A Systematic Review of the Role of Thiamine Supplementation in Treatment of Refeeding Syndrome

Home , Hypokalemia

Top Clin Nutr Vol. 36, No. 1, pp. 36–51 Copyright c 2021 Wolters Kluwer Health, Inc. All rights reserved. NARRATIVE REVIEW A Systematic Review of the Role of Thiamine Supplementation in Treatment of Refeeding Syndrome

Lea Steiner, MS, RD, CSG; Susan Hewlings, PhD, RD

The purpose of this systematic review is to identify studies where measurable thiamine supplementation was provided to patients at risk for or with refeeding syndrome to improve treatment guidelines. A systematic review of PubMed and CINAHL Plus databases was conducted using the terms refeeding syndrome, hypophosphatemia, thiamine, and vitamin B1. A total of 173 articles were retrieved and 11 case studies and 1 retrospective study met inclusion criteria. All studies identiﬁed symptoms of thiamine deﬁciency, and all studies indicated thiamine supplementation was associated with improved clinical symptoms and no harmful outcomes. Average dose provided was 173-mg thiamine/day. Key words: B1, hypophosphatemia, refeeding, refeeding syndrome, thiamine

EFEEDING syndrome is defined as the case studies in eating disorders or prolonged R metabolic process in response to the voluntary fasts6 where refeeding syndrome is reintroduction of calories after starvation.1-3 self-induced because ethical barriers inhibit It is often diagnosed by electrolyte abnormal- controlled trials. Related to the paucity of ities and poor management can be fatal.1,2,4 studies and lack of comparability within the Refeeding syndrome was first recognized research available, evidence-based treatment in prisoners of war following the Second is not clearly defined.5 However, slow reintro- World War but continues to lack definitive duction of calories, electrolyte repletion, and criteria and remains poorly recognized vitamin supplementation including thiamine in the hospital setting despite significant is often recommended to manage refeeding incidence.2,3 For example, some sources sydrome.4,7,8 indicate that refeeding syndrome affects up to 25% of cancer patients and 14% of the geriatric population.4,5 The majority of PATHOPHYSIOLOGY OF REFEEDING evidence on refeeding syndrome is limited to SYNDROME

Refeeding syndrome represents the shift Author Afﬁliation: Boise Veterans Affairs Medical to anabolic metabolism as nutrition is Center, Boise, Idaho. reinitiated.5 This metabolism shift contributes The authors have disclosed that they have no signif- to corresponding electrolyte abnormalities icant relationships with, or ﬁnancial interest in, any especially abnormal potassium, magnesium, commercial companies pertaining to this article. and phosphorus.5 During starvation, fat and Correspondence: Lea Steiner, MS, RD, CSG (9steinl protein become the main source of energy @gmail.com). because glycogen stores are exhausted and DOI: 10.1097/TIN.0000000000000235 insulin is suppressed.7,9,10 Once eating is 36

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Thiamine Supplementation in Treatment of Refeeding Syndrome 37 reinitiated, blood glucose increases promot- able thiamine stores are depleted.4,5 For ex- ing insulin secretion and contributes to a shift ample, thiamine pyrophosphate is needed in in electrolytes, as energy synthesis pathways synthesis of branched chain amino acids and are upregulated.4,5,10 Hypophosphatemia is fatty acids, anabolic pathways that are up- not exclusive in recognition of refeeding syn- regulated once subjects begin eating again drome but is often the hallmark feature.3,5,10 after starvation.5,14 Thiamine pyrophosphate Hypophosphatemia is precipitated from the is also a cofactor in carbohydrate metabolism insulin surge as eating restarts because serum associated with pyruvate dehydrogenase.12-16 phosphorus is depleted quickly.4,11 Phos- In this pathway, thiamine deficiency could phorus is depleted related to increased de- be rate limiting causing pyruvate to be used mand in phosphorylated intermediates such in anaerobic metabolism instead of aerobic as creation of adenosine triphosphate for resulting in lactic acidosis.12-16 Lactic acido- glucose phosphorylation.4,11 Hypokalemia is sis is frequently one of the clinical symp- likely caused by cellular uptake of potas- toms of refeeding syndrome, which could sium, as pathways like glycogen synthesis be explained by thiamine deficiency.12-16 are upregulated.4 It is also possible that the In protein and lipid metabolism, thiamine sodium/potassium adenosine triphosphatase is needed for adenosine triphosphate pro- pump, which generally maintains blood potas- duction and here thiamine deficiency limits sium, is overwhelmed with refeeding con- the ability of pyruvate to convert to acetyl tributing to increased urinary excretion and CoA.12-16 In amino and fatty acid synthesis, hypokalemia.12 Potassium abnormalities are thiamine is required in the pentose-phosphate often what can make refeeding syndrome shunt for nicotinamide adenine dinucleotide fatal, but any of the electrolyte abnormal- phosphate and thiamine deficiency limiting ities can contribute to symptoms.4,10 The the pentose-phosphate shunt could inhibit clinical features of refeeding syndrome in- myelin sheath repair and impair nucleic acid cluding delirium, seizures, edema and heart synthesis.12-17 In refeeding syndrome, these failure, metabolic alkalosis, and rhabdomy- metabolic pathways are upregulated increas- olysis can be attributed to these electrolyte ing thiamine needs and depleting thiamine if abnormalities.4,10,12 However, these symp- intake or stores are inadequate. toms could have causes besides electrolyte Inadequate thiamine is likely in refeed- abnormalities in refeeding syndrome such as ing syndrome for reasons in addition to in- thiamine deficiency.5,13 creased needs. Thiamine cannot be synthe- sized endogenously and storage is limited; therefore, inadequate exogenous intake can THIAMINE IN REFEEDING SYNDROME rapidly precipitate deficiency.4,5 Inadequate thiamine intake independent of refeeding syn- Wernicke-Korsakoff syndrome or symp- drome can contribute to deficiency in as toms associated with wet or dry beriberi such little as 2 weeks.13 Prolonged starvation is as ophthalmoplegia, ataxia, paralysis, con- one of the key risk factors in refeeding syn- fusion, congestive heart failure (CHF), and drome, predisposing patients for thiamine de- edema are often identified in refeeding syn- ficiency in addition to refeeding induced in- drome and could be explained by thiamine creased metabolic demand for thiamine and deficiency.5,14 Thiamine deficiency is likely increased cellular thiamine use.4,5 Malnutri- in refeeding syndrome because of increased tion and alcohol intake are additional risk metabolic needs. Thiamine is required as a co- factors for refeeding syndrome that predis- factor in many of the metabolic pathways that pose patients for poor thiamine intake or de- are upregulated once feeding is reinitiated.4,5 ficiency at baseline.4,5 For example, thiamine This could contribute to thiamine deficiency supplementation is frequently recommended if there is a deficiency at baseline or avail- as part of treatment in alcohol withdrawal

