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Refeeding Syndrome — References

References supporting the QSP model in this directory. They are grouped by the part of the model each one constrains, and the annotation says what the model took from it — because the calibration claim in rfs_mrgsolve_model.R is that only three numbers were fitted to refeeding syndrome itself and everything else came from normal physiology or non-refeeding pharmacology. These are the sources for "everything else".

1. Definition, incidence and the guideline disagreement

  1. Friedli N, Stanga Z, Sobotka L, et al. Revisiting the refeeding syndrome: results of a systematic review. Nutrition 2017;35:151–160. — https://pubmed.ncbi.nlm.nih.gov/28241991/
  2. da Silva JSV, Seres DS, Sabino K, et al. ASPEN Consensus Recommendations for Refeeding Syndrome. Nutr Clin Pract 2020;35(2):178–195. — the 2020 consensus definition, risk criteria, and the explicit position that hypophosphataemia should be treated rather than used as a reason to withhold feeding. https://pubmed.ncbi.nlm.nih.gov/32115791/
  3. National Institute for Health and Care Excellence. Nutrition support for adults (CG32). 2006, updated 2017. — the 10 kcal/kg/d starting rate, the 5 kcal/kg/d extreme-risk rate, and the history-based risk criteria the model reproduces in rfs_sweep_history(). https://www.nice.org.uk/guidance/cg32
  4. Mehanna HM, Moledina J, Travis J. Refeeding syndrome: what it is, and how to prevent and treat it. BMJ 2008;336(7659):1495–1498. — https://pubmed.ncbi.nlm.nih.gov/18583681/
  5. Friedli N, Stanga Z, Culkin A, et al. Management and prevention of refeeding syndrome in medical inpatients: an evidence-based and consensus-supported algorithm. Nutrition 2018;47:13–20. — https://pubmed.ncbi.nlm.nih.gov/29429529/
  6. Doig GS, Simpson F, Heighes PT, et al. Restricted versus continued standard caloric intake during the management of refeeding syndrome in critically ill adults: a randomised, parallel-group, multicentre, single-blind controlled trial. Lancet Respir Med 2015;3(12):943–952. — the principal randomised evidence on caloric restriction; the comparison rfs_sweep_gir() and scenarios 01/02/07 are aimed at it. https://pubmed.ncbi.nlm.nih.gov/26597128/
  7. Olthof LE, Koekkoek WACK, van Setten C, et al. Impact of caloric intake in critically ill patients with, and without, refeeding syndrome: a retrospective study. Clin Nutr 2018;37(5):1609–1617. — https://pubmed.ncbi.nlm.nih.gov/28866138/
  8. Marvin VA, Brown D, Portlock J, Livingstone C. Factors contributing to the development of hypophosphataemia when refeeding using parenteral nutrition. Pharm World Sci 2008;30(4):329–335. — https://pubmed.ncbi.nlm.nih.gov/18204995/
  9. Rio A, Whelan K, Goff L, et al. Occurrence of refeeding syndrome in adults started on artificial nutrition support: prospective cohort study. BMJ Open 2013;3(1):e002173. — incidence in an unselected artificial-nutrition cohort. https://pubmed.ncbi.nlm.nih.gov/23315514/
  10. Crook MA, Hally V, Panteli JV. The importance of the refeeding syndrome. Nutrition 2001;17(7-8):632–637. — https://pubmed.ncbi.nlm.nih.gov/11448586/
  11. Boateng AA, Sriram K, Meguid MM, Crook M. Refeeding syndrome: treatment considerations based on collective analysis of literature case reports. Nutrition 2010;26(2):156–167. — https://pubmed.ncbi.nlm.nih.gov/19913393/
  12. Schnitker MA, Mattman PE, Bliss TL. A clinical study of malnutrition in Japanese prisoners of war. Ann Intern Med 1951;35(1):69–96. — the original description; the historical mortality the hazard scale is anchored against. https://pubmed.ncbi.nlm.nih.gov/14847450/

