Symposium on Diabetes Mellitus
Hyperosmolar Nonketotic Coma in the Elderly Diabetic Stephen Podolsky, M.D.*
Although normal aging is associated with increasing blood glucose levels,6,74 there is no question that the vast majority of patients with overt diabetes mellitus are middle aged or elderly. These patients are generally thought to have asymptomatic and mild disease, but appear to be consuming a disproportionately increasing amount of available medical resources. 73 , 92 Elderly diabetics can and do develop ketoacidosis,14 are especially prone to develop hypoglycemic reactions after either insulin or sulfonylurea agents, and may develop hypo glycemia associated with neoplastic disease. 62 Hyperglycemic, hyperosmolar nonketotic coma is characteristic of this age group and not uncommonly develops insidiously in patients without previously diagnosed diabetes. 7, 10,25,65,69 The syndrome occurs rarely in childhood40 or infancy.27 In 1957 Sament and Schwartz90 called attention to a syndrome of severe diabetic stupor without ketosis, relating it to lipoatrophic diabetes in which there is resistance to ketosis. 80 This syndrome, hyperosmolar nonketotic coma, is being diagnosed with increasing frequency5, 11, 46, 47, 51, 68, 77, 86 and probably accounts for 10 to 20 per cent of cases of severe hyperglycemia with or without ketoacidosis. Unfortunately, it is still probably not recognized as often as it occurs. The major clinical features are severe hyperglycemia (blood glucose greater than 600 mg per 100 ml), absence of ketosis or ketoacidosis, profound dehydration, and variable neurologic signs including depressed sensorium or frank coma. Serum osmolarity is elevated to 350 mOsm per kg or above. The gravity of this disorder may not be recognized because patients are usually middle-aged or elderly with mild diabetes. Slightly more women may be affected than men, reflecting the fact that diabetes mellitus is more prevalent in women. Acetone is absent from breath or urine, and there is usually no Kussmaul breathing (except in cases with associated lactic acidosis). A lack of urgency on the part of "Chief, Endocrinology and Metabolism Section, Boston VA Outpatient Clinic; Chief, Diabetes Section, Medical Service, West Roxbury VA Hospital, Boston Massachusetts Supported by a Veterans Administration Clinical Investigator grant.
Medical Clinics of North America- Vol. 62, No. 4, July 1978
815
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STEPHENPODOLSKY
clinicians in treating these patients is probably the cause of the widely reported mortality rate of 40 to 70 per cenU' 30, 77 Depressed sensorium closely parallels hyperosmolarity in hyperglycemic nonketotic diabetes,S,34 and there is. also a good correlation between conscious state and hyperosmolarity in diabetic ketoacidosis,33 Intracellular dehydration of the brain leads to neurological abnormalities, Hemoconcentration may be followed by arterial and venous thromboses, which often complicate hyperosmolar nonketotic coma, Early diagnosis and aggressive therapy should prevent death in the majority of patients, provided that any underlying medical illness is appropriately treated, Table 1 differentiates hyperosmolar nonketotic coma from other types of metabolic coma in the diabetic patient, Hyperosmolar nonketotic coma is always an emergency, The typical patient is brought to the hospital in a sleepy or confused state, or actually comatose, with a history of days or even weeks of polyuria and increasing thirst, One patient was reported to have consumed 9 quarts of skimmed milk in a single day,lOS and another to have said "I'm drinking so much water that my stomach thinks my mouth is taking in washing!"77 As the syndrome progresses, thirst is impaired, possibly because of alteration of the hypo thalamic thirst center secondary to hyperosmolarity or severe hyperglycemia, Not infrequently the patient ends up on a neurological service, particularly if coma is present, a cerebrovascular accident is mistakenly diagnosed, or a recent seizure has occurred, and there is no history of diabetes mellitus, Heavy glycosuria with minimal or no ketonuria or ketonemia is noted. Physical examination reveals a striking and profound dehydration, shallow respiration (rather than acidotic type breathing, with hyperpnea and tachypnea), and there is no odor of acetone on the breath, The total absence of ketonuria is not essential for the diagnosis. Sometimes the profound dehydration is not appreciated because the patient's urinary output appears adequate owing to the osmotic diuresis. 