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 38 TOPIC IN CLINICAL NUTRITION/JANUARY–MARCH 2021 often to avoid Wernicke’s encephalopathy but malities with thiamine supplementation.13 also because thiamine use is impaired in alco- Cases also identify the concept that supple- holic patients because of changes in gluco- mentation prior to initiating feeding may neogenesis or decreased intestinal absorption be beneficial in avoiding clinical symptoms making deficiency likely.18 from precipitating because thiamine avail- It is not conclusive whether thiamine defi- ability would be adequate for the increased ciency is present at baseline in refeeding syn- metabolic needs.14 This theory explains why drome or caused by refeeding syndrome.14,15 National Institute for Health and Care Ex- Lack of evidence differentiating this can be cellence (NICE) criteria recommend starting attributed to limited thiamine measurement thiamine supplementation prior to reintro- in the research because some measures ducing calories. NICE guidelines recommend are not accurate and others are difficult to thiamine supplementation 200 to 300 mg/day measure. Serum thiamine is not an accurate orally or 200 to 300 mg/day intravenously (IV) measurement because it only identifies a as part of an undefined B vitamin preparation portion of total body thiamine and concentra- if needed, initiated before refeeding and for tions are not indicative of thiamine stores.5,18 the first 10 days of calorie reintroduction.8 Thiamine is a cofactor for transketolase, an The NICE guidelines do not define when to enzyme involved in many metabolism path- use IV supplementation instead of oral.8 NICE ways and its activity increased in response to guidelines were selected for comparison increased thiamine.5 Erythrocyte transketo- in this review because multiple treatment lase activity and a thiamine loading test are the guidelines for refeeding syndrome base thi- best measure to identify thiamine deficiency amine recommendations on them or have the because enzyme activity increases after same recommendations as these guidelines thiamine pyrophosphate loading.5 However, for thiamine supplementation in refeeding erythrocyte transketolase activity requires syndrome including Friedli et al,4 the Irish high-performance liquid chromatography for Society for Clinical Nutrition and Metabolism, measurement, which requires a specialized and CNSG East Cheshire guidelines.20,21 One laboratory for evaluation that may not be source states that the NICE guidelines are the readily available in a hospital laboratory.5 In most widely used guidelines for treatment of addition, it lacks specificity and sensitivity, is refeeding syndrome.4 However, utilization expensive, and is time consuming to measure, remains poor.8,22,23 A retrospective audit so deficiency is often assumed.5,13 Thiamine on physicians and dietitians has already supplementation is commonly initiated identified limited compliance in following without measuring erythrocyte transketo- NICE guidelines, and per the American lase because it is low risk and refeeding Society of Parenteral and Enteral Nutrition syndrome requires immediate treatment.5,13 (ASPEN), the guidelines had poor validity Lack of clinical measurement also makes it as a screening tool for identifying risk of difficult to differentiate acute thiamine defi- refeeding syndrome.8,22,23 It is also noted ciency from refeeding syndrome-associated that differentiated from NICE guidelines, in deficiency because clinical symptoms are one source, ASPEN states current guidelines identical.19 recommend 300-mg thiamine provided Whether present at baseline or induced as IV prior to feeding and an additional metabolically in refeeding syndrome, thi- 200 to 300 mg/day IV or orally for 3 days amine deficiency can be attributed to many and possibly continuing 100 mg/day after of the clinical symptoms, so supplementation this in treatment of refeeding; however, is often recommended in management of there is no source included for these refeeding syndrome. Case reports indicate guidelines.18 Additionally, different from resolution of clinical symptoms of refeeding these previous ASPEN recommendations, in syndrome such as edema or cardiac abnor- the 2020 ASPEN consensus recommendations