2. Body phosphorus: how much, and where — the model's central ratio

  1. Bansal VK. Serum Inorganic Phosphorus. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods, 3rd ed. Boston: Butterworths; 1990, ch. 198. — total body phosphorus ~700 g, the 85 % bone / 14 % intracellular / <1 % extracellular partition that gives the 0.06 % figure the whole model turns on. https://www.ncbi.nlm.nih.gov/books/NBK311/
  2. Berndt T, Kumar R. Phosphatonins and the regulation of phosphate homeostasis. Annu Rev Physiol 2007;69:341–359. — https://pubmed.ncbi.nlm.nih.gov/17002593/
  3. Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington DC: National Academies Press; 1997. — dietary phosphorus intake, fractional absorption 0.55–0.70, and the balance the model's FABSP reproduces. https://www.ncbi.nlm.nih.gov/books/NBK109825/
  4. Marks J, Debnam ES, Unwin RJ. Phosphate homeostasis and the renal-gastrointestinal axis. Am J Physiol Renal Physiol 2010;299(2):F285–F296. — https://pubmed.ncbi.nlm.nih.gov/20534871/
  5. Sabbagh Y, O'Brien SP, Song W, et al. Intestinal NaPi-IIb plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol 2009;20(11):2348–2358. — https://pubmed.ncbi.nlm.nih.gov/19729436/
  6. Forster IC, Hernando N, Biber J, Murer H. Phosphate transporters of the SLC20 and SLC34 families. Mol Aspects Med 2013;34(2-3):386–395. — the PiT-1/PiT-2 and NaPi-II kinetics behind KMPUP. https://pubmed.ncbi.nlm.nih.gov/23506879/
  7. Payne RB. Renal tubular reabsorption of phosphate (TmP/GFR): indications and interpretation. Ann Clin Biochem 1998;35(Pt 2):201–206. — the threshold formulation GFR × max(0, Pser − TmP/GFR) and the 0.80–1.35 mmol/L normal range the model derives 0.96 for. https://pubmed.ncbi.nlm.nih.gov/9547891/
  8. Walton RJ, Bijvoet OL. Nomogram for derivation of renal threshold phosphate concentration. Lancet 1975;2(7929):309–310. — https://pubmed.ncbi.nlm.nih.gov/50513/
  9. Blaine J, Chonchol M, Levi M. Renal control of calcium, phosphate, and magnesium homeostasis. Clin J Am Soc Nephrol 2015;10(7):1257–1272. — https://pubmed.ncbi.nlm.nih.gov/25287933/

3. Hypophosphataemia: consequences, thresholds, and the energetic mechanism

  1. Amanzadeh J, Reilly RF Jr. Hypophosphatemia: an evidence-based approach to its clinical consequences and management. Nat Clin Pract Nephrol 2006;2(3):136–148. — the <0.32 mmol/L severity threshold used for the cardiac and respiratory terms. https://pubmed.ncbi.nlm.nih.gov/16932412/
  2. Knochel JP. The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med 1977;137(2):203–220. — https://pubmed.ncbi.nlm.nih.gov/836118/
  3. O'Connor LR, Wheeler WS, Bethune JE. Effect of hypophosphatemia on myocardial performance in man. N Engl J Med 1977;297(17):901–903. — the myocardial contractility term. https://pubmed.ncbi.nlm.nih.gov/909464/
  4. Aubier M, Murciano D, Lecocguic Y, et al. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med 1985;313(7):420–424. — the diaphragm arm and the reason RESULT 10 attributes most of the PaCO2 gap to the pump rather than the CO2 load. https://pubmed.ncbi.nlm.nih.gov/4022081/
  5. Lichtman MA, Miller DR, Cohen J, Waterhouse C. Reduced red cell glycolysis, 2,3-diphosphoglycerate and adenosine triphosphate concentration, and increased hemoglobin-oxygen affinity caused by hypophosphatemia. Ann Intern Med 1971;74(4):562–568. — the 2,3-DPG compartment and the left-shifted oxygen curve. https://pubmed.ncbi.nlm.nih.gov/5551159/
  6. Travis SF, Sugerman HJ, Ruberg RL, et al. Alterations of red-cell glycolytic intermediates and oxygen transport as a consequence of hypophosphatemia in patients receiving intravenous hyperalimentation. N Engl J Med 1971;285(14):763–768. — the original parenteral-nutrition observation. https://pubmed.ncbi.nlm.nih.gov/5570340/
  7. Davis SV, Olichwier KK, Chakko SC. Reversible depression of myocardial performance in hypophosphatemia. Am J Med Sci 1988;295(3):183–187. — https://pubmed.ncbi.nlm.nih.gov/3348135/
  8. Subramanian R, Khardori R. Severe hypophosphatemia: pathophysiologic implications, clinical presentations, and treatment. Medicine (Baltimore) 2000;79(1):1–8. — https://pubmed.ncbi.nlm.nih.gov/10670405/
  9. Brautbar N, Baczynski R, Carpenter C, et al. Impaired energy metabolism in rat myocardium during phosphate depletion. Am J Physiol 1982;242(4):F699–F704. — the ATP/phosphocreatine dependence on inorganic phosphate. https://pubmed.ncbi.nlm.nih.gov/7072654/
  10. Cirillo M, Ciacci C, De Santo NG. Age, renal tubular phosphate reabsorption, and serum phosphate levels in adults. N Engl J Med 2008;359(8):864–866. — https://pubmed.ncbi.nlm.nih.gov/18716307/
  11. Boyd JW. The relationships between blood haemoglobin concentration, packed cell volume and plasma protein concentration in dehydration. Br Vet J 1981;137(2):166–172. — background for the haemoconcentration correction on measured concentrations.

