown associated with the
inflammatory process but also with bed-rest and disuse of muscle. The amount of protein
loss was shown to be independent of the energy expenditure when many observational
studies were combined in a recent systematic review. (9). Most probably there is an
association between protein loss and lean body mass, the muscle being the largest part.
Lean body mass typically decreases with age and thus protein need may depend on age
and lean body mass. No practical methods to relate measurements of lean body mass
with protein supply have been proposed to date.
There are no large trials that have modified the amount of protein independently from
the amount of energy given. Many observational trials have suggested that patients with
a higher protein supply and a good coverage of calculated energy needs have the best
prognosis. This observation could also be seen as showing that a good tolerance of large
amounts of enteral nutrition is associated with a better prognosis. It has repeatedly been
shown that patients needing prolonged ICU care rarely have more than 60% of
calculated needs covered by enteral nutrition. The special benefit of meeting calculated
protein and energy target was only seen for 28 day mortality and was associated with
the highest mortality in the ICU and the hospital (10).
Moreover some recent trials suggest that providing larger amounts of protein and glucose
impair the repair mechanism associated with autophagy. A trial with large amounts of
glutamine also failed to show a positive effect (11).
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Thus a progressive increase in protein supply over a few days up to a level of 1-1.5 g.kg-
1.day-1 is probably safe. Given the usually low amounts given in clinical practice,
achieving 1g.kg-1.day-1 is already ambitious. Larger amounts should not be considered
until randomized trials have shown their efficacy and benefit.
3. Amount of Nutrients Needed
A general physiological rule is that energy consumption is tightly related to lean body
mass (12). In shock of any origin energy consumption is lower than estimated (13) by up
to 50%; during reconvalescence when patients begin to be effectively mobile and
anabolic energy consumption will increase above estimated resting energy expenditure.
Modification of estimated energy consumption should not be applied during ICU stay
because these factors tend to change during critical illness, often below but also
sometimes above estimations. Use clinical judgment and consider that 2/3 of energy is
consumed by brain, liver, kidney and heart representing 5% of total body weight. Only
the brain weight does not decrease during starvation and catabolism of acute illness.
Another ¼ of energy is consumed by muscles that, in healthy young adults, represent
about 20-35 kg or 30% to 50% of body weight. A recent trial showed that during the
first two weeks of critical illness 220-250 g of nitrogen or 5-6 kg of muscle have typically
been lost (14).
The ESPEN guidelines state that:
- 20-25 kcal.kg-1.h-1
in the acute and initial phase of critical illness and
- 25-30 kcal.kg-1.h-1
in the anabolic recovery phase should be given to patients. ACCP guidelines recommend
25 kcal.kg-1.h-1.
Fig. 4 Individualized estimated daily caloric need versus body weight
Actual body weight is replaced by normal body weight (kg) derived from height (cm) as
height -100 and 25% of the difference between actual and normal body weight is added.
All coloured fields have an associated BMI>25, orange (daily calories > 2500), pink (daily
calories> 3000).
A further suggestion is to decrease energy provided by 1% for each year above 60 years.
This suggestion may correct actual formula for the decreasing lean body mass with age.
A decrease of energy need by 20% between the age of 60 and 80 has been reported. As
an example a frail octagenerian with a BMI of 27 had a measured energy consumption of
800-1400 kcal.day-1 whereas estimated energy consumption was 1600-2100 (15).
One of the most accurate formulae for estimation of energy need has been proposed by
Faisy et al. (16) and includes weight, height and minute-ventilation. Minute-ventilation
may serve as a good surrogate for CO2 production.
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Little information about individualization of therapy is given and thus only two options
exist: measuring energy expenditure with indirect calorimetry or using clinical
observation, lab values and judgment to adjust nutrition care. The observation of trends
is of crucial importance as is also the combination of several signs and symptoms in any
of these situations. Guidelines currently do not offer problem solving
algorithms for diagnosis of under- or overnutrition. We consider that most of the
recommendations apply for “mean” patients and that clinical judgment needs to be used
for patients outside this category. A cartoon shows conceptually the adaptation of
nutrient intake that may be considered for the young and very old as well as in the acute
and the stable phases of illness. The duration until stabilization certainly varies from
patient to patient. Age is also an important factor for energy requirements. Energy
requirements decrease at higher age (17).
Fig. 5 Conceptual graph: actual body weight vs caloric intake:
The arrows represent the progressive increase in calories that may be appropriate after
initial stabilization and when patients are becoming anabolic.
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Fig. 6 Conceptual graph relating body weight (actual or normal depending on BMI) to
caloric intake:
The arrows represent the progressive increase in calories that may be appropriate after
initial stabilization and when patients are becoming anabolic.