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Thiamine Supplementation in Treatment of Refeeding Syndrome 39 for refeeding syndrome, 100 mg of thiamine is METHODS recommended before initiating feeding or IV fluids and 100 mg/day for 5 to 7 days or longer Given the paucity of data on thiamine in patients with severe starvation, chronic supplementation and refeeding syndrome, a alcoholism, or signs of deficiency or high systematic review was conducted to iden- risk for deficiency, which is slightly lower tify studies of hospitalized individuals with than NICE supplementation guidelines.23 refeeding syndrome or risk for refeeding syn- No reviews identify whether thiamine sup- drome that included treatment with mea- plementation recommendation per NICE or surable doses of thiamine. Supplementation other guidelines is followed in the literature. dosage provided was compared to NICE Additional higher quality studies are guidelines. Additionally, symptoms indicative needed to define evidence-based guidelines of thiamine deficiency and documentation of for refeeding syndrome treatment including improvement in these symptoms were includ- thiamine supplementation and to increase ing to further understand the role of thiamine awareness and recognition of refeeding supplementation in refeeding syndrome and syndrome in the hospital setting. Evidence dosage needed for clinical improvement. Data identifies a correlation between refeeding were extracted individually from the literature syndrome and thiamine deficiency and by researchers. suggests thiamine supplementation may be A comprehensive database search for beneficialintreatment.8,13,14 To date the publications was conducted in PubMed and authors of this article found no systematic CINAHL Plus with full text on September 7, review addressing thiamine supplementation 2019. MeSH terms searched included refeed- and dosage in cases of refeeding syndrome. ing syndrome, refeeding, hypophosphatemia, The purpose of this review was to system- thiamine, and B1. There were no exclusion atically evaluate and identify the studies terms and no exclusions based on publication available that identified refeeding syndrome date. References were exported to Mendeley or refeeding risk with a measurable dose of Desktop and duplicates were removed using thiamine supplementation included in treat- authors, title, and year. No authors were ment intervention. The authors also identified contacted for additional information and no how the doses provided compared to NICE studies were excluded based on funding guidelines for thiamine supplementation. source. Table 1 identifies some key questions this The Preferred Reporting Items for System- systematic review aims to address. atic Reviews and Meta-Analyses (PRISMA)

Table 1. Aims of Systematic Review: Key Questions

What is already known about this subject? • Refeeding syndrome has a high incidence in many populations in the hospital setting but definition and management continue to lack consensus and the majority of evidence available is limited to case reports. Thiamine supplementation is often recommended in management. What does this study add? • This is a systematic review of case studies describing signs, symptoms, diagnosis, and management of refeeding syndrome with thiamine supplementation doses and outcomes. This is the only systematic review identified to date by the authors on thiamine supplementation dosage in refeeding syndrome. How might this impact clinical practice? • Causation cannot be concluded but these case studies identify that thiamine likely has a role in refeeding syndrome and supplementation is not likely harmful in nature and could be beneficial in improving clinical outcomes.