4. Glucose, insulin, the incretin effect, and the transcellular shift

  1. Bergman RN, Ider YZ, Bowden CR, Cobelli C. Quantitative estimation of insulin sensitivity. Am J Physiol 1979;236(6):E667–E677. — the minimal-model structure (remote insulin compartment X) used for the glucose–insulin submodel. https://pubmed.ncbi.nlm.nih.gov/443421/
  2. Nauck MA, Homberger E, Siegel EG, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 1986;63(2):492–498. — the ~35 % incretin share of fed insulin secretion, and the oral-vs-intravenous asymmetry the model uses to separate enteral feed from IV dextrose. https://pubmed.ncbi.nlm.nih.gov/3522621/
  3. Nauck MA, Meier JJ. Incretin hormones: their role in health and disease. Diabetes Obes Metab 2018;20(Suppl 1):5–21. — https://pubmed.ncbi.nlm.nih.gov/29364588/
  4. DeFronzo RA, Felig P, Ferrannini E, Wahren J. Effect of graded doses of insulin on splanchnic and peripheral potassium metabolism in man. Am J Physiol 1980;238(5):E421–E427. — the insulin–potassium shift and its saturation, which set EMAXK. https://pubmed.ncbi.nlm.nih.gov/6990783/
  5. Sterns RH, Grieff M, Bernstein PL. Treatment of hyperkalemia: something old, something new. Kidney Int 2016;89(3):546–554. — the 0.6–1.0 mmol/L fall in serum potassium from insulin-dextrose, used as a non-refeeding calibration point. https://pubmed.ncbi.nlm.nih.gov/26880451/
  6. Newsholme EA, Start C. Regulation in Metabolism. London: Wiley; 1973. — glycolytic intermediate pools and the phosphate they sequester.
  7. Klein S, Sakurai Y, Romijn JA, Carroll RM. Progressive alterations in lipid and glucose metabolism during short-term fasting in young adult men. Am J Physiol 1993;265(5 Pt 1):E801–E806. — https://pubmed.ncbi.nlm.nih.gov/8238506/
  8. Soeters MR, Soeters PB, Schooneman MG, et al. Adaptive reciprocity of lipid and glucose metabolism in human short-term starvation. Am J Physiol Endocrinol Metab 2012;303(12):E1397–E1407. — https://pubmed.ncbi.nlm.nih.gov/23074240/
  9. Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab 2014;25(1):42–52. — https://pubmed.ncbi.nlm.nih.gov/24140022/
  10. Boden G. Effects of free fatty acids on gluconeogenesis and glycogenolysis. Life Sci 2003;72(9):977–988. — https://pubmed.ncbi.nlm.nih.gov/12495777/