36 The diagnosis can be rapidly confirmed with blood Dextrostix or urine Acetest or Ketostix, In addition to altered consciousness, patients with hyperosmolar nonketotic coma often present with a variety of neurologic signs, including grand mal seizures, hemiparesis, Babinski reflexes, aphasia, muscle fasciculations, hyperthermia, hemianopsia, nystagmus, visual hallucinations, and so forth,42. 59. 77 These findings suggest possible diffuse cortical or subcortical damage.!2 Treatment with diphenylhydantoin may be hazardous. Not only is it ineffective in relieving seizures associated with hyperosmolar states, but it may worsen the hyperglycemia by impairing endogenous release of insulin. Many of these localizing neurologic signs are completely reversed in the successfully treated patient. In several patients I have witnessed complete reversal of seizures, visual loss, and even central hyperpyrexia of 105.6° F. Occasionally prolonged and persistent mental confusion has followed treatment, but correction of dehydration and hyperglycemia often results in the disappearance of even the most alarming neurologic signs. Blood glucose levels in hypersomolar nonketotic coma are often extremely elevated, as high as 4800 mg per 100 ml, prompting
Inadequate fluid intake, increasing somnolence, polyuria
Increasing obtundation, preexistent liver, cardiac or renal disease
24 hr2 wks
1-24 hr
24 hr
Nonketotic hyperosmolar hyperglycemic coma
Lactic acidosis
Alcoholic ketoacidosis
Omission of solid food for 24 to 72 hr preceded by intake of large amounts of alcohol
Polyuria, polydipsia, nausea, vomiting, diarrhea, abdominal pain
1-24 hr
Diabetic ketoacidosis
Sweating, faintness, personality changes, behavior disturbances
HISTORY
Sudden
ONSET
Hypoglycemia
CONDITION
Alcohol excess
Phenformin
Noninsulin-using diabetics; newly discovered diabetics (40%) Steroids, thiazides, antimetabolites, etc. Peritoneal dialysis Hyperalimentation
(l5 Ck)
Insulin requiring diabetics; newly discovered diabetics
Insulin or oral hypoglycemic agents Alcohol ingestion
DRUG HISTORY
Large liver Minimal or no dehydration Blood sugar 162 (25-235) Serum acetone: up to 3+ undiluted Arterial pH 7.25 (7.09-7.28) Osmolarity 299
Warm skin, vasodilation Deep sighing respirations Deep coma Large anion gap without significant ketonemia
Profound dehydration Obtunded to deep coma Often localizing neurologic signs (focal seizures) Blood sugar 1,096 (400-2,760) Serum Acetone: < 2-'- at 1: 1 dilution Arterial pH 7.26 (6.81-7.53) Osmolarity 405 (348-456)
Deep sighing rapid respirations Moderate dehydration Confusion to deep coma Blood sugar 675 + 17 Serum acetone: >4+ at 1: 1 dilution Arterial pH 7.07 (6.92-7.22) Osmolarity 323
Dilated pupils, sweating, tachycardia Confusion to coma Hypoglycemia
LABORATORY RESULTS
PHYSICAL SIGNS AND
Table 1. Differential Diagnosis of Coma OccuTTing in the Diabetic Patient'lo ><
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Knowles"o to use the term "syrupy blood." Jackson and Forman 4G stated that in several of their patients the "blood resembled treacle." Even at lower blood glucose levels, i.e., under 800 mg per 100 ml, one has the impression that a patient with hyperosmolar nonketotic coma shows more marked alteration of sensorium than does a patient with diabetic ketoacidosis who has the same blood glucose level. Serum osmolarity may be measured by determination of its freezing point with an osmometer,77 or may be calculated by the following formula:':' mOsm per kg ~ /L) '- blood glucose (mg/lOO ml) + BUN (mg/lOO ml) 2 x ( serum N a +. K) ( m E q , 18 2.8