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 40 TOPIC IN CLINICAL NUTRITION/JANUARY–MARCH 2021 statement24 for systematic reviews and the The majority of the literature available was PRISMA checklist24 were used in conducting case studies, which limited which quality this study. A total of 173 abstracts identified in evaluation tools could be used. The Downs the initial search were screened individually and Black Checklist was used to assess and excluded if they did not meet inclusion quality at the study level because it has been criteria. If the abstract did not have enough validated to evaluate noncontrolled trials.26 detail for inclusion, the full-text article was screened for inclusion criteria. Studies were Study selection included if they were written in English, refeeding syndrome was identified, or at least The Figure is a flowchart identifying 1 risk factor for refeeding syndrome was the study selection process. Initially 173 present in human subjects. Additionally, thi- references were identified through electronic amine dose provided needed to be measurable database searches in PubMed and CINAHL and articles could not be reviews. NICE crite- Plus full text. Once duplicates were removed, ria for patients at risk for refeeding syndrome 76 references remained for screening. Using (Table 2) were included in identifying studies the exclusion and inclusion criteria, 55 refer- because cases where refeeding syndrome ences were excluded initially. The majority of was not identified could help to determine references were excluded because they were if thiamine could decrease symptoms and review articles, but references were also severity of refeeding syndrome or if thiamine excluded because they were not available in supplementation prior to feeding could pre- English, used animal populations, or because vent refeeding syndrome from occurring in they were not addressing refeeding syndrome at-risk patients.4,25 NICE criteria were used to or refeeding risk factors (eg, a case study on identify risk for refeeding syndrome in this re- vitamin D and rickets or a case of vitamin C de- view; however, other sources like the ASPEN ficiency in Parkinsonism). After screening, 21 consensus statement have different criteria references were identified and read in full text used to identify risk for refeeding syndrome.23 and reevaluated using the exclusion and inclusion criteria. Of the remaining 21 references, Table 2. NICE Criteria for Identifying 9 more were excluded primarily because Patients at Risk for Refeeding Syndromea thiamine supplementation was not addressed at all or the dosage of thiamine supplemented Patient has a minimum of 1 of the following criteria: was not quantifiable. For example, a case of • Body mass index <16 kg/m2 refeeding syndrome where a multivitamin • Unintentional weight loss >15% in the past supplement was prescribed, however, brand 3–6 mo and dosing were not identified so amount • Minimal or no nutritional intake for the of thiamine given could not be defined or past ≥10 d another case where 2 different doses of • Hypomagnesemia, hypokalemia, or thiamine were described were excluded.27,28 hypophosphatemia before feeding Studies were also excluded after full-text Or patient has at least 2 of the following review because refeeding syndrome was not criteria: identified or there was not sufficient data • Body mass index <18.5 kg/m2 included to identify a risk factor for refeeding • Unintentional weight loss >10% in the past 3–6 mo syndrome. Twelve studies met inclusion • Minimal or no nutritional intake for the criteria. past ≥5d • A history of alcohol abuse or drug use Quality assessment including diuretics, chemotherapy, insulin, or antacids The literature review revealed no con- aSource: NICE.8 Used with permission. trolled trials and the majority of studies

Figure. Flowchart of study selection based on PRISMA guidelines. Sources: PRISMA.24 included were case studies. However, it is stay) introduced bias because, regardless of important to assess the available research so refeeding or thiamine supplementation, more that health care professionals can identify acutely ill patients had longer hospital stays. evidence-based guidelines for treatment No studies had a control group for compari- within the limitations of the literature. Many son. External validity was also poor because limitations and barriers to higher quality recruitment was not defined and studies with studies of refeeding syndrome exist such as a population of 1 lacked generalizability to the ethics. Case studies included were gener- population. Internal validity bias was high be- ally observational and retrospective. Quality cause no studies had a control group or were assessment26 revealed that all studies included blinded, which limited validity and reliability. were poor quality evidence and no studies Population of 1 and lack of control group sub- that met inclusion criteria had a score higher jected each case study to a high probability than 14/31 per Downs and Black. The one for confounding and selection bias. For ex- retrospective study included29 had a score of ample, there are other causes for electrolyte 11, the highest score but was still poor quality abnormalities in the hospital setting.5 It is evidence per Downs and Black related to difficult to compare the case studies related lack of control group and blinding. All studies to performance bias because the treatment based on Downs and Black scores indicated protocols in the case studies were not clearly high chance of reporting bias because out- defined and there was a high number of comes were poorly described, no statistical cointerventions such as differing feeding analysis was used, and confounders were methods. None of the studies included can not addressed. Outcomes used (eg, hospital address causality.30

RESULTS excluded them from following NICE recommendations directly. Cases included in the case review by Stanga et al31 were addressed individually in tables Change in thiamine dosage because individual data from the cases could In 10 or 67% of the cases,31,34,36-40 dosage be extrapolated. The retrospective study by of thiamine remained the same during Chen et al29 was counted as 1 study in text and hospital stay or throughout duration of tables except in the case of identifying symp- supplementation. In 2 cases, initial dose was toms (where proportions of 11 participants started lower then dosage was increased.29,33 were used) because individual data could not In 2 cases, in which the highest doses were be extrapolated. initiated, dosage was steadily decreased over time.32,41 In 1 case, dose was decreased Initial thiamine dose then increased again; however, this was attributed to medical error because 75% of Despite the fact that there are recognized the initial dose prescribed was missed related guidelines for refeeding syndrome,4,8,22 no to transfer of medical care and administered case or retrospective study identified fol- once the error was identified.35 Contrary lowed NICE guidelines for thiamine sup- to some of the cases, NICE guidelines8 and plementation. In the cases identified, initial ASPEN consensus23 do not recommend doses of thiamine supplementation ranged changing thiamine dosage during 10-day from 2.0 ± 0.5 mg/day29 to 1500 mg in a supplementation. day.32 It is notable that in 1 case of low initial supplementation, the subject was only 6yearsold33 where subjects in the major- Route of thiamine supplementation ity of other cases were adults. However, The majority of thiamine supplementation in other cases, age did not affect dosage.34 provided was initiated as IV often with For example, in a case of a 13-month-old, fluids or with parenteral nutrition. Eleven thiamine supplementation was provided at cases or 73% of cases presented started with 200 mg/day comparable to adult doses initial thiamine supplementation provided as provided.34 The most common initial dose IV.31-33,35-37,39-41 In 1 case, initial thiamine was prescribed was 100 mg, which was used in 5 provided orally and as IV.39 In 2 cases, thi- or 33% of the cases identified.31,35-38 This cor- amine supplementation was started orally31,38 responds with recommendations in the AS- and route of administration was unclear in PEN consensus statement.23 Four cases pre- 1case.34 Another retrospective study of sented used an initial dose of 200 mg/day cases started with oral supplements but then including a pediatric case.31,34,39 Two cases it was unclear whether patients remained started initial dose at 300 mg/day.31,40 Low- on an oral supplementation once dose was dosage outliers started supplementation at 2.5 increased.29 In 3 cases, supplementation was mg/day including a pediatric case29,33 and initially started as IV and then transitioned high-dosage outliers started supplementation to oral.32,33,41 In 1 case, supplementation at 300 mg 3 times per day41 or 500 mg 3 alternated between IV and oral but intended times per day in adult cases.32 Excluding these to deliver all as IV doses and then transition 4 outliers average initial dose was 173 mg to oral.35 However, IV doses were initially thiamine/day compared to NICE guidelines, missed due to medical error.35 In another which recommend 200 to 300 mg/day.8 Six case, administration of supplementation cases31,34,39,40 or 40% of cases identified did remained as IV but supplementation was provide initial doses within the NICE guide- stopped and restarted related to changes line range; however, length of supplementa- in feeding and intake during hospital tion and when supplementation was initiated stay.31

