We present a case of severe diabetic ketoacidosis in a 19-year-old male with a history of poor compliance to insulin therapy. At arrival to our Emergency Department, the patient was comatose with extreme hyperglycemia, severe diabetic ketoacidosis, lactic acidosis and dehydration. The treatment consisted of intensive fl uid replacement and correction of all metabolic disturbances until complete recovery. In the vast majority of severe diabetic ketoacidosis cases, relatively fast and successful treatment result can be expected if intensive therapy is applied and if ketoacidosis is not triggered by a serious illness. Some essential contemporary guidelines and the importance of individual treatment approach are pointed out in the article. The role of high serum procalcitonin value in diabetic ketoacidosis is discussed.Prikazan je slučaj 19-godišnjeg bolesnika od dijabetesa koji nije redovito primjenjivao inzulin. Bolesnik je doveden na naš objedinjeni hitni prijam u komatoznom stanju, s ekstremnom hiperglikemijom, teškom dijabetičkom ketoacidozom, laktacidozom i dehidracijom. Liječen je intenzivnom nadoknadom volumena i korekcijom svih metaboličkih poremećaja do potpunog oporavka. U velikoj većini slučajeva teških dijabetičkih ketoacidoza može se očekivati relativno brza i uspješna korekcija ako se primijeni intenzivno liječenje i ako ketoacidoza nije potaknuta ozbiljnom bolesti. U članku su navedene neke bitne suvremene smjernice u liječenju i naglašena je važnost individualnog pristupa. Raspravljena je i uloga visoke serumske vrijednosti prokalcitonina u dijabetičkoj ketoacidozi

