FORUM 50% dextrose
5 0 % Dextrose: A n t i d o t e or Toxin? [Brow~ing RG, Olson DW, Stueven HA, Mateer JR: 50% Dextrose: Antidote or toxin? Ann Emerg Med June 1990;19:683-687.] INTRODUCTION Recent advances in the study of ischemic brain injury have identified glucose as a major factor in the pathogenesis of this disease. 1 Investigators have demonstrated that even mild degrees of hyperglycemia may result in accentuated neurologic damage from an ischemic insult. 2 This is of major clinical importance to an emergency physician with a patient suffering from acute or impending cerebral ischemia such as stroke, severe hypotension, or cardiac arrest. Glucose-containing IV solutions are widely used in emergency departments and prehospital settings. A 5% dextrose in water solution is generally used to keep IV lines open during cardiac resuscitation, s Plum and Posner 4 have recommended that 25 g glucose (50 mL of 50% dextrose, 0.35 g/kg based on a 70-kg patient} be administered to any patient presenting with coma of undetermined etiology. This recommendation was based on the concern that waiting for laboratory confirmation of hypoglycemia before instituting treatment may result in irreversible brain damage. 5 The empiric administration of IV glucose has become a standard of care in the emergency management of the comatose patient.6, 7 This standard of care has evolved to include the empiric administration of 50% dextrose to any overdose patient presenting with altered mental statusS, 9 and is based on the knowledge that several medications or toxins can cause hypoglycemia, including ethanol, insulin, propranolol, salicylates, and sulfonylureas. 9 In addition, certain drugs are known to alter glucose m e t a b o l i s m in p a t i e n t s u n d e r g o i n g t h e r a p y for d i a b e t e s (eg, B-blockers, chloramphenicol, dicoumarol, disopyramide, ethanol, MAO inhibitors, phenytoin, probenecid, propranolol, salicylates, steroids, and sulfonamide). 9 The practice of empiric IV glucose administration to patients presenting with altered mental status is based not only on the concern that irreversible brain damage may result from delayed recognition and treatment of hypoglycemia but also on the untested assumption that the administration of glucose is harmless to patients w h o are n o r m o g l y c e m i c or hyperglycemic, s Recent understanding of the role of glucose in the pathogenesis of ischemic neuronal injury necessitates a reevaluation of empiric glucose administration in the ED.
Randall G Browning, MD David W Olson, MD, FACEP Harlan A Stueven, MD, FACEP James R Mateer, MD, FACEP Milwaukee, Wisconsin From the Department of Emergency Medicine, Medical College of Wisconsin, Milwaukee. Received for publication February 22, 1989. Revision received December 22, 1989. Accepted for publication January 30, 1990. Address for reprints: David W Medical College of Wisconsin, of Emergency Medicine, 8700 Wisconsin Avenue, Milwaukee, 53226.
OIson, MD, Department West Wisconsin
STUDIES IN ANIMALS Interest in the effects of hyperglycemia on outcome after cerebral ischemia was sparked by the observation of Myers and Yamaguchi 1° that monkeys given 5% dextrose in saline before cardiac arrest suffered greater neurologic i m p a i r m e n t than saline-treated animals. In a later study, normoglycemic rats were found to tolerate ten minutes of global cerebral ischemia with only minor neurologic deficit, whereas rats receiving 3 g/kg glucose before ischemia uniformly convulsed and died within 12 hours. 11 Pulsinelli et a112 confirmed these findings while controlling for changes in plasma osmolality, arguing against an osmotic mechanism for accentuated neurologic injury.
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50% DEXTROSE Browning et al
To t e s t these o b s e r v a t i o n s in a more clinically applicable setting, D'Aleey et a113 compared the outcome of dogs treated with 500 mL of either lactated Ringer's solution or 5% dextrose in lactated Ringer's (1.25 g/kg glucose) before cardiac arrest and resuscitation, with an additional 500 mL of the same fluid administ e r e d d u r i n g t h e s u b s e q u e n t six hours. All six animals receiving the dextrose-free solution survived a 24hour o b s e r v a t i o n period, whereas four of the six animals receiving the d e x t r o s e - c o n t a i n i n g s o l u t i o n convulsed and died within nine hours of resuscitation. The two surviving dextrose-treated animals demonstrated significantly greater neurologic impairment after 24 hours than the animals receiving the dextrose-flee solution (P < .05) as judged by a neurologic score i n c o r p o r a t i n g level of consciousness, motor and respiratory function, cranial nerve function, and spinal reflexes. T h e authors thus d e m o n s t r a t e d that the addition of 5% dextrose to standard IV solutions significantly increased the morbidity and mortality associated with cardiac arrest and resuscitation. With a similar motivation to test the effect of glucose administration in clinically relevant doses, Lanier et al 2 compared neurologic and histologic o u t c o m e after 17 m i n u t e s of complete cerebral i s c h e m i a in primates pretreated with the equivalent of 1 L/70 kg body wt of either lactated Ringer's solution or 5% dextrose in 0.45% saline solution (0.7 g/kg glucose). Only animals with preischemic blood glucose levels of less than 250 mg% were included for analysis. Four of the six animals receiving the lactated Ringer's solution demonstrated complete return of neurologic function by the end of a 96-hour obs e r v a t i o n period. In c o n t r a s t , all seven dextrose-treated animals showed persistent neurologic deficits. Overall neurologic scores were significantly worse in the dextrosetreated animals (P < .05). Furthermore, a highly significant correlation was noted between the preischemic blood glucose level and the neurologic outcome, regardless of the IV solution used (rs --- .76, P < .005). Histopathologic scores demonstrated greater cellular injury in the dextrose-treated animals (P < .05). The striking finding in this study is that 114/684
the detrimental effect of preischemic glucose administration may be demonstrated well w i t h i n the range of c o m m o n l y e n c o u n t e r e d levels of mild hyperglycemia.
