MILESTONES IN NEPHROLOGY J Am Soc Nephrol 11: 1776–1788, 2000 Mark A. Knepper, Feature Editor Studies on Mechanisms of Cerebral Edema in Diabetic Comas EFFECTS OF HYPERGLYCEMIA AND RAPID LOWERING OF PLASMA GLUCOSE IN NORMAL RABBITS ALLEN I. ARIEFF AND CHARLES R. KLEEMAN WITH THE TECHNICAL ASSISTANCE OF ALICE KEUSHKERIAN AND HELEN BAGDOYAN From the Departments of Medicine, Wadsworth Veterans Administration Center and Cedars-Sinai Medical Center, and the Cedars-Sinai Medical Research Institute, and University of California Los Angeles Medical Center, Los Angeles, California 90048 with comments by ALLEN I. ARIEFF AND RICHARD STERNS Reprinted from J. Clin. Invest. 52:571–583, 1973 A BSTRACT To investigate the pathophysiology of cerebral edema occurring during treatment of diabetic coma, the effects of hyperglycemia and rapid lowering of plasma glucose were AUTHOR COMMENTARY evaluated in normal rabbits. During 2 h of hyperglycemia (plasma glucose = 61 mM), both brain (cerebral cortex) and Allen I. Arieff muscle initially lost about 10% of water content. After 4 h of hyperglycemia, skeletal muscle water content remained low University of California, but that of brain was normal. Brain osmolality (Osm) (343 San Francisco mosmol/kg H2O) was similar to that of cerebrospinal fluid Sausalito, California (CSF) (340 mosmol/kg), but increases in the concentration of Na+, K+, Cl–, glucose, sorbitol, lactate, urea, myoinositol, and amino acids accounted for only about half of this increase. n 1936, Dillon, Riggs, and Dyer described a syndrome The unidentified solute was designated “idiogenic osmoles”. Iwhereby individuals who were being treated for diabetic When plasma glucose was rapidly lowered to normal with coma and apparently recovering suddenly deteriorated, with insulin, there was gross brain edema, increases in brain content worsening of coma, respiratory insufficiency, hypotension, of water, Na+, K+, Cl– and idiogenic osmoles, and a signifi­ tachycardia, high fever, and death (1). Similar groups of cant osmotic gradient from brain (326 mosmol/kg H2O) to plas­ patients were subsequently described (2­4). At autopsy, cere­ ma (287 mosmol/kg). By similarly lowering plasma glucose bral edema and brain stem herniation were present. Usually, with peritoneal dialysis, increases in brain Na+, K+, C–, and the diabetic coma had been treated appropriately and deteri­ water were significantly less, idiogenic osmoles were not pres­ oration occurred when the blood glucose had been decreased ent, and brain and plasma Osm were not different. It is con­ below 17 mmol/L (300 mg/dl) (3,4). I had just begun my cluded that during sustained hyperglycemia, the cerebral cortex nephrology research fellowship at UCLA in the laboratory of adapts to extracellular hyperosmolality primarily by accumula­ Dr. Charles Kleeman. While I was a resident at Kings County tion of idogenic osmoles rather than loss of water or gain in Hospital working with Dr. Hugh Carroll, we had completed solute. When plasma glucose is rapidly lowered with insulin, an several studies of various aspects of diabetic coma, during osmotic gradient develops from brain to plasma. Despite the which time several deaths were encountered. There was no brain to plasma osmotic gradient, there is no net movement obvious difference between the patients with diabetic coma of water into brain until plasma glucose has fallen to at least who died versus those who recovered. I had wanted to inves­ 14 mM, at which time cerebral edema occurs. tigate this phenomenon, and this, plus the obvious charms of Southern California, were the major reasons that I decided to study with Dr. Kleeman, perhaps the only nephrologist pur­ suing research on the blood­brain barrier. Because rapid low­ This work was presented in part at International Symposium on the ering of plasma glucose involved osmotic shifts in the brain, Occasion of the 50th Anniversary of the Discovery of Insulin, Jerusalem, it was necessary to develop a method for measurement of Israel, 25–27 October 1971. brain tissue osmolality, as well as an animal model of dia­ Dr. Arieff is a Clinical Investigator, Veterans Administration betic coma. It took approximately 6 mo to develop the (Wadsworth), Los Angeles, Calif. method for evaluation of brain tissue osmolality, using Received for publication 17 January 1972 and in revised extraction of liquid­nitrogen frozen brain in boiling distilled form 24 October 1972. Milestones in Nephrology 1777 INTRODUCTION water (5). An animal model of diabetic coma was developed The problem of cerebral edema complicating diabetic coma has in the glucose­infused alloxan­diabetic rabbit. When the been known at least since the studies of Dillon, Riggs, and Dyer plasma glucose was rapidly lowered with insulin and 77 (1). These workers reviewed 21 uncomplicated deaths in patients mmol/L NaCl infusion, some diabetic rabbits developed with diabetic ketoacidosis and in eight of these, the clinical pic­ cerebral edema and others did not. However, because of Dr. ture and postmortem examination (excluding cranial contents) Kleeman’s interest in the blood­brain barrier, a