GORANA MIROŠEVIĆ

VESNA DEGORICIJA

VESNA TRKEŠ

VESNA VUCELIĆ

ŽELJKO VUČIČEVIĆ

English

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215Case ReportActa Med Croatica, 73 (2019) 215-218INTRODUCTION Diabetic ketoacidosis (DKA) is most common among patients with type 1 diabetes mellitus (DM) and de-velops when insulin levels are insuffi  cient to meet the body’s basic metabolic requirements. It is characte-rized by modest or rarely extreme hyperglycemia, hyperketonemia, ketonuria and metabolic acidosis (1). Excessive glucose secretion by kidneys overco-mes the glucose tubular maximum reabsorption cre-ating a hyperosmolar state in renal tubules, whichcauses osmotic diuresis with signifi cant fl uid and ele-ctrolyte loss. Almost absolute lack of insulin forces the body to metabolize triglycerides and amino acids instead of glucose for energy, which in return results in excessive production of ketones (2). Hyperglycemic nonketotic state is more oft en seen in type 2 DM whe-re even minimal pancreatic insulin secretion does not allow excessive ketone production (3).CASE REPORTA 19-year-old male with a fi ve-year history of poor regulation of DM was admitted to our Intensive Care Unit (ICU) for clinical and laboratory signs of severe DKA, extreme hyperglycemia, hypovolemia, dehydra-tion, hypotension and lactic acidosis. He was found at home unresponsive, tachypneic, with nausea and vo-miting, which had lasted for four days until hospital arrival. During that time, there was no liquid or food intake or insulin application. Laboratory tests were as follows: RBC 4.9x1012/L, Hb 154 g/L, Htc 0.53 L/L, MCV 110.6 fL, L 25.6x109/L, platelet count 348x109/L, C-reactive protein (CRP) 132.2 mg/L; venous blood gas analysis: pH 6.83, pCO2 2.3 kPa, BE -30.5 mmo-l/L, pO2 11.24 kPa, bicarbonates 2.9 mmol/L, total CO2 3.4 mmol/L, O2 saturation 84.7 percent, blood glucose 87.9 mmol/L, creatinine 317 μmol/L, urea 11.8 mmo-l/L, lactic acid 3.2 mEq/L, AST 48 U/L, ALT 62 U/L, MANAGEMENT OF SEVERE DIABETIC KETOACIDOSIS IN A YOUNG ADULTVESNA VUCELIĆ1, ŽELJKO VUČIČEVIĆ1, VESNA DEGORICIJA1,GORANA MIROŠEVIĆ2 and VESNA TRKEŠ3Sestre milosrdnice University Hospital Centre, Department of Medicine, 1Department of Intensive Care, 2Department of Endocrinology and 3Zagreb University Hospital Centre, Jordanovac Hospital for Lung Diseases, Zagreb, CroatiaWe present a case of severe diabetic ketoacidosis in a 19-year-old male with a history of poor compliance to insulin therapy. At arrival to our Emergency Department, the patient was comatose with extreme hyperglycemia, severe diabetic ketoacidosis, lactic acidosis and dehydration. The treatment consisted of intensive fl uid replacement and correction of all metabolic disturbances until complete recovery. In the vast majority of severe diabetic ketoacidosis cases, relatively fast and successful treatment result can be expected if intensive therapy is applied and if ketoacidosis is not triggered by a serious illness. Some essential contemporary guidelines and the importance of individual treatment approach are pointed out in the article. The role of high serum procalcitonin value in diabetic ketoacidosis is discussed.Key words: diabetic ketoacidosis, hyperosmolar state, hypovolemia, treatment of diabetic ketoacidosisAddress for correspondence: Vesna Vucelić, MD Department of Intensive Care University Department of Medicine Sestre milosrdnice University Hospital Centre Vinogradska 29 10 000 Zagreb, Croatia Phone: +385 1 3787 935 E-mail: vesnavucelic@gmail.comV. Vucelić, Ž. Vučičević, V. Degoricija, G. Mirošević, V. TrkešManagement of severe diabetic ketoacidosis in young adultActa Med Croatica, 73 (2019) 215-218216K 7.2 mmol/L, Na 116 mmol/L, Cl 75 mmol/L, and procalcitonin (PCT) 34.9 ng/mL. Upon arrival to the ICU, the patient was comatose and smelled of acetone, with Kussmaul breathing 27 breaths/min, tachycardia 105/min, hypotension 85/45 mm Hg, oxygen satura-tion of 86% on pulse oximetry at room air (hypoten-sion!). Glasgow Coma Score was 7 and central venous pressure (CVP) was -4 cm H20. Urgent chest x-ray was normal. Neurological exami nation showed slightly delayed refl exes and decreased muscle tone consistent with altered mental status. Electrocardiography was within the normal range. Urine bacteriology, blood and stool cultures were sterile. In order to establish normotension and diuresis to induce glycosuria and ketonuria and