5. Starvation physiology, body composition and the metabolic adaptation

  1. Keys A, Brozek J, Henschel A, Mickelsen O, Taylor HL. The Biology of Human Starvation. Minneapolis: University of Minnesota Press; 1950. — the Minnesota Starvation Experiment: the reference dataset for the starvation phase, including the body-composition and cardiac changes.
  2. Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006;26:1–22. — https://pubmed.ncbi.nlm.nih.gov/16848698/
  3. Forbes GB. Lean body mass-body fat interrelationships in humans. Nutr Rev 1987;45(8):225–231. — the fat/lean partition rule used in the starvation phase. https://pubmed.ncbi.nlm.nih.gov/3306482/
  4. Hall KD. What is the required energy deficit per unit weight loss? Int J Obes (Lond) 2008;32(3):573–576. — energy densities of adipose and lean tissue (9440 and 1800 kcal/kg). https://pubmed.ncbi.nlm.nih.gov/17848938/
  5. Cunningham JJ. A reanalysis of the factors influencing basal metabolic rate in normal adults. Am J Clin Nutr 1980;33(11):2372–2374. — the REE equation. https://pubmed.ncbi.nlm.nih.gov/7435418/
  6. Rosenbaum M, Leibel RL. Adaptive thermogenesis in humans. Int J Obes (Lond) 2010;34(Suppl 1):S47–S55. — the adaptive-thermogenesis floor and its slow recovery, reused as the marker of the insulin-resistant adapted state. https://pubmed.ncbi.nlm.nih.gov/20935667/
  7. Pierson RN Jr, Wang J, Colt EW, Neumann P. Body composition measurements in normal man: the potassium, sodium, sulfate and tritium spaces. J Chronic Dis 1982;35(6):419–428. — the ~70 mmol total body potassium per kg fat-free mass the model uses (72). https://pubmed.ncbi.nlm.nih.gov/7042769/
  8. Wang Z, St-Onge MP, Lecumberri B, et al. Body cell mass: model development and validation at the cellular level of body composition. Am J Physiol Endocrinol Metab 2004;286(1):E123–E128. — https://pubmed.ncbi.nlm.nih.gov/14532167/
  9. Björntorp P. Effects of energy reduction on metabolic rates and body composition. Int J Obes 1981;5(Suppl 1):119–124.
  10. Newton JL, Travis SPL. Nutrition and the gut: refeeding. Clin Med (Lond) 2006;6(2):141–146. — https://pubmed.ncbi.nlm.nih.gov/16688969/

6. Thiamine: stores, kinetics, transport, and Wernicke encephalopathy

  1. Ariaey-Nejad MR, Balaghi M, Baker EM, Sauberlich HE. Thiamin metabolism in man. Am J Clin Nutr 1970;23(6):764–778. — the whole-body store (~25–30 mg) and the biological half-life (9–18 d) from which the model predicts the 1.1–1.4 mg/d requirement rather than assuming it. https://pubmed.ncbi.nlm.nih.gov/5445068/
  2. Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington DC: National Academies Press; 1998. — the published RDA the emergent check is scored against. https://www.ncbi.nlm.nih.gov/books/NBK114310/
  3. Smithline HA, Donnino M, Greenblatt DJ. Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects. BMC Clin Pharmacol 2012;12:4. — the saturation of oral absorption, and the data behind the model's refuted prediction that oral cannot replete. https://pubmed.ncbi.nlm.nih.gov/22305197/
  4. Thomson AD, Baker H, Leevy CM. Patterns of 35S-thiamine hydrochloride absorption in the malnourished alcoholic patient. J Lab Clin Med 1970;76(1):34–45. — ethanol impairment of intestinal thiamine uptake. https://pubmed.ncbi.nlm.nih.gov/5449328/
  5. Said HM. Intestinal absorption of water-soluble vitamins in health and disease. Biochem J 2011;437(3):357–372. — ThTR-1/ThTR-2 kinetics and the passive route at high concentrations, which is the mechanistic basis of the "two clocks" result. https://pubmed.ncbi.nlm.nih.gov/21749321/
  6. Rindi G, Laforenza U. Thiamine intestinal transport and related issues: recent aspects. Proc Soc Exp Biol Med 2000;224(4):246–255. — https://pubmed.ncbi.nlm.nih.gov/10964259/
  7. Donnino MW, Vega J, Miller J, Walsh M. Myths and misconceptions of Wernicke's encephalopathy: what every emergency physician should know. Ann Emerg Med 2007;50(6):715–721. — including the "thiamine before glucose" question the timing sweep addresses directly. https://pubmed.ncbi.nlm.nih.gov/17681641/
  8. Schabelman E, Kuo D. Glucose before thiamine for Wernicke encephalopathy: a literature review. J Emerg Med 2012;42(4):488–494. — the evidence base for the rule the model only partly supports. https://pubmed.ncbi.nlm.nih.gov/22104258/
  9. Galvin R, Bråthen G, Ivashynka A, et al. EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. Eur J Neurol 2010;17(12):1408–1418. — the 200–500 mg IV dosing used in the thiamine arms. https://pubmed.ncbi.nlm.nih.gov/20642790/
  10. Sechi G, Serra A. Wernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol 2007;6(5):442–455. — https://pubmed.ncbi.nlm.nih.gov/17434099/
  11. Klein M, Weksler N, Gurman GM. Fatal metabolic acidosis caused by thiamine deficiency. J Emerg Med 2004;26(3):301–303. — type B lactic acidosis from a blocked pyruvate gate. https://pubmed.ncbi.nlm.nih.gov/15028328/
  12. Attaluri P, Castillo A, Edriss H, Nugent K. Thiamine deficiency: an important consideration in critically ill patients. Am J Med Sci 2018;356(4):382–390. — https://pubmed.ncbi.nlm.nih.gov/30360807/
  13. Patel MS, Korotchkina LG. Regulation of the pyruvate dehydrogenase complex. Biochem Soc Trans 2006;34(Pt 2):217–222. — TPP dependence of the PDH gate. https://pubmed.ncbi.nlm.nih.gov/16545080/
  14. Frank LL. Thiamin in clinical practice. JPEN J Parenter Enteral Nutr 2015;39(5):503–520. — https://pubmed.ncbi.nlm.nih.gov/25564426/