most distin­ revealed no obvious cause of death. All patients were under 45 guished visiting professor was at UCLA. Dr. Hugh Davson, years old and had developed a characteristic clinical picture con­ the eminent British physiologist, was of course not a physi­ sisting of hyperpyrexia, hypotension, increasing depth of coma, cian and thus looked at the problem without any precon­ and tachycardia. These signs usually developed when the ceived bias. He noticed that cerebral edema occurred only patients were showing biochemical improvement, and presaged when the plasma glucose had been lowered to below 14 a rapid downhill course which terminated fatally within a few mmol/L with insulin and that in those animals with cerebral hours. At autopsy, all such patients had gross and/or microscopic edema, brain content of potassium was elevated. He suggested evidence of cerebral edema. that we lower plasma glu­ The aformentioned findings were largely unappreciated, cose without insulin. When although there were several sporadic reports of unexplained this was done (using deaths from diabetic ketoacidosis (2, 3). Recent awareness of glucose­free peritoneal the syndrome of cerebral edema complicating treatment for dialysis), cerebral ede­ diabetic coma was stimulated by descriptions of the deaths of ma did not occur. These two young patients apparently recovering from ketoacidotic findings led to the identi­ coma (4). There have since been several similar reports (5–7) as fication of undetermined well as two cases of cerebral edema associated with nonketotic solute (idiogenic osmoles) hyperosmolar coma with hyperglycemia (non­ketotic coma) (8, in the brain, which, along 9). Recent evidence suggests that most patients being treated with transport of potassi­ for diabetic ketoacidosis develop increased intracranial pres­­­­­ um into brain by insulin, sure (10) and that rapid lowering of blood glucose in hyper­ creat ed the physiologic glycemic dogs is often associated with increased cerebrospinal environ ment wherein fa­ fluid (CSF)1 pressure (11). tal cerebral edema could The mortality among patients with such cerebral edema has develop. These findings been close to 100% (3, 4), and treatment has generally been permitted subsequent re­ ineffectual. Although there have been some studies on the Allen I. Arieff in the laboratory at search into its potential changes which occur in the CSF during rapid lowering of plas­ Cedars­Sinai Medical Center, Los Angeles, in 1973. prevention. ma glucose, alterations in water, electrolyte, and carbohydrate metabolism in brain under these circumstances are largely References unknown. Furthermore, in previous experimental work, plasma 1. Dillon E, Riggs H, Dyer W: Cerebral lesions in uncomplicated fatal diabetic aci­ glucose has been lowered by intravenous hydration rather than dosis. Am J Med Sci 192: 360, 1936 with insulin (12), so that any possible effects of insulin on brain 2. Greenaway JM, Read J: Diabetic coma: A review of 69 cases. Australasian Ann have not been studied. It is the purpose of the present investi­ Med 7: 151–158, 1958 gation to study the changes which occur in brain and CSF during 3. Young E, Bradley RF: Cerebral edema with irreversible coma in severe diabetic ketoacidosis. N Engl J Med 276: 665–669, 1967 sustained hyperglycemia, and to elucidate the pathophysiology 4. Fitzgerald MG, O’Sullivan DJ, Malins JM: Fatal diabetic ketoacidosis. of cerebral edema which may occur during rapid lowering of Br Med J 1: 247–250, 1961 plasma glucose. Skeletal muscle, representing about 40% of 5. Arieff AI, Kleeman CR, Keushkerian A, Bagdoyan H. Brain tissue osmolality: body weight, was also studied in order to compare changes in Method of determination and variations in hyper­ and hypo­osmolar states. J Lab brain with those occurring in other tissues. Clin Med 79: 334–343, 1972 METHODS GUEST COMMENTARY Studies were done in New Zealand white rabbits, weight 1.8–2.7 kg, main tained on an ad lib. diet of Purina Chow and water. Animals were anesthetized with intravenous sodium pentobarbital. A tracheostomy Richard Sterns was performed after which mechanical ventilation was carried out for the duration of each experi ment (Harvard Respirator No. 661; Harvard Apparatus Co., Inc., Millis, Mass.) at a respiratory rate of 25 per min and Department of Medicine tidal volume based on the weight of the animal (13). Hyperglycemia was University of Rochester induced by infusion of 50% glucose into the inferior vena cava via a poly- School of Medicine ethylene catheter in the femoral vein. A bolus of 2.4 g/kg was followed Rochester, New York by an average sustained infusion of 36 mg/kg per min. The rate of infu- sion was adjusted to maintain plasma glucose at about 60 mM for periods of 1–4 h. The bolus contained 25 μCi of uniformly labeled [14C]glucose ost physicians have heard the term idiogenic osmoles (Nuclear Dynamics, Inc., El Monte, Calif., specific activity 298 mCi/ (although many will admit to being a bit rusty about mmole), at an average concentration of 0.9 μCi/mmol and the infusion M contained 25 μCi at a mean concentration of 0.2 μCi/mmol.