to correct lactic acidosis, the patient re-ceived 1500 mL of normosaline volume replacement in the fi rst 90 minutes. Normosaline infusions conti-nued up to the total of 7 L in the fi rst 24 hours at the average infusion rate of 245 mL/hour and periodical control of CVP. At the very beginning, the patient re-ceived an intravenous bolus of 12 i.u. of rapid acting insulin, which was continued as a rapid acting insulin infusion at the average dose of 12 i.u. per hour, and close monitoring of blood glucose level every 2 hours. Total amount of rapid acting insulin applied intrave-nously in the fi rst 24 hours was 300 i.u. Due to the se-verely low pH and consecutive high serum potassium, sodium bicarbonate infusion was included in therapy at the rate of 30 mL/hour. In the next fi ve hours, the level of 7.2 and 5.9 mmol/L was reached for pH and potassium, respectively, which allowed bicarbonate therapy to be stopped. However, as blood glucose level and ketoacidosis improved, severe serum depletion of potassium occurred, which required replacement of 400 mL of KCL in the fi rst 48 hours and monitoring of serum potassium level every 6 hours. Following improvement of laboratory parameters, the patient’s mental status recovered, and so did his food and water intake per os. Insulin therapy was switched to subcuta-neous application. Aft er two days of treatment, com-plete resolution of DKA was reached, the patient was transferred to the Department of Endocrinology and soon discharged from the hospital. DISCUSSIONRegular clinic attendance is recommended to facilitate self‐management of diabetes. Poor attendance is com-mon among young adults with type 1 DM, which pre-cipitates acute diabetic complications (4). Psychosocial factors such as socioeconomic status, parental separa-tion and lack of family cohesiveness, unemployment, psychological and mental health factors including eat-ing disorders and substance abuse play a crucial role in the management of DM in young adults.Th e high frequency of DKA in known type 1 DM in-dicates the need of particular focus on adolescents (5). Spaic et al. found that structured transition program for young adults with type 1 diabetes improved clinic attendance, glycemic control, diabetes-related distress, quality of life, and satisfaction with care in regard to standard care (6).In our patient, history data were not indicative of so-cioeconomic or family problems, but his compliance was very poor and probably associated with psycho-logical profi le.Hypovolemia induced by osmotic diuresis includes the loss of fl uid, sodium and potassium (7). However, serum potassium is usually raised because of ketoaci-dosis, which is responsible for cell potassium reaching serum. Low serum potassium level at arrival means severe exhaustion of potassium cell backup. Hypo-volemia and consecutive hypotension stimulate the release of counter-regulatory diabetogenic hormones such as adrenaline and cortisol, thus causing further increase in serum glucose level. Th erefore, immediate volume replacement is of crucial importance and as urgent as the administration of rapid acting insulin (8). Any therapy during hypotension must be applied intravenously. Normosaline infusion is generally the best choice because of the usually low sodium level and high blood glucose level (9). Th e optimal rate of isotonic saline infusion depends on the patient’s clinical condition. Primary goal is to reach normotension and diuresis as soon as possible. Although the fl uid challenge therapy might be a do-uble-edge sword, we found it safe and useful for our young patient in severe hypovolemic state. When re-placing the volume, special attention must be paid to older patients or patients with heart or renal insuffi  -ciency (10). Insulin therapy should be initiated with IV bolus of re-gular insulin (0.1 units/kg body weight), followed by continuous infusion of regular insulin of 0.1  units/kg per hour (11). Th e bolus dose can be omitted if a higher dose of continuous IV regular insulin is ini-tiated (0.14  units/kg  per hour). Higher doses do not produce a more prominent hypoglycemic eff ect due to saturation of insulin receptors. In mild DKA, patients can be safely treated with subcutaneous, rapid-acting insulin analogs. Th ere is no diff erence in treating DKA with IV regular insulin and rapid-acting insulin ana-logs, along with much lower cost of regular insulin therapy. When