STUDIES IN H U M A N BEINGS Several studies in h u m a n beings have examined the relationship between blood glucose level on admission to the hospital after a cerebral ischemic event and neurologic outcome. Pulsinelli et a114 have prospectively analyzed the relationship between admission blood glucose level and neurologic outcome after ischemic stroke in 31 consecutive nondiabetic patients. They reported that 13 of 17 patients (76%) with admission blood glucose levels less than 1 2 0 m g % were able to r e t u r n to work, whereas only six of 14 patients (43%) with higher admission blood glucose levels regained this level of function (P < .006). Candelise et a115 e x a m i n e d the prognostic significance of fasting blood glucose level within 48 hours of acute, completed stroke in 61 consecutive patients without a history of diabetes. They reported a positive c o r r e l a t i o n b e t w e e n fasting blood glucose level and both size of the lesion on computed tomography scan (F = 4.88, P < .05) and the degree of neurologic impairment as judged by a standardized neurologie score (F = 5.39, P < .01). Although patients in this study were without diabetes by history, elevated fasting blood glucose levels may have been an indicator of early or undiagnosed diabetes. Neurologic outcome after stroke is known to be worse in diabetic patients than in patients without diabetesA4,16 Multiple factors, including increased central nervous system microangiopathy, have been implicated. 14 The association of greater neurologic injury with higher fasting blood glucose levels m a y be a reflection of increased stroke severity in patients with early or undiagnosed diabetes. Longstreth et aPT have reported a relationship between admission blood glucose level and neurologic outcome in 430 consecutive patients resuscitated from out-of-hospital cardiac arrest. Patients received variable a m o u n t s of 5% dextrose solution during prehospital resuscitation. The mean blood glucose level on admission in 154 patients who never reAnnals of Emergency Medicine
gained c o n s c i o u s n e s s was h i g h e r than that of patients who awakened (341 vs 262 rag%, P < .0005). Of those patients who awakened, 90 patients with persistent neurologic impairment had a higher mean glucose level than those without persistent impairment (286 vs 251 mg%, P < .02). This relationship between admission blood glucose level and neurologic outcome remained significant after excluding patients with blood glucose level exceeding 500 rag% and after controlling for several potentially confounding variables such as history of diabetes, age, sex, medication history, time from arrest to initiation of resuscitation, and first cardiac rhythm. Interpretation of these human data is difficult for several reasons. First, it is difficult to control for underlying disorders that might be associated w i t h b o t h h i g h e r a d m i s s i o n blood glucose levels and increased morbidity and mortality from cerebral ischemic events, such as diabetes or dehydration. Second, an inherent difficulty in h u m a n studies is the inability to measure blood glucose level at the time of onset of the ischemic event. Transient, or " r e a c t i v e , " hyperglyc e m i a has b e e n r e p o r t e d a f t e r a variety of physiologically stressful events, including surgery, is infection, 19 trauma, 19 myocardial infarct i o n , 2° s t r o k e , 2 1 , 22 c a r d i o g e n i c shock, 23 and hypovolemie shock, m Reactive hyperglycemia thus may be considered a nonspecific reaction to physiologic stress and probably represents a secondary m a n i f e s t a t i o n of t h e c o m p l e x n e u r o e n d o c r i n e res p o n s e to s h o c k a n d t i s s u e injury.21, 24 Catecholamines, insulin, glueagon, corticosteroids, and somatotropin are the p r i m a r y g l u c o r e g u l a t o r y horm o n e s i m p l i c a t e d in the h y p e r glycemic reaction. Increased urinary excretion of catecholamines has been o b s e r v e d in p a t i e n t s w i t h a c u t e stroke, 2s and e l e v a t e d blood eatecholamine levels have been reported in animal models of h y p o v o l e m i c shock. 24 Although somatotropin and corticosteroid release in response to stress m a y play a role in reactive hyperglycemia,18, 24 information regarding this issue is lacking. The development of hyperglycemia on hospital admission may therefore be a result rather than a cause of in19:6 June 1990
creased neurologic injury. To circumvent the phenomenon of reactive hyperglycemia, glycosylated serum protein (fructosamine) and glycosylated hemoglobin (HbAl) , known indexes of medium- and long-term exposure to blood glucose, have been used as an indicator of blood glucose level at the onset of ischemia. Woo et al 2~ found no correlation between mortali t y f r o m a c u t e s t r o k e and fruct o s a m i n e or H b A 1 concentrations. Neurologic outcome other than mort a l i t y was n o t e x a m i n e d in this study. Actual blood glucose levels at the time of onset of ischemia remain u n k n o w n w i t h this method, however, because fructosamine and HbA 1 are not i n f l u e n c e d by s h o r t - t e r m fluctuations in blood glucose level. ~2 Studies in animals have demonstrated that blood glucose level at the onset of cerebral ischemia is a determ i n a n t of neurologic outcome. Results of studies in human beings are consistent with animal studies but remain inconclusive due to the limitations inherent in h u m a n studies. Debate continues as to the effect of stress-induced or iatrogenic hyperglycemia on neurologic outcome after cerebral ischemic events in human beings.
