refeeding syndrome

Introduction

Physiology of Starvation and Refeeding Syndrome

Raghuveer Choudhary1 Vinode Kumar Chawala2, Jayant Kumar3, Raj Kumar Rathore4

AbstractRefeeding syndrome represents a series of metabolic complications that sometimes results by provisionof nutrients, primarily carbohydrate, to a patient in a nutritionally compromised state. Refeedingsyndrome is associated with hypophosphatemia, hypokalemia and hypomagnesaemia, fluid retentionand vitamin deficiencies including thiamin are also of concern. If severe, refeeding syndrome mayresult in respiratory, cardiac, and neuromuscular dysfunction, especially in the stressed, elderly, orseverely malnourished patient. This article discuss the physiology of starvation and thepathophysiology behind refeeding syndrome, identify the patients at greatest risk, and provide practicaltips for prevention. As increased awareness and understanding of refeeding syndrome may help,prevent further such incidents and clinicians learn to recognize patients at risk and avoid over-aggressive nutrition support regimes.

Key words: Starvation, Refeeding SyndromeJ Bangladesh Soc Physiol. 2010 December; 5(2): 101-110

For author affiliations, see end of text.

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nowledge of the dangers of refeedingfamine victims dates back manycenturies. Historically, problems such

patients at risk and avoid over aggressivenutrition support regimes.

Incidence of refeeding syndromeThe incidence of Refeeding Syndrome isunknown. In studies of patients on totalparenteral nutrition (TPN), the incidence ofhypophosphatemia ranged from 30%-38% whenphosphorous was provided in the solution, to100% when TPN without phosphorous wasadministered5. In cancer patients, it has beenreported as high as 25%6. It is more common inthe elderly, although it may be masked by co-morbid conditions7.

There are no reports of randomized clinical trials,controlled trials looking at the incidence of Refeeding Syndrome itself. Mild symptoms often gounnoticed or may be attributed to other cause.Conversely, low serum levels of phosphorus,potassium and magnesium thought to be due toRefeeding Syndrome may be due to other factorsincluding decreased dietary intake, insufficientgastrointestinal absorption, increased renal or non-renal losses and transcellular shifts. (Table-I).

as cardiac dysfunction, edema and neurologicalchanges were observed when malnourishedrefugees were suddenly provided with adequatefood. Such problems have also been observedwhen relief efforts provide food to victims offamine. After world war-II a number ofinvestigators reported the unexpected death ofstarved prisoners of war (POW) shortly afterreintroduction of high-caloric, high-carbohydratefood. Autopsies on those individuals did notreveal any obvious cause. 1-3

These potentially life threatening refeedingcomplications became apparent once again in the1970’s and 1980’s with the widespread use oftotal parenteral nutrition (TPN) in hospitalizedpatients who were often malnourished4.

An increased awareness and understanding ofRefeeding Syndrome may help to prevent furthersuch incidents as clinicians learn to recognize

K

Review

101 J Bangladesh Soc Physiol. 2010 December; 5(2): 101-110

Table I: Potential Causes of Hypokalemia, Hypophosphatemia, and Hypomagnesemia22

( A) Hypophosphatemia

General Metabolic MedicationsMalabsorption Hypomagnesemia DiureticsGlucose administration Hypokalemia Beta-agonistsvitamin D deficiency Hypocalcemia EpinephrineVolume repletion systemic alkalosis InsulinRhabdomyolysis Hyperparathyroidism AntacidsHemodialysis Hyperaldosteronism CarafateInitiation of CVVHD GlucagonDiabetic ketoacidosis BicarbonateAlcoholism CorticosteroidsSepsis CisplatinGram-negative bacteremia TheophyllineRefeeding Syndrome

(B) Hypokalemia

General Metabolic MedicationsVomiting / Diarrhea Hypomagnesemia AlbuterolDiureticsInsulin delivery Metabolic Alkalosis InsulinRefeeding syndrome Carbenicillin

TerbutalineTicarcillin

(C) Hypomagnesemia

General Metabolic MedicationsDiarrhea Diabetes Mellitus Amphotericin BMalabsorption CisplatinAlcoholism CyclosporinRefeeding Syndrome Ticarcillin

CarbenicillinDigoxinAlcoholGentamycinInsulinDiuretics

What is refeeding syndrome?