serum glucose in DKA falls to less than 12 mmol/L, but bicarbonate and pH values are not nor-malized, glucose infusion is recommended (12). Each V. Vucelić, Ž. Vučičević, V. Degoricija, G. Mirošević, V. TrkešManagement of severe diabetic ketoacidosis in young adultActa Med Croatica, 73 (2019) 215-218217500 mL of 5% and 10% glucose infusion must contain 8 and 16 IU of rapid acting insulin, respectively, in or-der to provide glucose utilization and therefore eno-ugh energy to stop ketogenesis.In patients with euglycemic DKA, both insulin and glucose therapy is necessary, and the response to low-dose insulin therapy improves with adequate rehydration (13). We strongly advise to synchronize potassium repla-cement with laboratory monitoring. When potassi-um level is high, any replacement in advance is not recommended.Insulin therapy promotes potassium uptake by the cells along with glucose and may trigger cardiac arrhy-thmias. In severe hypokalemia (below 3.3 mEq/L), potassium administration in 500 mL of normosali-ne infusion at the rate of 10 to 20 mEq/hour will be suffi  cient for most patients. It must be followed by se-rum potassium measurements every two hours and stopped immediately when normal range is reached (14). Patients at risk of volume overload can receive more concentrated potassium infusion via central ve-nous catheter at the same dose but at a lower rate per hour. Th e indications for bicarbonate therapy in DKA are controversial and there is not enough evidence for its benefi t (15). If arterial pH is 6.9 or less, as in our patient, it might be of certain help, although most au-thors will cease this therapy as soon as the pH value reaches 7.0. In patients with potentially life-threa-tening potassium level over 6.4 mEq/L, bicarbonate therapy should be used until the level falls below 6.4 mEq/L (16).Initially, monitoring involves measurements of serum glucose every hour until the profi le becomes relative-ly stable. Serum electrolytes, creatinine, and venous blood gas analysis should be measured every two to four hours, depending on DKA severity and clinical response (17). When ketoacidosis is resolved and the patient is ready for oral intake, subcutaneous insulin schedule should be started and IV insulin infusion should be continued for one or two hours aft er initiating subcutaneous in-sulin to prevent recurrence of hyperglycemia or keto-acidosis. In patients previously treated with insulin, the established insulin regimen may be restarted. It is well-established that DKA is associated with leu-kocytosis and an increase in acute phase proteins, inc-luding CRP, tumor necrosis factor alpha, interleukin 1 beta (IL-1β), IL-2, IL-6 and IL-8.2 (18). Moderate increase of serum levels of procalcitonin in DKA is less known but practitioners should be aware that in-creases in CRP and PCT may occur in patients with DKA in the absence of bacterial infection, thus avoid-ing unnecessary examinations such as blood cultures and treatments (antibiotics) if other signs of infection are not present (19).Extremely high value of procalcitonin as in our pa-tient, in the proved absence of bacterial infection is very rare. However, it may be a consequence of syner-gistic eff ect of ketoacidosis and extremely high blood glucose level. It has been reported that correction of plasma glucose levels leads to a decrease of PCT con-centrations in patients presenting with acute hyper-glycemia (20), which is exactly what happened in our patient. CONCLUSIONTh erapeutic approach to DKA should be individual, the patient must receive adequate volume, adequate dose of insulin, appropriate electrolyte replacement, and must be carefully monitored. At the same time, precipitating events or triggers of ketoacidosis such as infection should be intensively looked for. DKA is frequently accompanied by moderate increase of se-rum levels of CRP and procalcitonin, which does not necessarily refl ect the presence of bacterial infection. As a result of actual therapy guidelines, further possi-ble complications of DKA have become less common. R  E  F  E  R  E  N  C  E  S1. Kitabchi AE, Umpierrez GE, Fisher JN et al. Th irty years of personal experience in hyperglycemic crises: diabetic ketoa-cidosis and hyperglycemic hyperosmolar state. J Clin Endocri-nol Metab 2008; 93: 1541-52.2. Arieff  AI, Carroll HJ. Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fl uid equili-bria and the eff ects of therapy in 37 cases. Medicine (Baltimore) 1972; 51: 73-94.3. Brown PM, Tompkins CV, Juul S, Sonksen PH. Mecha-nism of action of insulin in diabetic patients: a dose-related eff ect on glucose production and utilisation. Br Med J 1978; 1: 1239-42.4. Hynes L, Byrne M, Dinneen SF et al. Barriers and faci-litators associated with attendance at hospital diabetes clinics among young adults (15-30 years) with type 1 diabetes mellitus: a systematic review. Pediatr Diabetes 2016; 17: 509-18.5. Finn BP, Trayer J, Cronin C, O’Connell SM. High rates of diabetic ketoacidosis in patients with new and known type 1 diabetes over a six-year period. Ir Med J. 2019; 112: 898.V. Vucelić, Ž. Vučičević, V. Degoricija, G. Mirošević, V. TrkešManagement of severe diabetic ketoacidosis in young adultActa Med Croatica, 73 (2019) 215-2182186. Spaic T, Robinson T, Goldbloom E et al., for the JDRF Canadian Clinical Trial CCTN1102 Study Group. Closing the gap: results of the multicenter Canadian randomized controlled trial of structured transition in young adults with type 1 diabe-tes. Diabetes Care 2019; 42: 1018-26.7. Liamis G, Liberopoulus E, Barkas F, Elisaf M. Diabetes mellitus and electrolyte disorders. World J Clin Cases 2014; 2: 488-96.8. Kitabchi AE, Murphy MB, Spencer J et al. Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis? Diabetes Care 2008; 31: 2081-5.9. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyper-glycemic crises in adult patients with diabetes. Diabetes Care 2009; 32: 1335-43.10. Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med 2006; 34: 1333-7.11. Umpierrez GE, Jones S, Smiley D et al. Insulin analogs versus human insulin in the treatment of patients with diabe-tic ketoacidosis: a randomized controlled trial. Diabetes Care 2009; 32: 1164-9.12. Gosmanov AR, Gosmanova EO, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes 2014; 7: 255-64. 13. Kitabchi AE, Ayyagari V, Guerra SM. Th e effi  cacy of low-dose versus conventional therapy of insulin for treatment of diabetic ketoacidosis. Ann Intern Med 1976; 84: 633-8.14. Murthy K, Harrington JT, Siegel RD. Profound hypoka-lemia in diabetic ketoacidosis: a therapeutic challenge. Endocr Pract 2005; 11: 331-4.15. Morris LR, Murphy MB, Kitabchi AE. Bicarbonate the-rapy in severe diabetic ketoacidosis. Ann Intern Med 1986; 105: 836-40.16. Fraley DS, Adler S. Correction of hyperkalemia by bicar-bonate despite constant blood pH. Kidney Int 1977; 12: 354-60.17. Kitabchi AE, Umipierrez GE, Murphy MB et al. Mana-gement of hyperglycemic crises in patients with diabetes. Dia-betes Care 2001; 24: 131-53.18. Karavanaki K, Karanika E, Georga S et al. Cytokine res-ponse to diabetic ketoacidosis (DKA) in children with type 1 diabetes (T1DM). Endocr J 2011; 58: 1045-53.19. Cipriano A, Rebelos E, Park N, Santini M. Moderate in-crease of serum levels of procalcitonin in diabetic ketoacidosis. (Letter). Neth J Med 2018; 76: 454.20. Aksu NM, Aksoy DY, Akkas M et al. 25-OH-Vitamin D and procalcitonin levels aft er correction of acute hyperglyce-mia. Med Sci Monit 2013; 19: 264-8.Prikazan je slučaj 19-godišnjeg bolesnika od dijabetesa koji nije redovito primjenjivao inzulin. Bolesnik je doveden na naš Objedinjeni hitni prijam u komatoznom stanju, s ekstremnom hiperglikemijom, teškom dijabetičkom ketoacidozom, lak-tacidozom i dehidracijom. Liječen je intenzivnom nadoknadom volumena i korekcijom svih metaboličkih poremećaja do potpunog oporavka. U velikoj većini slučajeva teških dijabetičkih ketoacidoza može se očekivati relativno brza i uspješna korekcija ako se primijeni intenzivno liječenje i ako ketoacidoza nije potaknuta ozbiljnom bolesti. U članku su navedene neke bitne suvremene smjernice u liječenju i naglašena je važnost individualnog pristupa. Raspravljena je i uloga visoke serumske vrijednosti prokalcitonina u dijabetičkoj ketoacidozi.Ključne riječi: dijabetička ketoacidoza, hiperosmolarno stanje, hipovolemija, liječenje dijabetičke ketoacidozeS A Ž E T A KLIJEČENJE TEŠKE DIJABETIČKE KETOACIDOZE U MLADE OSOBEV. VUCELIĆ1, Ž. VUČIČEVIĆ1, V. DEGORICIJA1, G. MIROŠEVIĆ2 i V. TRKEŠ3Klinički bolnički centar Sestre milosrdnice, Interna klinika, 1Odjel za intenzivnu skrb, 2Odjel za endokrinologiju i 3Klinički bolnički centar Zagreb, Klinička bolnica za plućne bolesti Jordanovac, Zagreb, Hrvatska

LIJEČENJE TEŠKE DIJABETIČKE KETOACIDOZE U MLADE OSOBE

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