Hyperglycemic Hyperosmolar Syndrome in Children: Pathophysiological Considerations and Suggested Guidelines for Treatment
2010; Elsevier BV; Volume: 158; Issue: 1 Linguagem: Inglês
10.1016/j.jpeds.2010.09.048
ISSN1097-6833
AutoresPhilip Zeitler, Andrea M. Haqq, Arlan L. Rosenbloom, Nicole Glaser,
Tópico(s)Cancer, Hypoxia, and Metabolism
ResumoHyperglycemic hyperosmolar syndrome (HHS), characterized by extreme elevations in serum glucose concentrations and hyperosmolality without significant ketosis, has historically been infrequent in children. However, recent case reports and series describing HHS in children suggests that the incidence of this disorder may be increasing.1Fourtner S.H. Weinzimer S.A. Levitt Katz L.E. Hyperglycemic hyperosmolar non-ketotic asyndrome in children with type 2 diabetes.Pediatr Diabetes. 2005; 6: 129-135Crossref PubMed Scopus (70) Google Scholar, 2Canarie M.F. Bogue C.W. Banasiak K.J. Weinzimer S.A. Tamborlane W.V. Decompensated hyperglycemic hyperosmolarity without significant ketoacidosis in the adolescent and young adult population.J Pediatr Endocrinol Metab. 2007; 20: 1115-1124Crossref PubMed Scopus (42) Google Scholar, 3Hollander A.S. Olney R.C. Blackett P.R. Marshall B.A. Fatal malignant hyperthermia-like syndrome with rhabdomyolysis complicating the presentation of diabetes mellitus in adolescent males.Pediatrics. 2003; 111: 1447-1452Crossref PubMed Scopus (64) Google Scholar, 4Morales A.E. Rosenbloom A.L. Death caused by hyperglycemic hyperosmolar state at the onset of type 2 diabetes.J Pediatr. 2004; 144: 270-273Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 5Rosenbloom A.L. Hyperglycemic crises and their complications in children.J Pediatr Endocrinol Metab. 2007; 20: 5-18Crossref PubMed Scopus (58) Google Scholar The epidemiology of HHS in children and adolescents has been reviewed recently.6Rosenbloom A.L. Hyperglycemic hyperosmolar state: an emerging pediatric problem.J Pediatr. 2010; 156: 180-184Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar HHS has a high mortality rate, and an understanding of the unique pathophysiology (Figure 1) of this condition is important to guide clinical decision-making. However, although treatment of diabetic ketoacidosis (DKA) in children is familiar to most clinicians, the management of HHS in youth presents a unique set of clinical challenges for which little guidance is currently available. The aim of this review is to discuss the pathophysiology of HHS and to provide broad treatment recommendations on the basis of the available literature and known physiological principles.Criteria for the diagnosis of HHS are listed in Table I. Although HHS is distinct from DKA (Table II; available at www.jpeds.com), patients may present with features of both conditions. HHS occurs less frequently in children than DKA, and some children with DKA can have severe hyperosmolality, complicating the recognition of HHS as a distinct entity. As a result, children with HHS are often treated with DKA protocols. However, the pathophysiology of HHS differs from DKA, and these differences should be considered in planning a rational therapeutic approach.Table IDiagnostic feature of HHSSerum glucose concentration >600 mg/dL (33 mmol/L)Serum osmolality >330 mOsm/KgAbsence of significant ketosis and acidosis (serum bicarbonate concentration >15 mEq/L, urine ketone (acetoacetate) concentration < 15 mg/dL (1.5 mmol/L; negative or "trace" on urine dipstick) Open table in a new tab Unlike the usual symptoms of DKA (hyperventilation, vomiting, and abdominal pain), which typically bring children to medical attention, the gradually increasing polyuria and polydipsia of HHS may go unrecognized.7Belmonte M.M. Colle E. Murphy D.A. Wiglesworth F.W. Nonketotic hyperosmolar diabetic coma in Down's syndrome.J Pediatr. 