|Ahmed Al Hazmi, MBBS||University of Maryland Medical Center, Department of Emergency Medicine, Baltimore, Maryland|
|Sara Manning, MD||University of Maryland School of Medicine, Department of Emergency Medicine, Baltimore, Maryland|
A 61-year-old male with a recent diagnosis of pemphigus vulgaris was brought to the emergency department for altered mental status. He had recently started taking prednisone to manage his autoimmune disease and had a progressive decline in his mental status along with decreased oral intake. Evaluation revealed hyperosmolar hyperglycemic state (HHS) and occlusive arterial thrombosis, a rare but known complication of HHS. He was resuscitated aggressively with intravenous fluids, insulin, and heparin and admitted to the intensive care unit. Emergency physicians should remain vigilant for ischemic complications in patients with HHS. Early recognition and treatment can reduce the morbidity and mortality associated with this endocrine emergency.
Hyperosmolar hyperglycemic state (HHS) is defined as severe hyperglycemia, a marked increase in serum osmolarity with clinical signs of severe dehydration in the absence of ketoacids.1 The hyperosmolar state is a serious hyperglycemic emergency that affects patients with type 2 diabetes mellitus and is associated with significant morbidity and mortality.2 About 1% of emergency department (ED) patients with diabetes-related conditions have HHS.3,4 The mortality rate associated with HHS is five times higher than that associated with diabetic ketoacidosis (DKA).5 The prognosis for patients with HHS is significantly worse at the extreme of ages and in the presence of hypoperfusion, especially coma.6
A 61-year-old man was transported to the ED by ambulance with a complaint of confusion. His past medical history was significant for recently diagnosed pemphigus vulgaris that was being treated with steroids. His family described gradual functional decline over the prior two weeks with no changes in his skin lesion. On the day of ED presentation, he was no longer responding verbally to his family members. He had no history of diabetes mellitus or peripheral vascular disease.
On assessment in the ED, he was found to have a waxing and waning level of consciousness and was alert to self only. His initial vital signs were heart rate of 134 beats per minute, blood pressure of 141/86 millimeters of mercury, respiration of 16 breaths per minute, temperature of 37.1°C (98.8°F), and oxygen saturation of 95% on room air. He was ill-appearing with dry mucous membranes and poor skin turgor. He was also found to have a cold, pulseless, right lower extremity. Laboratory evaluation revealed marked hyperclycemia (blood glucose, 1077 milligrams per deciliter [mg/dL]), hemoconcentration (hemoglobin, 20 grams/dL), sodium concentration of 172 millimoles/L, anion gap of 23, and acute kidney injury (creatinine, 2.47 mg/dL). Urinalysis revealed a urinary tract infection without ketones. His thyroid-stimulating hormone level and a noncontrast computed tomography of his head were unremarkable. Duplex ultrasound of the lower extremity demonstrated total occlusion of the right proximal common iliac and popliteal arteries.
Based on these results, we diagnosed HHS with limb ischemia and sepsis from urinary tract infection. The patient was treated with insulin, heparin, and broad-spectrum antibiotics in the ED. His free water deficit was calculated to be greater than 10 L. Fluid management included initial volume resuscitation with 3 L of Plasma-Lyte. He was then transitioned to slow sodium correction with normal saline over 24 hours. He was admitted to an intensive care unit (ICU) with vascular surgery consultation for management of the limb ischemia.
The patient underwent through-the-knee amputation due to irreversible tissue damage on hospital day three. During his ICU stay, his blood glucose and sodium levels were corrected gradually and the acute kidney injury resolved. The patient did well during hospitalization and was discharged to an inpatient rehabilitation facility on hospital day 11.
