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Hyperglycemic hyperosmolar nonketotic coma1
The Journal of Emergency Medicine, Vol. 20, No. 3, pp. 285–290, 2001 Copyright © 2001 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/01 $–see front matter
PII S0736-4679(01)00283-9
Case Presentations of the Harvard Emergency Medicine Residency
HYPERGLYCEMIC HYPEROSMOLAR NONKETOTIC COMA Michael R. Filbin,
MD,*
David F. M. Brown,
MD,*†
and Eric S. Nadel,
MD*†‡
*Harvard Affiliated Emergency Medicine Residency, Division of Emergency Medicine, Harvard Medical School; †Department of Emergency Medicine, Massachusetts General Hospital; and ‡Department of Emergency Medicine, Brigham & Women’s Hospital, Boston, Massachusetts Reprint Address: David F. M. Brown, MD, Department of Emergency Medicine, CLN-115, Massachusetts General Hospital, Boston, MA 02114
cardia in addition to rapid determination of the blood glucose level. Empiric naloxone also should be given at this point. Dr. Filbin: There were no pills missing from her Valproic Acid bottle, and there was no evidence in the home that would suggest a toxic ingestion. The patient was next placed on a cardiac monitor by the paramedics and was found to have ventricular tachycardia (VT) at a rate of approximately 150 bpm (Figure 1). An 18-gauge intravenous (IV) line was placed and 500 cc of normal saline was administered as a bolus. Glucometry showed a blood glucose level exceeding 500 mg/dL. Lidocaine 100 mg IV was administered, and after 2 min she converted to a sinus rhythm at approximately 70 bpm (Figure 2). Her mental status remained depressed, and she was intubated for airway protection without complication. During transport to the hospital, she had another episode of VT that again resolved with an additional 100 mg bolus of lidocaine IV. A lidocaine drip was started at 2 mg per minute IV. Dr. David Brown: The paramedics might have initially opted for immediate synchronized cardioversion in this patient with VT, hypotension, and altered mental status. If medications are chosen as primary therapy, another option would have been to administer amiodarone, which recently has been added to the Advanced Cardiovascular Life Support (ACLS) guidelines for the management of VT and wide complex tachycardia of
Dr. Michael Filbin: Today’s case is that of a 46-yearold woman found unconscious on the floor of her apartment by her boyfriend who immediately called 911. Upon paramedic arrival the patient was noted to be unresponsive, lying on the bedroom floor. The boyfriend told paramedics that she had a history of bipolar disorder for which she took Valproic Acid. She had not been depressed recently and had never made a suicide attempt in the past. She had no known drug allergies. She did not smoke, drink alcohol, or use illicit drugs. The vital signs on EMS arrival included a heart rate of 148 beats per minute (bpm), blood pressure of 90/60 mm Hg, and shallow respirations of 14 breaths per minute. The Glascow Coma Scale was noted to be 4, with eyes opening to painful stimulus but without verbal or motor response. Dr. Eric Nadel: Are there any questions or comments at this point? Dr. Theodore Benzer: In a 46-year-old female found unresponsive with a psychiatric history, a medication overdose is a likely etiology. Did you ask the medics whether empty pill bottles were evident at the scene? Valproic Acid in overdose leads to depressed consciousness and eventual coma, although I wouldn’t expect it to account for such a rapid heart rate. In any comatose patient, definitive airway control is of primary importance, and I would strongly consider immediate endotracheal intubation in this woman. I would also advocate cardiac monitoring to elucidate the nature of the tachy-
Case Presentations of the Harvard Emergency Medicine Residency is coordinated by David F. M. Brown, Eric S. Nadel, MD, of the Harvard Medical School, Boston, Massachusetts
RECEIVED: 21 November 2000; ACCEPTED: 11 December 2000 285
MD,
and
286
M. R. Filbin et al.
Figure 1. Prehospital initial rhythm strip reveals ventricular tachycardia at ⬃150 bpm.