4. Excessive Nutrient Intake
Excessive nutrient intake is considered to be much less frequent than undernutrition but
recent observational data from the NutritionDay ICU project 2007-2008 suggest that
almost as many patients receive an amount of nutrients below or above a target zone of
20-30 Kcal.kg-1.h-1. Prescription of parenteral nutrition may be associated with
overfeeding in more than half of the patients (18).
Measured energy consumption may suggest an excessive intake if RQ is > 0.85 for
patients that are not exercising during the measurement period. An elevated RQ suggest
an increased CO2 production that may be related to either high energy intake or high
glucose load and ongoing lipogenesis (19).
The organ systems most affected by excessive intake are the lung, the heart and the
endocrine system but a few general symptoms such as fever or decreased level of
consciousness may also relate to larger than tolerated intake of single nutrients.
4.1 The Lung and Ventilation
Elevated minute volume e.g. above 150 ml.kg-1.min-1, persistently elevated arterial pCO2
despite normal minute ventilation or difficulty to wean from the ventilator in otherwise
unstressed patients should trigger thoughts about nutrient intake. In the case that an
excessive nutrient intake appears to be a possibility, a trial of decreasing intake by 30%
for a few days to allow weaning may be necessary (20).
4.2 The Heart and Circulation
Nutrient intake induces a typical response with an increase in oxygen consumption that is
followed by an increase in cardiac output and a slight decrease in peripheral vascular
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resistance and thus no major change in blood pressure. In patients with decreased
cardiovascular reserve, patients with congestive heart failure or patients who have lost
heart muscle because of prolonged starvation, e.g. anorexia nervosa, this increase in
demand for cardiac work may be associated with new or worsening heart failure (21-23).
Pulmonary oedema and new cardiac rhythm disturbances such as atrial fibrillation are
possible. Cardiac inotropic support and careful volume adjustment may be the treatment
of choice.
4.3 Endocrine System
Hyperglycaemia and hyperlipidaemia can be symptoms of excessive nutrient intake. In
this case a decrease in nutrients needs to be considered. This decision is particularly
difficult since acute disease states, injury and starvation for a few days are associated
with increased insulin resistance (24). This phenomenon is by far the most likely reason
for hyperglycaemia. Tolerance to glucose also decreases with age (25).
4.4 General Signs and Symptoms
Fever may be a sign of an excessive load of amino acids with their thermogenic effect
(26). In some patients, especially those with a severe catabolic state, an increased load
of amino acids that may appear indicated to prevent a further deterioration in nutritional
status, may lead to a decreased level of consciousness due to a sharp rise in blood
ammonium. Hyperlipidaemia may occur in some patients and can be related either to a
high glucose load or to poor lipid clearance. Lipid should probably only be reduced if
triglyceride levels are very high and excessive glucose intake has been excluded.
5. Insufficient Nutrient Intake
A cumulative deficit of nutrients compared with actual energy consumption has been
found to be associated with an increase in complications (27 28). Especially, infectious
complications have been shown to be increased in patients with an energy deficit of
>50% of needs compared with the recommendations for energy supply in the ACCP
guidelines. Few centres routinely use indirect calorimetry to assess patients’ energy
needs, thus most centres have to rely on formulae and clinical judgment (29-31).
Discrepancies between measurements in different groups of critically ill patients were
between 1300 and 2200 calories (31).
The effect of an energy supply below needs is not easily detected since the clinical
manifestation of semi-starvation needs time to be obvious in an individual patient.
Moreover the effect of semi-starvation is similar to the effect of severe catabolism
induced by the acute disease process.
Sleepiness, loss of physical strength, repeated skin defects, or pressure sores should
raise the suspicion of a severe energy deficit.
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Fig. 7 Risk of complications when energy provision is not on target
The arrows represent the progressive increase in calories that may be appropriate after
initial stabilization and when patients are becoming anabolic.
6. Composition of the Diet
Modifications in the composition of the diet are considered in three clinical situations:
- Difficult to handle hyperglycaemia
- Excessive hyperlipidaemia ( > 400 mg.dl-1)
- High CO2 values and weaning problems
In the case of difficult to control hyperglycaemia (usually considered when insulin need is
>100 IU. day-1) there are several options. The first option is excessive energy intake, the
second an unbalanced nutrition regimen with a relatively high glucose (32) content or a
poorly controlled septic process.
Elevated lipids (usually triglycerides > 400 mg.dl-1) happen from time to time in the ICU.
There are several possibilities that need to be considered:
- Excessive lipid intake (maximum clearance 3.5 g.kg-1.day-1)
- Excessive glucose intake
- Acquired poor lipid clearance
o Acute renal failure
o Chronic renal failure
o Hypodynamic sepsis
- Inborn poor lipid clearance or abnormal metabolism
In all cases where lipid intake is limited the minimal requirement in LCT of 10 g. week-1
should be considered. LCT are an essential component for cell membranes.