7. Potassium and magnesium: renal handling and the coupling between them

  1. Youn JH, McDonough AA. Recent advances in understanding integrative control of potassium homeostasis. Annu Rev Physiol 2009;71:381–401. — https://pubmed.ncbi.nlm.nih.gov/18759644/
  2. Palmer BF. Regulation of potassium homeostasis. Clin J Am Soc Nephrol 2015;10(6):1050–1060. — the aldosterone/ROMK control the model uses, including potassium as the dominant aldosterone secretagogue. https://pubmed.ncbi.nlm.nih.gov/24721891/
  3. Squires RD, Huth EJ. Experimental potassium depletion in normal human subjects. I. Relation of ionic intakes to the renal conservation of potassium. J Clin Invest 1959;38(7):1134–1148. — the incomplete renal adaptation to potassium depletion (a floor of roughly 10–20 mmol/d) that the model's KOBL and ROMK term reproduce; the absence of this was one of the defects the Python verification exposed. https://pubmed.ncbi.nlm.nih.gov/13664789/
  4. Huang CL, Kuo E. Mechanism of hypokalemia in magnesium deficiency. J Am Soc Nephrol 2007;18(10):2649–2652. — the intracellular magnesium block on ROMK, i.e. the mechanism behind refractory hypokalaemia. https://pubmed.ncbi.nlm.nih.gov/17804670/
  5. Whang R, Whang DD, Ryan MP. Refractory potassium repletion. A consequence of magnesium deficiency. Arch Intern Med 1992;152(1):40–45. — the clinical phenomenon the model reproduces only modestly, and says so. https://pubmed.ncbi.nlm.nih.gov/1728927/
  6. Agus ZS. Hypomagnesemia. J Am Soc Nephrol 1999;10(7):1616–1622. — https://pubmed.ncbi.nlm.nih.gov/10405219/
  7. de Baaij JHF, Hoenderop JGJ, Bindels RJM. Magnesium in man: implications for health and disease. Physiol Rev 2015;95(1):1–46. — total body magnesium, the exchangeable fraction, and the renal threshold that makes a bolus wasteful. https://pubmed.ncbi.nlm.nih.gov/25540137/
  8. Elin RJ. Assessment of magnesium status for diagnosis and therapy. Magnes Res 2010;23(4):S194–S198. — https://pubmed.ncbi.nlm.nih.gov/20736141/
  9. Rude RK, Oldham SB, Singer FR. Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency. Clin Endocrinol (Oxf) 1976;5(3):209–224. — magnesium dependence of PTH secretion, which in this model is what disables the skeletal phosphate supply line. https://pubmed.ncbi.nlm.nih.gov/947478/
  10. Vormann J. Magnesium: nutrition and metabolism. Mol Aspects Med 2003;24(1-3):27–37. — https://pubmed.ncbi.nlm.nih.gov/12537987/