unclear etiology. Amiodarone also is particularly recommended in cases complicated by left ventricular dysfunction (1). Amiodarone is a class 3 antidysrhythmic agent that actually exhibits all four Vaughan Williams class effects. The dose in this setting is 150 mg IV administered over 10 min followed by a continuous IV infusion of 1 mg/min for 6 h. Now, of course, the question is how are the VT and the hyperglycemia related in this patient? Did the medics provide any history as to whether she had diabetes or underlying cardiovascular disease? Dr. Filbin: According to EMS records, the boyfriend only knew of her history of bipolar disorder. Upon arrival in the Emergency Department (ED), the patient had spontaneous respirations with the aid of supplementary mechanical ventilation. She opened her eyes spontaneously and exhibited purposeful movement of all her extremities. Her initial vital signs included a pulse of 138 bpm with sinus rhythm on the monitor, blood pressure of 84/40 mm Hg, rectal temperature of 35.5°C (96°F), and an oxygen saturation of 100% with peak flow oxygen. The patient was an obese female who did not appear chronically ill. Examination of the head was remarkable for dry mucous membranes, but there were no face or scalp contusions, ecchymoses, or bony step-offs. Pupils were 3 mm and reactive bilaterally. The neck was supple without thyromegaly, jugular venous distension, or cer-
vical adenopathy. The chest was clear to auscultation bilaterally. Heart sounds were regular without murmurs or rubs. The abdomen was soft, nondistended, and nontender with no masses or bruits. The rectal examination revealed normal tone and brown heme-negative stool. There was no peripheral edema; peripheral pulses were weak throughout. The skin was normothermic, dry, and without rashes, purpura, or petichiae. On neurologic examination, she withdrew all four extremities to noxious stimulus. Clonus was absent, reflexes were normal and symmetric, and toes were downgoing bilaterally. Dr. Nadel: This patient was in shock. There was no evidence of pulmonary congestion to suggest cardiac dysfunction as the cause, so we need to distinguish between hypovolemic, septic, and vasomotor shock. Are there any thoughts on how to proceed? Dr. J.T. Nagurney: The physical examination doesn’t seem to provide any further clues as to the etiology of the altered mentation. The patient appears more responsive now than she was at the scene, which is likely the result of correcting the ventricular dysrhythmia. In addition to obtaining better IV access and beginning aggressive fluid resuscitation, I would obtain a 12-lead electrocardiogram (EKG) and bedside finger stick glucose to reconfirm the hyperglycemia found in the field. If she were in fact hyperglycemic, I would suspect diabetic ketoacidosis (DKA) as the etiology of
Figure 2. Prehospital rhythm strip after treatment with lidocaine shows sinus rhythm at ⬃70 bpm.
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Figure 3. EKG demonstrates a regular tachycardia with a slightly widened QRS interval and diffuse ST-T-wave abnormalities.
her symptoms, despite the fact that she has no history of diabetes. Hyperosmolar diabetic coma is also a possibility given her altered mental status and that DKA would be expected to present earlier in life. As to the etiology of the VT, I can think of two explanations. First, it may have been a result of underlying myocardial infarction that led to an intraventricular conduction abnormality. Myocardial infarction is also known to precipitate DKA, which would explain hyperglycemia in this setting. Conversely, DKA or hyperosmolar coma might be the primary process here, resulting in electrolyte disturbances and subsequent VT (2). My leading hypothesis in this case is DKA with electrolyte disturbances leading to VT. Dr. Filbin: After confirmation of endotracheal tube placement by CO2 capnometry, the patient was placed on a mechanical ventilator in assist control mode with an FiO2 of 1.0, respirations of 10 breaths per minute, and a tidal volume of 700 cc. A 12-lead electrocardiogram (EKG) showed a widened QRS interval and diffuse ST segment and T wave abnormalities (Figure 3). A left subclavian triple-lumen catheter was placed and blood was sent to the laboratory. The lidocaine drip was continued at 2 mg/min. The results of a venous blood gas analysis included a pH of 6.98, pCO2 of 23 mm Hg, pO2 of 50 mm Hg, glucose greater than 500 mg/dL, and potassium less than assay (value less than 1.6 mmol/L). Based on what appeared to be profound hypokalemia, insulin therapy was withheld. The first liter of normal saline was administered centrally over 30 min with 60 meq of potassium chloride. In addition, magnesium sulfate 2 g IV was administered over 20 min. After the first liter of fluid, we redrew a chemistry panel that showed sodium 130 mmol/L, potassium 4.5
mmol/L, chloride 101 mmol/L, bicarbonate 16 mmol/L, BUN 54 mg/dL, creatinine 2.6 mg/dL, and glucose 2214 mg/dL. A complete blood count included a WBC count of 16.2 K/cumm with a left-shifted differential; the hematocrit was 53% and platelet count was normal. Dr. Brown: I am concerned that the initial very low serum potassium may have been spurious, especially given the change in level from 1.6 mmol/L to 3.5 mmol/L after the administration of only 60 meq of potassium repletion. Perhaps the venous blood gas was drawn above a running IV line. Although there is always total body potassium depletion in these cases, often the initial serum potassium, prior to therapy, will be normal or elevated in response to the accompanying metabolic acidosis. If this is the case, then administering such large doses of potassium IV could precipitate dangerous hyperkalemia and further cardiac electrical instability. I think it would have been more prudent to recheck the potassium and start initially with aggressive normal saline rehydration. The blood glucose over 2000 mg/dL is consistent with the diagnosis of hyperglycemic hyperosmolar nonketotic coma (HHNC), provided she was not ketotic. In the absence of ketosis, the acidosis with a modest anion gap was likely due to some combination of renal insufficiency and lactic acidosis related to tissue hypoperfusion. This in turn was likely due to hypovolemia or sepsis. In any case, it was prudent to withhold insulin administration because this would act to drive potassium into the cells and worsen any hypokalemia (3). This might also precipitate cardiac dysrhythmias. Were electrolytes tested on the initial blood draw,