PATHOPHYSIOLOGY The effect of glucose on ischemic brain tissue is thought to be mediated by lactic acid that accumulates through anaerobic glycolysis.2¢ ~7 It has been firmly established that conditions that promote the metabolism of glucose to lactate in i s c h e m i c brain result in increased cellular damage. 1 The amount of lactate that a c c u m u l a t e s during complete ische m i a is d e t e r m i n e d by t h e preischemic tissue glucose stores.l,26, 28 Preischemic hyperglycemia results in increased tissue glucose s t o r e s , 2,29 providing the substrate for anaerobic glycolysis during the ischemic event, w i t h s u b s e q u e n t a c c u m u l a t i o n of lactic acid to cytotoxic levelsY, 29-3~ Animal models of severe incomplete cerebral ischemia, such as fourvessel occlusion or bilateral carotid artery occlusion in combination with lowering of blood pressure, demonstrate increased i s c h e m i c damage compared w i t h animals undergoing equal p e r i o d s of c o m p l e t e ischemia.27, 32 It is postulated that conditions of severe incomplete ischemia allow small amounts of substrate to 19:6 June 1990
enter into the tissues while failing to provide adequate oxygen to support the oxidative m e t a b o l i s m of glucose. 26 The resulting anaerobic metabolism of glucose to lactate would result in enhanced cellular damage. E x p e r i m e n t a l s u p p o r t for s u c h a mechanism is provided by the observation of increased tissue lactic acid accumulation in animals undergoing severe incomplete cerebral ischemia compared with animals undergoing an equal duration of complete cerebral ischemia.27, 32 These experimental models m a y have clinical relevance in low-flow conditions such as CPR during cardiac arrest, severe hypotension, and marginally perfused areas of brain tissue during stroke. Histologic studies show that preischemic hyperglycemia results in enhanced cellular destruction in isc h e m i c a r e a s , t2, 31,33 increased volume of i n f a r c t , 34-36 and the conversion of selective neuronal ischemic injury to complete infarction. 37 The extent of histopathologic damage appears to be related to the degree of tissue lactic acidosis attained. 37 Several investigators have demonstrated that under conditions of either complete or severe incomplete cerebral ischemia, the degree of neur o l o g i c i n j u r y is r e l a t e d to t h e amount of lactate accumulated in the t i s s u e . 27,29,31,37,38 T h e m o l e c u l a r mechanism for lactate-induced cellular damage remains largely speculative. An increase in tissue lactate concentration m a y induce osmotic shifts 26 and result in a demonstrable decrease in intracellular and extrac e l l u l a r pH. 3° Either of these effects could result in cytotoxicity. Tissue acidosis probably causes alterations in protein structure and function. Hypotheses involving alterations in cellular membrane function and acidosis-induced free radical formation have attracted recent interest. 1 CLINICAL CORRELATES Investigation of the effect of glucose on brain i s c h e m i a has been largely focused on preischemic hyperglycemia. This approach may appear somewhat limited as it is difficult to control blood glucose level in most patients before an unexpected ischemic event occurs. However, the model is relevant to the diabetic patient and supports the argument for careful control of blood glucose. It is also relevant to ED patients who preAnnals of Emergency Medicine
sent with evolving ischemic stroke, impending cardiac arrest, or severe h y p o t e n s i o n and m a y receive glucose-containing IV solutions during initial evaluation and treatment. The frequency with which such patients present to the ED may be substantial. In a collaborative study of 500 patients admitted with nontraumatic coma to New York City Hospital, the Royal Victoria Infirmary (England), or San Francisco General Hospital, 264 (53%) had either brain infarcts, profound hypotension, or cardiac arrest. 39 A l t h o u g h this study does not include patients with coma lasting less than six hours or coma due to drug overdose, it does suggest that a significant percentage of patients presenting with coma are suffering from cerebral ischemia and thus potentially harmed by hyperglycemia produced by glucose-containing IV solutions or the empiric administration of 50% dextrose. Several investigators have recommended avoiding glucose-containing IV s o l u t i o n s in p a t i e n t s suffering f r o m c e r e b r a l ischemia.2,13j6,23, ~6 Reagent test strips for blood glucose e s t i m a t i o n eliminate delays in the diagnosis of hypoglycemia. N e w e r test strips provide a rapid and accurate estimation of blood glucose level when properly used 4°-a2 and serve as a reliable screen for hypoglycemia, 43 obviating the need for empiric glucose therapy in patients with altered mental status. Several issues of clinical importance r e m a i n unresolved. Study of the effect of glucose administration during the recirculation phase after cerebral i s c h e m i a has yielded conflicting results. Some investigators 32-44 report accentuated neurologic injury with postischemic glucose administration, whereas others12, 26 h a v e failed to c o n f i r m these findings. The amount of glucose required to produce a clinical effect is unknown. It remains to be determined whether the effects of preischemic glucose adm i n i s t r a t i o n d e m o n s t r a t e d in animals can be extrapolated to the relatively small amounts of glucose del i v e r e d t h r o u g h t h e u s e of 5% dextrose in water to keep IV lines open in patients with acute cerebral ischemia. A role for actively m a i n t a i n i n g n o r m o g l y c e m i a w i t h i n s u l i n has been suggested by preliminary study 685/115
50% DEXTROSE Browning et al
in the rat. 44 Further investigation is required to clarify the value of active reduction in blood glucose level during cerebral ischemia.
