Konstantinos Makrilakis, MD, PhD
Nikolaos Katsilambros, MD, PhD.
The management of HHS is similar to that of DKA. It includes correction of the fluid and electrolyte abnormalities that are typically present and administration of insulin. 1,3,15
Therapy should also aim at simultaneous identification and treatment of the precipitating factors that led to the hyperglycemic decompensation (Box 3.1). Frequent monitoring of the patient is essential (Table 1.3). Protocols for the management of HHS are summarized in Figure 3.1….
Figure 3.1 General protocol for the management of adult patients with HHS. Adapted from: Kitabchi AE, et al. Diabetes Care 2001; 24: 131-153 (with permission).
The serum glucose should initially be measured every hour until stable, while serum electrolytes, BUN, creatinine, and arterial (or venous) pH should be measured every 2-4 hours, depending on disease severity and the clinical response.1,3 Effective serum osmolality can be calculated as analyzed above.
Initial fluid therapy is directed toward expansion of the intravascular, interstitial, and intracellular volume — all of which are reduced in HHS — and restoration of renal perfusion. The typical total body water and electrolyte deficits are shown in Table 1.2. The aim of therapy is to replete the extracellular fluid volume without inducing cerebral edema due to too rapid a reduction in the plasma osmolality.
In patients with hypovolemic shock, 0.9% normal saline should be infused as quickly as possible. Otherwise, as long as there is no cardiac failure, isotonic saline (0.9% NaCl) is infused at a rate of 15-20 ml/kg per hour (usually 1.0-1.5 L during the first hour). This solution will replace the fluid deficit, correct the extracellular volume depletion more rapidly than one-half isotonic saline, lower the plasma osmolality (since it is still hypo-osmotic to the patient), and reduce the serum glucose concentration, both by dilution and by increasing urinary glucose excretion as renal perfusion is increased. The subsequent choice for fluid replacement depends upon the state of hydration, serum electrolyte levels, and urinary output. If corrected serum Na+ is low, infusion of normal saline is continued at a rate of 4-14 ml/kg per hour for a few more hours. If corrected serum Na+ is normal or high, one-half isotonic saline (0.45% normal saline) at a rate of 4-14 ml/kg per hour is initiated, depending on the state of hydration (to replace the free water loss induced by the glucose osmotic diuresis). Potassium supplementation (often necessary to replete the K+ deficit) will also affect the osmolarity of the infused fluid because K+ is as osmotically active as Na+ and thus the addition of K+ to isotonic saline results in the generation of a hypertonic fluid that will not decrease the serum hyperosmolality. Thus, half-normal saline is indicated in this situation.16
The progress of successful fluid and electrolyte replacement is judged by frequent monitoring of hemodynamics (improvement in blood pressure), laboratory evaluation, fluid intake/output, and clinical examination. Fluid replacement should correct the estimated deficits within the first 24 hours. In patients with renal or cardiac compromise, more frequent monitoring must be performed during fluid resuscitation to avoid iatrogenic pulmonary edema.
When blood glucose concentration reaches -300 mg/dl (16.7 mmol/L), fluid infusion is switched to 5% dextrose to allow continued insulin administration at a decreased rate (see below) while at the same time avoiding hypoglycemia. Some authors1 prefer to infuse a mixture of 5% dextrose with 0.45% NaCl, instead of 5% dextrose alone. This should continue until plasma osmolality is close to 315 mOsm/kg and the patient is mentally alert.