Length of supplementation not directly identified, 3/832 or 5/836,38,41 of Length of supplementation was highly vari- the risk factors were most commonly present able and difficult to compare ranging from a or an average of 56% of the risk factors. 1-time dose31 to long-term supplementation of In comparison, in cases where refeeding 29,33 18 months or more.32 In 6 of the cases or stud- syndrome was directly diagnosed, 1/8 to 35 ies, the researcher was unable to determine 7/8 risk factors were present with an av- length of supplementation.29,31,32,35,38,39 In erage of 3.5/8 risk factors present. However, general, these were the cases where supple- this average was skewed by outliers. In these 28,32,34,37 mentation was prescribed long-term after hos- cases, supplementation improved pital discharge. Of the cases where length clinical symptoms but it cannot be deter- of supplementation was quantified, length in- mined without a control group if symptoms cluded 1 day,31 5days,31 7days,31 11 days,34 would be worsened or unresolved without 2 weeks,36,40 3 weeks,33 28 days,37 and 31 supplementation. days.41 In many of these cases, supplementation was prescribed the entire length of hos- Timing of thiamine supplementation pital stay and length of stay was variable re- and feeding lated to comorbidities. An average length of supplementation was not found because of NICE guidelines and ASPEN consensus high variability in supplementation length and recommend starting thiamine supplementa- 8,23 outliers. NICE guidelines recommend supple- tion prior to reintroducing calories. Thi- mentation for the first 10 days of feeding,8 amine supplementation and feeding tim- and no studies identified had length of supple- ingwereunabletobedeterminedin 32,35,36,41 mentation congruent with this. ASPEN con- 4 studies. The majority of cases 31,33,34,39 sensus recommends a minimum of 5 days of (7/15) started thiamine supplemen- supplementation.23 tation after initiating feeding and symptoms still showed improvement. Four cases started supplementation at the same time Supplementation in cases where as feeding.29,37,38,40 Of the cases where refeeding is not directly identified refeeding syndrome was not directly diag- NICE guidelines and ASPEN consensus also nosed, feeding timed with supplementation recommend starting thiamine supplementa- was unable to be determined32,36,41 and tion prior to starting oral intake in patients at in 1 case,38 supplementation started at the risk for or with refeeding syndrome because same time as feeding. It is notable that in it is possible that initiating supplementation all cases32,36,38,41 where refeeding syndrome prior to feeding could help to avoid refeeding was not directly diagnosed, electrolyte ab- syndrome or lessen symptoms. Therefore, normalities were present. In 1 case,38 hy- cases where refeeding syndrome was not pophosphatemia present before feeding be- directly identified32,36,38,41 and thiamine sup- came more severe within 24 hours of feeding plementation was provided were included and the initiation of the thiamine supplement. due to the possibility of refeeding syndrome In this case it cannot be determined whether developing without supplementation. These starting thiamine prior to feeding would have cases were included if 1 or more risk factors had a positive effect on phosphorus or refeed- were present per NICE criteria identified in ing symptoms.38 It can also not be determined Table 2. Risk criteria identified in each of the from the cases identified where refeeding syn- cases or studies can be identified in Table 3. drome was diagnosed if supplementation of In many cases some criteria were unable to thiamine prior to refeeding would have af- be determined, but a sufficient number of fected symptoms or electrolytes. Regardless other risk factors were present for inclusion. of supplement timing, all cases showed some Of the cases where refeeding syndrome was improvement with thiamine.

