Hyperglycemic hyperosmolar nonketotic syndrome
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《美国医学杂志》
Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research Center, Chandigarh, India
Abstract
Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) was infrequently diagnosed till recently. Now it is being diagnosed with increasing frequency in obese children with type 2 diabetes mellitus (T2 DM) and its incidence is likely to go up, given global increase in incidence of childhood obesity, increased insulin resistance, and T2 DM. The syndrome is characterized by severe hyperglycemia, a marked increase in serum osmolality and dehydration without accumulation of β -hydroxybutyric or acetoacetic ketoacids. Significant ketogenesis is restrained by the ability of the pancreas to secrete small amount of insulin. Prolonged phase of osmotic diuresis leads to severe depletion of body water, which excees that of sodium, resulting in hypertonic dehydration. These children, usually obese adolescents with T2 DM, present with signs of severe dehydration and depressed mental status but continue to have increased rather than decreased urine output and are at increased risk of developing rhabdomyolysis and malignant hyperthermia. Emergency treatment is directed at restoration of the intravascular volume, followed by correction of deficits of fluid and electrolyte (Na+, K+, Ca++, Mg++, PO4++), hyperglycemia and serum hyperosmolarity, and a thorough search for conditions that may lead to this metabolic decompensation and their treatment. Use of iso-osomolar isotonic fluid (0.9% saline) until hemodynamic stabilization initially, followed by 0.45% saline with insulin infusion at the rate of 0.1 units/kg/hour, addition of 5% dextrose in fluids and reduction of insulin infusion once the blood glucose is 250 to 300 mg/dl is generally recommended. However, evidence-based guidelines about composition and tonicity of fluids and electrolyte solutions for early resuscitation and rehydration, the rate of infusion-rapid vs slow, and insulin dose-low vs normal, in treatment of HHNS in children are awaited. Careful monitoring of glucose levels and ensuring adequate hydration in patients 'at risk' of HHNS, including those receiving medications that interfere with the secretion or effectiveness of insulin should decrease the risk of HHNS.
Keywords: Hyperglycemic hyperosmolar nonketotic syndrome; Hyperglycemia; Fluid therapy; Electrolyte imbalance; Hypertonic dehydration
Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) is a life-threatening complication commonly associated with uncontrolled type 2 diabetes mellitus (T2 DM). It was first recognized over a century ago but was infrequently diagnosed until the report by Sament and Schwartz in 1957[1]. New HHNS accounts for between 5 and 15 percent of all adult and pediatric diabetic hyperglycemic emergencies.[2] In adults HHNS occurs at a frequency of 17.5 cases/100,000 persons / year.[3] Population-based data for children are not available. A recent estimate suggests in USA that nearly 4% of newly diagnosed pediatric T2 DM patients will have HHNS with a case fatality of 12%.[4] T2 DM accounts for as much as half of newly diagnosed DM in children between 12-21 years in USA.[2] Similar trends are beginning to appear in adolescents in U.K.[5] More recently the syndrome has been recognized with increasing frequency in obese adolescents and children with T2 DM.[6]-[8] The incidence is therefore likely to increase with global increase in incidence of obesity[9],[10],[11], increased insulin resistance and T2 DM.[10],[12],[13] HHNS may rarely occur in younger patients[14] and following acute stress of sepsis or trauma, use of several drugs, and other conditions without underlying T2DM[15] table1. In this review, we discuss issues in diagnosis and management of this resurgent problem with a pediatric perspective.
Pathogenesis
The syndrome is characterized by severe hyperglycemia, a marked increase in serum osmolality and clinical evidence of dehydration without the accumulation of b-hydroxybutyric or acetoacetic ketoacids Figure1. Hyperglycemia results from either an absolute or relative deficiency of insulin or due to decreased tissue responsiveness to insulin (Increased insulin resistance). This results in increased gluconeogenesis and glycogenolysis,[2] reduced rate of glucose uptake and utilization by peripheral tissues[16], and thus a rise in blood glucose level. Glycogenolysis, however, contributes much less to the severity of hyperglycemia as these patients are usually quite ill and may not have eaten for several days, thus depleting their hepatic glycogen stores. HHNS evolves when insulin resistance permits development of hyperglycemia in the absence of significant ketone production and limited ability of the kidney to excrete large quantities of glucose. HHNS therefore is more likely to occur in children with renal disease associated with increased renal threshold for the excretion of glucose.[17]
A rise in osmolality in the extracellular fluid causes a shift of water from the intracellular to the extracellular space resulting in intracellular dehydration. Initially, this redistribution of water causes a slight expansion of the extracellular fluid volume and lowers the serum sodium, but the effect is transient.[18] Glycosuria and osmotic diuresis ensue once the blood glucose exceeds the renal threshold (normal range 180-250 mg/dl). The initial glycosuria temporarily protects the patients from hyperglycemia, but as the osmotic diuresis continues profound depletion of intravascular volume occurs, decreasing renal perfusion and the ability of the kidneys to excrete large quantities of glucose.[19] At this point, profound hyperglycemia and a further increase in plasma osmolality occur. The stress of profound hyperglycemia and resultant hyperosmolarity and dehydration, as well as the precipitating illness, contributes to increased production of counter regulatory hormones like cortisol, catecholamines and glucagon. The increased secretion of the counter-regulatory hormones further accentuates the degree of hyperglycemia.[2]
In addition to glucose, electrolytes such as sodium, potassium, phosphate and magnesium are also lost during the osmotic diuresis. Sodium depletion leads to further decrease in intravascular volume but urinary losses of water always exceeds that of sodium leading to development of hypertonic dehydration.