Re feeding Syndrome represents a host of metabolic complications that sometimes results when

Starvation and Refeeding Review

J Bangladesh Soc Physiol. 2010 December; 5(2): 101-110 102

feeding a malnourished patient. By definitions,Re feeding Syndrome describes a potentially fatalmedical condition that may affect malnourished/ill patients in response to an inappropriately highprotein-caloric intake. This commonly occursfollowing the institution of nutritional support,either parenteral or enteral or unrestricted oralintake.

Numerous Physiological changes occur duringrefeeding that may result in increased patientmorbidity and mortality. Intracellular mineraldepletion (eg. hypophosphatemia, hypo-magnesemia, hypokalemia), body fluiddisturbances (refeeding edema),vitamindeficiencies (eg. thiamine), life threatening cardiacarrhythmias, respiratory arrest and congestiveheart failure are among the most often reportedevents associated with refeeding. 4,8 Death mayhave been avoided by recognition of the patientsrisk for Refeeding Syndrome, appropriatenutritional support management, effectivemonitoring, and therapy for complications.

Physiology of starvationUnder normal conditions, glucose is the body’spreferred fuel. Glucose is primarily derived fromcarbohydrates in the diet. The body depends ona consistent intake of carbohydrate for continuedglucose supply. Glucose is available in the bloodstream for fuel for 2-3 hours after ingestion andcan be stored as glycogen, & 300gms of glucoseare stored as glycogen in the liver and muscles.In absence of oral intake, glycogen can provideenergy up to 24 hours. A minimum of 100-150 gmof glucose per day is needed to provide adequateglucose to the brain and to prevent proteinbreakdown for glucose production.10

When adequate glucose is available, protein isused for non-fuel functions, such as buildingmuscle and the synthesis of enzymes, hormones,anti-bodies and transport proteins.Carbohydrate, protein and fat intake in excess ofneeds is stored as fat. Fat is the primary storagefuel in the human body.

During the short period of fasting (upto 24hours.) obligatory glucose is obtained byglycogenolysis. After depletion of glycogenstores, amino-acids are mobilized from muscleand fatty acids are mobilized from adiposetissues. Both are degraded further to produceglucose and glycerol respectively fromgluconeogenesis. Glucose is also produced viagluconeogenesis from lactate and pyruvate. Theinitial period of starvation is marked by increasedprotein catabolism. As the nutrient deprivationis prolonged, the rate of proteolysis decreasesas the body further adapts to the decreasednutrient intake, basal metabolic rate slows by asmuch as 20% - 25%11. Peripheral tissues and mostorgans can adapt to using fatty acids as a fuelsource. The brain, as a primary end user ofglucose, switches over to Ketones as a partialfuel source and decreases it’s reliance on glucoseas a substrate. These adaptive mechanisms, inthe non-stressed state, decrease the need forglucose, thereby sparing muscle mass.

Prolonged starvation leads to loss of lean bodymass, adipose tissue and fluid. Eventually,starvation also affects the visceral protein massand the function of vital organs. Respiratoryfunction may decline due to respiratory musclewasting which may limit Co2 excretion12. Cardiacmass and output are also decreased as well. Inthe absence of additional stressors, such asillness or injury, serum protein levels aremaintained at relatively normal levels during pureprotein, calorie malnutrition. A severelymalnourished patient may have a normal albuminlevel despite prolonged starvation. This is duein part to decreased break down of serum proteinsand to extravasations of fluid into the interstitialspace that may make serum levels appear falselyelevated. In fact, it is not uncommon for a severelymalnourished patient to initially loose weightafter nutrition support is started due to diuresisof this additional extracellular fluid. (Table II)

Review Starvation and Refeeding


Decreased nutrient intake and poor nutritionalstatus may lead to depleted vitamin and mineralstatus, including depletion of phosphorus,magnesium and potassium. Unlike glucosemetabolism, fatty acid oxidation does not require

phosphorous intermediates; hence phosphorusrequirements is decreased during starvation.

Metabolic response to refeedingThere are many consequences that occur whennutrition namely carbohydrate, is provided to astarved patient. (Table III).