The profound osmotic diuresis occurring as a result of persistent hyperglycemia results in loss of water in excess of electrolytes. Plasma concentrations of sodium and potassium are of no value in estimating the magnitude of net ion losses, except for the fact that initial hypokalemia indicates very severe potassium loss. Although one would expect the presence of hypernatremia in hyperosmolar states such as this, serum sodium concentrations can be high, normal or low in patients with hyperosmolar nonketotic coma. Serum sodium levels would be considerably higher in the absence of severe hyperglycemia, at the same serum osmolarity levels. Hyponatremia develops when hyperglycemia causes water to be withdrawn from the cells into the plasma in an attempt to maintain a normal serum osmolarity. Serum sodium is also affected by urinary loss of sodium. When fluid loss and dehydration become severe, hypernatremia gradually ensues. The hyponatremia often seen does not signify adrenal insufficiency.82 As a rule of thumb, the serum sodium concentration is slightly less than 3 mEq per liter lower for each 100 mg per 100 ml of blood glucose rise above normal. Thus, serum sodium levels often rise with fluid replacement therapy in hyperosmolar nonketotic coma, while other parameters such as glucose, osmolarity, potassium, blood urea nitrogen, and hematocrit fall. Jackson and Forman46 reported two patients who presented with hematocrit levels of 90 per cent. Patients with a normal hematocrit on admission are actually anemic. Virtually all patients with hyperosmolar nonketotic coma present with azotemia, which may be renal as well as prerenal in origin. Blood urea nitrogen was found to be 87 ± 10 mg per 100 ml and serum creatinine 5.5 ± 1.1 mg per 100 ml (mean ± SEM).7,lO
The net result of the hyperglycemia-induced osmotic diuresis is a "contraction of the intracellular compartment and an infusion into the extracellular space of a fluid that may be beneficial so far as it helps to restore the extracellular fluid volume but that, by virtue of its high potassium concentration, presents a potentially lethal threat to the organism. "58 However, hyperkalemia per se is rarely a serious problem, unless severe oliguria develops, because of the capacity of even se':'The numbers 18 and 2.8 are derived from the molecular weights of 180 for glucose and 14 for each of the two nitrogens released from urea.
819
HYPEROSMOLAR NONKETOTIC COMA
verely damaged kidneys to excrete potassium. The shift of intracellular potassium into the plasma followed by urinary loss results in considerable depletion of body potassium, from 400 to 1000 mEq.4." 70, 7", 76 Potassium deficits this great (1000 mEq or 10 mEq per kg or more) have been determined by measurement of total body potassium in a series of patients two to four days after treatment of spontaneous episodes of hyperosmolar nonketotic coma, and comparing the values to baseline data determined one week to several months after or before the acute episode. 7Q ,76 Figure 1 shows gradual lowering of body potassium in markedly uncontrolled diabetes, initially with development of mild ketosis, and at a later time with more prolonged and severe hyperglycemia without ketosis, (Body potassium is normally a very stable parameter,) Even if initial hyperkalemia is present, iatrogenic hypokalemia may be precipitated later when insulin therapy drives both glucose and potassium intracellularly. Elderly patients frequently receive long-term therapy with potassium-wasting thiazide diuretic drugs, and so are particularly susceptible to hypokalemia in diabetic coma. 3 Potassium depletion itself results in impaired insulin secretion,'1. 72, 78 which may worsen hyperglycemia in the untreated patient with hyperosmolar nonketotic coma. 77 About half the patients exhibit some degree of metabolic acidosis
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DAYS Figure 1. Male patient with two prior spontaneous episodes of hyperosmolar nonketotic coma complicating high-dose propranolol therapy of hypertension, in whom total body potassium was measured during prolonged period of uncontrolled diabetes, after informed consent. Ketosis was prevented by oral propranolol despite worsening hyperglycemia. Note more marked negative potassium balance during nonketotic propranolol period, probably reflecting a longer interval of osmotic diuresis. (From Podolsky, S., and Pattavina, C. G.: Metabolism, 22:685-693, 1973. By permission.)
