Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Hyperosmolar hyperglycemic state (HHS) is a serious complication of diabetes with a much higher mortality than diabetic ketoacidosis. The dehydration and hyperosmolality are responsible for most of the symptoms and signs of HHS. The residual endogenous insulin in type 2 diabetic individuals prevent the development of ketosis in HHS. Blood glucose levels more than 600 mg/dL without ketosis and with an effective plasma osmolarity more than 320 mOsm/L is diagnostic of HHS. Aggressive fluid replacement with low dose insulin therapy and correction of underlying cause is the mainstay of treatment.
Hyperosmolar hyperglycemic state (HHS) is a life-threatening metabolic decompensation seen most often in type 2 diabetic patients. However, it has also been reported in children and young adults.1 It is mainly characterized by symptoms and signs due to dehydration caused by excessive hyperglycemia and consequent hyperosmolality and osmotic diuresis, with varying degree of alteration in consciousness. HHS is a serious complication with a mortality rate ranging from 5 to 20% which is ten times more than that of diabetic ketoacidosis (DKA). Mortality is higher at extremes of age and when patient presents with coma. True mortality rates are difficult to assess because of the high prevalence of associated comorbidities. Due to the dramatic increase in the prevalence of type 2 diabetes mellitus and increasing elderly population, HHS is encountered more frequently these days.
Diabetic ketoacidosis and HHS represent two ends of diabetes, differing in the degree of insulin deficiency, dehydration, metabolic derangement spectrum ketosis and acidosis. DKA occurs in the setting of profound insulin deficiency, where very low levels of insulin leads not only to hyperglycemia, but also to ketosis and acidosis. HHS is caused by relative insulin deficiency which leads to hyperglycemia, dehydration, and a hyperosmolar state.
Von Frerichs and Dreschfeld described the first cases of HHS in the 1880s in patients with an ‘unusual diabetic coma’.2 The initial definition and diagnostic criteria of HHS was derived from a few case series reported by Gerich et al3 and Arieff and Carroll4 in 1971. Arieff and Carroll in 1971 proposed a diagnostic criteria for this entity they named as ‘hyperglycemic hyperosmolar nonketotic coma’. Later, the terminology was revised to ‘hyperglycemic hyperosmolar state’ as a significantly large number of patients present without coma and mild ketosis may be present in a few patients.5,6 Only one-third of patients present with coma and 20% of patients may have combined biochemical picture of DKA and HHS.7,8
WHY THERE IS NO KETOSIS IN HYPEROSMOLAR HYPERGLYCEMIC STATE?
The lack of ketoacidosis in HHS may be the result of several factors. HHS develops in type 2 diabetic patients, who still have varying degrees of residual endogenous insulin secretion. This residual endogenous insulin while unable to stimulate glucose utilization and to repress hepatic glucose production, is able to control lipolysis. This is because lipolysis is more sensitive to insulin, thus, limiting the free fatty acids afflux to liver and therefore, the ketogenesis process. The higher circulating ratio of insulin/glucagon in patients with HHS also prevents ketogenesis and the development of ketoacidosis. Glucagon resistance has also been described.5,9
Compared with DKA, HHS usually occurs with lesser degree of insulin deficiency, but the pathophysiology is otherwise thought to be similar. There is a decrease in net effective insulin action with concomitant elevation of counter-regulatory hormones like glucagon, cortisol, catecholamines, and growth hormone in both these conditions. In the setting of relative insulin deficiency, these counter-regulatory hormones stimulate hepatic glucose production through glycogenolysis and gluconeogenesis. High catecholamines and low insulin reduce peripheral glucose uptake mainly in muscles. Quantitatively, increased hepatic glucose production represents the major pathogenic disturbance responsible for hyperglycemia.10 There is adequate insulin present to restrain lipolysis and ketogenesis.