The mechanisms responsible for limiting significant accumulation of ketoacidosis in HHNS have been a subject of debate.[20] Most data support the hypothesis that significant ketogenesis is restrained by the ability of the pancreas to secrete small amount of insulin.[21] Inhibition of lipolysis and stimulation of lipogenesis occurs at much lower concentrations, while glucose uptake and inhibition of gluconeogenesis require considerably greater concentration of insulin.[16] Hyperosmolality and dehydration have also been reported to inhibit release of free fatty acids from adipose tissue.
Diagnosis
HHNS is a medical emergency that requires prompt recognition and treatment. Delayed diagnosis and treatment is one of the important factors responsible for the high mortality associated with HHNS.[7],[22] There is no symptom or sign specific of HHNS and hence there is often a delay in seeking medical care. Patients typically have no prior knowledge of glucose intolerance, and experiences polyuria, polydipsia and weight loss as osmotic diuresis sets in. The lack of significant ketonaemia and acidosis and absence of Kussumal breathing and fruity scent in breath usually allows patients with HHNS to lapse into prolonged phase of osmotic diuresis and a greater degree of dehydration compared to patients with diabetic ketoacidosis (DKA) before presenting for medical attention.[17]
Usually, these patients at presentation have poor skin turgour, dry mucus membrane, tachycardia, low jugular venous pressure and may be hypotensive. The sensorium may vary from normal to profound coma. In some patients focal neurological signs (hemiparesis or hemianopsia) and seizures may be the dominant clinical features[23].The physical findings of fluid depletion in a patient who continues to have increased rather than decreased urine output, especially in the presence of depressed mental status, should lead the physician to strongly consider a diagnosis of HHNS. In some instances HHNS was not suspected even when the patients presented with neurological signs and symptoms associated with glycosuria[18] . Hence, a high index of suspicion for HHNS should be maintained, especially in obese adolescents at risk of T2 DM or in children who are on drugs known to precipitate hyperglycemia. Due to severe dehydration, patients with HHNS are at increased risk of developing vascular thrombosis including cerebral and mesenteric artery occlusions.[24]
Rhabdomyolysis and malignant hyperthermia have been reported in HHNS, especially in obese adolescents with T2 DM. [7],[25] It is believed that defects in the fatty acid oxidation in the skeletal muscles of such individuals lead to excess lipid deposition in their muscles and predisposes them to rhabdomyolysis.[7]
Laboratory Findings
Diagnostic criteria for HHNS are summarized in table2. The initial laboratory evaluation of patients with suspected HHNS should include immediate determination of blood glucose, blood urea and creatinine, serum electrolytes, osmolality and ketones and arterial blood gases. Urine analysis and blood counts with differentials should be done. Bacterial cultures of urine, blood and other tissues should be obtained and appropriate antibiotics should be administered if infection is suspected. Approximately, 50% of the patients with HHNS have an increased anion gap metabolic acidosis because of increased serum lactate level[18].
Sodium: All patients with HHNS, regardless of the initial serum sodium concentration from low to high, are in a state of hypertonic dehydration. It must be appreciated that due to transcellular shifts of water, the serum sodium concentration decreases approximately 1.6 mEq/l for every 100 mg/dl increment in blood glucose.[26] Reduction of the blood glucose concentration following administration of fluids and insulin causes an increase in serum sodium levels as water is transported back into the intracellular space.
Potassium : Its depletion results from the osmotic diuresis and poor oral intake and in some case due to vomiting and kaliuretic drugs. However, insulin deficiency causes a shift of potassium to the extracellular fluid, and the initial serum potassium values may be normal or elevated. With fluid and insulin therapy there is a danger of rapid fall in serum potassium.
Dehydration also causes an elevation in serum urea and creatinine, and these parameters may not normalize in patients with renal disease. Leucocytosis may be observed due to increased levels of catecholamines and glucocorticoids, but it should be remembered that even sepsis could raise the levels of white cell count. Normal hemoglobin at presentation may indicate an underlying anemia, which will manifest after rehydration.
Elevation of muscle enzymes such as creatinine phosphokinase and lactic dehydrogenase aid in the diagnosis of rhabdomyolysis.
Management
Total body water deficit in HHNS may range from 100 - 200 ml/kg. The early objective of management of HHNS is therefore rapid restoration of circulatory volume, replacement of fluid and electrolyte deficits and correction of hyperglycemia and hyperosmolarity
Fluid therapy: The principal objective at the outset is restoration of the intravascular volume to assure adequate perfusion of the brain, heart and kidneys.[27] However, evidence-based guidelines to achieve the above treatment objectives in children are not available. The issues about composition and tonicity of fluid and electrolyte solutions for early resuscitation and rehydration, the rate of infusion-rapid vs slow, insulin dose-early high dose for rapid lowering of glucose etc. remain unresolved in the absence of studies in children. One of the reasons for the controversy is fear of cerebral edema with rapid fluid correction as seen in patients with diabetic ketoacidosis. A rapid decline in blood glucose concentration after initiation of treatment with insulin might decrease brain/blood glucose ratio resulting in fluid shift to the brain[28].