Table II: Pathophysiology of Starvation

Starvation↓

↓ Insulin and ↑ glucagon↑ Gluconeogenesis → Protein and Fat catabolism → negative nitrogen balance →

free fatty acids and ketones.

↓Decreased lean body mass

↓↓Total body water (TBW) and minimal depletion within cells

↓Adjustment to new metabolic state

During starvation there is a change in the hormonal milieu in addition to a reduction in the basal metabolicrate, conservation of proteins, prolongation of organ function, preferential catabolism of skeletal musclesand loss of visceral cell mass9. The concentration of insulin is deceased whilst glucagon increasesresulting in the conversion of glycogen to glucose in addition to gluconeogenesis from lipid and proteinstores. Free fatty acids and ketones bodies replace glucose as the primary source of energy 8

Table III: Pathophysiology of Refeeding

Refeeding↓

Conversion of glucose as major energy source instead of protein and ketones↓

↑ requirement for phosphorus for kreb’s cycle↓

↑ Insulin release*↓

↑ Cellular glucose, calcium, phosphorus, magnesium and total body water uptake.↓

↑ Protein synthesis and utilization of thiamine.*Intracellular shifts of calcium,phosphorus,magnesium and potassium.* Insulin release stimulates the sodiumpotassium ATPase pump (which requires magnesium as a co-factor). This drives potassium into the cells andmoves sodium out. Carbohydrate load and insulin release stimulate phosphate shifts into the cells andphosphate depletion is associated with increased urinary magnesium excretion. This leads to low extracellularphosphate, magnesium and potassium may precipitate the symptoms of Refeeding Syndrome. Thiamine isan essential coenzyme in carbohydrate metabolism. The symptoms of thiamine deficiency e.g. Wernicke’sencephalopathy, can be precipitated by feeding with carbohydrate in a vitamin B depleted patient.



Table IV: Complications associated with refeeding syndrome22

Hypophosphatemia Hypokalemia HypomagnesemiaRespiratory Cardiac Dysfunction Cardiac Abnormalities- Failure - Arrhythmia - Arrhythmias- Ventilator dependency - Cardiac arrest - TachycardiaCardiac - EKG changes Neurologic- Arrhythmia - Digoxin toxicity - Altered mental status- Congestive heart failure Neurologic - Weakness- Cardiomyopathy - Weakness - Tetany- Decreased cardiac contractility - Paralysis - Paresthesia- Seizures- Hypotension - Rhabdomyolysis -AtaxiaSkeletal - Lethargy/confusion - Vertigo- Rhabdomyolysis Metabolic - Tremors- Weakness - Metabolic alkalosis Gastrointestinal ProblemsNeurologic Gastrointestinal - Abdominal pain- Altered mental status - Paralytic ileus - Diarrhea- Paralysis - Constipation - Constipation- Seizures - AnorexiaEndocrine Electrolyte- Insulin resistance - Hypokalemia- Osteomalacia - HypocalcemiaHematologic Hematologic- Leukocyte dysfunction - Anemia- Altered RBC morphology- Thrombocytopenia- Decreased platelet function- Hemolytic anemia- Decreased oxygen release fromoxyhemoglobin

The driving factor for refeeding complications isinsulin secretion. Insulin promotes glucoseuptake, along with phosphorus and otherelectrolytes into the cells. This intracellular shift,along with already depleted electrolyte pool, canlead to dangerously low levels of serumphosphorus, potassium and magnesium (but notnecessarily all three). Serious respiratory, cardiacand neurological complications can occur. Inmost severe cases, they can be fatal (Table IV).

Excess glucoseGlucose is an important substrate in specializednutrition support. As previously discussed

overfeeding carbohydrates (enteral or parenteral)may result in adverse consequences.Hyperglycemia is a common complication ofspecialized nutrition support. Critically ill patientsare often hypermetabolic and insulin resistantbecause of the metabolic response to stress andinfection. Gluconeogenesis continues in thestressed patient because of hormonal mediatorsinspite of high circulating levels of insulin.Hyperglycemia develops in non diabetic patientsif given large amounts of glucose. This isespecially true in the hypercatabolic, stressedstate13. Uncontrolled hyperglycemia can lead tohyper osmolar non ketotic coma, which has a

Article Starvation and Refeeding


mortality rate as high as 40%14. Hyperglycemiamay also place the compromised, critically illpatient at higher risk of the development ofsepsis15.Serum glucose levels should be kept inthe range of 100-200 mg/dL15.

