Nutrition 30 (2014) 1090–1092

Contents lists available at ScienceDirect

Nutrition

journal homepage: www.nutritionjrnl.com

Case report Refractory hypoglycemia and subsequent cardiogenic in and refeeding: Report of three cases

Kentaro Shimizu M.D. a,*, Hiroshi Ogura M.D. a, Masafumi Wasa M.D. b, Tomoya Hirose M.D. a, Takeshi Shimazu M.D. a, Hironori Nagasaka M.D. c, Ken-ichi Hirano M.D. d a Department of and Acute Critical , Osaka University Graduate School of Medicine, Osaka, Japan b Medical Education Center, Osaka University Graduate School of Medicine, Osaka, Japan c Department of , Takarazuka City Hospital, Hyogo, Japan d Laboratory of Cardiovascular Disease, Novel, Non-invasive and Nutritional Therapeutics (CNT), Graduate School of Medicine, Osaka University, Osaka, Japan article info abstract

Article history: Objective: Although starvation is associated with high in-hospital mortality, its related cardiac Received 8 September 2013 complications are not sufficiently understood. The aim of this study was to determine the clinical Accepted 10 January 2014 course and pathogenesis of cardiac complications in malnourished patients. Methods: We reviewed three cases of hypoglycemia and hypotriglyceridemia with cardiac com- Keywords: plications in starvation. Starvation Results: This report concerns three patients, respectively suffering from nervosa, esoph- Refeeding ageal carcinoma, and Parkinson’s disease. Their ages ranged from 18 to 70 y, body mass index was Hypoglycemia 2 Hypotriglyceridemia 11.5 1.5 kg/m (mean SD), and the main symptom was . The average blood glucose level was 15.7 7.8 mg/dL without any history of use or diabetes mellitus. In all cases, hypo- Takotsubo cardiomyopathy glycemia was refractory and repetitive so that continuous glucose administration was required to maintain euglycemia. triglyceride and non-esterified fatty acid levels were also very low (7 4 mg/dL and 10 9.1 mEq/L, respectively). Levels of serum , phosphate, and magne- sium were almost normal at admission. The main cardiac complications included Takotsubo car- diomyopathy and cardiac arrest. All patients survived as a result of intensive treatment. Conclusions: Repetitive severe hypoglycemia without known background causes should be viewed as an important sign. Once this occurs, the administration of a much higher caloric input than usual accompanied by intensive will be required to maintain appropriate glucose levels. The early identification of such patients seems to be essential to reduce the high risk for cardiac complications during starvation and refeeding. Ó 2014 Elsevier Inc. All rights reserved.

Introduction mortality [3]. However, starvation-related cardiac complications are not sufficiently recognized and only a few reports have in hospitals has been increasing despite pro- described the related metabolic profiles [4]. longed life span and progress in medical treatments [1] and Hypoglycemia represents an important metabolic emergency malnourished patients are associated with longer hospital in the critical care field and especially hypoglycemia without the lengths of stay and poorer survival rates [2]. Patients suffering use of insulin features higher mortality. Low body mass index from starvation, i.e., a severely malnourished state, show higher (BMI) is an important risk factor for hypoglycemia, the clinical course of which is still poorly understood [5,6]. KS, TH, and TS analyzed the data from the perspective of critical care. MW and In this study, we reviewed three hospitalized cases with sud- HN analyzed the data from the perspective of nutrition. KH analyzed the data den cardiac complications related to severe starvation. In all cases, from the perspective of . KS, HO, and KH organized and wrote the both hypoglycemic coma and hypotriglyceridemia preceded the manuscript. * Corresponding author. Tel.: þ81 6 6879 5707; fax: þ81 6 6879 5720 . onset of cardiac complications. We also discuss how such cases E-mail address: [email protected] (K. Shimizu). might be identified and cardiac complications prevented.