1970; 77: 879-881Abstract Full Text PDF PubMed Scopus (15) Google Scholar As a result, both dehydration and electrolyte loss are profound in HHS; in adults, fluid losses in HHS have been estimated to be twice those of DKA. Furthermore, obesity and hyperosmolality can make the clinical assessment of dehydration unreliable.9Matz R. Management of the hyperosmolar hyperglycemic syndrome.Am Fam Physician. 1999; 60: 1468-1476PubMed Google Scholar, 10Delaney M.F. Zisman A. Kettyle W.M. Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome.Endocrinol Metab Clin North Am. 2000; 29: 683-705Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 11Ellis E.N. Concepts of fluid therapy in diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma.Pediatr Clin North Am. 1990; 37: 313-321PubMed Google Scholar, 12Kitabchi A.E. Umpierrez G.E. Fisher J.N. Murphy M.B. Stentz F.B. Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state.J Clin Endocrinol Metab. 2008; 93: 1541-1552Crossref PubMed Scopus (122) Google Scholar, 13Kitabchi A.E. Nyenwe E.A. Hyperglycemic crises in diabetes mellitus: diabetic ketoacidosis and hyperglycemic hyperosmolar state.Endocrinol Metabol Clin North Am. 2006; 35: 725-751Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 14Kitabchi A.E. Umpierrez G.E. Murphy M.B. Barrett E.J. Kreisberg R.A. Malone J.I. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (446) Google Scholar It has been suggested on the basis of information from small case series that intake of copious quantities of carbonated sugar-enriched drinks before presentation may be a common feature of patients presenting with severe hyperglycemia. Because these case series lack control data, however, it is unclear whether this finding is specific to these patients.8McDonell C.M. Pedreira C.C. Vadamalayan B. Cameron F.J. Werther G.A. Diabetic ketoacidosis, hyperosmolarity and hypernatremia: are high-carbohydrate drinks worsening initial presentation?.Pediatr Diabetes. 2005; 6: 90-94Crossref PubMed Scopus (54) Google ScholarDespite severe electrolyte losses and total body volume depletion, hypertonicity leads to preservation of intravascular volume, and signs of dehydration may be less evident (Figure 2, A and B; available at www.jpeds.com). During therapy, however, declining serum osmolality (a consequence of urinary glucose excretion and insulin-mediated glucose uptake) results in movement of water out of the intravascular space, with a decline in intravascular volume (Figure 2, C).15Sjostrand F. Berndtson D. Olsson J. Strandberg P. Hanh R.G. The osmotic link between hypoglycaemia and hypovolaemia.Scand J Clin Lab Invest. 2008; 68: 117-122Crossref PubMed Scopus (5) Google Scholar In addition, osmotic diuresis may persist for hours as markedly elevated glucose concentrations slowly decrease. Therefore ongoing urinary fluid losses early in treatment may be considerable. Because of the greater dehydration in HHS, the substantial ongoing urinary fluid losses, and the potential for rapid decline in intravascular volume during treatment (Figure 2, D), children with HHS require more aggressive replacement of intravascular volume during treatment than do children with DKA to avoid the vascular collapse that contributes to the high mortality rate.10Delaney M.F. Zisman A. Kettyle W.M. Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome.Endocrinol Metab Clin North Am. 2000; 29: 683-705Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 16Nugent B.W. Hyperosmolar hyperglycemic state.Emerg Med Clin North Am. 2005; 23: 629-648Abstract Full Text Full Text PDF PubMed Scopus (41) Google ScholarThe effect of HHS on the brain may differ from that seen in DKA. Studies of chronic hypertonicity suggest that brain cells produce "idiogenic osmoles," osmotically active substances that preserve intracellular volume by increasing intracellular osmolality.5Rosenbloom A.L. Hyperglycemic crises and their complications in children.J Pediatr Endocrinol Metab. 