820
STEPHEN PODOLSKY
with an "anion gap" of twice the normal level of 16 mEq per liter. The cause of this acidosis is often not known, although the unmeasured serum anions are thought to represent one or more of the following: lactate accumulation, acute renal insufficiency with prerenal azotemia, unidentified organic acids including betahydroxybutyric acid (a ketone body which is not detected on the standard Acetest or Ketostix tese).
TREATMENT Therapy of hyperosmolar nonketotic coma is directed toward (1) correction of the extreme degree of volume depletion, (2) correction of the hyperosmolar state, and (3) detection and correction of an underlying precipitating cause such as associated illness or drug administration. The need of these patients for insulin is clear, as is the need for free water, since their average fluid deficit is 25 per cent of the total body water. Table 2 summarizes the treatment program. Fluids It is important to recognize that the hyponatremia sometimes associated with hyperosmolar nonketotic coma is not an indication for administration of hypertonic saline or for water restriction. These patients need just the opposite-large quantities of free water. A patient with insulin dependent diabetes and fatal hyperosmolar nonketotic coma was mistakenly diagnosed as being in hypoglycemic coma. He was immediately treated with 50 ml of hypertonic glucose (50 per cent), and then given hypertonic saline (5 per cent) after initial laboratory data indicated the presence of hyponatremia with a serum sodium concentration of 113 mEq per liter (and a serum glucose level of 1840 mg per 100 ml). Anuria then developed, for which hypertonic mannitol was administered, and was followed by the patient's demise. In the past there were vigorous debates about the proper composition of the initial intravenous fluid to be administered in the treatment of this syndrome. Isotonic saline (0.9 per cent NaCl), hypotonic saline (1/2, 1/4 or 1/5 normal), isotonic glucose (5 per cent D/W) or even hypotonic glucose were proposed. Both isotonic saline and isotonic glucose appear to be associated with higher mortality rates. (Isotonic saline does nor provide free water, and isotonic glucose may worsen the hyperglycemia, although it does supply free water.) Although there was concern about the danger of dehydrated body cells taking up free water too rapidly after the infusion of hypotonic saline, this fear has generally not been borne out, and half-normal saline (0.45 per cent NaCI) definitely is the fluid of choice. Balance studies have suggested that the fluid lost in hyperosmolar nonketotic coma contains about 60 ':'Anion gap is calculated as the difference between the serum Na+ concentration and the sum of the serum Cl- plus serum CO, - concentration (in mEq per !iter). It is normally 16 mEq per !iter or less, and is largely accounted for by HCO,,- concentration.
HYPEROSMOLAR NONKETOTIC COMA
Table 2.
821
Treatment of Hyperosmolar Nonketotic Diabetic Coma':'
A. Early recognition and prompt therapy are essential. B. Immediate therapy l. Give 2 liters of hypotonic saline (0.45%) very rapidly, over a 2 hour period. Ideally, central venous pressure (CVP) should be monitored. If hypotension is present, isotonic saline should be infused until the CVP begins to rise. 2. Give 25 units regular insulin i.v. plus 25 units regular insulin s.c. Entire dose should be administered i.v. in hypotensive patients. Low-dose regimen: As an alternative, give 20 units regular insulin i.m., followed by 5 units regular insulin i.m. per hour. 3. Add potassium chloride to initial infusions at a rate of 10 to 20 mEq per hour when admission serum K+ is below 3.5 mEq per liter or EKG reveals hypokalemic changes, if urine output is adequate. Monitor EKG as gUide to potassium replacement. C. Subsequent therapy 1. Continue giving hypotonic saline infusions at a rate of 1 liter every 2 hours, titrating according to central venous pressure. Change to 5% D/W when blood glucose falls to 250 to 300 mg per 100 ml. Total fluid replacement required may be quite large (6 to 18 liters). 2. Draw blood glucose after initial dose of insulin and regularly after. 3. If necessary, give insulin as initially (25 units i.v. and 25 units s.c.) until blood glucose falls to or below 300 mg per 100 ml. If low-dose method is used, give 5 units i.m. every hour until blood glucose falls to or below 300 mg per 100 ml. 4. Because of severe depletion of total body potassium, with adequate urinary output potassium chloride should be added to the intravenous infusion at a rate not to exceed 25 mEq per hour or 200 mEq per 24 hour period. Occasionally larger quantities of potassium will be needed. D. Therapy after recovery 1. Search for underlying cause. 2. Continue oral potassium replacement or orange juice for 5 to 7 days. 3. Give daily injection of intermediate acting insulin (lente or NPH insulin) after treatment of acute episode. 4. Many of these patients can be eventually treated with a diabetic diet alone or diet plus a sulfonylurea agent. ':'For a more detailed outline of treatment see discussion in Podolsky, S., cd.: Clinical Diabetes: Modern Management. New York, Appleton-Century-Crofts, 1979, in preparation.