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 44 TOPIC IN CLINICAL NUTRITION/JANUARY–MARCH 2021 ) continues ( Antacids Insulin or History of Alcohol Use or Diuretics, Chemo, YUTD YUTD YUTD 5d ≥ Minimal or No Nutrition Intake 2y Y UTD 4mo × × 3y × 12.5% 10% in the 35 kg − > 50% − addressed) percentile) − Past 3–6 mo Loss loss from 50th to 3rd but initial weight not Unintentional Weight 2 18.5 < YY YUTD YUTD, Y UTD (over 9 mo weight Y UTD Y Y, alcohol YUTD, Y UTD UTD Y, alcohol NUTD( kg/m BMI Prior to Feeding Hypokalemia, or hypokalemia, hypophosphatemia after 3 d of feeding) hypokalemia within 24 h of hospital feeding) hypophosphatemia (but hospital nutrition not addressed) hypophosphatemia following feeding) (hypomagnesemia, hypokalemia, and further hypophosphatemia after feeding) after feeding) Hypomagnesemia, Hypophosphatemia N (hypomagnesemia, Y, hypophosphatemia YY, hypomagnesemia, N (hypophosphatemia Y Y UTD Y, hypomagnesemia, N (hypokalemia, Y, hypophosphatemia × × 4mo) × 10 d ≥ a 14 d Nutrition Intake 1000 kcal/d Minimal or No with sugar < majority fruit and vegetables) fruit, and cucumber only) × dieting 14 d) 3y) Y (restricting intake to 2 wk Y (only coffee and tea × 6mo × 17% 15% in the Past 3–6 mo Weight Loss − > Unintentional 2 16 < Y 42% weight loss YY UTD Y UTD (eating 1 cup yogurt, Y, decreased oral intake N UTD Y, history of restrictive kg/m BMI 34 (1) Y(2) Y, (3) N Y UTD(4) Y UTD (only sips of liquids N Y (only eating apples UTD UTD N (hypomagnesemia 36 31 31 31 31 35 Risk Factors for Refeeding Syndrome 41 Al Sharkawy et al Stanga et al Saad et al Mushtaq et al Stanga et al Reference Peters et al Stanga et al Stanga et al Table 3.

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Thiamine Supplementation in Treatment of Refeeding Syndrome 45 Antacids Insulin or History of Alcohol Use or Diuretics, Chemo, YUTD 5d ≥ Minimal or No Nutrition Intake × 30 kg − 10% in the 3mo) > Past 3–6 mo Loss Unintentional Weight 2 18.5 < Y UTD UTD Y, chemotherapy Y UTD Y UTD NY YUTD NN YY,diuretics UTD UTD UTD Y, furosemide kg/m BMI Prior to Feeding Hypokalemia, or (more severe hypophosphatemia within 24 h of eating) hypokalemia, and hypophosphatemia after feeding) hypokalemia, and hypophosphatemia after feeding) hypokalemia (hypophosphatemia with initiation of feeding and further hypomagnesemia) (hypophosphatemia and further hypokalemia after eating) Hypomagnesemia, Hypophosphatemia Y, hypophosphatemia N (hypomagnesemia, Y, hypokalemia N UTD (stated Y, hypokalemia ) 2 × 10 d ≥ Continued are reported individually in the table in order of appearance in the article. ( a 31 Nutrition Intake Minimal or No intake) diet lacking protein) broth, tea, water mo prior to admit) admit) Y (anorexia prior to 44 d) Y (44-d fast, water only × 1y”) × 25% 15% in the weight loss Past 3–6 mo Weight Loss − > prior to admit (“considerable Unintentional 2 16 < YUTD NN N Y UTD (malabsorption and UTDNY( Y, hypomagnesemia, N UTD Y (liquid only diet UTD UTD UTD N (hypomagnesemia, Some Some Some Some Some Some Some Some kg/m BMI 39 40 37 38 33 Risk Factors for Refeeding Syndrome 29 32 (Subjects enrolled in study based on NICE risk factors) et al Chen et al Yamashita et al Hershkowitz et al Korbonits et al Chiappetta et al Reference Vicinanza et al Karakonstantis Sources: Details from each case presented in Stanga et al Table 3. Abbreviations: BMI, body massa index; Chemo, chemotherapy; N, no; UTD, unable to determine; Y, yes.