With increasing degree of hyperglycemia, the osmolality of extracellular fluid increases and an osmolar gradient is created that draws water out of the cells. A normally functioning kidney does not allow hyperglycemia to persist and compensates by increasing the glomerular filtration, leading to glucosuria and osmotic diuresis. This initial glucosuria delays the rapid development of severe hyperglycemia as long as the glomerular filtration rate is normal. But with continued osmotic diuresis, hypovolemia eventually occurs, leading to progressive decline in glomerular filtration rate and worsening hyperglycemia. This will lead to both intracellular and extracellular dehydration including brain dehydration, causing altered consciousness and hypovolemic shock (Figure 1).11
It has also been shown that hyperglycemia causes an increase in oxidative stress markers, such as membrane lipid peroxidation.12 With insulin therapy and normalization of blood glucose, these abnormalities revert back to normal.
Hyperosmolar hyperglycemic state is most commonly seen in elderly institutionalized individuals with low perception of thirst and inability to take free water. Precipitating factors may be divided into six categories: infections, medications, noncompliance, undiagnosed diabetes, substance abuse, and coexisting diseases. Most common precipitating cause of HHS is infection (40–60%), the most common infections being pneumonia and urinary tract infections.8,13,14 Other underlying medical illnesses like cerebrovascular accidents, myocardial infarction, pancreatitis, trauma, etc. lead to release of counter-regulatory hormones and may lead to HHS in predisposed individuals. Restricted water intake when being bedridden and poor perception of thirst also contributes. Poor compliance with antidiabetic medications, total parenteral nutrition, and drugs like steroids, phenytoin, mannitol, thiazide diuretics, β-blockers or atypical antipsychotics can all lead to precipitation of HHS.15 20% of patients presenting with HHS may not have a previous diagnosis of diabetes.7
Hyperosmolar hyperglycemic state has also been reported in children and adolescents, and also in individuals with type 1 diabetes mellitus. Again the most common precipitating factor in these patients is infection, especially of the nervous and genitourinary systems.16–18
Hyperosmolar hyperglycemic state usually has a slower onset than DKA, with symptoms developing over several days or weeks. In addition to the precipitating factors described above, patient presents with weakness, lethargy, leg cramps, nausea, and vomiting. Eventually, if untreated, these patients develop confusion, seizures, and coma. Physical findings include profound dehydration that is evidenced by poor skin turgor (which may be difficult to evaluate in older patients), dry buccal mucosa and tongue, sunken eyeballs, cool extremities, rapid, thready pulse, and hypotension. Fever may be present which indicates underlying infection. Changes in mental status may range from alertness to disorientation to lethargy to coma. The degree of neurologic impairment is directly proportional to the effective serum osmolarity. Coma usually supervenes once when the serum osmolarity is greater than 350 mOsm/L. In a case series including 275 uncontrolled diabetic patients published by Carroll et al, 45% of patients with an effective osmolarity of greater than 350 mOsm/L were comatosed on presentation.19 Twenty five percent of the patients may have generalized or focal seizures or myoclonic jerks; hemiparesis which is reversible on fluid therapy, may also occur.
Current diagnostic criteria of HHS recommended by the American Diabetes Association and international guidelines include a plasma glucose level of more than 600 mg/dL, plasma effective osmolarity more than 320 mOsm/L, and an absence of significant ketoacidosis.20,21
Blood glucose levels are markedly elevated, usually higher than that occurring in DKA, reaching a level of more than 600 mg/dL. This will cause an increase in serum osmolality. Other laboratory tests should include serum and urine ketones, serum electrolytes, arterial blood gases, blood urea nitrogen, and creatinine. In contrast to DKA, in patients of HHS, the metabolic acidosis is very mild or absent and serum bicarbonates are normal. Acidosis, when present, is due to the retention of inorganic acids, i.e., a small amount of ketone bodies and lactate formed due to tissue hypoperfusion due to dehydration.
Hyperosmolar hyperglycemic state produces volume depletion and prerenal azotemia and hence, hemoconcentration. An elevated serum sodium in the presence of hyperglycemia indicates severe dehydration. Even though there is a significant potassium loss, serum potassium may be normal or elevated because of extracellular shift due to hyperosmolarity and insulin deficiency. The main differentials are DKA and diabetes insipidus treated with intravenous (IV) dextrose (Table 1).
Investigations should be carried out to find the underlying infection or condition that precipitated the event. Complete hemogram, urine analysis, and blood and urine cultures should be sent. Electrocardiogram, chest X-ray, and head computed tomography, whenever indicated, should be done.