Rapid restoration of circulating volume using iso-osomolar isotonic fluid (0.9% saline) until stabilization of pulse, blood pressure and other vital signs, followed by 0.45% saline with insulin infusion at the rate of 0.1 units/kg/hour is recommended[2],[18]. The decrease in plasma glucose level should be 75 to 100mg/dl (4.0 to 5.5 mmol/l). Once the blood glucose is in the range of 250 to 300 mg/dl, 5% dextrose may be added to the fluids and insulin infusion reduced. The fluid, electrolyte and glucose therapy should be directed at a gradual decrease in plasma osmolality and corrected serum sodium levels[28]. Rapid corrections of metabolic abnormality and hyperosmolarity by administration of hypotonic fluids and insulin should be avoided in younger patients to decrease the risk of cerebral edema[29]. American Diabetic Association guidelines recommend slower correction of fluid deficit (over 48 hours) in patients below 20 years than in adults.[2]
Insulin Therapy: The intravenous route of insulin administration is preferred in dehydrated patients in whom the absorption of insulin from subcutaneous or even intramuscular sites may not be predictable. A lower dose of insulin (0.1 unit/kg/hour without an initial loading dose) is required to correct the metabolic abnormalities in children with HHNS in comparison to those used in DKA.[2],[29] This is also expected to prevent cerebral edema and hypotension, which develop because of rapid shift of extracellular fluid into intracellular compartment due to lowering of blood sugar, and worsening of hypokalemia and hypophostemia because of rapid insulin therapy.
Potassium therapy: Potassium deficits in HHNS approximate those seen in diabetic ketoacidosis (5 to 15 mEq/kg). The initial serum potassium levels may be low or normal, or occasionally elevated due to a shift of intracellular potassium to extracellular fluid. Treatment with insulin and fluid will cause a further decline in potassium level due to its ingress into the cells. Potassium replacement, 0.2 to 0.3 mEq/kg/hour, should therefore be started early, once oliguria is ruled out. Subsequent adjustments of potassium infusion rate, which may go upto 0.5-0.75 mEq/kg/hour, is made according to serum K+ levels.[2],[18] Potassium phosphate may be used instead of potassium chloride if concomitant hypophosphatemia is present.
Phosphate therapy: Hypophosphatemia is uncommon. It can lead to respiratory and skeletal muscle weakness, hemolytic anemia and systolic cardiac dysfunction.[30] Phosphate depletion is believed to lead to decreased 2,3-diphosphoglycate, shifting of the oxygen dissociation curve to the left. Phosphate replacement (0.2-0.3 mEq/kg by infusion over several hours) is indicated at a serum phosphate concentration < 1 mg/dl or in patients with moderate hypophosphatemia and concomitant hypoxia, anemia or cardio-respiratory compromise.[2] The serum calcium and magnesium concentration should be checked at the time of presentation and during therapy: repletion is instituted if levels fall below the normal range. Low dose infusion of dopamine (1 to 5 mg/kg/min) in neurosurgical patients with HHNS has been associated with reduced incidence of cerebral edema, renal failure and cardiac failure[31].
Immediate post-hyperglycemic care: Low dose insulin therapy provides a circulating insulin concentration of 60-100 μg/ml. However, because of the short half-life of intravenous regular insulin, sudden interruption of insulin infusion can lead to rapid lowering of insulin concentration resulting in a relapse of HHNS.[2] Subcutaneous insulin can be started once the patient's intravenous volume has been corrected; sensorium improves and is able to accept fluids orally.[2]
Treatment of precipitating causes and complications: Optimal management of patients with HHNS requires a thorough search for conditions that may lead to this metabolic decompensation and their treatment table1. Some authors recommend institution of empiric broad-spectrum antibiotics particularly for Gram-negative organisms pending the results of bacterial cultures.[24]
Thromboembolic events are frequently reported in patients with HHNS and may in part be responsible for the high mortality rate associated with this condition.[32] Low-dose subcutaneous heparin is advised for prophylactic anticoagulant administration in older patients[24],[32]; however, guidelines for its use in children with HHNS are not available.
Fatal cases of cerebral edema have been reported with HHNS. Clinically, cerebral edema is characterized by deterioration in the level of consciousness, lethargy, decrease in arousal and headache. These symptoms progress rapidly as brainstem herniation occurs, to pupillary changes, bradycardia and respiratory arrest; the progression may be so rapid that papilledema may not be found. To avoid cerebral edema the blood glucose level should be maintained between 250-300mg/dl until hyperosmolarity and mental status improve and the patient becomes clinically stable.