mEq per liter of sodium plus potassium, which closely approximates half-normal saline. IO Hypotonic saline has been successfully supplemented with tap water given by gastric intubation, in overcoming this syndrome. The response of serum glucose, osmolarity, sodium and potassium to therapy are shown in Figure 2. The key to adequate therapy of hyperosmolar nonketotic coma is vigorous hypotonic fluid replacement. After confirmation of the diagnosis, 2 liters of hypotonic (half-normal) saline should be infused very rapidly, i.e., to run in within 2 hours. Thereafter, 1 liter of hypotonic saline should be administered every 2 hours, titrating according to the central venous pressure. The infusion solution should be changed to 5 per cent dextrose in water when the blood glucose has fallen to 250 mg per 100 ml. Half the estimated water deficit, including urinary losses, should be replaced in the first 12 hours, and the remainder in the next 24 hours. At least 6 and as much as 18 liters of fluid may be necessary, with 9liters being the average amount retained. 20 The dangers inherent in aggressive intravenous fluid therapy of the
822
STEPHEN PODOLSKY
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Figure 2. Response to successful aggressive therapy of hyperosmolar non ketotic coma in a 75 year old digitalized man not previously known to be diabetic. Note fall of serum glucose, osmolarity and potassium, but increase in serum sodium with treatment. Blood urea nitrogen and hematocrit also fell but are not recorded. A total of 125 units of regular insulin, 16,000 ml of intravenous fluid (predominantly hypotonic saline) and 200 mEq of potassium chloride was administered.
geriatric patient with hyperosmolar nonketotic coma can be reduced by monitoring the central venous pressure (CVP). The CVP is initially very low, reflecting profound dehydration. The necessarily rapid rate of administration of intravenous infusions can be quickly reduced if the CVP begins to rise excessively, avoiding the complication of congestive heart failure. If hypotension is present, isotonic saline should be infused until the CVP begins to rise. Blood or plasma should be given if the systolic blood pressure remains below 80 mm Hg. Intravenous furosemide (50 to 100 mg) has resulted in a marked increase in urine volume in patients in whom acute renal failure has developed. 7 , 10 The specter of intravascular hemolysis rarely occurring as a direct result of administration of hypotonic fluids is still occasionally raised. This was reported by Blackwell and Burns-Cox,16 after the infusion of 6 liters of 1/5 normal saline (0.18 per cent NaCI), in a patient who recovered from hyperosmolar nonketotic coma, Acute cerebral edema could theoretically result from excessive use of hypotonic solutions, but is far less common in hyperosmolar nonketotic coma than in diabetic ketoacidosis, This author agrees with Beigelman's statement ~!!at it is not justified to accuse aggressive treatment of this complication,15 particularly when such therapy will prevent an almost inevitable death,
HYPEROSMOLAR NONKETOTIC COMA
823
If 0.45 per cent saline is not available, sterile water for intravenous infusion can be carefully added to isotonic saline to make a 1: 1 mixture for treating hyperosmolar nonketotic coma. 77