As in DKA, insulin therapy is essential in HHS (together with aggressive fluid hydration) to lower plasma glucose concentration (it primarily acts by decreasing hepatic glucose production rather than enhancing peripheral utilization). The route and the dose of insulin administration have been the subject of many studies in the past. It has been shown that any route of administration (intravenous, intramuscular, or subcutaneous) is ultimately effective, but the intravenous route is preferred because of concerns about decreased absorption with intramuscular or subcutaneous injections (at least initially) in dehydrated patients with vasoconstriction. The administration of continuous intravenous infusion of regular insulin is the preferred route also because of its short half-life and easy titration. Regarding dose, low doses of insulin have been shown to be as effective as high doses, with much less risk of hypoglycemia.17,18
Insulin resistance is present in most patients with Type 2 diabetes. During HHS there are additional confounding factors such as stress (elevated counter-regulatory hormones), free fatty acids (FFAs), hemoconcentration, electrolyte deficiencies, ketone bodies, and particularly hyperosmolality that exaggerate the insulin resistance state. However, replacement of fluid and electrolytes alone may diminish this insulin resistance by decreasing levels of counter-regulatory hormones and hyperglycemia as well as by decreasing osmolality, making the cells more responsive to insulin. Low-dose insulin therapy is therefore most effective when preceded or accompanied by initial fluid and electrolyte replacement. Thus, after an initial infusion of isotonic saline to increase insulin responsiveness by lowering the plasma osmolality, the only indication for delaying insulin therapy is a serum potassium < 3.3 mEq/L, since insulin will worsen the hypokalemia by driving potassium into the cells (see below).
Intravenous regular insulin infusion
An initial regular insulin bolus of 0.1 IU per kg of body weight (i.e., 8 units in an 80 kg person) is given intravenously, followed by a continuous infusion of 0.1 IU/kg per hour (i.e., 8 units per hour in an 80 kg person). The purpose of the initial bolus is to more rapidly activate insulin receptors.19 However, a recent randomized trial (in DKA patients) showed that a bolus dose was not necessary if intravenous insulin was infused at a rate of 0.14 IU/kg per hour (i.e., 11 units per hour in an 80 kg person).20
An easy way to construct the insulin infusate is to mix 50 IU of regular insulin with 500 ml of 0.9% NaCl, thus creating a solution with a concentration of 1 IU insulin for every 10 ml solution and then infusing at the desired rate (for example 80 ml/h if 8 IU/h are needed).
The low dose of regular insulin usually decreases the serum glucose concentration by 50-70 mg/dl (2.8-3.9 mmol/L) per hour or more.19,21 Higher insulin doses do not generally produce a more prominent hypoglycemic effect, possibly because the insulin receptors are already saturated. If the serum glucose level does not fall by 50-70 mg/dl (2.8-3.9 mmol/L) from the initial value in the first hour, the insulin infusion rate should be doubled every hour until a steady decline in serum glucose is achieved. If serum glucose levels fail to fall, the intravenous access should be checked to make certain that the insulin is being delivered and that no filters are interposed that may bind insulin. The rate of fall in serum glucose may be more pronounced in patients with HHS (rather than with DKA) because the former are typically more volume depleted and aggressive rehydration has a more pronounced effect on their glucose levels. More rapid falls in glucose levels (more than 50-70 mg/dl [2.8-3.9 mmol/L] per hour) should be avoided to reduce the risk of cerebral edema.
As mentioned above, when the serum glucose concentration reaches 250-300 mg/dl (13.9-16.7 mmol/L), the intravenous saline solution is switched to 5% dextrose in saline, and it may be possible to decrease the insulin infusion rate to 0.02-0.05 IU/kg per hour (i.e. 1.6-4.0 units per hour in an 80 kg person). This will decrease the risk of cerebral edema.
Other routes of insulin administration
If intravenous insulin infusion is not possible (due to either lack of intravenous access or local technical problems), intramuscular (IM) or subcutaneous (SC) administration is equally effective, albeit maybe at a more delayed pace.17 Most studies have evaluated IM or SC insulin administration in DKA patients (rather than HHS ones) but the results are expected to be similar.22 Intravenous administration has been shown to produce a more rapid fall in plasma glucose (and ketone bodies) in the first two hours, when compared with regular insulin used in the sc injections. Thereafter, there were no significant differences in the rate of decline of plasma glucose or ketones, or in the time required for glucose to reach 250-300 mg/dl (13.9-16.7mmol/L) or for complete recovery from diabetic decompensation.
Patients with HHS usually have a high total-body K+ deficit (Table 1.2) at presentation, due mainly to renal but also to gastrointestinal losses during the development of hyperglycemic decompensation. The increase in renal potassium excretion is primarily related to the glucose osmotic diuresis and to hypovolemia-induced hyperaldosteronism. Despite the total-body potassium deficit, the serum K+ concentration is usually normal or, in some cases, elevated at presentation, due primarily to insulin deficiency and hyperosmolality, both of which result in potassium shift out of the cells. This change in K+ distribution is rapidly reversed with the administration of insulin, resulting in an often dramatic fall in the serum K+ concentration.