2007; 20: 5-18Crossref PubMed Scopus (58) Google Scholar, 17Goldman S.L. Hyperglycemic hyperosmolar coma in a 9-month-old child.Am J Dis Child. 1979; 133: 181-183PubMed Google Scholar, 18Gordon E.E. Kabadi U.M. the hyperglycemic hyperosmolar syndrome.Am J Med Sci. 1976; 271: 252-268Crossref PubMed Scopus (22) Google Scholar, 19Conley S. Hypernatremia.Pediatr Clin North Am. 1990; 37: 365-372PubMed Google Scholar Patients are believed to be at risk for cerebral edema (CE) if the rate of decline in serum osmolality exceeds the rate at which brain cells can eliminate osmotically active particles. Therefore, in theory, children with HHS who experience prolonged, persistent hypertonicity should be at greater risk for CE than those with DKA. However, in one case report of a patient with severe hyperglycemia and hyperosmolality (435 mosm/Kg) who had intracranial pressure monitoring during treatment, no increase in intracranial pressure occurred during fluid resuscitation.20Vernon D.D. Postellon D.C. Nonketotic hyperosmolal diabetic coma in a child: management with low-dose insulin infusion and intracranial pressure monitoring.Pediatrics. 1986; 77: 770-772PubMed Google Scholar Furthermore, demise typical of CE has been recorded in only one adolescent with HHS and an abnormal magnetic resonance imaging result, whereas all other reported brain imaging study results have been normal.4Morales A.E. Rosenbloom A.L. Death caused by hyperglycemic hyperosmolar state at the onset of type 2 diabetes.J Pediatr. 2004; 144: 270-273Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 21Ahlsson F. Gedeborg R. Hesselager G. Tuvemo T. Enblad P. Treatment of extreme hyperglycemia monitored with intracerebral microdialysis.Pediatr Crit Care Med. 2004; 5: 89-92Crossref PubMed Scopus (17) Google Scholar, 22Arieff A.I. Cerebral edema complicating nonketotic hyperosmolar coma.Miner Electrolyte Metab. 1986; 12: 383-389PubMed Google Scholar, 23Carchman R.M. Dechert-Zeger M. Calikoglu A.S. Harris B.D. A new challenge in pediatric obesity: pediatric hyperglycemic hyperosmolar syndrome.Pediatr Crit Care Med. 2005; 6: 20-24Crossref PubMed Scopus (45) Google Scholar Cerebral vasoconstriction caused by hypocapnia may be important in the pathogenesis of DKA-related CE.24Lam T.I. Anderson S.E. Glaser N. O'Donnell M.E. Bumetanide reduces cerebral edema formation in rats with diabetic ketoacidosis.Diabetes. 2005; 54: 510-516Crossref PubMed Scopus (57) Google Scholar, 25Glaser N.S. Wootton-Gorges S.L. Marcin J.P. Buonocore M.H. Dicarlo J. Neely E.K. et al.Mechanism of cerebral edema in children with diabetic ketoacidosis.J Pediatr. 2004; 145: 164-171Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 26Glaser N. Cerebral edema in children with diabetic ketoacidosis.Curr Diab Rep. 2001; 1: 41-46Crossref PubMed Scopus (18) Google Scholar Diminished circulatory volume combined with cerebral vasoconstriction may lead to cerebral hypoperfusion, with edema occurring during reperfusion. The absence of hypocapnia in children with HHS may therefore account for the decreased incidence of CE in HHS.Although both DKA and HHS are associated with an increased risk of thrombosis, the risk is far greater in HHS.27Gutierrez J.A. Bagatell R. Samson M.P. Theodorou A.A. Berg R.A. Femoral central venous catheter-associated deep venous thrombosis in children with diabetic ketoacidosis.Crit Care Med. 2003; 31: 80-83Crossref PubMed Scopus (60) Google Scholar, 28Keenan C.R. Murin S. White R.H. High risk for venous thromboembolism in diabetics with hyperosmolar state: comparison with other acute medical illnesses.J Thromb Haemost. 