0899-9007/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nut.2014.01.007 K. Shimizu et al. / Nutrition 30 (2014) 1090–1092 1091

Case 1 IU/L, total 6.3 g/dL, phosphate 9.3 mg/dL, and TG 3 mg/ dL. He was in hypoglycemic coma accompanied by hypo- An ambulatory 18-y-old woman with pre- triglyceridemia with elevated liver enzymes. Acetate Ringer’s sented with appetite loss. Her BMI was 9.9 kg/m2. On the day of solution with 5% dextrose was administered at 100 mL/h, but admission, enteral nutrition was administered via nasal tube, his blood glucose had dropped to 39 mg/dL at 11 h after 250 mL (250 kcal) in 3 h. After administration, she became admission, when he suddenly became bradycardic followed by comatose and was transferred to the . Arterial cardiac arrest. He was resuscitated successfully 7 min after 1 blood gases were pH 7.43, PaCO2 40.3 mm Hg, PaO2 83.7 mm Hg, cardiac arrest and required dopamine 14 mg$min$kg for cir- HCO3 26.5 mmol/L, and base excess 2.5 mmol/L. Blood tests culatory support. Acetated Ringer’s solution with 5% dextrose findings were sodium 141 mEq/L; potassium 4.4 mEq/L; glucose was administered at 100 mL/h to maintain euglycemia and at 21 mg/dL (normal range: 70–110 mg/dL); phosphate 6.2 mg/dL 480 kcal/d on day 2 without signs of hypoglycemia. His Glasgow (normal range: 2.9–4.8 mg/dL); triglyceride (TG) 11 mg/dL Coma Scale had recovered to E3 V-M4 on hospital day 3. (normal range: 30–150 mg/dL); aspartate aminotransferase Because the patient’s NEFA level was markedly low (3 mEq/L) on (AST) 3961 IU/L; and total protein 6.5 g/dL. She was in day 4, we began continuous enteral nutrition at 20 kcal/h (480 hypoglycemic coma accompanied by hypotriglyceridemia with kcal/d) on day 6. Cardiac function recovered gradually and elevated liver enzymes. We administered intravenous (IV) dopamine was reduced to 3 mg$min$kg 1 on day 7 after which Ò glucose and a vitamin, Alinamin -F (fursultiamine 100 mg, a his condition became stable. He was then transferred to another derivative), but the blood glucose level took 1 h to rise hospital. to normal after repetitive infusion of 44 g glucose in total. Her consciousness became clear after she had recovered from re- Case 3 fractory hypoglycemia. Administration of acetated Ringer solu- tion with 5% dextrose was initiated and gradually increased to a A 58-y-old woman was admitted due to anemia. She had a total of 480 kcal/d. On day 2, her blood pressure suddenly began past history of postoperative laryngeal and esophageal tumor, for to decrease. Echocardiography revealed apical ballooning with which she was not taking medication. Her BMI was 11.8 kg/m2, relatively strong contraction in the basal left ventricle. She was blood pressure 98/65 mm Hg, and pulse rate 66/min. Her con- diagnosed with Takotsubo cardiomyopathy because, apart from sciousness was lucid. Prophylactic administration of a vitamin Ò malnutrition, she had no known previous abnormalities. The (Vitamedine ) was initiated with saline. On day 3, the patient patient’s non-esterified fatty acid (NEFA) level was markedly low became drowsy, and her blood glucose was 19 mg/dL. Because at 17 mEq/L (normal: 130–770 mEq/L). Enteral nutrition was hypoglycemia was refractory, 30 g IV glucose was needed for initiated at 10 kcal/h (240 kcal/d) on day 6 and by day 12, cardiac recovery to normal and infusion with 744 kcal/d to maintain wall motion had returned to normal. On day 18, the patient was euglycemia. White blood cell count was 9780/mm3, red blood transferred to the psychiatric ward. cell count 220 104/mm3, hemoglobin 7.4 g/dL, hematocrit 21.7%, and platelet count 4.2 104/mm3. Biochemical findings Case 2 included sodium 129 mEq/L, potassium 3.7 mEq/L, glucose 68 mg/dL, AST 617 IU/L, total protein 5.2 g/dL, albumin 2.1 g/dL and A 70-y-old man with Parkinson’s disease was admitted as an TG 7 mg/dL. The patient was suffering from anemia, hypo- emergency patient because of loss of consciousness. His blood triglyceridemia with elevated liver enzymes, and severe malnu- pressure was 117/37 mm Hg, pulse rate 87/min, and BMI 12.8 trition. On day 4, the patient suffered congestive . kg/m2. Because his blood glucose level was 7 mg/dL, he required Echocardiography revealed apical ballooning with relatively Ò infusion of glucose 30 g and vitamin (Vitamedine :Thiamine strong contraction in the basal left ventricle, requiring 2 disulfide phosphate 107.13 mg, pyridoxine hydrochloride 100 mg$min$kg 1 of dobutamine and furosemide. On day 6, total mg, and cyanocobalamin 1 mg) before the level returned to was initiated at 819 kcal/d. The patient’s normal. He was intubated because he did not recover con- blood pressure had recovered to normal gradually and dobut- sciousness due to refractory hypoglycemia. Initial blood test amine was stopped on day 17, after which she gradually recov- results were sodium 144 mEq/L, potassium 5.2 mEq/L, AST 2830 ered and was transferred to another hospital.