Rhabdomyolysis has been observed frequently with HHNS and is often associated with high mortality[7],[25], whether it is related to hyperosmolality or metabolic disturbances associated with HHNS or their treatment is not clear. No proven therapy exists for rhabdomyolysis, although therapy with carnitine and dantrolene has been tried.[7],[25]
Monitoring
Rapid changes in volume status and fluid and electrolyte balance necessitate meticulous documentation of the therapeutic actions taken, as well as the patient's response to such therapy. Volume of fluid administered, urine output, blood glucose concentration, serum electrolyte levels, including sodium, potassium, magnesium, calcium and phosphate, blood urea, nitrogen (BUN) and creatinine must be monitored and recorded hourly initially.[28] It may be useful to monitor glucose corrected sodium level to minimize the consequences of rapid decrease in serum osmolality.[28] The brain/subcutaneous glucose monitoring using the microdialysis may be helpful in guiding the insulin and fluid therapy as any rapid increase in the above ratio can forewarn the clinician about the risk of impending cerebral edema.[33]
Prevention
Careful monitoring of glucose levels and ensuring adequate hydration in patients 'at risk' of HHNS including those receiving medications that interfere with the secretion or effectiveness of insulin should decrease the risk of HHNS. Screening programmes directed at identifying T2 DM in the community will help identify patients at risk for HHNS.
Conclusion
Life-threatening hyperglycemic hyperosmolar syndrome, which is characterized by severe hyperglycemia without ketoacidosis, and very high serum osmolality and dehydration, appears to be on rise in adolescents with extreme obesity and T2 DM. Population-based estimates of the magnitude of the problem are needed. High index of suspicion in dehydrated patients who continue to have increased rather than decreased urine output may help in early diagnosis. Although the emergency treatment guidelines recommend early restoration of the intravascular volume, correction of fluid and electrolyte-deficits, hyperglycemia and hyperosmolarity, prospective studies are needed to resolve controversy surrounding tonicity and electrolyte composition of the resuscitation and rehydration fluids, the rate of fluid infusion and insulin doses in children.[34]
References
1. Sament S, Schwartz MD. Severe diabetic stupor without ketosis. S Afr Med J 1957; 31: 893-894.
2. Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JL et al. Management of hyperglycemic crisis in patient with diabetes. Diabetes Care 2001; 24: 131-153.
3. Lober D: Nonketotic hypertonicity in diabetic mellitus. Med Clin North An; 1995; 79 : 39-52.
4. Fourtner SH, Weinzimer SA, Murphy KL, Levitt Katz LE. Hyperglycemic hyperosmolar nonketotic (HHNK) syndrome in children. Proc Endocr Soc 85th Annual Meeting; Philadelphia, June 22, 2003,
Abstract OR 42-46.
5. Skidmore PM, Yarnell JW. The obesity epidemic: prospects for prevention. QJM 2004; 97: 817-825.
6. Umpierrez GE, Kelly JP, Navarrete JE, Casals MM, Kitabci AE. Hyperglycemic crises in urban blacks. Arch Intern Med 1997; 24; 157: 669-675.
7. Hollander AS, Olney RC, Blackett PR, Marshall BA. Fatal malignant hyperthermia-like syndrome with rhabdomyo-lysis complicating the presentation of diabetes mellitus in adolescent males. Pediatrics 2003; 111: 1447-1452.
8. Carchman RM, Dechert-Zeger M, Calikoglu AS et al. A new challenge in pediatric obesity: Pediatric hyperglycemic hyperosmolar syndrome. Pediatr Crit Care Med 2005;6:20-24
9. Clinton Smith J. The current epidemic of childhood obesity and its implications for future coronary heart disease. Pediatr Clin North Am 2004; 51 : 1679-1695.
10. Uckun-Kitapci A, Tezic T, Firat S, Sipahi T, Barrier R, Edwards LJ, Calikoglu AS. Obesity and type 2 diabetes mellitus: a population-based study of adolescents. J Pediatr Endocrinol Metab 2004; 17 : 1633-1640.
11. Mohan V. Why are Indians more prone to diabetes J Assoc Physicians India 2004; 52 : 468-474.
12. Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, Allen K, Lopes M, Savoye M, Morrison J, Sherwin RS, Caprio S. Obesity and the Metabolic Syndrome in Children and Adolescents. Obstet Gynecol Surv 2004; 59 : 822-824.
13. Viner RM, Segal TY, Lichtarowicz- Krynska E, Hindmarsh P. Prevalence of the insulin resistance syndrome in obesity. Arch Dis Child 2005; 90: 10-14.
14. Goldman SL. Hyperglycemic hyperosmolar coma in a 9 month-old child. Am J Dis Child 1979; 133: 181-183.
15. Wachtel TJ, Silliman RA, Lamberton P. Predisposing factors for the diabetic hyperosmolar state. Arch Intern Med 1987; 147 : 499-501.
16. Rosenthal NR, Barrett EJ. An assessment of insulin action in hyperosmolar hyperglycemic non ketotic diabetic patients. J Clin Endocrinol Metab 1985; 60: 607-610.
17. Delaney MF, Zisman A, Kettyle WM. Diabetic ketoacidosis and hyperglycemic hyperosmolar non ketotic syndrome. Endocrinol Metab Clin North Am 2000; 29 : 683-705.