2007; 5: 1185-1190Crossref PubMed Scopus (45) Google Scholar Hypertonicity may directly result in osmotic disruption of endothelial cells, leading to release of tissue thromboplastins and elevated vasopressin caused by the fluid status may also contribute to enhanced coagulation.29Grant P.J. Tate G.M. Hughes J.R. Davies J.A. Prentice C.R. Does hypernatraemia promote thrombosis?.Thromb Res. 1985; 40: 393-399Abstract Full Text PDF PubMed Scopus (33) Google ScholarTreatment of HHSThere are no prospective data to guide treatment of children and adolescents with HHS. Nonetheless, experience with adults and awareness of the physiological differences between HHS and DKA suggest a rational approach for children and adolescents (Figure 3). All patients with HHS, as well as patients with hyperosmolality with DKA, should be admitted to an intensive care unit or equivalent setting in which expert medical, nursing, and laboratory services are available.Figure 3Treatment of HHS in pediatric patients.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fluid TherapyThe goal of initial fluid therapy is expansion of the intravascular and extravascular volume and restoration of normal renal perfusion. Vigorous fluid replacement is recommended for adults with HHS and rates of fluid replacement in children should be more rapid than those recommended for DKA. A minimum initial bolus of 20 mL/kg of isotonic saline solution (0.9% NaCl) should be administered and fluid deficits of approximately 12% to 15% of body weight should be assumed.9Matz R. Management of the hyperosmolar hyperglycemic syndrome.Am Fam Physician. 1999; 60: 1468-1476PubMed Google Scholar, 12Kitabchi A.E. Umpierrez G.E. Fisher J.N. Murphy M.B. Stentz F.B. Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state.J Clin Endocrinol Metab. 2008; 93: 1541-1552Crossref PubMed Scopus (122) Google Scholar, 13Kitabchi A.E. Nyenwe E.A. Hyperglycemic crises in diabetes mellitus: diabetic ketoacidosis and hyperglycemic hyperosmolar state.Endocrinol Metabol Clin North Am. 2006; 35: 725-751Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 14Kitabchi A.E. Umpierrez G.E. Murphy M.B. Barrett E.J. Kreisberg R.A. Malone J.I. et al.Management of hyperglycemic crises in patients with diabetes.Diabetes Care. 2001; 24: 131-153Crossref PubMed Scopus (446) Google Scholar, 16Nugent B.W. Hyperosmolar hyperglycemic state.Emerg Med Clin North Am. 2005; 23: 629-648Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Additional fluid boluses should be given to restore peripheral perfusion. Subsequently, 0.45% to 0.75% NaCl should be administered to replace the deficit over 24 to 48 hours, with a goal of promoting a gradual decline in serum sodium and osmolality. The specific choice for subsequent fluid replacement is dependent on serum electrolyte and glucose concentrations, urinary output, and clinical hydration status.Adult studies suggest that administration of isotonic fluids (0.9% saline solution) during ongoing osmotic diuresis may increase serum sodium concentration because the urine sodium concentration is typically hypotonic to that of serum9Matz R. Management of the hyperosmolar hyperglycemic syndrome.Am Fam Physician. 1999; 60: 1468-1476PubMed Google Scholar, 30Hillman K. Fluid resuscitation in diabetic emergencies—a reappraisal.Intensive Care Med. 1987; 13: 4-8Crossref PubMed Scopus (63) Google Scholar, 31Lorber D. Nonketotic hypertonicity in diabetes mellitus.Med Clin North Am. 1995; 79: 39-52PubMed Scopus (70) Google Scholar and elevated aldosterone concentrations, secondary to hypoperfusion, promote sodium retention and potassium loss. A rise in serum sodium concentration is undesirable as it may perpetuate the hyperosmolar state. However, isotonic fluids are more effective in maintaining circulatory volume. Therefore isotonic fluids are recommended initially to restore perfusion, followed by more hypotonic (0.45%-0.75% saline solution) fluids. Isotonic fluids should be restarted if perfusion and hemodynamic status become problematic as osmolality declines. Serum sodium concentrations should be frequently monitored, and the concentration of sodium in fluids adjusted to promote a gradual decline in corrected serum sodium. Although there are no data to indicate an optimal rate of decline in serum sodium, a rate of 0.5 mEq/L per hour has been recommended for hypernatremic dehydration.32Kronan K. Normal M.E. Renal and Electrolyte Emergencies.in: Fleischer G.R. Ludwig S. Textbook of Emergency Medicine. 