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along with the venous blood gas? And how did the patient respond to therapy? Dr. Filbin: Yes, serum electrolytes were drawn from a different site, at the same time the venous blood gas was obtained. The serum sample demonstrated a potassium of 6.0 mmol/L, in contrast to the measurement of ⬍1.6 mmol/L on the venous blood gas. Upon review of the venous blood gas results, the hematocrit was 15%, which was considerably less than the 53% found on the subsequent venous specimen. This led us to conclude that the blood gas specimen was dilute. The patient’s condition remained unchanged at this point and we continued with saline rehydration. Dr. James Gordon: Were you able to obtain any additional history? Dr. Filbin: The patient’s boyfriend arrived and told us she had been ill for about 1 week with what they thought to be “the flu.” She had not complained of fevers, chills, cough, or pain anywhere. However, she had been urinating much more than usual and was drinking up to 3 gallons of water and Gatorade daily because of extreme thirst. She did not complain of dysuria or diarrhea. Dr. Brown: It appears this woman had been compensating for her hyperglycemic polyuria for quite some time with aggressive self-rehydration. It is important to recognize that her serum sodium will go up markedly as her hyperglycemia resolves. The current serum sodium of 130 mmol/L represents “pseudohyponatremia” due to the osmotic effect of the pronounced hyperglycemia. The sodium can be corrected for this by adding 1.6 meq/L of sodium for every 100 mg/dL of glucose above 150 mg/dL (4). This calculation predicts a serum sodium of over 160 meq/L, indicative of profound dehydration and free water deficit. Please continue with the further management in the ED. Dr. Filbin: A portable chest radiograph showed the endotracheal tube and left subclavian line in good position. There was no airspace disease, mediastinal widening, pneumothorax, or subdiaphragmatic air. Serum lactate was mildly elevated at 3.4 mmol/L and serum acetones were trace postive undiluted. Urinalysis showed trace ketones and 3⫹ glucose, but no white cells, red cells, casts, or bacteria. She remained hypotensive with a blood pressure of 80/40 mm Hg. A low-dose insulin infusion was started at 1 unit per hour. Two additional liters of normal saline were administered over the next hour. Potassium chloride 20 meq was given via the central venous catheter. Ampicillin 2 g IV, Gentamicin 100 mg IV, and Flagyl 500 mg IV were administered for possible sepsis. The patient was admitted to the medical intensive care unit (ICU). Dr. David Tancredi: Your laboratory tests have confirmed the diagnosis of HHNC. Empiric antibiotics are
M. R. Filbin et al.
warranted as the clinical picture suggests possible sepsis, which may trigger the onset of HHNC. I think that Gentamicin is a suboptimal choice for Gram-negative coverage in this patient with elevated creatinine and presumably some degree of acute tubular necrosis. There are other less nephrotoxic agents available including quinolones and second and third generation cephalosporins. What was your strategy for fluid resuscitation and why did you use such a low dose of insulin? Dr. Filbin: Patients with HHNC tend to be more dehydrated than those with DKA. The fluid deficit in patients with HHNC is up to 20 –25% of the total body water (5). This is equivalent to about 8 –10 liters of free water in an average-sized person. Despite seemingly normal or high serum sodium values, there is a total body sodium deficit. Therefore, fluid resuscitation must be started with normal saline to restore sodium, and in turn, intravascular volume. The recommendation is 3 liters over the first 2 h. Fluid can be switched to half normal saline once hypotension is corrected and urine output is established. This hypotonic fluid will act to restore the free water deficit. After restoring intravascular volume with the initial bolus of normal saline, fluid should not be administered faster than one liter per hour to avoid thirdspacing and development of pulmonary or cerebral edema. The recommended dose of insulin for HHNC is 0.01 U/kg/h with or without a bolus (6). This is in contrast to the recommended dosing for DKA of 0.1 U/kg bolus plus 0.1 U/kg/h drip. The reason for this is twofold. First, patients with HHNC already produce a small amount of endogenous insulin that prevents ketogenesis. Thus, the need to reverse ketogenesis as one would do in DKA is not necessary. Second, large doses of insulin may cause a precipitous fall in serum glucose, and subsequently, serum osmolarity. Because the blood-brain barrier prevents the rapid flow of electrolytes between the serum and the central nervous system (CNS), a rapid fall in serum osmolarity leads to a relative hyperosmolar cerebrospinal fluid (CSF), thus drawing fluid into the brain. This leads to cerebral edema that may result in poor neurologic outcome or even death (7). For unknown reasons, children are more prone to this complication. The goal is to prevent a decrease in serum glucose of more than 100 mg/dL per hour (8). Dr. Nadel: Please describe the patient’s hospital course. Dr. Filbin: In the ICU, the patient’s blood glucose levels continued to be elevated above 2000 mg/dL and the insulin drip was increased to 8 units per hour. She began to run a fever as high as 41.5°C (106.8°F). She continued to be hypotensive and was started on vasopressors. She received normal saline at a rate of approximately one liter per hour. Twelve hours after admission
Hyperglycemic Hyperosmolar Nonketoic Coma