As a result, careful monitoring of serum K+ is an essential part of the management of HHS.23
If initial serum K+ concentration is > 5.3 mEq/L, no extra K+ is added to the infused fluids. In patients with serum K+ concentration < 5.3 mEq/L, potassium chloride (20-30 mEq in each L) is generally added to the replacement fluid to prevent hypokalemia, assuming an adequate urine output (> 50 ml/h). If the patient is hemodynamically stable, one-half isotonic saline is preferred, since the addition of potassium to isotonic saline will result in a hypertonic solution that will delay correction of the serum hyperosmolality. The goal of K+ supplementation is to maintain the serum potassium level between 4.0 and 5.0 mEq/L.1,3
In patients who are hypokalemic at presentation (serum K+ concentration < 3.3 mEq/L), potassium repletion is more urgent. Such patients require aggressive potassium replacement (20-30 mEq/h), which usually requires 40-60 mEq/L added to one-half isotonic saline. Since insulin will worsen the hypokalemia, insulin therapy should be delayed until the serum potassium is > 3.3 mEq/L to avoid possible arrhythmias, cardiac arrest, and respiratory muscle weakness.24
Despite a significant total-body phosphate deficit at presentation (Table 1.2), most patients have normal or elevated serum phosphate levels.14 As with potassium balance, phosphate depletion is revealed following the institution of insulin therapy, frequently leading to hypophosphatemia, which is usually asymptomatic. Clinically evident hemolysis and rhabdomyolysis with myoglobinuria are rare complications of hypophosphatemia.
No studies are available on the use of phosphate in the treatment of HHS. In DKA patients, however, prospective randomized studies have failed to show any benefit of phosphate supplementation on the clinical outcome, and overzealous phosphate administration can lead to hypocalcemia and hypomagnesemia.25 However, to avoid potential cardiac and skeletal muscle weakness and respiratory depression due to hypophosphatemia, careful phosphate replacement may sometimes be indicated in patients with cardiac dysfunction, anemia, or respiratory depression and in those with serum phosphate concentration < 1.0 mg/dl (0.32 mmol/L).26 When needed, 20-30 mEq potassium phosphate can be added to each L of the replacement fluids. The maximal rate of phosphate replacement generally regarded as safe to treat severe hypophosphatemia is 4.5 mmol/h (1.5 ml/h of potassium phosphate).
- Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes (technical review). Diabetes Care 2001; 24: 131-53.
- Daugirdas JT, Kronfol NO, Tzalaloukas AH, et al. Hyperosmolar coma: Cellular dehydration and the serum sodium concentration. Ann Intern Med 1989; 110: 855-7.
- Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2009; 32: 1335-43.
- Fishbein HA, Palumbo PJ. Acute metabolic complications in diabetes. In: Diabetes in America. National Diabetes Data Group, National Institutes of Health, 1995, p. 283 (NIH publ. no: 95-1468).
- www.cdc.gov/diabetes/statistics/ (accessed August 1, 2010).
- Katsilambros N. Epidemiology of acute manifestations and complications. In: Williams R, Papoz L, Fuller J (ed), Diabetes in Europe, A Monograph on Diabetes Epidemiology in Europe produced as part of the "Eurodiab" Concerted Action Programme of the European Community, London, UK: John Libbey & Company Ltd, 1994: 39-45.
- Ennis ED, Stahl EJVB, Kreisberg RA. The hyperosmolar hyperglycemic syndrome. Diabetes Rev 1994; 2: 115-26.
- Delaney MF, Zisman A, Kettyle WM. Diabetic ketoacidosis and hyperglycaemic hyperosmolar nonketotic syndrome. Endocrinol Metab Clin North Am 2000; 29: 683-705.
- Kitabchi AE, Fisher JN, Murphy MB, et al. Diabetic ketoacidosis and the hyperglycemic hyperosmolar nonketotic state. In: Kahn CR, Weir GC (ed), Joslin’s Diabetes Mellitus, 13th edn, Philadelphia, USA: Lea & Febiger, 1994: 738-70.