SUMMARY T h e e m p i r i c a d m i n i s t r a t i o n of 50% dextrose to all patients presenting to the ED with altered mental status is a standard of care predicated on the assumption that glucose adm i n i s t r a t i o n is h a r m l e s s to n o n hypoglycemic patients. C o n s i d e r a b l e e v i d e n c e n o w disputes this assumption. Glucose adm i n i s t r a t i o n before c o m p l e t e cerebral i s c h e m i a in e x p e r i m e n t a l animals worsens neurologic and histologic outcome. Administration of glucose during severe incomplete ischemia has a similar detrimental effect. The translation of these experimental findings into clinical practice has been slow, perhaps hindered by the frequent use of rodent models and large bolus doses of glucose. 13 However, evidence is now provided by primate and h u m a n studies and by experimental designs using clinically relevant doses of glucose. These clinical and experimental findings in conjunction with the wide availability of a rapid bedside screen for hypoglycemia provide the rationale for an alteration in the standard of care. The empiric administration of glucose should be avoided in patients at risk for cerebral ischemia, such as those with acute stroke, impending cardiac arrest, or severe hypotension or receiving CPR. A bedside fingerstick blood glucose estimation should be performed immediately on all patients presenting with altered mental status. The administration of 50% dextrose should be reserved for t h o s e p a t i e n t s in w h o m h y p o glycemia is demonstrated; this practice will uphold Hippocrates' most basic principle of clinical medicine, " T h e p h y s i c i a n m u s t . . . do no harm.,,4s T h e a u t h o r s t h a n k N a n c y R o b i n s o n for her assistance in preparing this manuscript.
REFERENCES 1. Siesjo BK: Mechamisms of ischemic brain damage. Crit Care ivied 1988;16:954-963. 2. Lanier WL, Strangland KJ, Scheithauer BW, et al: The effects of dextrose infusion and head position on neurologic outcome after complete ce-
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rebral ischemia in primates: Examination of a model. Anesthesiology 1987;66:39-48. 3. American Heart Association: Standards and guidelines for cardiopulmonary resuscitation and emergency cardiac care. JAMA 1986;255: 2841-3044. 4. Plum F, Posner JB (eds): The Diagnosis of Stupor and Coma, ed 3. Philadelphia, FA Davis Co, 1980, p 352. 5. Posner JB: The comatose patient. JAMA 1975;233:1313-1314. 6. Henry GL: Coma and altered states of consciousness, in Tintinalli JE, Krome RL, Ruiz E (eds): Emergency Medicine: A Comprehensive Study Guide, ed 2. St Louis, McGraw-Hill Book Co, 1988, p 128. 7. Huff SJ: Coma, in Rosen P~ Baker FJ II, Barkin RM, et al: (eds): Emergency Medicine: Concepts and Clinical Practice, ed 2. St Louis, CV Mosby, 1988, vol 1, p 249. 8. Bryson PD: Comprehensive Review in Toxicology. Rockville, Maryland, Aspen, 1986, p 7. 9. Goldfrank LR: Toxicologic Emergencies, ed 3. Norwalk, C o n n e c t i c u t , A p p l e t o n - C e n t u r y Crofts, 1986, p 8, 266-268. 10. Myers RE, Yamaguchi S: Nervous system effects of cardiac arrest in monkeys. Arch Neurol 1977;34:65-74. 11. Siemkowicz E, Hansen AJ: Clinical restitution following cerebral i s c h e m i a in hypo-, normo-, and hyperglycemic rats. Acta Neurol Scand 1978;58:1-8. 12. Pulsinelli WA, Waldman S, Rawlinson D, et al: Moderate hyperglycemia augments ischemic brain damage: A neuropathic study in the rat. Neurology {NY) 1982;32:1239-1246. 13. D'Alecy LG, Lundy EF, Barton KJ, et al: Dextrose containing intravenous fluid impairs outcome and increases death after eight minutes of cardiac arrest and resuscitation in dogs. Surgery 1986;100:505-511. 14. Pulsinelli WA, Levy DE, Sigsbee B, et ah Increased damage after i s c h e m i c stroke in patients with hyperglycemia with or without established diabetes mellitus. A m J Med 1983;74: 540-544. 15. Candelise L, Landi G, Orazio E, et al: Prognostic significance of hyperglycemia in acute stroke. Arch Neurol 1985;42:661-733. 16. Asplund K, Hagg E, Helmers C, et ah The natural history of stroke in diabetic patients. Acta Med Scand 1980;207:417-424. 17. Longstreth WT Jr, Inui TS: High blood glucose level on hospital admission and poor neurological recovery after cardiac arrest. Ann N e w rol 1984;15:59-63. 18. Ross H, Johnston IDA, Welbom TA, et ah Effect of abdominal operation on glucose tolerance and serum levels of insulin, growth hormones, and hydrocortisone. Lancet 1966;2: 563-566. 19. Kinney JM, Long CL, Duke ]H: Carbohydrate and nitrogen metabolism after injury, in Porter R, Knight l (eds): Energy Metabolism in Trauma. London, J and A Churchill, 1970, p 103. 20. McDonald L, Baker C, Bray C, et ah Plasma catecholamines after cardiac infarction. Lancet 1969;2:1021-1023. 21. Melamed E: Reactive hyperglycemia in patients with acute stroke. J Neurol Sci 1976;29:
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267-275. 22. Woo E, Ma JTC, Robinson JD, et ah Hyperglycemia is a stress response in acute stroke. Stroke 1988;19:1359-1364. 23. Mackenzie GJ, Taylor SH, Henley DC, et ah Circulatory and respiratory studies in myocardial infarction and cardiogenic shock. Lancet 1964;2:825-832. 24. Garcia-Barreno P, Balibrea JL: Metabolic response in shock. Surg Gyneecol Obstet 1978; 146:182-190. 25. Tomomatsu T: ECG observations and urinary excretion of catecholamines in cerebrovascular accidents. Jap Cite J 1964;28:905-912. 26. Plum F: What causes infarction in ischemic brain? The Robert Wartenberg lecture. Neurology 1983;33:222-233. 27. Rehncrona S, Rosen I, Siesjo BK: Brain lactic acidosis and ischemic cell damage: 1. Binchemistry and neurophysiology. 1 Cereb Blood Flow Metab 1981;1:297-311. 28. Siesjo BK: Cell damage in the brain: A speculative synthesis, ] Cereb Blood Flow Metab 1981;1:155-185. 29. Welsh FA, Ginsberg MD, Rieder W, et al: Deleterious effect of glucose pretreatment on recovery from diffuse cerebral ischemia in the cat: II. Regional m e t a b o l i t e levels. Stroke 1980;11:355-363. 30. Smith ML, yon H a n w e h r R, Siesjo BK: Changes in extra- and intracelhilar pH in the brain during and following ischemia in hyperglycemic and in moderately hypoglycemic rats. J Cereb Blood Flow Metab 1986;6:574-583. 31. Inamura K, Smith M-L, Olsson Y, et ah Pathogenesis of substantia nigra lesions following hyperglycemic ischemia: Changes in energy metabolites, cerebral blood flow, and morphology of pars reticulata in a rat model of ischemia. l Cereb Blood Flow Metab 1988;8:375-384. 32. de Courten-Myers GM, Yamaguchi S-I, Myers RE: Accentuation of hypoxic-anoxic brain injury by postexposure infusion of glucose solutions (abstract). Neurology (NY} 1982;32: All0. 33. Nedergaard M, Diemer NH: Focal ischemia of the rat brain, with special reference to the influence of plasma glucose concentration. Acta Neuropathol (Berl) 1987;73:131-137. 34. Duverger D, Mackenzie ET: The quantification of cerebral infarction following focal ischemia in the rat: Influence of strain, arterial pressure, blood glucose concentration, and age. ] Cereb Blood Flow Metab 1988;8:449-461. 35. Prado R, Ginsberg MD, Dietrich WD, et al: Hyperglycemia increases infarct size in collaterally perfused but not end-arterial vascular territories. ] Cereb Blood Flow Metab 1988;8: 186-192. 36. de Courten-Myers G, Myers RE, Schoolfield L: Hyperglycemia enlarges infarct size in cerebrovascular occlusion in cats. Stroke 1988;19: 623-630. 37. Kalimo H, Rehncrona S, Soderfeldt B, et ah Brain lactic acidosis and ischemic cell damage: 2. Histopathology. J Cereb Blood Flow Metab 1981;1:313-327. 38. Nedergaard M: Transient focal ischemia in hyperglycemic rats is associated with increased cerebral infarction. Brain Res 1987;408:79-85. 39. Levy DE, Bates D, Caronna lJ, et al: Prog-
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nosis in nontraumatic coma. Ann Intern ivied 1981;94:293-301,
ordering and alternatives to the laboratory. Ann Emerg Med 1986;15:372-376.
40. Godine JEp Hurxthal K, Nahtan DM: Bedside capillary glucose measurement by staff nurses in a general hospital. A m J Med 1986~80: 803-806.
42. Chernow B: Bedside blood glucose determinations in critical care medicine. Crit Care Med 1982;10:463-465.
41. Pointer JE: Glucose analysis: Indications for
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43. Maisels MJ, Lee CA: Chemstrip glucose test strips: Correlation with true glucose values less
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than 80 mg/dl. Crit Care Med 1983;11:293-295. 44. 8iernkowicz E: Hyperglycemia in the reperfusion period hampers recovery from cerebral i s c h e m i a . A c t a N e u r o l S t a n d 1981~64: 207-216. 45. Adams F (transl}: The Genuine Works of Hippocrates. New York, William Wood and Co, 1886, vol l, p 300.
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5 0 % Dextrose: A n t i d o t e or Toxin? [Brow~ing RG, Olson DW, Stueven HA, Mateer JR: 50% Dextrose: Antidote or toxin? Ann Emerg Med June 1990;19:683-687.] INTRODUCTION Recent advances in the study of ischemic brain injury have identified glucose as a major factor in the pathogenesis of this disease. 1 Investigators have demonstrated that even mild degrees of hyperglycemia may result in accentuated neurologic damage from an ischemic insult. 2 This is of major clinical importance to an emergency physician with a patient suffering from acute or impending cerebral ischemia such as stroke, severe hypotension, or cardiac arrest. Glucose-containing IV solutions are widely used in emergency departments and prehospital settings. A 5% dextrose in water solution is generally used to keep IV lines open during cardiac resuscitation, s Plum and Posner 4 have recommended that 25 g glucose (50 mL of 50% dextrose, 0.35 g/kg based on a 70-kg patient} be administered to any patient presenting with coma of undetermined etiology. This recommendation was based on the concern that waiting for laboratory confirmation of hypoglycemia before instituting treatment may result in irreversible brain damage. 5 The empiric administration of IV glucose has become a standard of care in the emergency management of the comatose patient.6, 7 This standard of care has evolved to include the empiric administration of 50% dextrose to any overdose patient presenting with altered mental statusS, 9 and is based on the knowledge that several medications or toxins can cause hypoglycemia, including ethanol, insulin, propranolol, salicylates, and sulfonylureas. 9 In addition, certain drugs are known to alter glucose m e t a b o l i s m in p a t i e n t s u n d e r g o i n g t h e r a p y for d i a b e t e s (eg, B-blockers, chloramphenicol, dicoumarol, disopyramide, ethanol, MAO inhibitors, phenytoin, probenecid, propranolol, salicylates, steroids, and sulfonamide). 9 The practice of empiric IV glucose administration to patients presenting with altered mental status is based not only on the concern that irreversible brain damage may result from delayed recognition and treatment of hypoglycemia but also on the untested assumption that the administration of glucose is harmless to patients w h o are n o r m o g l y c e m i c or hyperglycemic, s Recent understanding of the role of glucose in the pathogenesis of ischemic neuronal injury necessitates a reevaluation of empiric glucose administration in the ED.