The success of treatment of HHS depends primarily on the adequate replacement of volume deficit and correction of hyperosmolality, hyperglycemia, and electrolyte disturbances, as well as management of the underlying illness that precipitated the metabolic decompensation.22,23
Aggressive fluid replacement is essential in order to prevent cardiovascular collapse, with repletion of intravascular and extravascular volume and restoration of renal perfusion. The severity of fluid and sodium deficits is determined mainly by duration of hyperglycemia, renal function, and patient's oral intake of solute and water. In HHS, the mean fluid loss is approximately 9 L. A calculation of effective osmolarity can serve as a guide in determining the type of fluid replacement to use. The use of isotonic fluids may cause fluid overload and hypotonic fluids may correct deficits too rapidly with a potential for diffuse myelinolysis and death.24
Normal serum osmolarity is 290 ± 5 mOsm/L. Effective osmolality is defined as 2 (measured Na+) (mEq/L) + glucose (mg/dL)/18 (urea is an ineffective osmole, so not included in calculation). Corrected serum sodium concentrations of more than 140 mEq/L and calculated total osmolality of more than 340 mOsm/kg H2O are associated with large fluid deficits.25
If the patient is not having any major cardiovascular issues, treatment may be started with infusion of isotonic saline (0.9% sodium chloride) at a rate of 15–20 mL/kg/hour during the first hour (about 1–1.5 L in an average adult) to rapidly expand the extracellular volume. The subsequent choice of fluid depends on the state of hydration, electrolyte levels, and urine output. If serum sodium levels are normal or elevated, half normal saline (0.45% sodium chloride) may be used for replacement at a rate of about 10 mL/kg/hour. Care should be taken to correct one-half of the estimated fluid deficit in initial 18–24 hours and rest over next 24 hours and not to cause a decrease in plasma osmolality by more than 3 mmol/kg/hour. When blood glucose values reach below 300 mg/dL, 5% dextrose should be the choice of fluid therapy. Alternatively, in alert patients, free water can be given orally or through Ryle's tube. The duration of IV fluid replacement in adults and children is ∼48 hours depending on the clinical response to therapy. However, in a child, once cardiovascular stability is achieved and vomiting has stopped, it is safer and effective to pursue oral rehydration because children are at greater risk of developing potentially fatal cerebral edema during treatment.26
The most important point regarding insulin management is to administer adequate fluids before insulin. If insulin is administered before fluids, the water will move intracellularly, causing potential worsening of hypotension, vascular collapse, or death. The general consensus regarding insulin administration is to give regular insulin as continuous IV infusion in low doses via infusion pump (0.1 units/kg/hour). This is more physiological and produces a gradual and steady fall in blood glucose levels with minimal chances of hypokalemia and hypoglycemia. If the glucose level does not decrease by 50–70 mg/dL/hour, this rate of administration may be doubled. When the plasma glucose level reaches 300 mg/dL, insulin infusion may be reduced to 0.05–0.1 units/kg/hour and dextrose can be added to the fluids to keep the glucose level between 250–300 mg/dL until hyperosmolality has resolved and the patient is alert.23
The treatment of HHS is associated with rapid decline in serum potassium values due to insulin mediated intracellular shift of potassium, expansion of extracellular volume and continuing osmotic dieresis. Insulin therapy should be withheld, if initial serum potassium is less than 3.3 mEq/L and replacement should be started for values less than 5 mEq/L. 20–30 mmol of potassium is to be added to each liter of infusion fluid to maintain the serum potassium concentration between 4 and 5 mmol/L. Despite a lack of evidence that treatment with phosphate, calcium, or magnesium alters outcomes,27 these electrolytes must be checked. Magnesium should be checked and repleted as necessary; this is important to prevent renal wasting of potassium with exacerbation of hypokalemia. Careful phosphate replacement can be considered in patients with very low levels, cardiac dysfunction, or respiratory distress.
IDENTIFY AND TREAT THE UNDERLYING CAUSE
Routine administration of antibiotics is not recommended in HHS, though elderly patients with clinical suspicion of sepsis and hypotension may be empirically started on antibiotics after sending cultures. Recent study by Gogos et al showed that elevated C-reactive protein and interleukin-6 levels are early indicators of sepsis in patients with HHS.28
Patients' medication chart should be reviewed to find any precipitant drug and appropriate investigations should be carried out to find the underlying cause.