- Kitabchi AE, Umpierrez GE, Murphy MB, et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2006; 29: 2739-48.
- Al-Kudsi RR, Daugirdas JT, Ing TS, et al. Extreme hyperglycemia in dialysis patients. Clin Nephrol 1982; 17: 228-31.
- Katz, MA. Hyperglycemia-induced hyponatremia: Calculation of expected sodium depression. N Engl J Med 1973; 289: 843-4
- Adrogue HJ, Lederer ED, Suki WN, et al. Determinants of plasma potassium levels in diabetic ketoacidosis. Medicine (Baltimore) 1986; 65: 163-72.
- Kebler R, McDonald FD, Cadnapaphornchai P. Dynamic changes in serum phosphorus levels in diabetic ketoacidosis. Am J Med 1985; 79: 571-6.
- Ioannidis I. Diabetic coma. In: Katsilambros N, Diakoumopoulou E, Ioannidis I, Liatis S, Makrilakis K, Tentolouris N, Tsapogas P (ed), Diabetes in Clinical Practice, Questions and Answers from Case Studies, West Sussex, England: John Wiley & Sons Ltd, 2006: 81-91.
- Kamel KS, Bear RA. Treatment of hyponatremia: A quantitative analysis. Am J Kidney Dis 1993; 21: 439-43.
- Fisher JN, Shahshahani MN, Kitabchi AE. Diabetic ketoacidosis: Low-dose insulin therapy by various routes. N Engl J Med 1977; 297: 238-41.
- Krentz AJ, Nattrass M. Acute metabolic complications of diabetes: diabetic ketoacidosis, hyperosmolar non-ketotic hyperglycemia and lactic acidosis. In: Pickup JC, Williams G (ed), Textbook of Diabetes Mellitus, 3rd edn, Oxford, UK: Blackwell Publishing, 2003: 32.1-24.
- Rosenthal NR, Barrett EJ. An assessment of insulin action in hyperosmolar hyperglycemic nonketotic diabetic patients. J Clin Endocrinol Metab 1985; 60: 607-10.
- 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.
- Luzi L, Barrett EJ, Groop LC, et al. Metabolic effects of low-dose insulin therapy on glucose metabolism in diabetic ketoacidosis. Diabetes 1988; 37: 1470-7.
- Kitabchi AE, Umpierrez GE, Fisher JN, et al. Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state. J Clin Endocrinol Metab 2008; 93: 1541-52.
- Nugent BW. Hyperosmolar hyperglycemic state. Emerg Med Clin North Am 2005; 23: 629-48.
- Beigelman PM. Potassium in severe diabetic ketoacidosis. Am J Med 1973; 54: 419-20.
- Fisher JN, Kitabchi AE. A randomized study of phosphate therapy in the treatment of diabetic ketoacidosis. J Clin Endocrinol Metab 1983; 57: 177-80.
- Kreisberg RA. Phosphorus defi ciency and hypophosphatemia. Hosp Pract 1977; 12: 121-8.
- Alberti KGGM, Hockaday TDR, Turner RC. Small doses of intramuscular insulin in the treatment of diabetic "coma." Lancet 1973; 5: 515-22.
- Kitabchi AE, Ayyagari V, Guerra SNO, Medical House Staff. Efficacy of low dose vs conventional therapy of insulin for treatment of diabetic ketoacidosis. Ann Intern Med 1976; 84: 633-8.
- Wolfsdorf J, Glaser N, Sperling MA. Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care 2006; 29: 1150-9.
- Roberts MD, Slover RH, Chase HP. Diabetic ketoacidosis with intracerebral complications. Pediatr Diabetes 2001; 2: 109-14.
Nikolaos Katsilambros, MD, PhD, FACP
Professor of Internal Medicine
Athens University Medical School
Evgenideion Hospital and Research Laboratory ‘Christeas Hall’
Associate Professor of Pediatric Endocrinology and Diabetology
First Department of Pediatrics, University of Athens
Agia Sofia Children’s Hospital
Consultant in Internal Medicine and Diabetology
Laiko General Hospital
Assistant Professor of Internal Medicine and Diabetology
Athens University Medical School
Laiko General Hospital
Assistant Professor of Internal Medicine and Diabetology
University of Athens
Laiko General Hospital