Randall G Browning, MD David W Olson, MD, FACEP Harlan A Stueven, MD, FACEP James R Mateer, MD, FACEP Milwaukee, Wisconsin From the Department of Emergency Medicine, Medical College of Wisconsin, Milwaukee. Received for publication February 22, 1989. Revision received December 22, 1989. Accepted for publication January 30, 1990. Address for reprints: David W Medical College of Wisconsin, of Emergency Medicine, 8700 Wisconsin Avenue, Milwaukee, 53226.
OIson, MD, Department West Wisconsin
STUDIES IN ANIMALS Interest in the effects of hyperglycemia on outcome after cerebral ischemia was sparked by the observation of Myers and Yamaguchi 1° that monkeys given 5% dextrose in saline before cardiac arrest suffered greater neurologic i m p a i r m e n t than saline-treated animals. In a later study, normoglycemic rats were found to tolerate ten minutes of global cerebral ischemia with only minor neurologic deficit, whereas rats receiving 3 g/kg glucose before ischemia uniformly convulsed and died within 12 hours. 11 Pulsinelli et a112 confirmed these findings while controlling for changes in plasma osmolality, arguing against an osmotic mechanism for accentuated neurologic injury.
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50% DEXTROSE Browning et al
To t e s t these o b s e r v a t i o n s in a more clinically applicable setting, D'Aleey et a113 compared the outcome of dogs treated with 500 mL of either lactated Ringer's solution or 5% dextrose in lactated Ringer's (1.25 g/kg glucose) before cardiac arrest and resuscitation, with an additional 500 mL of the same fluid administ e r e d d u r i n g t h e s u b s e q u e n t six hours. All six animals receiving the dextrose-free solution survived a 24hour o b s e r v a t i o n period, whereas four of the six animals receiving the d e x t r o s e - c o n t a i n i n g s o l u t i o n convulsed and died within nine hours of resuscitation. The two surviving dextrose-treated animals demonstrated significantly greater neurologic impairment after 24 hours than the animals receiving the dextrose-flee solution (P < .05) as judged by a neurologic score i n c o r p o r a t i n g level of consciousness, motor and respiratory function, cranial nerve function, and spinal reflexes. T h e authors thus d e m o n s t r a t e d that the addition of 5% dextrose to standard IV solutions significantly increased the morbidity and mortality associated with cardiac arrest and resuscitation. With a similar motivation to test the effect of glucose administration in clinically relevant doses, Lanier et al 2 compared neurologic and histologic o u t c o m e after 17 m i n u t e s of complete cerebral i s c h e m i a in primates pretreated with the equivalent of 1 L/70 kg body wt of either lactated Ringer's solution or 5% dextrose in 0.45% saline solution (0.7 g/kg glucose). Only animals with preischemic blood glucose levels of less than 250 mg% were included for analysis. Four of the six animals receiving the lactated Ringer's solution demonstrated complete return of neurologic function by the end of a 96-hour obs e r v a t i o n period. In c o n t r a s t , all seven dextrose-treated animals showed persistent neurologic deficits. Overall neurologic scores were significantly worse in the dextrosetreated animals (P < .05). Furthermore, a highly significant correlation was noted between the preischemic blood glucose level and the neurologic outcome, regardless of the IV solution used (rs --- .76, P < .005). Histopathologic scores demonstrated greater cellular injury in the dextrose-treated animals (P < .05). The striking finding in this study is that 114/684
the detrimental effect of preischemic glucose administration may be demonstrated well w i t h i n the range of c o m m o n l y e n c o u n t e r e d levels of mild hyperglycemia.