Catabolic malnourishment is very common in many patients with diabetes and HHS, hence, they are more prone to develop refeeding syndrome.29 Thus, the administration of a B-complex vitamin supplement, especially thiamine, is prudent.
The main concern regarding therapy is the potential to develop cerebral edema due to rapid fluid administration, rapid lowering of serum osmolality and plasma glucose. Fatal cerebral edema is extremely rare in adult population, but has been reported in pediatric patients especially when they have coexisting hyperosmolar hyperglycemia with ketoacidosis. Slowing the correction of hyperosmolarity in children may prevent cerebral edema.26
Vascular occlusions (mesenteric artery occlusion, myocardial infarction, disseminated intravascular coagulation)30 and rhabdomyolysis may occur due to inadequate treatment.31 The rate of these complications can be reduced to 2% with aggressive treatment. Complications like hypoglycemia and hypokalemia are low with current low dose insulin regimens.
The prognosis is determined by the severity of dehydration, presence of comorbidities, hemodynamic instability, and advanced age.8,13,32 The best prognostic markers according to various previous studies are the degree of dehydration and degree of consciousness at presentation.
Several case reports have indicated an increased risk of thrombosis, which is greater in HHS than in ketoacidosis.33,34 Severe dehydration and hypertonicity may result in osmotic disruption of endothelial cells, leading to a release of tissue thromboplastin and elevated vasopressin caused by the fluid status, which may contribute to enhanced coagulation.35 The risks and benefits of anticoagulation therapy in patients with HHS and DKA have not been evaluated prospectively.
Hyperglycemic hyperosmolar state, a serious complication of T2DM, if not promptly treated can cause significant fluid electrolyte abnormalities and mortality. High blood glucose (>600 mg/dL) absence of ketosis, presence of high plasma osmolarity (320 mOsm/L) establishes the diagnosis. With aggressive replacement of volume deficit and low dose insulin therapy and management of underlying disease, the mortality and morbidity can be significantly reduced.
- Wetter J, Gohlke BC, Woelfle JF. Hyperglycemic hyperosmolar state as initial manifestation of pediatric insulin-dependent diabetes. Klin Pädiatr. 2012;224(1):32–3.
- Dreschfeld J. The Bradshawe lecture on diabetic coma. Br Med J. 1886;2(1338):358–63.
- Gerich JE, Martin MM, Recant L. Clinical and metabolic characteristics of hyperosmolar nonketotic coma. Diabetes. 1971;20(4):228–38.
- Arieff AI, Carroll HJ. Hyperosmolar nonketotic coma with hyperglycemia: abnormalities of lipid and carbohydrate metabolism. Metabolism. 1971;20(6):529–38.
- Chupin M, Charbonnel B, Chupin F. C-peptide blood levels in keto-acidosis and in hyperosmolar non-ketotic diabetic coma. Acta Diabetol Lat. 1981;18(2):123–8.
- Alberti KG, Hockaday TD. Diabetic coma: a reappraisal after five years. Clin Endocrinol Metab. 1977;6(2):421–55.
- Umpierrez GE, Kelly JP, Navarrete JE, Casals MM, Kitabchi AE. Hyperglycemic crises in urban blacks. Arch Intern Med. 1997;157(6):669–75.
- Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335–43.
- Miles JM, Haymond MW, Nissen SL, Gerich JE. Effects of free fatty acid availability, glucagon excess, and insulin deficiency on ketone body production in postabsorptive man. J Clin Invest. 1983;71(6):1554–61.
- Luzi L, Barrett EJ, Groop LC, Ferrannini E, DeFronzo RA. Metabolic effects of low-dose insulin therapy on glucose metabolism in diabetic ketoacidosis. Diabetes. 1988;37(11):1470–7.
- Joffe BI, Goldberg RB, Krut LH, Seftel HC. Pathogenesis of nonketotic hyperosmolar diabetic coma. Lancet. 1975;1(7915):1069–71.
- Rains JL, Jain SK. Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med. 2011;50(5):567–75.
- Wachtel TJ, Tetu-Mouradjian LM, Goldman DL, Ellis SE, O'Sullivan PS. Hyperosmolarity and acidosis in diabetes mellitus: a three-year experience in Rhode Island. J Gen Intern Med. 1991;6(6):495–502.