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In patients with respiratory failure and elevated CO2 values there has been the idea to
move from a balanced nutrition solution to a more lipid-based nutrition because the RQ
of lipids is 30% lower than the RQ for glucose. Research in this field could demonstrate
that a reduction in CO2 is only achieved with limitation of energy intake to consumption,
but cannot be modified by modification of the composition of the diet (20, 32, 33).
In the obese severely obese patient a modification of the diet with low calories and 1.2 g
of protein per kg actual body weight had a similar nitrogen balance without difficult to
control hyperglycaemia (34).
7. Organs & Nutrition
7.1 Brain
The brain is affected by several nutrition related factors (22, 23, 35, 36):
- Glucose level
o Hyperglycaemia
o Hypoglycaemia
- High ammonium
- Electrolyte imbalance
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Fig. 8 Brain and nutrition related symptoms
7.2 Cardiovascular System
Hypophosphataemia, hypokalaemia and the consequences of muscle loss during reduced
nutrient intake favour the occurrence of severe cardiac complications in patients with
malnutrition, severe catabolism and refeeding.
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Fig. 9 Heart and nutrition related symptoms
7.3 Lung
The lung is affected by reduced cardiac function, diaphragmic strength and by the level of
CO2 that needs to be eliminated. Thus the main limiting factors are muscle loss during
starvation or severe catabolism that impair both the heart and the respiratory muscles.
The system is then stressed by the level of CO2 that needs to be eliminated. CO2
production is mainly affected by high energy intake or by a high glucose intake that, with
a RQ above 1, is converted to fat (20).
As a third consequence of inadequate nutrient intake the risk of pneumonia is increased.
7.4 Abdomen
The abdomen is not only affected directly by the disease and the tolerance of enteral
feeding but also by other nutrition related factors.
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Fig. 10 GI tract and nutrition related symptoms
7.5 Kidney Function
Reduced kidney function has a direct interaction with nutrition care. Poor excretion of
waste products induces azotaemia. During acute illness it is usually not advisable to
reduce protein intake or amino-acid infusion to a very low level. Thus renal replacement
therapy is indicated to allow a sufficient protein intake.
Other consequences such as hypokalaemia affect the capacity of the kidney to
concentrate urine, or hinder the resolution of the metabolic alkalosis often seen after
hypercapnic ventilatory failure or a shock state. Hypomagnesaemia has also been
associated with renal failure (37).
Uncontrolled hyperglycaemia may be associated with osmotic diuresis and hypovolaemia
(38, 39).
7.6 Haematological System
Leucocytes, erythrocytes and platelets are affected by deviations from electrolyte
homeostasis. The main reason for impaired blood cell function is hypophosphataemia.
Infection control, clotting function and oxygen unloading may be affected (40-42).
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7.7 Endocrine System/Metabolic Equilibrium
The endocrine system is affected by starvation, malnutrition and acute illness. After a
few days of reduced intake the capacity to metabolize glucose is reduced by almost 50%
(24). This effect is even more pronounced in phases of acute stress such as surgical
interventions. Hyperglycaemia is a common feature in acute illness even in a high
proportion of non-diabetic patients (43-49). Hyperglycaemia is often associated with
increased severity of illness and poorer prognosis especially in the group of patients
without known diabetes before hospital admission.
In 2001 Greet van den Berghe from Leuven could show that intensive control of
glycaemia to levels of 80-110 mg.dl-1 compared with treatment only for patients with
glucose levels >180 mg/dl immediately after ICU admission significantly improved
outcome and prevented morbidity (50). This effect could be found also in medical ICU
patients staying longer in the ICU and in children (51). The Leuven approach combines
early treatment of hyperglycaemia and simultaneous infusion of glucose, and early start
of enteral and parenteral nutrition therapy. These studies bolstered the interest in
hyperglycaemia and promoted research on treatment with continuous insulin to different
targets and in specific populations. None of the multicentre trials could replicate the
beneficial effects described by the Leuven group. Several trials were stopped prematurely
because of a high proportion of hypoglycaemic events in the intensive treatment arm
(52). A very large multicentre trial (NICE-SUGAR) in 6104 patients showed a small
unfavourable effect of intensive insulin control. A large debate on the reasons for these
conflicting results is still ongoing (51).