8. Calcium, PTH, vitamin D and FGF23

  1. Brown EM. Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract Res Clin Endocrinol Metab 2013;27(3):333–343. — the sigmoidal PTH–calcium relationship. https://pubmed.ncbi.nlm.nih.gov/23856263/
  2. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004;19(3):429–435. — https://pubmed.ncbi.nlm.nih.gov/15040831/
  3. Kuro-o M. The FGF23 and Klotho system beyond mineral metabolism. Clin Exp Nephrol 2017;21(Suppl 1):64–69. — https://pubmed.ncbi.nlm.nih.gov/28062938/
  4. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients. Am J Kidney Dis 1998;31(4):607–617. — the calcium–phosphate product threshold used in the precipitation term. https://pubmed.ncbi.nlm.nih.gov/9531176/
  5. Bushinsky DA, Monk RD. Electrolyte quintet: calcium. Lancet 1998;352(9124):306–311. — https://pubmed.ncbi.nlm.nih.gov/9690425/

9. Repletion pharmacology: doses, rates and their hazards

  1. Taylor BE, Huey WY, Buchman TG, et al. Treatment of hypophosphatemia using a protocol based on patient weight and serum phosphorus level in a surgical intensive care unit. J Am Coll Surg 2004;198(2):198–204. — the weight-based repletion protocol the model's P_DOSE band is taken from. https://pubmed.ncbi.nlm.nih.gov/14759775/
  2. Charron T, Bernard F, Skrobik Y, et al. Intravenous phosphate in the intensive care unit: more aggressive repletion regimens for moderate and severe hypophosphatemia. Intensive Care Med 2003;29(8):1273–1278. — https://pubmed.ncbi.nlm.nih.gov/12845429/
  3. Brown KA, Dickerson RN, Morgan LM, et al. A new graduated dosing regimen for phosphorus replacement in patients receiving nutrition support. JPEN J Parenter Enteral Nutr 2006;30(3):209–214. — https://pubmed.ncbi.nlm.nih.gov/16639067/
  4. Bugg NC, Jones JA. Hypophosphataemia: pathophysiology, effects and management on the intensive care unit. Anaesthesia 1998;53(9):895–902. — https://pubmed.ncbi.nlm.nih.gov/9849285/
  5. Kraft MD, Btaiche IF, Sacks GS, Kudsk KA. Treatment of electrolyte disorders in adult patients in the intensive care unit. Am J Health Syst Pharm 2005;62(16):1663–1682. — potassium, magnesium and phosphate repletion rates. https://pubmed.ncbi.nlm.nih.gov/16085929/
  6. Hébert P, Mehta N, Wang J, et al. Functional magnesium deficiency in critically ill patients identified using a magnesium-loading test. Crit Care Med 1997;25(5):749–755. — the renal-threshold behaviour behind the bolus-versus-infusion result. https://pubmed.ncbi.nlm.nih.gov/9187592/
  7. Ayuk J, Gittoes NJL. How should hypomagnesaemia be investigated and treated? Clin Endocrinol (Oxf) 2011;75(6):743–746. — https://pubmed.ncbi.nlm.nih.gov/21569071/

10. Route, formula composition and the respiratory cost of carbohydrate

  1. Askanazi J, Rosenbaum SH, Hyman AI, et al. Respiratory changes induced by the large glucose loads of total parenteral nutrition. JAMA 1980;243(14):1444–1447. — the CO2 load of glucose-based feeding. https://pubmed.ncbi.nlm.nih.gov/6767014/
  2. 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):551–555. — the finding that total calories matter more than carbohydrate fraction for CO2, which the model's RESULT 10 revisits and partly reinterprets. https://pubmed.ncbi.nlm.nih.gov/1643945/
  3. Wolfe RR, O'Donnell TF Jr, Stone MD, et al. Investigation of factors determining the optimal glucose infusion rate in total parenteral nutrition. Metabolism 1980;29(9):892–900. — the ~4–5 mg/kg/min ceiling on glucose oxidation used in the gas-exchange block. https://pubmed.ncbi.nlm.nih.gov/6774136/
  4. Singer P, Blaser AR, Berger MM, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr 2019;38(1):48–79. — https://pubmed.ncbi.nlm.nih.gov/30348463/
  5. Elia M, Cummings JH. Physiological aspects of energy metabolism and gastrointestinal effects of carbohydrates. Eur J Clin Nutr 2007;61(Suppl 1):S40–S74. — https://pubmed.ncbi.nlm.nih.gov/17992186/