4th ed. Lippincott, Williams and Wilkins, Philadelphia2000Google Scholar With adequate rehydration, serum glucose concentrations should decline by 75 to 100 mg/dL/hr (4.1-5.5 mmol/L).9Matz R. Management of the hyperosmolar hyperglycemic syndrome.Am Fam Physician. 1999; 60: 1468-1476PubMed Google Scholar, 10Delaney M.F. Zisman A. Kettyle W.M. Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome.Endocrinol Metab Clin North Am. 2000; 29: 683-705Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar A more rapid decline in serum glucose concentration is typical during the first few hours of treatment, when renal perfusion is improved by expansion of vascular volume. Lack of appropriate decline in serum glucose should prompt reassessment and evaluation of renal function. It has also been suggested that the presence of large quantities of sugar-containing liquids in the stomach at presentation may contribute to changes in both water and glucose as stomach contents are absorbed and should be considered in monitoring and ongoing evaluation.33Carlotti A.P. St George-Hyslop C. Guerguerian A.M. Bohn D. Kamel K.S. Halperin M. Occult risk factor for the development of cerebral edema in children with diabetic ketoacidosis: possible role for stomach emptying.Pediatr Diabetes. 2009; 10: 522-523Crossref PubMed Scopus (17) Google Scholar Recommended laboratory monitoring frequency is provided in Table III.Table IIIMonitoring of children and adolescents with HHSHourly: serum glucose, vital signs, clinical assessment of hydration statusEvery 2-3 hours: serum electrolytes, blood urea nitrogen, creatinine, osmolality, creatine kinase, determination of intake/output balanceEvery 3-4 hours: serum calcium, phosphate, magnesiumContinuous cardiac monitor Open table in a new tab Patients may be more dehydrated than assumed and frequent reassessment of fluid balance and peripheral perfusion is necessary. Central venous pressure monitoring may be helpful; however, the benefits should be balanced against the risks of thrombosis (see below). Replacement of urinary losses is recommended;12Kitabchi A.E. Umpierrez G.E. Fisher J.N. Murphy M.B. Stentz F.B. Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state.J Clin Endocrinol Metab. 2008; 93: 1541-1552Crossref PubMed Scopus (122) Google Scholar 0.45% saline solution approximates the typical urine sodium concentration during osmotic diuresis. Fluid with higher sodium content may be acceptable for replacement of urinary losses in situations where there is ongoing concern over adequate circulatory volume.Insulin TherapyKetosis in HHS is usually minimal and, although mild acidosis is common, it is typically the result of hypoperfusion (lactic acidosis). Therefore early insulin administration is unnecessary in non-ketotic HHS and may increase the risk of death.2Canarie M.F. Bogue C.W. Banasiak K.J. Weinzimer S.A. Tamborlane W.V. Decompensated hyperglycemic hyperosmolarity without significant ketoacidosis in the adolescent and young adult population.J Pediatr Endocrinol Metab. 