Table 2
Glycaemia management elements
Based on expert opinion and a recent meta-analysis current recommendations could be
summarized:
- Hyperglycaemia should not be left uncontrolled in acute illness
- The target should be to achieve values < 150 md.dl-1
- Avoid large changes in glucose values
- Avoid hypoglycemic events to values < 60 mg.dl-1
- Do not withhold appropriate nutrition care to avoid giving insulin
- Use a protocol that includes the following elements
o Target glucose range
o Insulin dosage for deviations from the target
o Step changes in insulin for rapid glucose changes
o Avoids insulin boluses being given intravenously
o Amount of glucose to be given in case of hypoglycaemia (usually 8-10 g as bolus)
o Intervals of glucose measurement adapted to the most recent changes in glucose
and insulin dosage
o Definition of responsibilities
Who measures glucose
Who interprets glucose levels
Who is allowed to modify insulin dosage
o Usually point of care glucose measurement is necessary unless glucose values can
be obtained within 10 minutes of sampling 24h/24h
o Glucose measurement from blood gas machines are usually the most convenient,
cost-effective and reliable point of care approach
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The most important part is the analysis of the treatment process, to provide adequate
training and to give the responsibility of measuring and modifying to one group of health-
care providers who work near to the patient (usually nurses but physicians possible
depending on local organization).
Fig. 11 An example for a glycaemia control protocol from the cardio-thoracic ICU at the
medical university of Vienna
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Treatment of stress induced hyperglycaemia outside ICU has not been formally assessed
to date.
8. Refeeding Syndrome
The refeeding syndrome is a potentially lethal and often forgotten condition associated
with feeding of chronic malnourished individuals or individuals with little or no nutrient
intake for 5-10 days. The hallmark biochemical feature is hypophosphataemia but many
other clinical signs are possible. The route of feeding does not have a specific effect on
the refeeding syndrome (23, 53).
Table 3
Key pathophysiological features of the refeeding syndrome
a- Fluid balance
b- Glucose homeostasis
c- Vitamin B1 deficiency …. Hyperlactataemia
d- Hypophosphataemia
e- Hypomagnesaemia
f- Hypokalaemia
The incidence of the refeeding syndrome may be as high as 25% for cancer patients and
as many as 34% of intensive care patients experienced hypophosphatemia within 2 days
of starting artificial nutrition. The clinical presentation may be variable; some symptoms
are even compatible with other disease and a poor general condition. Based on case
reports the syndrome is potentially fatal, often unrecognized and poorly treated
especially outside areas with close monitoring such as intensive care units.
According to the most recent NICE recommendations, refeeding should not be delayed
until biochemical abnormalities have been corrected (54). Progressive increase in
nutrient intake, correction of biochemical abnormalities and close monitoring allow early
and safe refeeding.
Table 4
Refeeding syndrome: high risk patients (53)
- Patients with anorexia nervosa
- Patients with chronic alcoholism
- Cancer patients
- Postoperative patients
- Elderly patients
- Patients with uncontrolled diabetes mellitus
- Patients with chronic malnutrition
o Marasmus
o Prolonged fasting or low energy diet
o Morbid obesity with profound weight loss
o High stress patients unfed for > 7 days
o Inflammatory bowel disease
o Chronic pancreatitis
o Cystic fibrosis
o Short bowel syndrome
- Long term antacid use
- Long term diuretic use
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Table 5
NICE recommendation to identify high risk patients based on cases and
expert opinion (23)
- One or more
o BMI < 16
o Unintentional weight loss > 15 % in 3-6 months
o Little or no nutritional intake for > 10 days
o Low potassium, phosphate, magnesium before feeding
- Two or more
o BMI <18.5
o Unintentional weight loss > 10 % in 3-6 months
o Little or no nutritional intake for > 5 days
o History of alcohol misuse or chronic drug use (insulin, antacids, diuretics)
8.1 Pathophysiology
The pathophysiology is determined by the occurrence of starvation followed by refeeding.
During starvation the basal needs in glucose are supplied by gluconeogenesis from
protein when glycogen stores have been depleted. The metabolic and hormonal changes
aim to minimize protein break-down. The main source of energy is lipids, and increased
levels of ketone bodies stimulate the brain to utilize ketone bodies instead of glucose.
The metabolic rate progressively decreases by 20-25%. During this phase cells tend to
shrink and lose large amounts of intracellular electrolytes. The serum levels may remain
normal despite severe depletion.
With refeeding insulin levels increase and glucagon levels decrease. Protein, glycogen
and fat synthesis is stimulated and cell volume increases again. This anabolic phase
necessitates nutrients but also large amounts of phosphate and magnesium as well as
cofactors such as thiamine. The role of depletion of micronutrients has not yet been well
investigated.
Insulin stimulates glucose uptake into cells with the help of the Na-K ATPase symporter.