a chemistry panel showed sodium 155 mmol/L, potassium 3.3 mmol/L, chloride 131 mmol/L, bicarbonate 15 mmol/L, BUN 38 mg/dL, creatinine 2.1 mg/dL, and glucose 1144 mg/dL. Serial cardiac enzymes were normal. Blood gas analysis continued to show a metabolic acidosis. She received bicarbonate 75 meq in 600 cc of D5W IV over 3 h and salt-poor albumin 500 cc because of persistent hypotension. The insulin drip was increased to 20 units per hour. She remained persistently tachycardic and hypotensive, and she died approximately 24 h after arrival to the hospital. A Student: If the diagnosis here was HHNC, how do you account for the presence of metabolic acidosis? Also, what is the utility of bicarbonate therapy in this setting? Dr. Filbin: It is reported that DKA and HHNC are part of a continuum of disease, and that patients with hyperglycemic hyperosmolar state also may have a component of ketosis and subsequent acidosis (9). Given the lack of urine or serum ketones, this is an unlikely explanation of metabolic acidosis in this case. A more likely explanation for acidosis in this patient is persistent hypovolemic shock perhaps with septic shock as well. This results in anaerobic metabolism and production of lactate, thus leading to lactic acidosis. The use of bicarbonate is still controversial in the setting of DKA or HHNC, but there are no studies that show decreased mortality with bicarbonate therapy in treating acidosis. Most of the studies have been performed in the setting of DKA. The argument for using bicarbonate is that the correction of severe acidosis may improve cardiovascular collapse caused by acidosis. Some experts have suggested that this benefit is appreciated for serum pH ⬍ 7.0, although the study that concluded this failed to show a difference in recovery rate or outcome in 21 DKA patients with pH from 6.9 to 7.1 randomized to bicarbonate therapy or placebo (10). A more recent trial with a similar study design randomized 39 patient with DKA and profound acidosis to bicarbonate therapy or placebo. Not only was there no difference in recovery rate or mortality, but the potassium requirement of the bicarbonate group was much higher (11). These authors conclude that bicarbonate is not advisable in the treatment of severe acidosis in DKA. A retrospective study in children with severe DKA showed that, controlling for the degree of acidosis, bicarbonate therapy was associated with longer hospitalizations (12). The theoretical disadvantages to bicarbonate therapy in severe acidosis of DKA are multiple. First, and most importantly, rapid correction of acidosis drives potassium into the cells and decreases serum potassium in patients who are already hypokalemic. This may lead to cardiac arrest. Second, administered bicarbonate is also thought to cause a paradoxical CSF acidosis because the
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blood-brain barrier is more permeable to carbon dioxide than it is to bicarbonate. Therefore, as acid and bicarbonate react in the serum, the end-product carbon dioxide crosses into the CNS and decreases cerebral pH. Third, as insulin is administered to patients with DKA, ketones are metabolized in part to bicarbonate, which causes a natural serum alkalinization. Additional administration of bicarbonate can cause an overshoot-alkalosis. Furthermore, alkalosis stops the feedback inhibition of ketogenesis, and ketone clearance is slowed. Lastly, alkalosis promotes a left shift of the carboxy-hemoglobin curve and oxygen binding to 2,3-DPG in red blood cells. This acts to inhibit oxygen release into hypoxic peripheral tissue, thus contributing to anaerobic metabolism and worsening of the underlying condition. Dr. Brown: The management of cases with this degree of electrolyte disturbance is extremely difficult. The mortality of HHNC is approximately 15% compared with the 1–2% mortality associated with DKA (13). This mortality is further increased in patients who present with extreme hyperosmolarity and dehydration such as was seen in this patient (14). Patients with HHNC tend to be older, have some degree of renal insufficiency, and often underlying cardiac disease. These patients have less capacity to correct metabolic disturbances and cope with the underlying illness that triggered HHNC in the first place. Sepsis seems the most likely precipitant here. Was an autopsy performed? Dr. Filbin: The conclusions of the autopsy were consistent with multi-organ system failure. Examination of the heart showed mild atherosclerosis and biventricular dilatation without evidence of infarct. The lungs were markedly congested and edematous. The pancreas exhibited diffuse inflammation and extensive fat necrosis consistent with necrotizing pancreatitis. The biliary system was unremarkable. The kidneys showed acute tubular necrosis. An autopsy of the brain was not performed, thus comment on cerebral edema could not be made. All cultures were negative. The presence of necrotizing pancreatitis on autopsy suggests that this may have been the underlying illness that precipitated HHNC.
REFERENCES 1. Anonymous. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: Advanced Cardiovascular Life Support: section 1: Introduction to ACLS 2000: overview of recommended changes in ACLS from the guidleines 2000 conference. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000;102(8 Suppl):I86 –9. 2. Jewett JF. Diabetes and cardiac arrest. N Engl J Med 1973;288: 737– 8. 3. Leventhal RI, Goldman JM. Immediate plasma potassium levels in treating diabetic ketoacidosis. Arch Intern Med 1987;147:1501–2. 4. Levinsky NG. Fluids and electrolytes. In: Braunwald E, Issel-
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5. 6. 7. 8. 9.
bacher KJ, et al., eds. Harrison’s Principals of Internal Medicine, 11th edition. New York: McGraw-Hill Book Company, 1987;202. Lorber D. Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am 1995;79:39 –52. Cydulka R. Diabetes mellitus and disorders of glucose homeostasis. In: Rosen P, ed. Emergency Medicine–Concepts and Clinical Practice, 4th ed. St. Louis: Mosby-Year Book; 1998:2456 –78. Winegrad AI, Kern EF, Simmons DA. Cerebral edema in diabetic ketoacidosis. Diabetes 1988;37:1470 –7. Gonzalez-Campoy JM, Robertson RP. Diabetic ketoacidosis and hyperosmolar nonketotic state. Postgrad Med 1996;99:143–52. Ennis ED, Stahl EJ, Kreisberg RA. The hyperosmolar hyperglycemic syndrome. Diabetes Rev 1994;2:115–26.