2007; 20: 1115-1124Crossref PubMed Scopus (42) Google Scholar Fluid administration alone results in a substantial decline in serum glucose as a result of dilution, improved renal perfusion, and increased tissue glucose uptake with improved circulation.34West M.L. Marsden P.A. Singer G.G. Halperin M.L. Quantitative analysis of glucose loss during acute therapy for hyperglycemic hyperosmolar syndrome.Diabetes Care. 1986; 9: 465-471Crossref PubMed Scopus (27) Google Scholar Furthermore, the osmotic pressure that glucose exerts within the vascular space contributes to maintenance of blood volume in these profoundly dehydrated patients. Therefore more rapid declines in serum glucose concentration and osmolality after insulin administration might lead to circulatory compromise and thromboembolism unless there is adequate fluid replacement.10Delaney M.F. Zisman A. Kettyle W.M. Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome.Endocrinol Metab Clin North Am. 2000; 29: 683-705Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 31Lorber D. Nonketotic hypertonicity in diabetes mellitus.Med Clin North Am. 1995; 79: 39-52PubMed Scopus (70) Google Scholar Additionally, patients with HHS have extreme deficits of potassium (see below), and the rapid insulin-induced shift of potassium from the circulation to intracellular space can result in arrhythmia.In general, insulin administration should be considered when serum glucose concentrations are no longer declining adequately (< 50 mg/dL/h [ 24 to 48 hours. The use of compression stockings in children in this setting has not been specifically evaluated but should be considered.Rhabdomyolysis may occur in children with HHS, and monitoring of creatine kinase concentration every 2 to 3 hours is recommended for early detection.41Schelpphorst E. Levin M.E. Rhabdomyolysis associated with hyperosmolar nonketotic coma.Diabetes Care. 1985; 8: 198-200PubMed Google Scholar, 42Wood M.L. Griffith D.N. Hooper R.J. Yudjkin J.S. Fatal rhabdomyolysis associated with hyperosmolar diabetic decompensation.Diabetes Res. 1988; 8: 97-99PubMed Google Scholar, 43Trump D. O'Hanlon S. Rinsler M. Sharp P. Hyperosmolar non-ketotic diabetic coma and rhabdomyolysis.Postgrad Med J. 1994; 70: 44-46Crossref PubMed Scopus (5) Google Scholar, 44Wang L.M. Tsai S.T. Ho L.T. Hu S.C. Lee C.H. Rhabdomyolysis in diabetic emergencies.Diabetes Res Clin Pract. 1994; 26: 209-214Abstract Full Text PDF PubMed Scopus (43) Google Scholar, 45Hoorn E.J. deVogel S. Zietse R. Insulin resistance in an 18-year-old patient with Down syndrome presenting with hyperglycaemic coma, hypernatraemia and rhabdomyolysis.J Intern Med. 2005; 258: 285-288Crossref PubMed Scopus (7) Google Scholar, 46Gangopadhyay K.K. Ryder R.E. Nontraumatic rhabdomyolysis: an unusual complication of diabetic hyperosmolar nonketotic (HONK) state.J R Soc Med. 2006; 99: 200Crossref PubMed Scopus (16) Google Scholar Rhabdomyolysis is potentially life-threatening; it may result in acute kidney failure, severe hyperkalemia, and hypocalcemia leading to cardiac arrest, and muscle swelling causing compartment syndrome.47Watemberg N. Leshner R.L. Armstrong B.A. Lerman-Sagie T. Acute pediatric rhabdomyolysis.J Child Neurol. 2000; 15: 222-227Crossref PubMed Scopus (50) Google Scholar If rhabdomyolysis is suspected, consultation with a nephrologist should be obtained promptly.A malignant hyperthermialike syndrome of unclear cause has been reported in several children with HHS.3Hollander A.S. Olney R.C. Blackett P.R. Marshall B.A. Fatal malignant hyperthermia-like syndrome with rhabdomyolysis complicating the presentation of diabetes mellitus in adolescent males.Pediatrics. 2003; 111: 1447-1452Crossref PubMed Scopus (64) Google Scholar, 4Morales A.E. Rosenbloom A.L. Death caused by hyperglycemic hyperosmolar state at the onset of type 2 diabetes.J Pediatr. 2004; 144: 270-273Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 23Carchman R.M. Dechert-Zeger M. Calikoglu A.S. Harris B.D. A new challenge in pediatric obesity: pediat
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