Magnesium and phosphate are also taken up by the cells. Water follows by osmosis, and
cell volume tends to increase. This is by itself an strong anabolic signal. As a
consequence the serum levels of these electrolytes may decrease dramatically within a
short period of time and the metabolic rate may increase above the physiological
tolerance of the cardio-respiratory system.
8.2 Clinical Symptoms
8.2.1 Fluid Equilibrium
Refeeding with carbohydrate can induce reduced sodium and water excretion with
extracellular volume expansion and weight gain. Volume expansion and poor fluid
tolerance due to the reduced cardiac mass of malnutrition may result in cardiac failure
(39, 55). Refeeding predominantly with protein and lipid may result in fluid loss.
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8.2.2 Glucose and Lipid Metabolism
The capacity to metabolize glucose decreases within a few days of even partial
starvation. During refeeding with glucose gluconeogenesis will be suppressed or at least
reduced in critically ill patients but tolerance for glucose is limited. Hyperglycaemia with
osmotic dieresis and metabolic acidosis is possible and should be detected early with
proper monitoring. Thus relative overnutrition and insufficient treatment of insulin-
resistance of starvation may promote lipogenesis. The maximal lipid tolerance is 3.8
g.kg-1.day-1 and can be much lower during critical illness (56).
8.2.3 Thiamine Deficiency
Thiamine is a cofactor of several enzymes such as transketolases. The vitamin deficiency
of malnutrition may be exacerbated with refeeding and the increasing intracellular need
for vitamins. Thiamine deficiency is associated with Wernicke’s encephalopathy
(confusion, ocular disturbance, ataxia, coma) and Korsakov’s syndrome (short-term
memory impairment and confabulation). Thiamine deficiency is also associated with
hyperlactataemia without other shock symptoms (57).
8.2.4 Hypophosphataemia
Hypophosphataemia is the most frequent sign of the refeeding syndrome. Phosphate is
the major intracellular anion and is involved in energy storage in the form of ATP, in
intracellular buffering, as an essential initial step of glycolysis, and as a structural part of
cell membranes. Many enzymes are activated by phosphate binding (40, 41).
Table 6
Phosphate functions
- General cell function
o Metabolic pathways
o Intracellular buffer
o Control of enzyme function
- Excitation-stimulus coupling and nervous system conduction
- Chemotaxis & phagocytosis of leucocytes
- Platelets: clot retraction
- Erythrocyte oxygen affinity
- Muscle function
- Neurological function
- Avoidance of thrombocytopenia
Phosphate is the major intra-cellular anion and is shifted rapidly between the intracellular
and extracellular compartments. The driving force for these shifts is the metabolic rate,
ingestion of carbohydrates and lipids and finally the acid-base balance. The majority of
phosphate (85%) is stored in the organic matrix of bone as hydroxyl-apatite crystals,
14% is in cells and 1% in blood. The intracellular concentration is 100 mmol.L-1. A small
portion is in the inorganic form and the majority is bound to intermediary carbohydrates,
proteins and lipids. In the blood, phosphate is present in organic and inorganic forms at a
concentration together of 3.5-4 mmol.L-1. Typically only the inorganic form is measured
by standard laboratory methods and the normal concentration of phosphate is 0.9-1.3
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mmol.L-1. Phosphate is present in sufficient amounts in a mixed diet; phosphate balance
is determined by the kidneys.
Hypophosphataemia is categorized into
- Mild 0.6-0.85 mmol/L
- Moderate 0.3-0.6 mmol/L
- Severe< 0.3 mmol/L
In moderate and severe hypophosphataemia immediate intravenous replacement therapy
is indicated. Current guidelines recommend the administration of 9 or 18 mmol
respectively within a 12 hour period (23). The next dose should be given after rechecking
serum phosphate. In the setting of intensive care units supplementation of 45 mmol
over a 3 hour period normalized phosphate in 98% of patients with moderate or severe
hypophosphataemia (58). The amount proposed should always be seen in addition to
continuous phosphate supplementation with typically 0.5 mmol.kg BW-1.d-1. Either
inorganic phosphate or organic phosphate has been used. K PO4- has often been used
when concomitant hypokalaemia has existed. Organic preparations such as glucose-1-
phosphate or fructose-1-6-diphosphate have the advantage of minimizing the risk of
precipitation when calcium is also present in the solution. In all cases where phosphate
is added to parenteral nutrition mixtures the organic preparation should be preferred.
Unfortunately organic preparations have not received approval in all countries.
Nutrition therapy should not be delayed until hypophosphataemia has been corrected.
Both interventions - nutrition and correction of electrolytes - should be done in parallel
(54).