PhosphorusHypophosphatemia is one of the most seriousmetabolic complications observed in responseto specialized nutrition support16,17. Plummetingserum phosphorus levels may be seen within 24to 72 hours after beginning of therapy. However,it is possible to see a delay in the development ofhypophosphatemia of 5 to 10 days in patientswho have normal body stores of phosphorus. Inresponse to refeeding, there is a movement ofinorganic phosphorus from the extracellular tothe intracellular space because of utilization ofphosphorus for the synthesis of phosphorylatedcompound. Insulin also promotes the uptake ofboth phosphorus and glucose in skeletal muscleand liver18. Severe hypophosphatemia (below 1.0mg/dL) is associated with serious life threateningcomplications involving all major organsystems.1,18 It can led to respiratory failure,cardiac abnormalities, central nervous systemdysfunction including seizures, red blood celldysfunction and leukocyte dysfunction4.6.19

One of the potential consequences ofhypophospatemia may be decreased oxygendelivery to the cell (ischemia) as hypohos-phatemia leads to decreased levels of 2,3diphosphoglyceride (2, 3 DPG) consequentlyimpairing oxygen release from hemoglobin20,21.

PotassiumRefeeding causes a shift of potassium into celland may result in hypokalemia if potassium isnot adequately supplied in the diet. Potassiummoves into cells along with glucose and otherenergy substrates.

Symptoms of hypokalamia include muscleweakness, paralysis, paralytic ileus, cardiacarrhythmias, cardiac arrest ,coronary ischemia,rhabdomyolysis, renal dysfunction, decreasedurinary concentrating ability, polyuria, dysuria,constipation, respiratory depression,exacerbation of hepatic encephalopathy. 4,6,19

MagnesiumMagnesium shifts intracellularly with refeedingand new tissue synthesis. Hypomagnesemia is afrequent complication of both enteral andparenteral nutrition support.

Adequate magnesium is essential for normalizingphosphorus and potassium levels and is alsorequired for over 300 metabolic pathways, includingthose involving ATP production. Thereforehypophosphatemia and hypokalemia associatedwith refeeding may be exacerbated by an underlyinghypomagenesemia.22 Clinical deficiency symptomsare associated with serum level below 1.0mEq/L.Hypomagnesemia may lead to arrhythmias,tachycardia, respiratory depression, abdominalpain, diarrhea, ataxia, confusion, muscle tremors,weakness and tetany.4,6,19

ThiamineWhile not a hall mark of Re feeding Syndrome,thiamin deficiency can still be of significantimportance to the malnourished patient at risk forrefeed. Thiamine (B1) is a water soluble vitaminwith a biological half life of 9½ to 18½ days23. Inpatients with suboptimal intake, it estimated thatdeficiency can occur in less than 28 days.12

Thiamin is the precursor for the active metabolitethiamin pyrophosphate (TPP), essential foroptimal glucose utilization and metabolism. TPPis a co-factor for three critical enzymes, inparticular, pyruvate dehydrogenase. In thiamindeficiency, the conversion of pyruvate to acetylcoenzyme A (CoA) is blocked and theaccumulating pyruvate is subsequentlyconverted to lactate. This results in anoverproduction of lactate and lactic acidosisfollows. Inadequate levels of thiamin can alsoprecipitate Wernicke’s Encephalopathy (WE) inmalnourished patients. Glucose load, whetherdelivered enterally or parenterally, will increasethe demand for thiamin. Thiamine depletion maybe exacerbated by dialysis, diuretics, diarrhea,alcohol, folate deficiency or malabsorption.24-,26

The 2004 guidelines of the British Association ofPharmacology recommend a minimum of 500mg.IV TID for a minimum of two days, followed by



500mg IV daily for five days for patients withsuspected or diagnosed WE.27

Fluid retentionInsulin secretion associated with suddencarbohydrate infusion also lead to sodium fluidretention. This is thought to be due to insulin’seffect on renal tubules leading to anti natriuresis.This antidiuretic effect causes an increase inextracelluler fluid volume. Therefore, excessivesodium containing fluid infusion can lead toedema or, in severe cases, the combination ofincreased extracellular fluid volume and thecardiomyopathy often present in severelymalnourished individuals & can lead topulmonary edema, respiratory compromise andcardiac failure.