18. Matz R. Management of the hyperosmolar hyperglycemic syndrome. Am Fam Physician 1999; 60 : 1468-1476.
19. Adrogue HJ, Tannen RL. Ketoacidosis, hyperosmolar states, and lactic acidosis. In Kokko JP and Tannen RL, eds. Fluid and Electrolytes, 3rd edn. WB Saunders; Philadelphia, 1996; 643-674.
20. English P, Williams G. Hyperglycemic crisis and lactic acidosis in diabetes mellitus. Postgrad Med J 2004; 80: 253-261.
21. Malchoff CD, Pohl SL, Kaiser DL, Carry RM. Determinants of glucose and ketoacid concentrations in acutely hyperglycemic diabetic patients. Am J Med 1984; 77: 275-285.
22. Morales AE, Rosenbloom AL. Death caused by hyperglycemic hyperosmolar state at the onset of type 2 diabetes. J of Pediatr 2003; 144: 270-273.
23. Kennedy DD, Fletcher SN, Ghosh IR, Coakley JH, Monson JP, Hinds CJ. Reversible tetraplegia due to polyneuropathy in a diabetic patient with hyperosmolar non-ketotic coma. Intensive Care Med 1999; 25: 1437-1439.
24. Mather HM. Management of hyperosmolar coma. J Royal Soc Med 1980; 73 : 134-138.
25. Wang LM, Tsai ST, Ho LT, Hu SC, Lee CH. Rhabdomyolysis in diabetic emergencies. Diabetes Res Clin Pract 1994; 26 : 209-214.
26. Katz MD. Hyperglycemia induced hyponatremia, calculation of expected serum sodium depression. NEJM . 1973; 289: 843-844.
27. Ellis EN. Concepts of fluid therapy in diabetic ketoacidosis and hyperosmolar hyperglycemic non ketotic coma. Pediatr clin North Am 1990; 37: 313-321.
28. Liamis G, Gianoutsos C, Elisaf MS. Hyperosmolar nonketotic syndrome with hypernatremia : how can we monitor treatmentDiabetes Metab 2000; 26: 403-405.
29. Magee MF, Bhatt BA. Management of decompensated diabetes. Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Crit Care Clin 2001; 17: 75-106.
30. Hasselstorm L, Wimberley PD, Nielsen VG. Hypophosphatemia and acute respiratory failure in a diabetic patient. Intensive Care Medicine 1986; 12 : 429-431.
31. Shimoda M, Yamada S, Shinoda M, Oda S, Hidaka M, Yamamoto I, Sato O, Tsugane R. Low-dose dopamine treatment of patients in nonketotic hyperosmolar hyperglycemic coma. Neurol Med Chir (Tokyo). 1989;29: 890-894.
32. Cho SJ, Won TK, Hwang SJ, Kwon JH. Bilateral putaminal hemorrhage with cerebral edema in hyperglycemic hyperosmolar syndrome. Yonsei Med J 2002; 43 : 533-535.
33. Ahlsson F, Gedeborg R, Hesselager G, Tuvemo T, Enblad P. Treatment of extreme hyperglycemia monitored with intracerebral microdialysis. Pediatr Crit Care Med 2004; 5: 89-92.
34. Singhi SC. Hyperglycemic hyperosmolar state and type 2 diabetes mellitus: Yet another danger of childhood obesity. Pediatr Crit Care Med 2005; 6 : 86-87.(Venkatraman R, Singhi Sun)
Abstract
Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) was infrequently diagnosed till recently. Now it is being diagnosed with increasing frequency in obese children with type 2 diabetes mellitus (T2 DM) and its incidence is likely to go up, given global increase in incidence of childhood obesity, increased insulin resistance, and T2 DM. The syndrome is characterized by severe hyperglycemia, a marked increase in serum osmolality and dehydration without accumulation of β -hydroxybutyric or acetoacetic ketoacids. Significant ketogenesis is restrained by the ability of the pancreas to secrete small amount of insulin. Prolonged phase of osmotic diuresis leads to severe depletion of body water, which excees that of sodium, resulting in hypertonic dehydration. These children, usually obese adolescents with T2 DM, present with signs of severe dehydration and depressed mental status but continue to have increased rather than decreased urine output and are at increased risk of developing rhabdomyolysis and malignant hyperthermia. Emergency treatment is directed at restoration of the intravascular volume, followed by correction of deficits of fluid and electrolyte (Na+, K+, Ca++, Mg++, PO4++), hyperglycemia and serum hyperosmolarity, and a thorough search for conditions that may lead to this metabolic decompensation and their treatment. Use of iso-osomolar isotonic fluid (0.9% saline) until hemodynamic stabilization initially, followed by 0.45% saline with insulin infusion at the rate of 0.1 units/kg/hour, addition of 5% dextrose in fluids and reduction of insulin infusion once the blood glucose is 250 to 300 mg/dl is generally recommended. However, evidence-based guidelines about composition and tonicity of fluids and electrolyte solutions for early resuscitation and rehydration, the rate of infusion-rapid vs slow, and insulin dose-low vs normal, in treatment of HHNS in children are awaited. Careful monitoring of glucose levels and ensuring adequate hydration in patients 'at risk' of HHNS, including those receiving medications that interfere with the secretion or effectiveness of insulin should decrease the risk of HHNS.