Table 1 Patient characteristics and blood test results

Case 1 Case 2 Case 3 Age 18 70 58 Sex (M/F) FM F Body weight (kg) 26.5 32.0 27.0 BMI (kg/m2) 9.9 12.8 11.8 Past history Anorexia nervosa Parkinson’s disease Esophageal carcinoma Glucose (mg/dL) 21 7 19 Calories administered to maintain euglycemia during hypoglycemia (kcal/d) 25.2 11.9 27.6 Maximum daily frequency of hypoglycemia 5 3 5 Non-esterified fatty acids (mEq/L) (normal: 130–770) 17 3 – Triglyceride (mg/dL) (normal: 30–150) 11 3 7 Potassium (mEq/L) (normal: 3.6–4.8) 4.7 5.3 3.4 Phosphate (mg/dL) (normal: 2.9–4.8) 6.2 9.3 2.9 (mg/dL) (normal: 1.8–2.4) 1.8 2.9 1.6 Lactate (mg/dL) (normal: 3–17) 5 5 – Cardiac complications Takotsubo Cardiac arrest Takotsubo Time from coma to cardiac complications (d) 1 2 1

BMI, body mass index; Takotsubo, Takotsubo cardiomyopathy 1092 K. Shimizu et al. / Nutrition 30 (2014) 1090–1092