8.2.5 Hypomagnesaemia
Hypomagnesaemia is also frequent with refeeding and several acute severe disease
states. Magnesium is a predominantly intracellular divalent cation. Magnesium levels <
0.5 mmol.L-1 are considered to be severe and are often accompanied by clinical
symptoms. Magnesium is an important cofactor in many enzyme systems such as those
involved in ATP production, maintains the structural integrity of DNA, RNA and
ribosomes, and affects the membrane potential.
The most prominent clinical symptoms are cardiac arrhythmias including torsade de
pointes, abdominal discomfort and anorexia, and neurological manifestations such as
tremor, paresthaesiae, tetany, seizures, weakness, etc. (59, 60).
Supplementation is best achieved with a continuous infusion until normalization. The
maintenance dose is 4-8 mmol.d-1. Oral magnesium supplementation can be associated
with diarrhoea.
8.2.6 Hypokalaemia
Hypokalaemia is frequently present in acute disease states especially those associated
with increased catecholamine release, but also during aggressive refeeding. Potassium is
the most abundant monovalent intracellular cation. Its main function is to maintain the
electrochemical membrane potential. A potassium < 3 mmol.L-1 is considered to be
severely low. The most severe features are cardiac arrhythmias, but many other systems
are also affected. Gastrointestinal symptoms include ileus and constipation, the kidney
has impaired concentration capacity, compensation of metabolic alkalosis is delayed,
Copyright © by ESPEN LLL Programme 2014
neuro-muscular function is impaired but also endocrine function is affected with impaired
glucose tolerance.
8.3 Treatment and Prevention
Table 7
Treatment and prevention of the refeeding syndrome: a stepwise approach
- Identify patients at risk
- Check electrolytes
- Start refeeding with 50% of recommended energy intake
o 8-10 kcal.kg-1.d-1 (actual body weight)
o Increase gradually to reach recommendations within 3-5 days
- Rehydrate carefully and monitor cardio-circulatory function
- Replace electrolytes in sufficient amounts
o Potassium 2-4 mmol.kg-1
o Phosphate 0.3-0.6 mmol.kg-1
o Magnesium 0.05-0.1 mmol.kg-1
o Calcium 0.05-0.1 mmol.kg-1
- Monitor electrolytes, metabolic tolerance and clinical situation closely during the
first 5-10 days of refeeding
9. References
1. Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in
critically ill adults. N Engl J Med 2011;365(6):506-17.
2. Doig GS, Simpson F, Early PNTIG. Early parenteral nutrition in critically ill patients
with short-term relative contraindications to early enteral nutrition: a full economic
analysis of a multicenter randomized controlled trial based on US costs.
ClinicoEconomics and outcomes research : CEOR 2013;5:369-79.
3. Heidegger CP, Berger MM, Graf S, et al. Optimisation of energy provision with
supplemental parenteral nutrition in critically ill patients: a randomised controlled
clinical trial. Lancet 2013;381(9864):385-93.
4. National Heart L, Blood Institute Acute Respiratory Distress Syndrome Clinical Trials
N, Rice TW, et al. Initial trophic vs full enteral feeding in patients with acute lung
injury: the EDEN randomized trial. JAMA 2012;307(8):795-803.
5. Singer P, Anbar R, Cohen J, et al. The tight calorie control study (TICACOS): a
prospective, randomized, controlled pilot study of nutritional support in critically ill
patients. Intensive care medicine 2011;37(4):601-9.
6. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J
Med 2013;368(7):651-62.
7. Muscaritoli M, Anker SD, Argiles J, et al. Consensus definition of sarcopenia,
cachexia and pre-cachexia: joint document elaborated by Special Interest Groups
(SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics".
Clinical nutrition (Edinburgh, Scotland) 2010;29(2):154-9.
8. Casaer MP, Langouche L, Coudyzer W, et al. Impact of Early Parenteral Nutrition on
Muscle and Adipose Tissue Compartments During Critical Illness. Critical care
medicine 2013.
9. Kreymann G, DeLegge MH, Luft G, Hise ME, Zaloga GP. The ratio of energy
expenditure to nitrogen loss in diverse patient groups--a systematic review. Clinical
nutrition (Edinburgh, Scotland) 2012;31(2):168-75.
Copyright © by ESPEN LLL Programme 2014
10. Weijs PJ, Stapel SN, de Groot SD, et al. Optimal protein and energy nutrition
decreases mortality in mechanically ventilated, critically ill patients: a prospective
observational cohort study. Jpen 2012;36(1):60-8.
11. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and
antioxidants in critically ill patients. N Engl J Med 2013;368(16):1489-97.
12. Wang Z, Heshka S, Gallagher D, Boozer CN, Kotler DP, Heymsfield SB. Resting
energy expenditure-fat-free mass relationship: new insights provided by body
composition modeling. American journal of physiology. Endocrinology and
metabolism 2000;279(3):E539-45.