11. Population-specific evidence: anorexia nervosa, alcohol, and critical illness

  1. Garber AK, Cheng J, Accurso EC, et al. Short-term outcomes of the study of refeeding to optimize inpatient gains for patients with anorexia nervosa: a randomized clinical trial. JAMA Pediatr 2021;175(1):19–27. — the higher-calorie refeeding trial in anorexia nervosa. https://pubmed.ncbi.nlm.nih.gov/33074282/
  2. O'Connor G, Nicholls D. Refeeding hypophosphatemia in adolescents with anorexia nervosa: a systematic review. Nutr Clin Pract 2013;28(3):358–364. — https://pubmed.ncbi.nlm.nih.gov/23515708/
  3. Whitelaw M, Gilbertson H, Lam PY, Sawyer SM. Does aggressive refeeding in hospitalized adolescents with anorexia nervosa result in increased hypophosphatemia? J Adolesc Health 2010;46(6):577–582. — https://pubmed.ncbi.nlm.nih.gov/20472215/
  4. Society for Adolescent Health and Medicine. Refeeding hypophosphatemia in hospitalized adolescents with anorexia nervosa: a position statement. J Adolesc Health 2022;71(4):517–520. — https://pubmed.ncbi.nlm.nih.gov/35970149/
  5. Sacks GS, Walker J, Dickerson RN, et al. Observations of hypophosphatemia and its management in nutrition support. Nutr Clin Pract 1994;9(3):105–108. — https://pubmed.ncbi.nlm.nih.gov/8065226/
  6. Palmese S, Scarano V, Bruno G. Hypophosphatemia and metabolic acidosis: a case of severe refeeding syndrome. Nutr Ther Metab 2010;28(2):89–92.
  7. Elnenaei MO, Alaghband-Zadeh J, Sherwood R, et al. Leptin and insulin growth factor 1: diagnostic markers of the refeeding syndrome and mortality. Br J Nutr 2011;106(6):906–912. — https://pubmed.ncbi.nlm.nih.gov/21736847/
  8. Pourhassan M, Cuvelier I, Gehrke I, et al. Risk factors of refeeding syndrome in malnourished older hospitalized patients. Clin Nutr 2018;37(4):1354–1359. — https://pubmed.ncbi.nlm.nih.gov/28647294/

12. QSP, mrgsolve and modelling method

  1. Baron KT, Gastonguay MR. Simulation from ODE-based population PK/PD and systems pharmacology models in R with mrgsolve. J Pharmacokinet Pharmacodyn 2015;42:S84–S85. — https://mrgsolve.org
  2. Peterson MC, Riggs MM. A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling. Bone 2010;46(1):49–63. — the reference QSP treatment of the calcium–phosphate–PTH–vitamin D system, and the structural model for this file's bone block. https://pubmed.ncbi.nlm.nih.gov/19664732/
  3. Riggs MM, Peterson MC, Gastonguay MR. Multiscale physiology-based modeling of mineral bone disorder in patients with impaired kidney function. J Clin Pharmacol 2012;52(1 Suppl):45S–53S. — https://pubmed.ncbi.nlm.nih.gov/22232755/
  4. Nijhout HF, Best JA, Reed MC. Systems biology of robustness and homeostatic mechanisms. Wiley Interdiscip Rev Syst Biol Med 2019;11(3):e1440. — on why a model whose healthy state is an exact steady state behaves differently from one that is merely initialised near it. https://pubmed.ncbi.nlm.nih.gov/30576081/
  5. Gadkar K, Kirouac DC, Mager DE, et al. A six-stage workflow for robust application of systems pharmacology. CPT Pharmacometrics Syst Pharmacol 2016;5(5):235–249. — https://pubmed.ncbi.nlm.nih.gov/27299936/

How these were used

The calibration policy stated in rfs_mrgsolve_model.R is that three numbers were fitted to refeeding syndrome itself: the size of the flux-driven rise in the cellular organic-phosphate set-point, the rate at which cells approach it, and one global mortality-hazard scale. Sections 2, 5, 6, 7 and 8 above supply the normal physiology; sections 4, 9 and 10 supply non-refeeding pharmacology; section 1 and section 11 supply the clinical outcomes the model's predictions are compared against rather than fitted to.

The strongest internal check comes from section 6: references 53 and 54 give the whole-body thiamine store and its half-life independently of any requirement figure, and the model then computes a dietary requirement of 1.42 mg/d against a published RDA of 1.1–1.4 mg/d — a number it was never shown.