Discussion carnitine transport system, and ketogenesis, could be needed [12]. These metabolic profiles could lead to future supplemental We reviewed three cases of cardiac complications related to treatment with certain kinds of fatty acids, carnitine, or ketone starvation (Table 1). These cases demonstrated two characteristic bodies. Prospective clinical trials would be needed to determine features. One is repetitive and refractory hypoglycemia without how to identify and treat patients with cardiac complications exogenous insulin administration. In these cases, the hypogly- related to starvation. cemic coma was refractory so that the patients needed >30 g glucose in total administered by IV to normalize their glucose Conclusions levels. Additionally, continuous glucose administration was required to maintain euglycemia. Hypoglycemia is usually pre- To the best of our knowledge, this is the first report of vented by physiological defenses such as , epinephrine, a syndrome consisting of hypoglycemic coma, hypotriglycer- cortisol, and growth hormone. Severe hypoglycemia is thought idemia, and subsequent . The early identifica- not to occur until the terminal stages of starvation when gluco- tion of such patients seems to be essential to reduce the high risk neogenesis from protein is no longer possible, although only a for cardiac complications during starvation and refeeding. modest reduction in blood glucose levels may have occurred during . Causes of hypoglycemia other than diabetes mellitus include drugs, critical illnesses, hormone deficiency, Acknowledgment endogenous hypoinsulinisms, and others [7]. Starvation could be another main cause, but severe prolonged hypoglycemia, as seen The authors acknowledge the contributions made by Profes- in the cases presented here, is uncommon. Although details of sor Jeremy Powell-Tuck (Emeritus Professor of Clinical Nutrition, the metabolic changes involved in fasting and feeding need to be Barts and the London School of Medicine and Dentistry), who clarified, we speculate that systemic utilization of glucose in the reviewed the manuscript. human body cannot be balanced by the energy supply. Addi- tionally, endogenous glucose production and fatty acid oxidation are reduced when glucose is administered [8], or feeding after a References long period of starvation may result in secretion of too much [1] Lean M, Wiseman M. Malnutrition in hospitals. BMJ 2008;336:290. insulin to maintain euglycemia. Another cause of hypoglycemia [2] Lim SL, Ong KC, Chan YH, Loke WC, Ferguson M, Daniels L. Malnutrition and is extremely low levels of plasma TGs and NEFA, both of which its impact on cost of hospitalization, length of stay, readmission and 3-year – are major energy sources for the heart [9]. We believe that mortality. Clin Nutr 2012;31:345 50. fi [3] Collins S. The limit of human adaptation to starvation. Nat Med insuf cient cardiac energy supply with glucose and lipids led to 1995;1:810–4. the development of cardiac complications. It is clear that further [4] Korbonits M, Blaine D, Elia M, Powell-Tuck J. Metabolic and hormonal metabolic studies are needed to clarify the underlying mecha- changes during the refeeding period of prolonged fasting. Eur J Endocrinol 2007;157:157–66. nisms of hypoglycemia. [5] Hypoglycaemia linked to excess deaths in critically ill adults. BMJ Guidelines from the National Institute for Health and Clinical 2012;345:e6411. Excellence (NICE) recommend that, in extreme cases of starva- [6] Finfer S, Liu B, Chittock DR, Norton R, Myburgh JA, McArthur C, et al. Hy- < 2 poglycemia and risk of death in critically ill patients. N Engl J Med tion in a person with BMI 14 kg/m , energy input should start at 2012;367:1108–18. a maximum of 5 kcal/kg daily and increase slowly to reach the [7] Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, et al. maximum by 4 to 7 d to avoid refeeding syndrome [10].How- Evaluation and management of adult hypoglycemic disorders: an Endo- crine Society Clinical Practice Guideline. J Clin Endocrinol Metab ever, because refractory hypoglycemia continued in our cases, 2009;94:709–28. we had to administer two to five times more calories than rec- [8] Sidossis LS, Wolfe RR. Glucose and insulin-induced inhibition of fatty acid ommended by NICE to maintain euglycemia [11]. Repetitive se- oxidation: the glucose-fatty acid cycle reversed. Am J Physiol 1996; – vere hypoglycemia without known background causes should be 270:E733 8. [9] Neubauer S. The failing heartdan engine out of fuel. N Engl J Med viewed as an important sign. Once this occurs, the administra- 2007;356:1140–51. tion of a much higher caloric input than usual, accompanied by [10] Nutrition support in adults: NICE guideline. http://guidance.nice.org.uk/ intensive monitoring, will be required to maintain appropriate CG32/NICEGuidance/pdf/English. [11] Boateng AA, Sriram K, Meguid MM, Crook M. Refeeding syndrome: treat- glucose levels. ment considerations based on collective analysis of literature case reports. A limitation of this study is that it is retrospective, and Nutrition 2010;26:156–67. more detailed metabolic information would be needed to [12] Frohlich J, Seccombe DW, Hahn P, Dodek P, Hynie I. Effect of fasting on free and esterified carnitine levels in human serum and urine: correlation with delineate this pathogenesis. Especially, more investigation into serum levels of free fatty acids and beta-hydroxybutyrate. the b-oxidation process, such as that of fatty acid fractions, the 1978;27:555–61.