The pathogenesis of HHS is not fully understood, but the syndrome is attributed to decreased insulin sensitivity coupled with increases in the counter-regulatory hormones—cortisol, catecholamines, growth hormone, and glucagon—all of which increase hepatic and renal glucose production.6 The hallmark of HHS is hyperglycemia leading to hyperosmolarity, which is secondary to dehydration from glucosuria and body fluid depletion caused by other precipitating factors. The level of hyperosmolarity best correlates with mental status changes in patients with HHS.7
In more than 50% of HHS cases, the precipitating factor is infection (e.g., pneumonia, urinary tract infection, or sepsis).8 Other precipitants are inadequate glucose control, surgery, cerebrovascular ischemia, and myocardial ischemia.8 Dehydration is more subtle, occurring slowly over the course of a few days. It is exacerbated by decreased oral intake, especially in the geriatric population.9 The use of corticosteroids has been linked to the development of hyperglycemia. Patients on high-dose steroids are particularly prone to HHS.10 The hyperosmolar state of HHS induces osmotic diuresis, leading to severe dehydration and fluid loss, which can be as high as 7–12 L, representing a 10–15% weight loss.3 The triad of hyperglycemia, hyperosmolar state, and dehydration leads to a catecholamine surge, with increased production of cortisol and glucagon, which worsens hyperglycemia and the hyperosmolar state.1
HHS develops over days to weeks. Its clinical manifestation starts as weakness and lethargy, progressing to obtundation and coma. These changes correlate with the plasma osmolality and usually become apparent at levels greater than 310 milliosmoles (mOsm) per kilogram.11,12 The physical examination usually reveals signs of dehydration (dry mucous membranes, dry axilla, decreased skin turgor, low jugular venous pressure, and hypotension6) with or without clinical evidence of the inciting event. The hyperosmolar state is a hypertonic state irrespective of the sodium level at presentation, because of intracellular sodium shifts. Measurable serum sodium levels can vary from hyponatremia to hypernatremia.1
At the onset of severe dehydration, intracellular fluid shift, and hyperglycemia, the serum sodium level does not reflect the body’s actual sodium level. The true sodium level is determined by adding 1.6 to the measured serum sodium value for every 100 mg/dL of glucose. If the uncorrected sodium level is normal or elevated, the patient has already lost a significant amount of fluid. The corrected sodium level reveals the true level of hypernatremia.13,14 Patients with HHS usually present with severe hyperglycemia (glucose >600 mg/dL). Those with end-stage renal disease can have levels exceeding 1000 mg/dL. These patients will also have hypokalemia and hypophosphatemia as a result of osmotic diuresis, leading to urinary loss of potassium and phosphate. These deficiencies are also associated with decreased oral intake.14
What do we already know about this clinical entity?
Hyperosmolar hyperglycemic state (HHS) is a clinical syndrome characterized by a state of profound dehydration, metabolic derangements, and multiorgan system failure.
What makes this presentation of disease reportable?
This case highlights a prothrombotic state accompanying a state of profound dehydration in a patient with HHS.
What is the major learning point?
Thromboembolic events should be considered in patients with HHS.
How might this improve emergency medicine practice?
Early recognition of complications of HHS allows early involvement of specialized services, which can improve outcomes in this population.
The successful treatment of HHS has five cornerstones: volume correction, glycemic control, electrolyte management, addressing the underlying cause, and managing complications (Table). Fluid correction should be started immediately, as soon as the HHS diagnosis has been established. The goals of volume resuscitation are intravascular volume repletion, restoring normal plasma tonicity, and improving end-organ perfusion. The initial intravenous (IV) fluid of choice is 0.9% normal saline, administered with the goal of achieving 50% fluid resuscitation within the first 12 hours.3,4 After the initial resuscitation period, the patient’s clinical status should be reassessed so that the fluid choice can be adjusted based on plasma tonicity and electrolyte levels.4
|Complications related to the disease process||Dehydration||HyperviscosityElectrolyte derangementMetabolic acidosisRhabdomyolysisMalignant hyperthermia|
|Prothrombotic factor activation*||Cerebral infarctsMyocardial infarctionPulmonary embolismAcute respiratory distress syndromeMesenteric vessel thrombosisLimb ischemiaDisseminated intravascular coagulation|
|Complications related to therapy||HypoglycemiaHypokalemiaCerebral edemaPulmonary edemaHyperchloremic non-anion gap acidosis|
*Can be worsened by profound dehydration.