Prevention of the refeeding syndromeThe key to prevent the Refeeding Syndrome isto be aware of it and it’s consequences.Prevention begins with recognition of thosepatients at greatest risk of the development ofpotentially lethal complications from rapidoverzealous feeding.

Initial assessment of refeeding syndrome:Your patient is at risk of refeeding syndrome ifthere is: History of chronic malnutrition; acuteweight loss of greater than 10% of pre-morbidbody weight; little or no nutritional intake of anyform for greater than 7-10 days.

The risks of refeeding syndrome are higherin patients withSignificant co-morbidity, e.g. infection, surgery,pressure sores, cancer; evidence of physiologicalstress, e.g. postoperatively or patients whorequire critical care input; prolonged fasting;anorexia nervosa; chronic alcoholism; electrolyteabnormalities (Potassium/Magnesium/Phosphate);the elderly (due to the increased risk ofmalnutrition in this patient group).

History and clinical examinationTo record weight, rate of weight loss, dietaryintake, reasons for malnutrition – physiological

impediment to oral or parenteral intake,swallowing difficulties, impaired intestinalfunction, heart rate, pulse rate, blood pressure,

respiratory rate and level of consciousness- 6hourly for first 72 hours, daily temperature,ECG if patient has:

Irregular pulse, abnormal heart rate, serumpotassium or phosphate level below normal range)

If evidence of cardiac abnormalities is present onassessment or during re feeding, patient will requirecardiac monitoring. If necessary, transfer to ICU

Initial management of refeeding syndromeFluid resuscitation and monitoring fluid balance

Assess and carefully restore circulatory volume,monitor pulse rate, fluid intake and output.Malnourished patients have a reduced toleranceof intravenous fluid in moderate to high intake(i.e. more than 2 liters per 24 hrs.) can lead toheart failure.

Administration of intravenous fluids may benecessary in the initial 72 hours until sufficientoral intake is achieved.

If evidence of dehydration, for careful rehydrationi.e. 1-2 liters in the first 24 hrs depending onresponse. Greater volumes only if severelydehydrated.

Total fluid intake (including i.v., enteral and oral)should aim for a maximum of 30ml/kg per day (i.e.commonly 1.5 liter or less).

At least 6 hourly monitoring of blood pressure,pulse and respiratory rate is necessary to detectevidence of heart failure or inadequate intravascular volume.

Correction of electrolyte abnormalitiesEnsure recent (last 48 hours) electrolyte levelsare available. These should include: urea andelectrolytes (Na +, K+), Phosphate,Magnesium, Calcium (add to standard bloodprofile) liver function tests, full blood counts.If electrolytes are deranged consider to treatpossible cause.



Administer: Potassium 0.3mmol/kg/hr for 4-6 hrs.Then 2-4mmol/kg/day; monitor ECG forarrhythmias during replacement therapy

If very low plasma electrolyte values aredemonstrated e.g. phosphate < 0.32mmol/l,Potassium is <2.5mmol/l and Magnesium is<0.5mmol/l, then the institution of feeding ornutritional support may result in a further dropof these electrolytes to possibly critical levels.Electrolyte correction with oral/I.V.supplementation is required to achieve levelsabove these thresholds before institution offeeding.

Correction of Hypoglycemia:Monitor blood glucose once to twice daily unlessmore frequent tests are indicated (i.e. for thosepatients with known diabetes or IGT).

If hypoglycemic replace intravenous fluids with5% glucose.

Management of Hypothermia:Monitor body temperature, and if necessaryrecord temperature at least daily.

Hypothermia is commonly associated withmalnutrition. It’s correction should besimultaneously with fluid rehydration and caninclude provision of hot drinks and blanket.