Insulin Regular insulin should be used early, rather than intermediate acting insulin such as lente or NPH. Twenty-five units intravenously plus 25 units subcutaneously is recommended as an initial dose. Insulin may be administered every 2 hours in the same quantity as the initial dose, if the blood glucose has not fallen by at least 100 mg per 100 ml. Often no additional insulin will be required after the initial dose. No additional regular insulin should be given after the blood glucose level reaches 300 mg per 100 ml. Insulin should not be added to the intravenous infusion bottles because a significant amount is lost by adsorption to bottles and tubing,83, 104 unless precautions are taken such as the addition of sterile albumin or some of the patient's own blood, which are adsorbed to glass in place of the insulin. Another approach to therapy is that recommended by Arieff,1' 10 who advocates that the initial insulin dose in units should be 10 per cent of the presenting blood glucose level in mg per 100 ml. Half the insulin is given intravenously and half subcutaneously, Blood glucose is determined every 2 hours and subsequent insulin administered accordingly. Foster32 advocates the use of 50 units of insulin every hour, with frequent monitoring of blood glucose. In all of these three approaches to therapy, less insulin will usually be required than for treatment of diabetic ketoacidosis by the traditional method. It should be recognized that resistance to insulin action occasionally occurs in hyperosmolar non ketotic coma, with very large quantities of insulin being required. 46 The conventional approach to the treatment of diabetic ketoacidosis, using large doses of insulin, dates back to the report by Root in 1945 that high doses are associated with a lower mortality rate. 87 In the last several years there have been many reports of the successful use of much smaller doses of insulin in the treatment of diabetic ketoacidosis. 4. 12,28,31,37,49,85 Low dose insulin therapy of ketoacidosis has been found to be effective at a rate of 5 to 10 units per hour given by intravenous infusion or by intramuscular injection. Complications such as hypo glycemia and hypokalemia appear to occur less frequently than with conventional high insulin doses, although hypokalemia has continued to be somewhat of a problem. Although Madison60 has expressed reservations about low-dose insulin regimens, it seems likely that they are appropriate for the treatment of many patients with hyperosmolar nonketotic coma as well. The intramuscular route of administration may be useful in more institutions, since constant infusion pumps are not always available. The protocol of Kitchabi et al. 49 or Alberti and Hockaday2, 4 should be followed, i.e., either 14 units or 20 units of regular insulin administered intramuscularly initially, followed by 5 units intramuscularly every hour until the blood glucose level reaches 300 mg per 100 ml. It cannot be overemphasized that adjusting the therapeutic regimen to the needs of the individual patient, with meticulous clinical
824
STEPHEN PODOLSKY
care, vigorous replacement of fluid and potassium, and correction of precipitating factors, are just as important as the details of insulin therapy. After recovery from the acute episode of nonketotic diabetic coma the patient should be given a daily subcutaneous injection of lente or NPH intermediate acting insulin. Many of these patients, and the majority of the geriatric patients, can be gradually changed from diet plus insulin therapy to diet plus sulfonylurea therapy on discharge from the hospital or shortly after. Potassium Patients with hyperosmolar nonketotic diabetic coma all present with depletion of body potassium stores, despite the fact that serum potassium concentrations can be high, normal, or 10w.1. 75. 71 The presence of hypokalemia on admission represents profound potassium depletion, which has been associated with acute quadriplegia. 