Symptoms of refeeding syndrome symptoms resolved but vertical nystagmus 31,35,41 Symptoms of refeeding syndrome that remained. In 4 cases, thiamine sup- were identified in the cases are addressed in plementation was associated with almost detail in Table 4. Symptoms of wet or dry immediate improvement of symptoms or beriberi indicative of thiamine deficiency improvement within 24 hours. Some patients 35 were identified. The most common symptom continued to improve after discharge, but in present was edema noted in 68% of some cases neurological symptoms remained 31 cases29,31,33,34,38-40 (in calculating the per- for longer than 30 days and memory deficits 41 cent 11 subjects were used from Chen were still present at 6-month follow-up. et al29 because symptoms were differentiated Follow-up time for cases was not the same. In 32,39 between participants). Other common symp- 2cases, symptoms showed improvement toms included nausea or vomiting,29,31,32,34,40 within 48 hours of thiamine supplementa- 32 ataxia,32,35,36,39-41 confusion,32,33,35-37,39-41 tion, but in 1 case, despite improvement in hypotension,31,35,38,39 Wernicke’s encephalo- some symptoms, ataxia remained longer than pathy,32,35,36,39,41 weakness,31,32,35,39,40 anx- 18 months. In another case, supplementation iety or breathing difficulty,29,31,35,39,40 and was started at a lower dose for 2 weeks opthalmoplegia.31,32,35,39-41 without improvement and then showed im- Although the majority of studies identified provement within 48 hours of starting higher 33 symptoms indicative of thiamine deficiency, dose supplementation. Onecaseidentified thiamine deficiency was only confirmed some resolution in symptoms after 5 days biochemically with laboratory values in 5 of supplementation, but some neurological 37 studies.31,37-40 In 2 cases,37,40 deficiency was symptoms remained long-term. It is impor- measured upon admission without follow-up tant to note that medically this patient was to confirm repletion, and in 1 case,31 de- unstable related to comorbidities including 37 36 29 ficiency was confirmed on the second day cancer. One case and 1 study found after feeding and thiamine supplementation improvement in symptoms after 2 weeks of started and repletion was not confirmed. supplementation, but it is noted that despite In another case, thiamine deficiency was clinical improvement 33% of these patients confirmed prior to supplementation but feed- had died at follow-up likely related to other ing had already been initiated and repletion comorbidities. In all cases, supplementation was not confirmed.39 Only 1 case confirmed contributed to improvement in clinical repletion after thiamine deficiency was iden- symptoms; however, symptoms were not tified with elevated erythrocyte transketolase completely resolved in all cases. activity upon admission prior to feeding.38 This case found that deficiency resolved and erythrocyte transketolase activity returned DISCUSSION to baseline within 3 days of oral intake and 100-mg oral thiamine supplement.38 Inter- Despite high prevalence in the hospitalized estingly, despite confirmation that deficiency population, refeeding syndrome continues resolved, in this case, thiamine supplementa- to lack recognition and defined guidelines tion was continued long-term for more than for treatment. Based on its mechanism of 48 days.38 action, thiamine undoubtedly plays a role Although repletion of thiamine was not although there is a lack of evidence from confirmed biochemically in most studies, im- randomized controlled trials to support its provement in symptoms was noted. Improve- efficacy in refeeding syndrome. The cases ment in symptoms had variable timelines and identified indicate that thiamine supplemen- in 5 cases31,34,38,40 the researcher was unable tation often contributes to improvement to determine timeline for improvement. How- in clinical outcomes and improvement of 20,29,35 ever, it was identified in 3 of these cases31,34,40 symptoms. Many of the cases identify that symptoms resolved. In 1 case,31 some almost immediate improvement in clinical

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Thiamine Supplementation in Treatment of Refeeding Syndrome 47 palsy palsy Diplopia Diplopia Asymmetric Ptosis Gaze lateral rectus Poor failure weaning Dyspnea ventilator Difﬁculty breathing noted in some Y Respiratory Y YY lethargy interval at admit) prolonged QTc interval (bradycardia Prolonged QT Diagnosed Bradycardia Weakness Wernicke’s Encephalopathy a Y Y 60 Diastolic) 90 Systolic or Hypotension < < ( Y Y Anisocoria Y Y Y Borderline 100) > (Heart Rate Tachycardia Poor are reported individually in the table in order of appearance in the article. Memory bradyphrenia Impairment Attention or 31 Y Y Syncope Y Y Y ness tion at admit Seizures, sciousness, altered con- Confusion, Disorienta- Unconscious unresponsive- YYYY, YYY Y y Y Y Y Y Y Y, dysarthria Both Y Y, fatigue Trembling, unsteady gait Gait disorders Y 39 34 40 37 38 33 (2)(3)(4) Y Y Y, orthopnea Tachypnea (1) Y 36 31 31 31 31 35 Refeeding Syndrome Symptoms at Admit or During Hospital Stay 29 41 32 et al Karakonstantis Chen et al Chiappetta et al Hershkowitz et al Al Sharkawy et al Stanga at al Mustaq et al Stanga et al Korbonits et al Stanga et al Yamashita et al ReferencePeters et al Ataxia Nystagmus Saad et al Stanga et al Vicinanza et al Sources: Details from each case presented in Stanga et al Table 4. Abbreviations: N, no; QTa interval, Q wave and T wave on electrocardiogram; Y, yes.