STUDIES IN H U M A N BEINGS Several studies in h u m a n beings have examined the relationship between blood glucose level on admission to the hospital after a cerebral ischemic event and neurologic outcome. Pulsinelli et a114 have prospectively analyzed the relationship between admission blood glucose level and neurologic outcome after ischemic stroke in 31 consecutive nondiabetic patients. They reported that 13 of 17 patients (76%) with admission blood glucose levels less than 1 2 0 m g % were able to r e t u r n to work, whereas only six of 14 patients (43%) with higher admission blood glucose levels regained this level of function (P < .006). Candelise et a115 e x a m i n e d the prognostic significance of fasting blood glucose level within 48 hours of acute, completed stroke in 61 consecutive patients without a history of diabetes. They reported a positive c o r r e l a t i o n b e t w e e n fasting blood glucose level and both size of the lesion on computed tomography scan (F = 4.88, P < .05) and the degree of neurologic impairment as judged by a standardized neurologie score (F = 5.39, P < .01). Although patients in this study were without diabetes by history, elevated fasting blood glucose levels may have been an indicator of early or undiagnosed diabetes. Neurologic outcome after stroke is known to be worse in diabetic patients than in patients without diabetesA4,16 Multiple factors, including increased central nervous system microangiopathy, have been implicated. 14 The association of greater neurologic injury with higher fasting blood glucose levels m a y be a reflection of increased stroke severity in patients with early or undiagnosed diabetes. Longstreth et aPT have reported a relationship between admission blood glucose level and neurologic outcome in 430 consecutive patients resuscitated from out-of-hospital cardiac arrest. Patients received variable a m o u n t s of 5% dextrose solution during prehospital resuscitation. The mean blood glucose level on admission in 154 patients who never reAnnals of Emergency Medicine
gained c o n s c i o u s n e s s was h i g h e r than that of patients who awakened (341 vs 262 rag%, P < .0005). Of those patients who awakened, 90 patients with persistent neurologic impairment had a higher mean glucose level than those without persistent impairment (286 vs 251 mg%, P < .02). This relationship between admission blood glucose level and neurologic outcome remained significant after excluding patients with blood glucose level exceeding 500 rag% and after controlling for several potentially confounding variables such as history of diabetes, age, sex, medication history, time from arrest to initiation of resuscitation, and first cardiac rhythm. Interpretation of these human data is difficult for several reasons. First, it is difficult to control for underlying disorders that might be associated w i t h b o t h h i g h e r a d m i s s i o n blood glucose levels and increased morbidity and mortality from cerebral ischemic events, such as diabetes or dehydration. Second, an inherent difficulty in h u m a n studies is the inability to measure blood glucose level at the time of onset of the ischemic event. Transient, or " r e a c t i v e , " hyperglyc e m i a has b e e n r e p o r t e d a f t e r a variety of physiologically stressful events, including surgery, is infection, 19 trauma, 19 myocardial infarct i o n , 2° s t r o k e , 2 1 , 22 c a r d i o g e n i c shock, 23 and hypovolemie shock, m Reactive hyperglycemia thus may be considered a nonspecific reaction to physiologic stress and probably represents a secondary m a n i f e s t a t i o n of t h e c o m p l e x n e u r o e n d o c r i n e res p o n s e to s h o c k a n d t i s s u e injury.21, 24 Catecholamines, insulin, glueagon, corticosteroids, and somatotropin are the p r i m a r y g l u c o r e g u l a t o r y horm o n e s i m p l i c a t e d in the h y p e r glycemic reaction. Increased urinary excretion of catecholamines has been o b s e r v e d in p a t i e n t s w i t h a c u t e stroke, 2s and e l e v a t e d blood eatecholamine levels have been reported in animal models of h y p o v o l e m i c shock. 24 Although somatotropin and corticosteroid release in response to stress m a y play a role in reactive hyperglycemia,18, 24 information regarding this issue is lacking. The development of hyperglycemia on hospital admission may therefore be a result rather than a cause of in19:6 June 1990
creased neurologic injury. To circumvent the phenomenon of reactive hyperglycemia, glycosylated serum protein (fructosamine) and glycosylated hemoglobin (HbAl) , known indexes of medium- and long-term exposure to blood glucose, have been used as an indicator of blood glucose level at the onset of ischemia. Woo et al 2~ found no correlation between mortali t y f r o m a c u t e s t r o k e and fruct o s a m i n e or H b A 1 concentrations. Neurologic outcome other than mort a l i t y was n o t e x a m i n e d in this study. Actual blood glucose levels at the time of onset of ischemia remain u n k n o w n w i t h this method, however, because fructosamine and HbA 1 are not i n f l u e n c e d by s h o r t - t e r m fluctuations in blood glucose level. ~2 Studies in animals have demonstrated that blood glucose level at the onset of cerebral ischemia is a determ i n a n t of neurologic outcome. Results of studies in human beings are consistent with animal studies but remain inconclusive due to the limitations inherent in h u m a n studies. Debate continues as to the effect of stress-induced or iatrogenic hyperglycemia on neurologic outcome after cerebral ischemic events in human beings.