61 Intracellular potassium deficiency with ileus and intestinal distention has been invoked to explain the acute abdominal pain which may complicate diabetic ketoacidosisl 9 although this is less common in nonketotic diabetic coma. (Such pain may develop in hyperosmolar nonketotic coma, with signs of an acute abdomen, and often signifies a life-threatening vascular thrombosis.)106 Insulin therapy can lead to a precipitous fall in serum potassium level in these patients. Without a doubt, the mortality in some cases of hyperosmolar nonketotic coma has been related to potassium depletion and its adverse effects upon the myocardium and respiratory muscles. Since the entry of potassium into cells is directly dependent upon insulin dose,9! late hypokalemia should be less common with low dose insulin regimens. Potassium replacement should be started earlier in the therapy of nonketotic diabetic coma than it would be in diabetic ketoacidosis. Addition of at least 20 to 40 mEq of potassium chloride to each liter of parenteral fluid early in the management of hyperosmolar nonketotic coma is important, once adequate urinary output has been established, unless the patient presents with hyperkalemia. Infusion of potassium can be stopped if serum potassium levels rise above 5.0 mEq per liter, or doubled if levels fall below 4.0 mEq per liter. As much as 200 to 300 mEq of potassium may be required during the first 36 hours, and even more in some cases. Potassium replacement can be started from the beginning of treatment if the patient presents with hypokalemia, provided the heart is monitored electrocardiographically and urinary output is adequate. Electrocardiographic evidence of T wave changes serves as a useful, but not infallible, guide to alterations in serum potassium levels. 97 As much as 70 per cent of the administered dose of potassium may be lost in the urine during the first 24 hours of therapY,2.44 further emphasizing the need to supply adequate quantities of this electrolyte. The significance of these findings is that serum potassium concentrations can fall to dangerously low levels after institution of intensive therapy for diabetic nonketotic coma, particularly in patients with initially normal or low serum potassium levels, unless supplemental
HYPEROSMOLAR NONKETOTlC COMA
825
potassium is given parenterally. These patients also have phosphate deficits, and potassium phosphate, 5 mM per liter, can be infused instead of potassium chloride. Red blood cell 2,3-diphosphoglycerate is depleted in phosphate deficiency states, affecting the affinity of hemoglobin to bind oxygen. While it is neither possible nor necessary to replace the total body potassium deficit acutely, therapy with oral potassium chloride or potassium phosphate may be advisable for short periods or up to one week after apparent recovery.
REFERENCES 1. Abrahamson, E., and Arky, R.: Diabetic acidosis with initial hypokalemia. J.A.M.A., 196 :40 1-403, 1966. 2. Alberti, K. G. M. M., and Hockaday, T. D. R.: Diabetic coma: A reappraisal after five years. Clin. Endocrinol. Metab., 6:421-455,1977. 3. Alberti, K. G. M. M., and Hockaday, T. D. R.: Thiazides and hypokalemia in diabetic ketoacidosis. Postgrad. Med. J., 49:29-31,1973. 4. Alberti, K. G. M. M., Hockaday, T. D. R., and Turner, R. C.: Small doses of intramuscular insulin in the treatment of diabetic "coma." Lancet, 2:515-522, 1973. 5. Anderson, J. W.: Hyperglycemic nonketotic coma. J. Ky. Med. Assoc., 73:211-213, 1975. 6. Andres, R.: Aging and diabetes. MED. CLIN. N. AMER., 55 :835-846, 1971. 7. Arieff, A. I.: Nonketotic hyperosmolar coma with hyperglycemia. In Sussman, K. E., and Metz, R. J. S., eds: Diabetes Mellitus. New York, American Diabetes Association, 4th ed., 1975. pp. 181-190. 8. Arieff, A. I., and Carroll, H. J.: Cerebral edema and depression of sensorium in non ketotic hyperosmolar coma. Diabetes, 23:525-531,1974. 9. Arieff, A. I., and Kleeman, C. R.: Cerebral edema in diabetic comas. n. Effects of hyperosmolarity, hyperglycemia and insulin in diabetic rabbits. J. Clin. Endocrinol. Metab., 38:1057-1067, 1974. 