M. R. Filbin et al. 10. Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med 1986;105:836 – 40. 11. Viallon A, Zeni F, Lafond P, et al. Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 1999;27:2690 –3. 12. Green SM, Rothrock SG, Ho JD. Failure of adjuctive bicarbonate to improve outcome in severe pediatric diabetic ketoacidosis. Ann Emerg Med. 1998;31:41– 8. 13. Kitabchi AE, Wall BM. Management of DKA. Am Family Physician 1999;60:455– 64. 14. Hamblin PS, Topliss DJ, Chosich N, et al. Deaths associated with diabetic ketoacidosis and hyperosmolar coma. Med J Aust 1990; 152:327– 8.
PII S0736-4679(01)00283-9
Case Presentations of the Harvard Emergency Medicine Residency
HYPERGLYCEMIC HYPEROSMOLAR NONKETOTIC COMA Michael R. Filbin,
MD,*
David F. M. Brown,
MD,*†
and Eric S. Nadel,
MD*†‡
*Harvard Affiliated Emergency Medicine Residency, Division of Emergency Medicine, Harvard Medical School; †Department of Emergency Medicine, Massachusetts General Hospital; and ‡Department of Emergency Medicine, Brigham & Women’s Hospital, Boston, Massachusetts Reprint Address: David F. M. Brown, MD, Department of Emergency Medicine, CLN-115, Massachusetts General Hospital, Boston, MA 02114
cardia in addition to rapid determination of the blood glucose level. Empiric naloxone also should be given at this point. Dr. Filbin: There were no pills missing from her Valproic Acid bottle, and there was no evidence in the home that would suggest a toxic ingestion. The patient was next placed on a cardiac monitor by the paramedics and was found to have ventricular tachycardia (VT) at a rate of approximately 150 bpm (Figure 1). An 18-gauge intravenous (IV) line was placed and 500 cc of normal saline was administered as a bolus. Glucometry showed a blood glucose level exceeding 500 mg/dL. Lidocaine 100 mg IV was administered, and after 2 min she converted to a sinus rhythm at approximately 70 bpm (Figure 2). Her mental status remained depressed, and she was intubated for airway protection without complication. During transport to the hospital, she had another episode of VT that again resolved with an additional 100 mg bolus of lidocaine IV. A lidocaine drip was started at 2 mg per minute IV. Dr. David Brown: The paramedics might have initially opted for immediate synchronized cardioversion in this patient with VT, hypotension, and altered mental status. If medications are chosen as primary therapy, another option would have been to administer amiodarone, which recently has been added to the Advanced Cardiovascular Life Support (ACLS) guidelines for the management of VT and wide complex tachycardia of
Dr. Michael Filbin: Today’s case is that of a 46-yearold woman found unconscious on the floor of her apartment by her boyfriend who immediately called 911. Upon paramedic arrival the patient was noted to be unresponsive, lying on the bedroom floor. The boyfriend told paramedics that she had a history of bipolar disorder for which she took Valproic Acid. She had not been depressed recently and had never made a suicide attempt in the past. She had no known drug allergies. She did not smoke, drink alcohol, or use illicit drugs. The vital signs on EMS arrival included a heart rate of 148 beats per minute (bpm), blood pressure of 90/60 mm Hg, and shallow respirations of 14 breaths per minute. The Glascow Coma Scale was noted to be 4, with eyes opening to painful stimulus but without verbal or motor response. Dr. Eric Nadel: Are there any questions or comments at this point? Dr. Theodore Benzer: In a 46-year-old female found unresponsive with a psychiatric history, a medication overdose is a likely etiology. Did you ask the medics whether empty pill bottles were evident at the scene? Valproic Acid in overdose leads to depressed consciousness and eventual coma, although I wouldn’t expect it to account for such a rapid heart rate. In any comatose patient, definitive airway control is of primary importance, and I would strongly consider immediate endotracheal intubation in this woman. I would also advocate cardiac monitoring to elucidate the nature of the tachy-
Case Presentations of the Harvard Emergency Medicine Residency is coordinated by David F. M. Brown, Eric S. Nadel, MD, of the Harvard Medical School, Boston, Massachusetts
RECEIVED: 21 November 2000; ACCEPTED: 11 December 2000 285
MD,
and
286
M. R. Filbin et al.
Figure 1. Prehospital initial rhythm strip reveals ventricular tachycardia at ⬃150 bpm.