Keywords: Hyperglycemic hyperosmolar nonketotic syndrome; Hyperglycemia; Fluid therapy; Electrolyte imbalance; Hypertonic dehydration
Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) is a life-threatening complication commonly associated with uncontrolled type 2 diabetes mellitus (T2 DM). It was first recognized over a century ago but was infrequently diagnosed until the report by Sament and Schwartz in 1957[1]. New HHNS accounts for between 5 and 15 percent of all adult and pediatric diabetic hyperglycemic emergencies.[2] In adults HHNS occurs at a frequency of 17.5 cases/100,000 persons / year.[3] Population-based data for children are not available. A recent estimate suggests in USA that nearly 4% of newly diagnosed pediatric T2 DM patients will have HHNS with a case fatality of 12%.[4] T2 DM accounts for as much as half of newly diagnosed DM in children between 12-21 years in USA.[2] Similar trends are beginning to appear in adolescents in U.K.[5] More recently the syndrome has been recognized with increasing frequency in obese adolescents and children with T2 DM.[6]-[8] The incidence is therefore likely to increase with global increase in incidence of obesity[9],[10],[11], increased insulin resistance and T2 DM.[10],[12],[13] HHNS may rarely occur in younger patients[14] and following acute stress of sepsis or trauma, use of several drugs, and other conditions without underlying T2DM[15] table1. In this review, we discuss issues in diagnosis and management of this resurgent problem with a pediatric perspective.
Pathogenesis
The syndrome is characterized by severe hyperglycemia, a marked increase in serum osmolality and clinical evidence of dehydration without the accumulation of b-hydroxybutyric or acetoacetic ketoacids Figure1. Hyperglycemia results from either an absolute or relative deficiency of insulin or due to decreased tissue responsiveness to insulin (Increased insulin resistance). This results in increased gluconeogenesis and glycogenolysis,[2] reduced rate of glucose uptake and utilization by peripheral tissues[16], and thus a rise in blood glucose level. Glycogenolysis, however, contributes much less to the severity of hyperglycemia as these patients are usually quite ill and may not have eaten for several days, thus depleting their hepatic glycogen stores. HHNS evolves when insulin resistance permits development of hyperglycemia in the absence of significant ketone production and limited ability of the kidney to excrete large quantities of glucose. HHNS therefore is more likely to occur in children with renal disease associated with increased renal threshold for the excretion of glucose.[17]
A rise in osmolality in the extracellular fluid causes a shift of water from the intracellular to the extracellular space resulting in intracellular dehydration. Initially, this redistribution of water causes a slight expansion of the extracellular fluid volume and lowers the serum sodium, but the effect is transient.[18] Glycosuria and osmotic diuresis ensue once the blood glucose exceeds the renal threshold (normal range 180-250 mg/dl). The initial glycosuria temporarily protects the patients from hyperglycemia, but as the osmotic diuresis continues profound depletion of intravascular volume occurs, decreasing renal perfusion and the ability of the kidneys to excrete large quantities of glucose.[19] At this point, profound hyperglycemia and a further increase in plasma osmolality occur. The stress of profound hyperglycemia and resultant hyperosmolarity and dehydration, as well as the precipitating illness, contributes to increased production of counter regulatory hormones like cortisol, catecholamines and glucagon. The increased secretion of the counter-regulatory hormones further accentuates the degree of hyperglycemia.[2]
In addition to glucose, electrolytes such as sodium, potassium, phosphate and magnesium are also lost during the osmotic diuresis. Sodium depletion leads to further decrease in intravascular volume but urinary losses of water always exceeds that of sodium leading to development of hypertonic dehydration.
The mechanisms responsible for limiting significant accumulation of ketoacidosis in HHNS have been a subject of debate.[20] Most data support the hypothesis that significant ketogenesis is restrained by the ability of the pancreas to secrete small amount of insulin.[21] Inhibition of lipolysis and stimulation of lipogenesis occurs at much lower concentrations, while glucose uptake and inhibition of gluconeogenesis require considerably greater concentration of insulin.[16] Hyperosmolality and dehydration have also been reported to inhibit release of free fatty acids from adipose tissue.