Glycemic control is achieved with IV administration of insulin after fluid repletion. The recommended dose is 0.1 units per kilogram (U/kg). The goal is to decrease osmolarity to below 310 mOsm/kg and to achieve a glucose level less than 250 mg/dL. Normally, with IV fluids and tight glycemic control, HHS patients’ mental status improves rapidly. Once the blood glucose concentration is less than 250 mg/dL, the fluid can be switched to a dextrose-containing solution to avoid hypoglycemia while the patient is being bridged to subcutaneous insulin.15 Special attention should be paid to electrolytes as well. Typically, these patients present with hyponatremia secondary to hyperglycemic osmotic force that drives water into the vascular space, causing dilutional hyponatremia. In contrast, hypernatremia denotes profound dehydration. Volume repletion normally corrects the sodium disturbance.9,16
Additionally, the potassium level might be elevated despite a total body deficit secondary to potassium transit to the extracellular space, creating relative hyperkalemia without the acidosis typically seen with DKA. Before starting insulin therapy, it is imperative to reassess the potassium level and the need to start potassium replacement. Starting treatment with insulin may lead to hypokalemia due to the potassium shift back into the cell that accompanies volume resuscitation.9,17,18 Additionally, the total body phosphate level can be relatively low despite a normal or high phosphate level because of molecular physiology similar to that of hypokalemia. Phosphate should be replaced if the patient is found to be hypophosphatemic, as insulin will drive phosphate, along with potassium, into the cells. Given that phosphate is needed in all muscular contractions, its uncorrected low levels can lead to cardiac arrest.9,19,20
It is important to look for the factors that precipitated HHS and to correct them as quickly as possible. Ischemia of any organ can precipitate HHS. Myocardial ischemia, cerebrovascular accidents, bowel ischemia, and limb ischemia can cause catecholamine and cortisol surges that can worsen preexisting hyperglycemia. It is imperative to identify these factors and treat them.7-10
HHS can affect coagulation by increasing the levels of coagulation factors, especially protein C and factor VIII complex, and decreasing fibrinolytic activities.21 In a crossover study, Stegenga and associates showed that hyperglycemia itself promotes coagulation through activation of thrombin-antithrombin complexes. The same study demonstrated that hyperinsulinemia can increase plasminogen-activating factors that decrease fibrinolysis.22,23 Severe dehydration can induce vasoconstriction and thromboembolic events such as cerebrovascular accidents, myocardial infarction, arterial insufficiency in the lower extremities, and mesenteric ischemia.24-26
Severe dehydration and the prothrombotic state provoked by HHS can lead to end-organ ischemic events. This prothrombotic state can lead to acute myocardial ischemia, cerebrovascular accidents, acute mesenteric ischemia, and lower extremity ischemia. Patients who present with altered mental status and do not improve after initial resuscitative measures warrant further workup.21-26
Management of limb ischemia is aimed at saving limb as well as life, restoring blood flow, and preventing further cellular damage from thrombosis or embolism. While awaiting evaluation by the specialty service, patients should be started on anticoagulation with heparin. The current recommendation is a bolus of 80–150 U/kg followed by maintenance at 18 U/kg per hour. However, if heparin is contraindicated because of documented heparin-induced thrombocytopenia or antithrombin III deficiency, direct thrombin inhibitors can be given. The only exception to anticoagulation is if the patient is actively bleeding.27 It is imperative that emergent vascular surgical consultation be obtained for consideration of emergent vs. urgent revascularization if the limb is salvageable. In irreversible ischemia, amputation might be the only definitive treatment.28
Emergency physicians should remain vigilant for ischemic complications in patients presenting with HHS. Early recognition and treatment can improve the morbidity and mortality rates associated with this endocrine emergency.
Documented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.
Section Editor: Rick A. McPheeters, DO
Full text available through open access at http://escholarship.org/uc/uciem_cpcem
Address for Correspondence: Ahmed Al Hazmi, MBBS, University of Maryland Medical Center, Department of Emergency Medicine, 110 S Paca St, 6th Floor, Suite 200, Baltimore, MD 21201. Email:email@example.com. 2:348 – 352
Submission history: Revision received July 19, 2018; Submitted September 4, 2018; Accepted September 7, 2018
Conflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.