Correction of micronutrient deficiencies

Administer thiamine 1-2mg/kg body weight IM.100 mg IV should be administered in 50-100 ml5% dextrose over 30 min., prior to refeeding asstat dose. Repeat the thiamine daily for 48 hoursthen weekly.

Administer vitamin B complex IV until oral routeis available.

Commencing feeding in patients at risk ofrefeeding syndrome

Provision of calories should be done graduallyduring first 5- 7 days; 20Kcal-25Kcal/Kg/Day (5-7 days) then after 7 day 25-35 Kcal./kg./day.4 or

Suggested guidelines for phosphorus replacement in adult I.V. 28, 29, 30

Serum Po4 Level (mg/dL) Recent Uncomplicated Prolonged or Complicatedmmol/kg. of Po4 mmol/kg of Po4

1.6 – 2.1 0.8 – 0.16 0.16 – 0.241.1 – 1.5 0.16 – 0.24 0.24 – 0.30< 1.1 0.24 – 0.30 0.50

Oral Repletion: Serum Phosphate > 1mg./dL, 1-2 g (32-64mmol) of Phosphorus/ day divided in 3 – 4 doses.

Suggestions for Magnesium Replacement 31

Condition Magnesium – doseDaily requirement 0.4m Eq/Kg./dayMild to Moderate hypomagnesemia Initial 1m Eq/Kg over 24 Hrs.(Serum level 1.2 – 1.7 mg/dl) Follow : 0.5 mEq/Kg over 24 Hrs. x 5 daysSevere Hypomagnesemia (Serum level < 1.2mg/dl) Initial : 2g over 2 minutes

Follow : 5g over 6 hours.Follow : 5g over 12 hrs. x 5 days

Suggestions for Potassium Replacement (If serum potassium < 3.0 mmol/L)



no more than 20% above BEE.11 or 1000Kcal/

day.4 or 50% of total needs based on HBEx1.3-1.5.32

For every 200-250 Kcal it is necessary to provide6.25g Protein, 1.8mmol/Ca++, 2.9mmolPhosphorus, 1.0mmol Magnesium, 10mmolPotassium, 7mmol Sodium and Chloride.

At the sight of a severely malnourished patient,the clinician should avoid the temptation toinitiate excessive amount of nutrition support,rather, begin nutrition repletion slowly. While itis appropriate to start nutrition intervention assoon as feasible, it is dangerous to provideexcessive calories or fluids to patients whosebody has adapted to starvation.

In initial period 20Kcal/Kg. should be given toseverely malnourished patients. A mixed fuelsource of protein, fat and carbohydrate should beprovided. Glucose infusion should not exceed 150-200 grams per day or 2mg/kg/min initially. 11 Proteincan generally be initiated at full goal. (Up to 1.5g/Kg/day). 11 For estimating nutritional needs, thepatients actual weight (or adjusted if obese) shouldbe used rather than an ideal weight, which may beover (or under) estimate needs.

ConclusionIn many cases, nutrition support is a life savingmodality. However, if nutrition is not deliveredproperly, Re feeding Syndrome represents asignificant risk of morbidity and mortality inmalnourished patients. Meticulous attention tothe replacement of electrolyte imbalances andslow re-introduction of calories and protein willdecrease the risk of cardiac and respiratory failure.Prospective, randomized controlled trials areneeded to better identify patients prone tocomplications from Refeeding Syndrome. This,in turn will help to determine the best approachto Refeeding the malnourished patients.

Authors Affiliation1. * Dr. Raghuveer Choudhary, Assistant Professor,

Dept. of Physiology, Dr S.N. Medical College,Jodhpur (342001) Rajasthan, India. 4F/54,New PowerHouse Road ,Jodhpur 342001 (Raj.) India. Email:[email protected], Cell: +91-9829216643

2. Dr. Vinode Kumar Chawala, Professor, Dept. ofPhysiology, Dr S.N. Medical College, Jodhpur(342001)Rajasthan, India.

3. Dr. Jayant Kumar, Associate Professor, Dept. ofPhysiology, Dr S.N. Medical College, Jodhpur(342001) Rajasthan, India.

4. Dr Raj Kumar Rathore, Assistant Professor Dept. ofPharmacology, Dr S.N. Medical College, Jodhpur(342001)Rajasthan, India. * for correspondence

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