Diagnosis
HHNS is a medical emergency that requires prompt recognition and treatment. Delayed diagnosis and treatment is one of the important factors responsible for the high mortality associated with HHNS.[7],[22] There is no symptom or sign specific of HHNS and hence there is often a delay in seeking medical care. Patients typically have no prior knowledge of glucose intolerance, and experiences polyuria, polydipsia and weight loss as osmotic diuresis sets in. The lack of significant ketonaemia and acidosis and absence of Kussumal breathing and fruity scent in breath usually allows patients with HHNS to lapse into prolonged phase of osmotic diuresis and a greater degree of dehydration compared to patients with diabetic ketoacidosis (DKA) before presenting for medical attention.[17]
Usually, these patients at presentation have poor skin turgour, dry mucus membrane, tachycardia, low jugular venous pressure and may be hypotensive. The sensorium may vary from normal to profound coma. In some patients focal neurological signs (hemiparesis or hemianopsia) and seizures may be the dominant clinical features[23].The physical findings of fluid depletion in a patient who continues to have increased rather than decreased urine output, especially in the presence of depressed mental status, should lead the physician to strongly consider a diagnosis of HHNS. In some instances HHNS was not suspected even when the patients presented with neurological signs and symptoms associated with glycosuria[18] . Hence, a high index of suspicion for HHNS should be maintained, especially in obese adolescents at risk of T2 DM or in children who are on drugs known to precipitate hyperglycemia. Due to severe dehydration, patients with HHNS are at increased risk of developing vascular thrombosis including cerebral and mesenteric artery occlusions.[24]
Rhabdomyolysis and malignant hyperthermia have been reported in HHNS, especially in obese adolescents with T2 DM. [7],[25] It is believed that defects in the fatty acid oxidation in the skeletal muscles of such individuals lead to excess lipid deposition in their muscles and predisposes them to rhabdomyolysis.[7]
Laboratory Findings
Diagnostic criteria for HHNS are summarized in table2. The initial laboratory evaluation of patients with suspected HHNS should include immediate determination of blood glucose, blood urea and creatinine, serum electrolytes, osmolality and ketones and arterial blood gases. Urine analysis and blood counts with differentials should be done. Bacterial cultures of urine, blood and other tissues should be obtained and appropriate antibiotics should be administered if infection is suspected. Approximately, 50% of the patients with HHNS have an increased anion gap metabolic acidosis because of increased serum lactate level[18].
Sodium: All patients with HHNS, regardless of the initial serum sodium concentration from low to high, are in a state of hypertonic dehydration. It must be appreciated that due to transcellular shifts of water, the serum sodium concentration decreases approximately 1.6 mEq/l for every 100 mg/dl increment in blood glucose.[26] Reduction of the blood glucose concentration following administration of fluids and insulin causes an increase in serum sodium levels as water is transported back into the intracellular space.
Potassium : Its depletion results from the osmotic diuresis and poor oral intake and in some case due to vomiting and kaliuretic drugs. However, insulin deficiency causes a shift of potassium to the extracellular fluid, and the initial serum potassium values may be normal or elevated. With fluid and insulin therapy there is a danger of rapid fall in serum potassium.
Dehydration also causes an elevation in serum urea and creatinine, and these parameters may not normalize in patients with renal disease. Leucocytosis may be observed due to increased levels of catecholamines and glucocorticoids, but it should be remembered that even sepsis could raise the levels of white cell count. Normal hemoglobin at presentation may indicate an underlying anemia, which will manifest after rehydration.
Elevation of muscle enzymes such as creatinine phosphokinase and lactic dehydrogenase aid in the diagnosis of rhabdomyolysis.
Management
Total body water deficit in HHNS may range from 100 - 200 ml/kg. The early objective of management of HHNS is therefore rapid restoration of circulatory volume, replacement of fluid and electrolyte deficits and correction of hyperglycemia and hyperosmolarity
Fluid therapy: The principal objective at the outset is restoration of the intravascular volume to assure adequate perfusion of the brain, heart and kidneys.[27] However, evidence-based guidelines to achieve the above treatment objectives in children are not available. The issues about composition and tonicity of fluid and electrolyte solutions for early resuscitation and rehydration, the rate of infusion-rapid vs slow, insulin dose-early high dose for rapid lowering of glucose etc. remain unresolved in the absence of studies in children. One of the reasons for the controversy is fear of cerebral edema with rapid fluid correction as seen in patients with diabetic ketoacidosis. A rapid decline in blood glucose concentration after initiation of treatment with insulin might decrease brain/blood glucose ratio resulting in fluid shift to the brain[28].
Rapid restoration of circulating volume using iso-osomolar isotonic fluid (0.9% saline) until stabilization of pulse, blood pressure and other vital signs, followed by 0.45% saline with insulin infusion at the rate of 0.1 units/kg/hour is recommended[2],[18]. The decrease in plasma glucose level should be 75 to 100mg/dl (4.0 to 5.5 mmol/l). Once the blood glucose is in the range of 250 to 300 mg/dl, 5% dextrose may be added to the fluids and insulin infusion reduced. The fluid, electrolyte and glucose therapy should be directed at a gradual decrease in plasma osmolality and corrected serum sodium levels[28]. Rapid corrections of metabolic abnormality and hyperosmolarity by administration of hypotonic fluids and insulin should be avoided in younger patients to decrease the risk of cerebral edema[29]. American Diabetic Association guidelines recommend slower correction of fluid deficit (over 48 hours) in patients below 20 years than in adults.[2]
Insulin Therapy: The intravenous route of insulin administration is preferred in dehydrated patients in whom the absorption of insulin from subcutaneous or even intramuscular sites may not be predictable. A lower dose of insulin (0.1 unit/kg/hour without an initial loading dose) is required to correct the metabolic abnormalities in children with HHNS in comparison to those used in DKA.[2],[29] This is also expected to prevent cerebral edema and hypotension, which develop because of rapid shift of extracellular fluid into intracellular compartment due to lowering of blood sugar, and worsening of hypokalemia and hypophostemia because of rapid insulin therapy.