13. Kreymann G, Grosser S, Buggisch P, Gottschall C, Matthaei S, Greten H. Oxygen
consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic
shock. Critical care medicine 1993;21(7):1012-9.
14. Gunst J, Derese I, Aertgeerts A, et al. Insufficient autophagy contributes to
mitochondrial dysfunction, organ failure, and adverse outcome in an animal model
of critical illness. Critical care medicine 2013;41(1):182-94.
15. Weiss CO, Cappola AR, Varadhan R, Fried LP. Resting metabolic rate in old-old
women with and without frailty: variability and estimation of energy requirements.
Journal of the American Geriatrics Society 2012;60(9):1695-700.
16. Faisy C, Guerot E, Diehl JL, Labrousse J, Fagon JY. Assessment of resting energy
expenditure in mechanically ventilated patients. The American journal of clinical
nutrition 2003;78(2):241-9.
17. Poehlman ET. Energy expenditure and requirements in aging humans. The Journal
of nutrition 1992;122(11):2057-65.
18. Nardo P, Dupertuis YM, Jetzer J, Kossovsky MP, Darmon P, Pichard C. Clinical
relevance of parenteral nutrition prescription and administration in 200 hospitalized
patients: a quality control study. Clinical nutrition (Edinburgh, Scotland)
2008;27(6):858-64.
19. Acheson KJ, Schutz Y, Bessard T, Anantharaman K, Flatt JP, Jequier E. Glycogen
storage capacity and de novo lipogenesis during massive carbohydrate overfeeding
in man. The American journal of clinical nutrition 1988;48(2):240-7.
20. Pingleton SK. Enteral nutrition in patients with respiratory disease. Eur Respir J
1996;9(2):364-70.
21. Cumming AD, Farquhar JR, Bouchier IA. Refeeding hypophosphataemia in anorexia
nervosa and alcoholism. British medical journal (Clinical research ed
1987;295(6596):490-1.
22. Kohn MR, Golden NH, Shenker IR. Cardiac arrest and delirium: presentations of the
refeeding syndrome in severely malnourished adolescents with anorexia nervosa. J
Adolesc Health 1998;22(3):239-43.
23. Mehanna HM, Moledina J, Travis J. Refeeding syndrome: what it is, and how to
prevent and treat it. BMJ (Clinical research ed 2008;336(7659):1495-8.
24. Svanfeldt M, Thorell A, Brismar K, Nygren J, Ljungqvist O. Effects of 3 days of
"postoperative" low caloric feeding with or without bed rest on insulin sensitivity in
healthy subjects. Clinical nutrition (Edinburgh, Scotland) 2003;22(1):31-8.
25. Watters JM, Kirkpatrick SM, Hopbach D, Norris SB. Aging exaggerates the blood
glucose response to total parenteral nutrition. Canadian journal of surgery
1996;39(6):481-5.
26. Henneberg S, Sjolin J, St Jernstrom H. Over-feeding as a cause of fever in intensive
care patients. Clinical nutrition (Edinburgh, Scotland) 1991;10(5):266-71.
27. Dvir D, Cohen J, Singer P. Computerized energy balance and complications in
critically ill patients: an observational study. Clinical nutrition (Edinburgh, Scotland)
2006;25(1):37-44.
28. Villet S, Chiolero RL, Bollmann MD, et al. Negative impact of hypocaloric feeding
and energy balance on clinical outcome in ICU patients. Clinical nutrition
(Edinburgh, Scotland) 2005;24(4):502-9.
29. Pirat A, Tucker AM, Taylor KA, et al. Comparison of measured versus predicted
energy requirements in critically ill cancer patients. Respiratory care
2009;54(4):487-94.
Copyright © by ESPEN LLL Programme 2014
30. Walker RN, Heuberger RA. Predictive equations for energy needs for the critically ill.
Respiratory care 2009;54(4):509-21.
31. Weekes CE. Controversies in the determination of energy requirements.
Proceedings of the Nutrition Society 2007;66:367-77.
32. Talpers SS, Romberger DJ, Bunce SB, Pingleton SK. Nutritionally associated
increased carbon dioxide production. Excess total calories vs high proportion of
carbohydrate calories. Chest 1992;102(2):551-5.
33. Pingleton SK, Harmon GS. Nutritional management in acute respiratory failure.
Jama 1987;257(22):3094-9.
34. Choban PS, Burge JC, Scales D, Flancbaum L. Hypoenergetic nutrition support in
hospitalized obese patients: a simplified method for clinical application. The
American journal of clinical nutrition 1997;66(3):546-50.