unclear etiology. Amiodarone also is particularly recommended in cases complicated by left ventricular dysfunction (1). Amiodarone is a class 3 antidysrhythmic agent that actually exhibits all four Vaughan Williams class effects. The dose in this setting is 150 mg IV administered over 10 min followed by a continuous IV infusion of 1 mg/min for 6 h. Now, of course, the question is how are the VT and the hyperglycemia related in this patient? Did the medics provide any history as to whether she had diabetes or underlying cardiovascular disease? Dr. Filbin: According to EMS records, the boyfriend only knew of her history of bipolar disorder. Upon arrival in the Emergency Department (ED), the patient had spontaneous respirations with the aid of supplementary mechanical ventilation. She opened her eyes spontaneously and exhibited purposeful movement of all her extremities. Her initial vital signs included a pulse of 138 bpm with sinus rhythm on the monitor, blood pressure of 84/40 mm Hg, rectal temperature of 35.5°C (96°F), and an oxygen saturation of 100% with peak flow oxygen. The patient was an obese female who did not appear chronically ill. Examination of the head was remarkable for dry mucous membranes, but there were no face or scalp contusions, ecchymoses, or bony step-offs. Pupils were 3 mm and reactive bilaterally. The neck was supple without thyromegaly, jugular venous distension, or cer-
vical adenopathy. The chest was clear to auscultation bilaterally. Heart sounds were regular without murmurs or rubs. The abdomen was soft, nondistended, and nontender with no masses or bruits. The rectal examination revealed normal tone and brown heme-negative stool. There was no peripheral edema; peripheral pulses were weak throughout. The skin was normothermic, dry, and without rashes, purpura, or petichiae. On neurologic examination, she withdrew all four extremities to noxious stimulus. Clonus was absent, reflexes were normal and symmetric, and toes were downgoing bilaterally. Dr. Nadel: This patient was in shock. There was no evidence of pulmonary congestion to suggest cardiac dysfunction as the cause, so we need to distinguish between hypovolemic, septic, and vasomotor shock. Are there any thoughts on how to proceed? Dr. J.T. Nagurney: The physical examination doesn’t seem to provide any further clues as to the etiology of the altered mentation. The patient appears more responsive now than she was at the scene, which is likely the result of correcting the ventricular dysrhythmia. In addition to obtaining better IV access and beginning aggressive fluid resuscitation, I would obtain a 12-lead electrocardiogram (EKG) and bedside finger stick glucose to reconfirm the hyperglycemia found in the field. If she were in fact hyperglycemic, I would suspect diabetic ketoacidosis (DKA) as the etiology of
Figure 2. Prehospital rhythm strip after treatment with lidocaine shows sinus rhythm at ⬃70 bpm.
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Figure 3. EKG demonstrates a regular tachycardia with a slightly widened QRS interval and diffuse ST-T-wave abnormalities.
her symptoms, despite the fact that she has no history of diabetes. Hyperosmolar diabetic coma is also a possibility given her altered mental status and that DKA would be expected to present earlier in life. As to the etiology of the VT, I can think of two explanations. First, it may have been a result of underlying myocardial infarction that led to an intraventricular conduction abnormality. Myocardial infarction is also known to precipitate DKA, which would explain hyperglycemia in this setting. Conversely, DKA or hyperosmolar coma might be the primary process here, resulting in electrolyte disturbances and subsequent VT (2). My leading hypothesis in this case is DKA with electrolyte disturbances leading to VT. Dr. Filbin: After confirmation of endotracheal tube placement by CO2 capnometry, the patient was placed on a mechanical ventilator in assist control mode with an FiO2 of 1.0, respirations of 10 breaths per minute, and a tidal volume of 700 cc. A 12-lead electrocardiogram (EKG) showed a widened QRS interval and diffuse ST segment and T wave abnormalities (Figure 3). A left subclavian triple-lumen catheter was placed and blood was sent to the laboratory. The lidocaine drip was continued at 2 mg/min. The results of a venous blood gas analysis included a pH of 6.98, pCO2 of 23 mm Hg, pO2 of 50 mm Hg, glucose greater than 500 mg/dL, and potassium less than assay (value less than 1.6 mmol/L). Based on what appeared to be profound hypokalemia, insulin therapy was withheld. The first liter of normal saline was administered centrally over 30 min with 60 meq of potassium chloride. In addition, magnesium sulfate 2 g IV was administered over 20 min. After the first liter of fluid, we redrew a chemistry panel that showed sodium 130 mmol/L, potassium 4.5
mmol/L, chloride 101 mmol/L, bicarbonate 16 mmol/L, BUN 54 mg/dL, creatinine 2.6 mg/dL, and glucose 2214 mg/dL. A complete blood count included a WBC count of 16.2 K/cumm with a left-shifted differential; the hematocrit was 53% and platelet count was normal. Dr. Brown: I am concerned that the initial very low serum potassium may have been spurious, especially given the change in level from 1.6 mmol/L to 3.5 mmol/L after the administration of only 60 meq of potassium repletion. Perhaps the venous blood gas was drawn above a running IV line. Although there is always total body potassium depletion in these cases, often the initial serum potassium, prior to therapy, will be normal or elevated in response to the accompanying metabolic acidosis. If this is the case, then administering such large doses of potassium IV could precipitate dangerous hyperkalemia and further cardiac electrical instability. I think it would have been more prudent to recheck the potassium and start initially with aggressive normal saline rehydration. The blood glucose over 2000 mg/dL is consistent with the diagnosis of hyperglycemic hyperosmolar nonketotic coma (HHNC), provided she was not ketotic. In the absence of ketosis, the acidosis with a modest anion gap was likely due to some combination of renal insufficiency and lactic acidosis related to tissue hypoperfusion. This in turn was likely due to hypovolemia or sepsis. In any case, it was prudent to withhold insulin administration because this would act to drive potassium into the cells and worsen any hypokalemia (3). This might also precipitate cardiac dysrhythmias. Were electrolytes tested on the initial blood draw,