Potassium therapy: Potassium deficits in HHNS approximate those seen in diabetic ketoacidosis (5 to 15 mEq/kg). The initial serum potassium levels may be low or normal, or occasionally elevated due to a shift of intracellular potassium to extracellular fluid. Treatment with insulin and fluid will cause a further decline in potassium level due to its ingress into the cells. Potassium replacement, 0.2 to 0.3 mEq/kg/hour, should therefore be started early, once oliguria is ruled out. Subsequent adjustments of potassium infusion rate, which may go upto 0.5-0.75 mEq/kg/hour, is made according to serum K+ levels.[2],[18] Potassium phosphate may be used instead of potassium chloride if concomitant hypophosphatemia is present.
Phosphate therapy: Hypophosphatemia is uncommon. It can lead to respiratory and skeletal muscle weakness, hemolytic anemia and systolic cardiac dysfunction.[30] Phosphate depletion is believed to lead to decreased 2,3-diphosphoglycate, shifting of the oxygen dissociation curve to the left. Phosphate replacement (0.2-0.3 mEq/kg by infusion over several hours) is indicated at a serum phosphate concentration < 1 mg/dl or in patients with moderate hypophosphatemia and concomitant hypoxia, anemia or cardio-respiratory compromise.[2] The serum calcium and magnesium concentration should be checked at the time of presentation and during therapy: repletion is instituted if levels fall below the normal range. Low dose infusion of dopamine (1 to 5 mg/kg/min) in neurosurgical patients with HHNS has been associated with reduced incidence of cerebral edema, renal failure and cardiac failure[31].
Immediate post-hyperglycemic care: Low dose insulin therapy provides a circulating insulin concentration of 60-100 μg/ml. However, because of the short half-life of intravenous regular insulin, sudden interruption of insulin infusion can lead to rapid lowering of insulin concentration resulting in a relapse of HHNS.[2] Subcutaneous insulin can be started once the patient's intravenous volume has been corrected; sensorium improves and is able to accept fluids orally.[2]
Treatment of precipitating causes and complications: Optimal management of patients with HHNS requires a thorough search for conditions that may lead to this metabolic decompensation and their treatment table1. Some authors recommend institution of empiric broad-spectrum antibiotics particularly for Gram-negative organisms pending the results of bacterial cultures.[24]
Thromboembolic events are frequently reported in patients with HHNS and may in part be responsible for the high mortality rate associated with this condition.[32] Low-dose subcutaneous heparin is advised for prophylactic anticoagulant administration in older patients[24],[32]; however, guidelines for its use in children with HHNS are not available.
Fatal cases of cerebral edema have been reported with HHNS. Clinically, cerebral edema is characterized by deterioration in the level of consciousness, lethargy, decrease in arousal and headache. These symptoms progress rapidly as brainstem herniation occurs, to pupillary changes, bradycardia and respiratory arrest; the progression may be so rapid that papilledema may not be found. To avoid cerebral edema the blood glucose level should be maintained between 250-300mg/dl until hyperosmolarity and mental status improve and the patient becomes clinically stable.
Rhabdomyolysis has been observed frequently with HHNS and is often associated with high mortality[7],[25], whether it is related to hyperosmolality or metabolic disturbances associated with HHNS or their treatment is not clear. No proven therapy exists for rhabdomyolysis, although therapy with carnitine and dantrolene has been tried.[7],[25]
Monitoring
Rapid changes in volume status and fluid and electrolyte balance necessitate meticulous documentation of the therapeutic actions taken, as well as the patient's response to such therapy. Volume of fluid administered, urine output, blood glucose concentration, serum electrolyte levels, including sodium, potassium, magnesium, calcium and phosphate, blood urea, nitrogen (BUN) and creatinine must be monitored and recorded hourly initially.[28] It may be useful to monitor glucose corrected sodium level to minimize the consequences of rapid decrease in serum osmolality.[28] The brain/subcutaneous glucose monitoring using the microdialysis may be helpful in guiding the insulin and fluid therapy as any rapid increase in the above ratio can forewarn the clinician about the risk of impending cerebral edema.[33]
Prevention
Careful monitoring of glucose levels and ensuring adequate hydration in patients 'at risk' of HHNS including those receiving medications that interfere with the secretion or effectiveness of insulin should decrease the risk of HHNS. Screening programmes directed at identifying T2 DM in the community will help identify patients at risk for HHNS.
Conclusion
Life-threatening hyperglycemic hyperosmolar syndrome, which is characterized by severe hyperglycemia without ketoacidosis, and very high serum osmolality and dehydration, appears to be on rise in adolescents with extreme obesity and T2 DM. Population-based estimates of the magnitude of the problem are needed. High index of suspicion in dehydrated patients who continue to have increased rather than decreased urine output may help in early diagnosis. Although the emergency treatment guidelines recommend early restoration of the intravascular volume, correction of fluid and electrolyte-deficits, hyperglycemia and hyperosmolarity, prospective studies are needed to resolve controversy surrounding tonicity and electrolyte composition of the resuscitation and rehydration fluids, the rate of fluid infusion and insulin doses in children.[34]
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