35. Sedlacek M, Schoolwerth AC, Remillard BD. Electrolyte disturbances in the intensive
care unit. Seminars in dialysis 2006;19(6):496-501.
36. Silvis SE, Paragas PD, Jr. Paresthesias, weakness, seizures, and hypophosphatemia
in patients receiving hyperalimentation. Gastroenterology 1972;62(4):513-20.
37. Whang R, Ryan MP, Aikawa JK. Magnesium deficiency: a cause of reversible renal
failure. Lancet 1973;1(7795):135-6.
38. Bloom WL. Carbohydrates and water balance. The American journal of clinical
nutrition 1967;20(2):157-62.
39. Bloom WL, Mitchell W, Jr. Salt excretion of fasting patients. Archives of internal
medicine 1960;106:321-6.
40. Amanzadeh J, Reilly RF, Jr. Hypophosphatemia: an evidence-based approach to its
clinical consequences and management. Nature clinical practice 2006;2(3):136-48.
41. Bugg NC, Jones JA. Hypophosphataemia. Pathophysiology, effects and management
on the intensive care unit. Anaesthesia 1998;53(9):895-902.
42. Camp MA, Allon M. Severe hypophosphatemia in hospitalized patients. Mineral and
electrolyte metabolism 1990;16(6):365-8.
43. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased
risk of death after myocardial infarction in patients with and without diabetes: a
systematic overview. Lancet 2000;355(9206):773-8.
44. Foo K, Cooper J, Deaner A, et al. A single serum glucose measurement predicts
adverse outcomes across the whole range of acute coronary syndromes. Heart
2003;89(5):512-6.
45. Gandhi GY, Nuttall GA, Abel MD, et al. Intraoperative hyperglycemia and
perioperative outcomes in cardiac surgery patients. Mayo Clin Proc
2005;80(7):862-6.
46. Marfella R, Siniscalchi M, Esposito K, et al. Effects of stress hyperglycemia on acute
myocardial infarction: role of inflammatory immune process in functional cardiac
outcome. Diabetes Care 2003;26(11):3129-35.
47. Norhammar A, Tenerz A, Nilsson G, et al. Glucose metabolism in patients with
acute myocardial infarction and no previous diagnosis of diabetes mellitus: a
prospective study. Lancet 2002;359(9324):2140-4.
48. Ouattara A, Lecomte P, Le Manach Y, et al. Poor Intraoperative Blood Glucose
Control Is Associated with a Worsened Hospital Outcome after Cardiac Surgery in
Diabetic Patients. Anesthesiology 2005;103(4):687-94.
49. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE.
Hyperglycemia: an independent marker of in-hospital mortality in patients with
undiagnosed diabetes. J Clin Endocrinol Metab 2002;87(3):978-82.
50. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the
critically ill patients. N Engl J Med 2001;345(19):1359-67.
51. Van den Berghe G, Schetz M, Vlasselaers D, et al. Intensive insulin therapy in
critically ill patients: NICE-SUGAR or Leuven blood glucose target? J Clin Endocrinol
Metab 2009.
52. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch
resuscitation in severe sepsis. N Engl J Med 2008;358(2):125-39.
53. Crook MA, Hally V, Panteli JV. The importance of the refeeding syndrome. Nutrition
(Burbank, Los Angeles County, Calif 2001;17(7-8):632-7.
Copyright © by ESPEN LLL Programme 2014
54. NICE. National Institute for Health and Clinical Excellence: Nutrition support in
adults. Clinical guideline CG32, 2006.
55. Veverbrants E, Arky RA. Effects of fasting and refeeding. I. Studies on sodium,
potassium and water excretion on a constant electrolyte and fluid intake. J Clin
Endocrinol Metab 1969;29(1):55-62.
56. Druml W, Fischer M, Sertl S, Schneeweiss B, Lenz K, Widhalm K. Fat elimination in
acute renal failure: long-chain vs medium-chain triglycerides. The American journal
of clinical nutrition 1992;55(2):468-72.
57. Madl C, Kranz A, Liebisch B, Traindl O, Lenz K, Druml W. Lactic acidosis in thiamine
deficiency. Clinical nutrition (Edinburgh, Scotland) 1993;12(2):108-11.
58. Charron T, Bernard F, Skrobik Y, Simoneau N, Gagnon N, Leblanc M. Intravenous
phosphate in the intensive care unit: more aggressive repletion regimens for
moderate and severe hypophosphatemia. Intensive care medicine
2003;29(8):1273-8.
59. Weisinger JR, Bellorin-Font E. Magnesium and phosphorus. Lancet
1998;352(9125):391-6.
60. Whang R. Magnesium deficiency: pathogenesis, prevalence, and clinical
implications. The American journal of medicine 1987;82(3A):24-9.
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