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 48 TOPIC IN CLINICAL NUTRITION/JANUARY–MARCH 2021 symptoms with thiamine supplementation and timing, thiamine contributed to improve- and continued improvement throughout hos- ment of symptoms. One case indicated higher pital stay with prolonged supplementation. doses are more beneficial because improve- Despite prolonged supplementation in some ment was not shown until a higher dose was cases,20,26,31,35 deficits like nystagmus, ataxia, administrated.27 and neurologic symptoms remained long- Few of the cases identified confirmed thi- term. None of the cases presented indicated amine deficiency or repletion with laboratory harmful or detrimental effects from thiamine values, which limits validation of supplemen- supplementation, indicating that even though tation guidelines. Thiamine is a difficult assay high-quality evidence is lacking, benefits of requiring a specialized laboratory to obtain,13 supplementation likely outweigh risks. All and the timeliness with which refeeding syn- cases showed some clinical improvement drome needs to be managed to avoid death with thiamine supplementation regardless will likely continue to inhibit higher qual- or timing, dosage, and length although this ity studies to address this. Several confound- could be related to confounding factors. ing variables limit studying thiamine. Similar Despite the paucity of evidence, thiamine symptoms and contributing factors make dif- supplementation in refeeding syndrome can- ferentiating acute thiamine deficiency from not be excluded as a contributing factor to deficiency induced by refeeding nearly im- clinical improvement. Some cases of refeed- possible. However, because of these similar- ing syndrome excluded from this review ities it cannot be ignored that they are likely demonstrate improvement without thiamine closely related and thiamine is beneficial in supplementation.38,39 treatment of refeeding.19 For example, malnu- The studies presented have strength in trition, prolonged inadequate intake, and al- the amount of detail provided, which can coholism, which are risk factors for refeeding help clinicians. However, they lack general- syndrome, are also risk factors for thiamine izability and comparability, have small sam- deficiency. Research is also confounded by ple sizes, and limited statistical power. These overlapping symptoms, which make identi- limitations in the research make developing fying refeeding syndrome and defining the guidelines for treatment of refeeding syn- role of thiamine compared with the contri- drome difficult. Randomized controlled tri- butions of other comorbidities difficult. For als are needed, although ethical barriers are example, in patients with CHF on furosemide a limitation and clinicians have to rely on (a potential risk factor), the CHF, a symp- the available evidence. For example, a ran- tom of both thiamine deficiency and refeed- domized controlled trial could not ethically ing syndrome, was likely independent of the starve patients and withhold treatment like 2 even though thiamine supplementation im- electrolyte correction. In order to improve proved ejection fraction.15 Thiamine needs evidence of refeeding syndrome, researchers and usage in the individual with refeeding syn- would also need to control and standardize drome could also be individualized.14 For ex- other variables that could be affecting the role ample, on the genetic level human thiamine of thiamine such as a protocol for reintroduc- transporter-2 has genetic differences and can tion of calories. The NICE guidelines attempt affect intestinal carrier-mediated thiamine up- to standardize guidelines but continue to be take and promote deficiency.14 poorly followed and no cases identified fol- Limitation in recognition, diagnosis, and lowed NICE guidelines for thiamine supple- standardization of treatment of refeeding syn- mentation. Consistent dosage, timing of sup- drome continues to inhibit research and is also plementation with introduction of calories, complicated by confounding variables. For ex- length of supplement, and route of supple- ample, there are many causes of the elec- mentation in studies would make comparative trolyte abnormalities and clinical outcomes analysis of thiamine more feasible. Current found in refeeding syndrome.5 Low phospho- evidence indicates that, regardless of dose rus, which is often the defining symptom of

Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Thiamine Supplementation in Treatment of Refeeding Syndrome 49 refeeding syndrome, can be caused by re- decreasing symptoms or avoiding refeeding nal tubular phosphate loss, phosphate binder syndrome. use, malabsorption, liver disease, alcoholism affecting intake, or IV glucose causing cellular phosphate redistribution.5 CONCLUSION Ethics is likely the biggest barrier in the advancement of higher quality research on Refeeding syndrome is often a complica- refeeding syndrome because lack of prompt tion of malnutrition that can be fatal if poorly interventions could be fatal. Currently, clini- managed. Thiamine deficiency has a role in cians need to rely on the evidence available clinical symptoms of refeeding syndrome. for management. Despite limitations, the case Refeeding syndrome continues to lack recog- studies included support that thiamine sup- nition and clear management in the hospital plementation improves clinical symptoms. setting, which limits standardized evidence- The evidence does not suggest a standard- based treatment. High-quality and conclusive ized amount to begin supplementation, but evidence is lacking, but thiamine deficiency the majority of cases initiate supplementa- could be closely related to refeeding syn- tion at approximately 200-mg IV and increase drome. No case identified used NICE guide- dosage if symptoms do not almost immedi- lines for thiamine supplementation, but all ately start to show some improvement. Tim- found clinical improvement regardless of the ing and length of supplementation also lacks amount, timing, or length of thiamine supple- definitive guidelines in the literature, but be- mentation. Ideally, randomized controlled tri- cause supplementation is not harmful, it is als would help to standardize treatment guide- likely beneficial to begin supplementation in lines for refeeding syndrome and thiamine patients with refeeding syndrome or at risk for supplementation dosing. Currently, health refeeding syndrome, as clinical improvement care professionals must rely on the paucity is identified in all cases. Supplementation is of- of evidence available for clinical guidance. ten continued throughout hospital stay. The Thiamine supplementation is not harmful and available evidence has not determined if sup- clinicians should consider supplementation in plementation prior to feeding or prior to patients at risk for or with refeeding syndrome refeeding syndrome diagnosis is beneficial in to improve clinical outcomes.

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