1. Levine SN, Sanson TH. Treatment of hyperglycaemic hyperosmolar non-ketotic syndrome. Drugs. 1989;38(3):462-72.
2. Milano A, Tadevosyan A, Hart R, et al. An uncommon complication of hyperosmolar hyperglycemic state: bilateral above knee amputations. Am J Emerg Med. 2016;34(2):341.e1-e2.
3. Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-43.
4. Corwell B, Knight B, Oliver L, et al. Current diagnosis and treatment of hyperglycemic emergencies. Emerg Med Clin North Am. 2014;32(2):437-52.
5. Hyperglycemic crises in patients with diabetes mellitus. Diabetes Care. 2001;24(11):1988-96.
6. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Hyperglycemic crises in diabetes. Diabetes Care. 2004;27(suppl 1):S94-S102.
7. MacIsaac RJ, Lee LY, McNeil KJ, et al. Influence of age on the presentation and outcome of acidotic and hyperosmolar diabetic emergencies. Intern Med J. 2002;32(8):379-85.
8. Nugent BW. Hyperosmolar hyperglycemic state. Emerg Med Clin North Am. 2005;23(3):629-48.
9. Maletkovic J, Drexler A. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Endocrinol Metab Clin North Am. 2013;42(4):677-95.
10. Fujikawa LS, Meisler DM, Nozik RA. Hyperosmolar hyperglycemic nonketotic coma: a complication of short-term systemic corticosteroid use. Ophthalmology. 1983;90(10):1239-42.
11. Paton RC. Haemostatic changes in diabetic coma. Diabetologia. 1981;21(3):172-7.
12. Stegenga ME, van der Crabben SN, Levi M, et al. Hyperglycemia stimulates coagulation, whereas hyperinsulinemia impairs fibrinolysis in healthy humans. Diabetes. 2006;55(6):1807-12.
13. Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complicat. 2001;15(1):44-54.
14. Kennedy DD, Fletcher SN, Ghosh IR, et al. Reversible tetraplegia due to polyneuropathy in a diabetic patient with hyperosmolar non-ketotic coma. Intensive Care Med. 1999;25(12):1437-9.
15. Sharieff GQ, Shad JA, Garmel G. An unusual case of mesenteric ischemia in a patient with new-onset diabetes mellitus. Am J Emerg Med. 1997;15(3):282-4.
16. Megarbane B, Marsanne C, Meas T, et al. Acute lower limb ischemia is a frequent complication of severe diabetic hyperosmolarity. Diabetes Metab. 2007;33(2):148-52.
17. Milionis HJ, Liamis GL, Elisaf MS. Hyperosmolar syndrome in a patient with uncontrolled diabetes mellitus. Am J Kidney Dis. 2001;37(5):E41.
18. Chiasson J-L, Aris-Jilwan N, Belanger R, et al. Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state. CMAJ. 2003;168(7):859-66.
19. Katz MA. Hyperglycemia-induced hyponatremia: calculation of expected serum sodium depression. N Engl J Med. 1973;289(16):843-44.
20. Milionis HJ, Elisaf MS. Therapeutic management of hyperglycaemic hyperosmolar syndrome. Expert Opin Pharmacother. 2005;6(11):1841-9.
21. Fayfman M, Pasquel FJ, Umpierrez GE. Management of hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Med Clin North Am. 2017;101(3):587-606.
22. Beck LH. Should the actual or the corrected serum sodium be used to calculate the anion gap in diabetic ketoacidosis?. Cleve Clin J Med. 2001;68(8):673-4.
23. Adrogué HJ, Lederer ED, Suki WM, et al. Determinants of plasma potassium levels in diabetic ketoacidosis. Medicine (Baltimore). 1986;65(3):163-72.
24. Arieff AI, Carroll HJ. Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine (Baltimore). 1972;51(2):73-94.
25. Warner EA, Greene GS, Buchsbaum MS, et al. Diabetic ketoacidosis associated with cocaine use. Arch Intern Med. 1998;158(16):1799-802.
26. Ng RS, Darko DA, Hillson RM. Street drug use among young patients with type 1 diabetes in the UK. Diabet Med. 2004;21(3):295-6.
27. Santistevan JR. Acute limb ischemia: an emergency medicine approach. Emerg Med Clin North Am. 2017;35(4):889-909.
28. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology / American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017;135(12):e686-e725.