- Wachtel TJ. The diabetic hyperosmolar state. Clin Geriatr Med. 1990;6(4):797–806.
- Chen WY, Chen CC, Hung GCL. Hyperglycemic hyperosmolar state associated with low-dose quetiapine treatment in a patient with bipolar disorder. Curr Drug Saf. 2011;6(3):207–8.
- Bagdure D, Rewers A, Campagna E, Sills MR. Epidemiology of hyperglycemic hyperosmolar syndrome in children hospitalized in USA. Pediatr Diabetes. 2013;14(1):18–24.
- Canarie MF, Bogue CW, Banasiak KJ, Weinzimer SA, Tamborlane WV. Decompensated hyperglycemic hyperosmolarity without significant ketoacidosis in the adolescent and young adult population. J Pediatr Endocrinol Metab. 2007;20(10):1115–24.
- Fourtner SH, Weinzimer SA, Levitt Katz LE. Hyperglycemic hyperosmolar non-ketotic syndrome in children with type 2 diabetes. Pediatr Diabetes. 2005;6(3):129–35.
- Carroll P, Matz R. Uncontrolled diabetes mellitus in adults: experience in treating diabetic ketoacidosis and hyperosmolar nonketotic coma with low-dose insulin and a uniform treatment regimen. Diabetes Care. 1983;6(6):579–85.
- Chiasson JL, Aris-Jilwan N, Bélanger R, Bertrand S, Beauregard H, Ékoé JM, et al. Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state. Can Med Assoc J. 2003;168(7):859–66.
- Pasquel FJ, Umpierrez GE. Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment. Diabetes Care. 2014;37(11):3124–31.
- Wolfsdorf JI, Allgrove J, Craig ME, Edge J, Glaser N, Jain V, et al. ISPAD clinical practice consensus guidelines 2014. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes. 2014;15(Suppl 20):154–79.
- Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care. 2001;24(1):131–53.
- Hillman K. Fluid resuscitation in diabetic emergencies—a reappraisal. Intensive Care Med. 1987;13(1):4–8.
- Gottschalk ME, Ros SP, Zeller WP. The emergency management of hyperglycemic-hyperosmolar nonketotic coma in the pediatric patient. Pediatr Emerg Care. 1996;12(1):48–51.
- Delaney MF, Zisman A, Kettyle WM. Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome. Endocrinol Metab Clin North Am. 2000;29(4):683–705.
- Gogos CA, Giali S, Paliogianni F, Dimitracopoulos G, Bassaris HP, Vagenakis AG. Interleukin-6 and C-reactive protein as early markers of sepsis in patients with diabetic ketoacidosis or hyperosmosis. Diabetologia. 2001;44(8):1011–4.
- Solomon SM, Kirby DF. The refeeding syndrome: a review. J Parenter Enteral Nutr. 1990;14(1):90–7.
- Keenan CR, Murin S, White RH. High risk for venous thromboembolism in diabetics with hyperosmolar state: comparison with other acute medical illnesses. J Thromb Haemost. 2007;5(6):1185–90.
- Paton RC. Haemostatic changes in diabetic coma. Diabetologia. 1981;21(3):172–7.
- Fadini GP, de Kreutzenberg SV, Rigato M, Brocco S, Marchesan M, Tiengo A, et al. Characteristics and outcomes of the hyperglycemic hyperosmolar non-ketotic syndrome in a cohort of 51 consecutive cases at a single center. Diabetes Res Clin Pract. 2011;94(2):172–9.
- Halmos PB, Nelson JK, Lowry RC. Hyperosmolar non-ketoacidotic coma in diabetes. Lancet. 1966;1(7439): 675–9.
- Tripodi A, Branchi A, Chantarangkul V, Clerici M, Merati G, Artoni A, et al. Hypercoagulability in patients with type 2 diabetes mellitus detected by a thrombin generation assay. J Thromb Thrombolysis. 2011;31(2):165–72.
- Grant PJ, Tate GM, Hughes JR, Davies JA, Prentice CR. Does hypernatraemia promote thrombosis? Thromb Res. 1985;40(3):393–9.