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along with the venous blood gas? And how did the patient respond to therapy? Dr. Filbin: Yes, serum electrolytes were drawn from a different site, at the same time the venous blood gas was obtained. The serum sample demonstrated a potassium of 6.0 mmol/L, in contrast to the measurement of ⬍1.6 mmol/L on the venous blood gas. Upon review of the venous blood gas results, the hematocrit was 15%, which was considerably less than the 53% found on the subsequent venous specimen. This led us to conclude that the blood gas specimen was dilute. The patient’s condition remained unchanged at this point and we continued with saline rehydration. Dr. James Gordon: Were you able to obtain any additional history? Dr. Filbin: The patient’s boyfriend arrived and told us she had been ill for about 1 week with what they thought to be “the flu.” She had not complained of fevers, chills, cough, or pain anywhere. However, she had been urinating much more than usual and was drinking up to 3 gallons of water and Gatorade daily because of extreme thirst. She did not complain of dysuria or diarrhea. Dr. Brown: It appears this woman had been compensating for her hyperglycemic polyuria for quite some time with aggressive self-rehydration. It is important to recognize that her serum sodium will go up markedly as her hyperglycemia resolves. The current serum sodium of 130 mmol/L represents “pseudohyponatremia” due to the osmotic effect of the pronounced hyperglycemia. The sodium can be corrected for this by adding 1.6 meq/L of sodium for every 100 mg/dL of glucose above 150 mg/dL (4). This calculation predicts a serum sodium of over 160 meq/L, indicative of profound dehydration and free water deficit. Please continue with the further management in the ED. Dr. Filbin: A portable chest radiograph showed the endotracheal tube and left subclavian line in good position. There was no airspace disease, mediastinal widening, pneumothorax, or subdiaphragmatic air. Serum lactate was mildly elevated at 3.4 mmol/L and serum acetones were trace postive undiluted. Urinalysis showed trace ketones and 3⫹ glucose, but no white cells, red cells, casts, or bacteria. She remained hypotensive with a blood pressure of 80/40 mm Hg. A low-dose insulin infusion was started at 1 unit per hour. Two additional liters of normal saline were administered over the next hour. Potassium chloride 20 meq was given via the central venous catheter. Ampicillin 2 g IV, Gentamicin 100 mg IV, and Flagyl 500 mg IV were administered for possible sepsis. The patient was admitted to the medical intensive care unit (ICU). Dr. David Tancredi: Your laboratory tests have confirmed the diagnosis of HHNC. Empiric antibiotics are
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warranted as the clinical picture suggests possible sepsis, which may trigger the onset of HHNC. I think that Gentamicin is a suboptimal choice for Gram-negative coverage in this patient with elevated creatinine and presumably some degree of acute tubular necrosis. There are other less nephrotoxic agents available including quinolones and second and third generation cephalosporins. What was your strategy for fluid resuscitation and why did you use such a low dose of insulin? Dr. Filbin: Patients with HHNC tend to be more dehydrated than those with DKA. The fluid deficit in patients with HHNC is up to 20 –25% of the total body water (5). This is equivalent to about 8 –10 liters of free water in an average-sized person. Despite seemingly normal or high serum sodium values, there is a total body sodium deficit. Therefore, fluid resuscitation must be started with normal saline to restore sodium, and in turn, intravascular volume. The recommendation is 3 liters over the first 2 h. Fluid can be switched to half normal saline once hypotension is corrected and urine output is established. This hypotonic fluid will act to restore the free water deficit. After restoring intravascular volume with the initial bolus of normal saline, fluid should not be administered faster than one liter per hour to avoid thirdspacing and development of pulmonary or cerebral edema. The recommended dose of insulin for HHNC is 0.01 U/kg/h with or without a bolus (6). This is in contrast to the recommended dosing for DKA of 0.1 U/kg bolus plus 0.1 U/kg/h drip. The reason for this is twofold. First, patients with HHNC already produce a small amount of endogenous insulin that prevents ketogenesis. Thus, the need to reverse ketogenesis as one would do in DKA is not necessary. Second, large doses of insulin may cause a precipitous fall in serum glucose, and subsequently, serum osmolarity. Because the blood-brain barrier prevents the rapid flow of electrolytes between the serum and the central nervous system (CNS), a rapid fall in serum osmolarity leads to a relative hyperosmolar cerebrospinal fluid (CSF), thus drawing fluid into the brain. This leads to cerebral edema that may result in poor neurologic outcome or even death (7). For unknown reasons, children are more prone to this complication. The goal is to prevent a decrease in serum glucose of more than 100 mg/dL per hour (8). Dr. Nadel: Please describe the patient’s hospital course. Dr. Filbin: In the ICU, the patient’s blood glucose levels continued to be elevated above 2000 mg/dL and the insulin drip was increased to 8 units per hour. She began to run a fever as high as 41.5°C (106.8°F). She continued to be hypotensive and was started on vasopressors. She received normal saline at a rate of approximately one liter per hour. Twelve hours after admission