PATHOPHYSIOLOGY The effect of glucose on ischemic brain tissue is thought to be mediated by lactic acid that accumulates through anaerobic glycolysis.2¢ ~7 It has been firmly established that conditions that promote the metabolism of glucose to lactate in i s c h e m i c brain result in increased cellular damage. 1 The amount of lactate that a c c u m u l a t e s during complete ische m i a is d e t e r m i n e d by t h e preischemic tissue glucose stores.l,26, 28 Preischemic hyperglycemia results in increased tissue glucose s t o r e s , 2,29 providing the substrate for anaerobic glycolysis during the ischemic event, w i t h s u b s e q u e n t a c c u m u l a t i o n of lactic acid to cytotoxic levelsY, 29-3~ Animal models of severe incomplete cerebral ischemia, such as fourvessel occlusion or bilateral carotid artery occlusion in combination with lowering of blood pressure, demonstrate increased i s c h e m i c damage compared w i t h animals undergoing equal p e r i o d s of c o m p l e t e ischemia.27, 32 It is postulated that conditions of severe incomplete ischemia allow small amounts of substrate to 19:6 June 1990
enter into the tissues while failing to provide adequate oxygen to support the oxidative m e t a b o l i s m of glucose. 26 The resulting anaerobic metabolism of glucose to lactate would result in enhanced cellular damage. E x p e r i m e n t a l s u p p o r t for s u c h a mechanism is provided by the observation of increased tissue lactic acid accumulation in animals undergoing severe incomplete cerebral ischemia compared with animals undergoing an equal duration of complete cerebral ischemia.27, 32 These experimental models m a y have clinical relevance in low-flow conditions such as CPR during cardiac arrest, severe hypotension, and marginally perfused areas of brain tissue during stroke. Histologic studies show that preischemic hyperglycemia results in enhanced cellular destruction in isc h e m i c a r e a s , t2, 31,33 increased volume of i n f a r c t , 34-36 and the conversion of selective neuronal ischemic injury to complete infarction. 37 The extent of histopathologic damage appears to be related to the degree of tissue lactic acidosis attained. 37 Several investigators have demonstrated that under conditions of either complete or severe incomplete cerebral ischemia, the degree of neur o l o g i c i n j u r y is r e l a t e d to t h e amount of lactate accumulated in the t i s s u e . 27,29,31,37,38 T h e m o l e c u l a r mechanism for lactate-induced cellular damage remains largely speculative. An increase in tissue lactate concentration m a y induce osmotic shifts 26 and result in a demonstrable decrease in intracellular and extrac e l l u l a r pH. 3° Either of these effects could result in cytotoxicity. Tissue acidosis probably causes alterations in protein structure and function. Hypotheses involving alterations in cellular membrane function and acidosis-induced free radical formation have attracted recent interest. 1 CLINICAL CORRELATES Investigation of the effect of glucose on brain i s c h e m i a has been largely focused on preischemic hyperglycemia. This approach may appear somewhat limited as it is difficult to control blood glucose level in most patients before an unexpected ischemic event occurs. However, the model is relevant to the diabetic patient and supports the argument for careful control of blood glucose. It is also relevant to ED patients who preAnnals of Emergency Medicine
sent with evolving ischemic stroke, impending cardiac arrest, or severe h y p o t e n s i o n and m a y receive glucose-containing IV solutions during initial evaluation and treatment. The frequency with which such patients present to the ED may be substantial. In a collaborative study of 500 patients admitted with nontraumatic coma to New York City Hospital, the Royal Victoria Infirmary (England), or San Francisco General Hospital, 264 (53%) had either brain infarcts, profound hypotension, or cardiac arrest. 39 A l t h o u g h this study does not include patients with coma lasting less than six hours or coma due to drug overdose, it does suggest that a significant percentage of patients presenting with coma are suffering from cerebral ischemia and thus potentially harmed by hyperglycemia produced by glucose-containing IV solutions or the empiric administration of 50% dextrose. Several investigators have recommended avoiding glucose-containing IV s o l u t i o n s in p a t i e n t s suffering f r o m c e r e b r a l ischemia.2,13j6,23, ~6 Reagent test strips for blood glucose e s t i m a t i o n eliminate delays in the diagnosis of hypoglycemia. N e w e r test strips provide a rapid and accurate estimation of blood glucose level when properly used 4°-a2 and serve as a reliable screen for hypoglycemia, 43 obviating the need for empiric glucose therapy in patients with altered mental status. Several issues of clinical importance r e m a i n unresolved. Study of the effect of glucose administration during the recirculation phase after cerebral i s c h e m i a has yielded conflicting results. Some investigators 32-44 report accentuated neurologic injury with postischemic glucose administration, whereas others12, 26 h a v e failed to c o n f i r m these findings. The amount of glucose required to produce a clinical effect is unknown. It remains to be determined whether the effects of preischemic glucose adm i n i s t r a t i o n d e m o n s t r a t e d in animals can be extrapolated to the relatively small amounts of glucose del i v e r e d t h r o u g h t h e u s e of 5% dextrose in water to keep IV lines open in patients with acute cerebral ischemia. A role for actively m a i n t a i n i n g n o r m o g l y c e m i a w i t h i n s u l i n has been suggested by preliminary study 685/115
50% DEXTROSE Browning et al
in the rat. 44 Further investigation is required to clarify the value of active reduction in blood glucose level during cerebral ischemia.
SUMMARY T h e e m p i r i c a d m i n i s t r a t i o n of 50% dextrose to all patients presenting to the ED with altered mental status is a standard of care predicated on the assumption that glucose adm i n i s t r a t i o n is h a r m l e s s to n o n hypoglycemic patients. C o n s i d e r a b l e e v i d e n c e n o w disputes this assumption. Glucose adm i n i s t r a t i o n before c o m p l e t e cerebral i s c h e m i a in e x p e r i m e n t a l animals worsens neurologic and histologic outcome. Administration of glucose during severe incomplete ischemia has a similar detrimental effect. The translation of these experimental findings into clinical practice has been slow, perhaps hindered by the frequent use of rodent models and large bolus doses of glucose. 13 However, evidence is now provided by primate and h u m a n studies and by experimental designs using clinically relevant doses of glucose. These clinical and experimental findings in conjunction with the wide availability of a rapid bedside screen for hypoglycemia provide the rationale for an alteration in the standard of care. The empiric administration of glucose should be avoided in patients at risk for cerebral ischemia, such as those with acute stroke, impending cardiac arrest, or severe hypotension or receiving CPR. A bedside fingerstick blood glucose estimation should be performed immediately on all patients presenting with altered mental status. The administration of 50% dextrose should be reserved for t h o s e p a t i e n t s in w h o m h y p o glycemia is demonstrated; this practice will uphold Hippocrates' most basic principle of clinical medicine, " T h e p h y s i c i a n m u s t . . . do no harm.,,4s T h e a u t h o r s t h a n k N a n c y R o b i n s o n for her assistance in preparing this manuscript.
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