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a chemistry panel showed sodium 155 mmol/L, potassium 3.3 mmol/L, chloride 131 mmol/L, bicarbonate 15 mmol/L, BUN 38 mg/dL, creatinine 2.1 mg/dL, and glucose 1144 mg/dL. Serial cardiac enzymes were normal. Blood gas analysis continued to show a metabolic acidosis. She received bicarbonate 75 meq in 600 cc of D5W IV over 3 h and salt-poor albumin 500 cc because of persistent hypotension. The insulin drip was increased to 20 units per hour. She remained persistently tachycardic and hypotensive, and she died approximately 24 h after arrival to the hospital. A Student: If the diagnosis here was HHNC, how do you account for the presence of metabolic acidosis? Also, what is the utility of bicarbonate therapy in this setting? Dr. Filbin: It is reported that DKA and HHNC are part of a continuum of disease, and that patients with hyperglycemic hyperosmolar state also may have a component of ketosis and subsequent acidosis (9). Given the lack of urine or serum ketones, this is an unlikely explanation of metabolic acidosis in this case. A more likely explanation for acidosis in this patient is persistent hypovolemic shock perhaps with septic shock as well. This results in anaerobic metabolism and production of lactate, thus leading to lactic acidosis. The use of bicarbonate is still controversial in the setting of DKA or HHNC, but there are no studies that show decreased mortality with bicarbonate therapy in treating acidosis. Most of the studies have been performed in the setting of DKA. The argument for using bicarbonate is that the correction of severe acidosis may improve cardiovascular collapse caused by acidosis. Some experts have suggested that this benefit is appreciated for serum pH ⬍ 7.0, although the study that concluded this failed to show a difference in recovery rate or outcome in 21 DKA patients with pH from 6.9 to 7.1 randomized to bicarbonate therapy or placebo (10). A more recent trial with a similar study design randomized 39 patient with DKA and profound acidosis to bicarbonate therapy or placebo. Not only was there no difference in recovery rate or mortality, but the potassium requirement of the bicarbonate group was much higher (11). These authors conclude that bicarbonate is not advisable in the treatment of severe acidosis in DKA. A retrospective study in children with severe DKA showed that, controlling for the degree of acidosis, bicarbonate therapy was associated with longer hospitalizations (12). The theoretical disadvantages to bicarbonate therapy in severe acidosis of DKA are multiple. First, and most importantly, rapid correction of acidosis drives potassium into the cells and decreases serum potassium in patients who are already hypokalemic. This may lead to cardiac arrest. Second, administered bicarbonate is also thought to cause a paradoxical CSF acidosis because the
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blood-brain barrier is more permeable to carbon dioxide than it is to bicarbonate. Therefore, as acid and bicarbonate react in the serum, the end-product carbon dioxide crosses into the CNS and decreases cerebral pH. Third, as insulin is administered to patients with DKA, ketones are metabolized in part to bicarbonate, which causes a natural serum alkalinization. Additional administration of bicarbonate can cause an overshoot-alkalosis. Furthermore, alkalosis stops the feedback inhibition of ketogenesis, and ketone clearance is slowed. Lastly, alkalosis promotes a left shift of the carboxy-hemoglobin curve and oxygen binding to 2,3-DPG in red blood cells. This acts to inhibit oxygen release into hypoxic peripheral tissue, thus contributing to anaerobic metabolism and worsening of the underlying condition. Dr. Brown: The management of cases with this degree of electrolyte disturbance is extremely difficult. The mortality of HHNC is approximately 15% compared with the 1–2% mortality associated with DKA (13). This mortality is further increased in patients who present with extreme hyperosmolarity and dehydration such as was seen in this patient (14). Patients with HHNC tend to be older, have some degree of renal insufficiency, and often underlying cardiac disease. These patients have less capacity to correct metabolic disturbances and cope with the underlying illness that triggered HHNC in the first place. Sepsis seems the most likely precipitant here. Was an autopsy performed? Dr. Filbin: The conclusions of the autopsy were consistent with multi-organ system failure. Examination of the heart showed mild atherosclerosis and biventricular dilatation without evidence of infarct. The lungs were markedly congested and edematous. The pancreas exhibited diffuse inflammation and extensive fat necrosis consistent with necrotizing pancreatitis. The biliary system was unremarkable. The kidneys showed acute tubular necrosis. An autopsy of the brain was not performed, thus comment on cerebral edema could not be made. All cultures were negative. The presence of necrotizing pancreatitis on autopsy suggests that this may have been the underlying illness that precipitated HHNC.
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M. R. Filbin et al. 10. Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med 1986;105:836 – 40. 11. Viallon A, Zeni F, Lafond P, et al. Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 1999;27:2690 –3. 12. Green SM, Rothrock SG, Ho JD. Failure of adjuctive bicarbonate to improve outcome in severe pediatric diabetic ketoacidosis. Ann Emerg Med. 1998;31:41– 8. 13. Kitabchi AE, Wall BM. Management of DKA. Am Family Physician 1999;60:455– 64. 14. Hamblin PS, Topliss DJ, Chosich N, et al. Deaths associated with diabetic ketoacidosis and hyperosmolar coma. Med J Aust 1990; 152:327– 8.