10. Arieff, A. I., and Carroll, H. J.: Nonketotic hyperosmolar coma with hyperglycemia: Clinical features, pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of therapy in 37 cases. Medicine (BaIt.), 51 :73-94, 1972. 1l. Arieff, A. I., and Massry, S. G.: Causes and treatment of nonketotic hyperosmolar coma. Med. Times, 100:65-73,1972. 12. Asplin, C. M., and Hartog, M.: Serum free insulin concentrations during the treatment of diabetic coma and precoma with low dose intramuscular insulin. Diabetologia, 13:475-480,1977. 13. Aviram, A., Pfau, A., Czazkes, J. W., et al.: Hyperosmolality with hyponatremia, caused by inappropriate administration of mannitol. Amer. J. Med., 42:648-650,1967. 14. Barnett, D. M., Wilco x, D. S., and Marble, A.: Diabetic coma in persons over 60. Geriatrics, 17:327-336,1962. 15. Beigelman, P. M.: Severe diabetic ketoacidosis (diabetic "coma"). 482 episodes in 257 patients: Experience of three years. Diabetes, 20:490-500, 1971. 16. Blackwell, S. W., and Burns-Cox, C. J.: Intravascular hemolysis complicating treated nonketotic hyperglycemic diabetic coma. Postgrad. Med. J., 49:656-657,1973. 17. Bleicher, S. J., Chowdhury, F., Podolsky, S., et al.: Studies of diazoxide-induced hyperglycemia: An extrapancreatic mechanism. Ann. N.Y. Acad. Sci., 150 :294-302, 1968. 18. Brenner, W. 1., Lansky, Z., Engelman, R. M., et al.: Hyperosmolar coma in surgical patients: An iatrogenic disease of increasing incidence. Ann. Surg., 178:651-654, 1973. 19. Campbell, I. W., Duncan, L. J. P., Innes, J. A., et al.: Abdominal pain in diabetic metabolic decompensation. Clinical significance. J.A.M.A., 233:166-168, 1975. 20. Carroll, H. J., and Arieff, A. I.: Osmotic equilibrium between extracellular fluid and cerebrospinal fluid during treatment of hyperglycemic, hyperosmolar, nonketotic coma. Trans. Assoc. Amer. Physicians, 84:113-121, 1971. 2l. Clements, R. S., Jr., Prockop, L. D., and Winegrad, A. I.: Acute cerebral oedema during treatment of hyperglycaemia: An experimental model. Lancet, 2:384-386, 1968.
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22. Colwell, J. A., Sagel, J., Crook, L., et a!.: Correlation of platelet aggregation, plasma factor activity, and megathrombocytes in diabetic subjects with and without diabetic vascular disease. Metabolism, 26:279-285, 1977. 23. Colwell, J. A., Halushka, P. V., Sarji, K., et al.: Altered platelet function in diabetes mellitus. Diabetes, 25 (SuppI. 2):826-831, 1976. 24. Curtis, J., Horrigan, F., Aheam, D., et a!.: Chlorthalidone-induced hyperosmolar hyperglycemic nonketotic coma. J.A.M.A., 220:1592-1593,1972. 25. Danowski, T. S.: Non-ketotic coma and diabetes mellitus. MED. CLIN. N. AMER., 55 :913-918, 1971. 26. Duck, S. C., Weldon, V. V., Pagiari, A. S., et a!.: Cerebral oedema complicating therapy for ketoacidosis. Diabetes, 25:111-115,1976. 27. Ehrlich, R. M., and Bain, H. W.: Hyperglycemia and hyperosmolarity in an 18-monthold child. New EngI. J. Med., 276:683-684, 1967. 28. Eskildsen, P. C., and Nerup, J.: Low dose insulin treatment of diabetic ketoacidosis. Acta Med. Scand., 202:295-300, 1977. 29. Evans, C. C., Littler, W. A., and Meade, J. B.: Hyperosmolar hyperglycemic non-ketotic diabetic coma complicating open heart surgery. Brit. Heart J., 34:1075-1077,1972. 30. Fineberg, S. E., and Levin, R. M.: Diabetic ketoacidosis and nonketotic hyperosmolar hyperglycemic coma. In Cohen, A. S., Freidin, R. B., and Samuels, M. A., eds.: Medical Emergencies: Diagnostic and Management Procedures from Boston City Hospital. Boston, Little Brown, 1977, pp. 163-180. 31. Fisher, N., Shahshahani, M. N., and Kitchabi, A. E.: Diabetic ketoacidosis: Low dose insulin therapy by different routes. New Engl. J. Med., 297:238-241, 1977. 32. Foster, D. W.: Insulin deficiency and hyperosmolar coma. Advanc. Intern. Med., 19:159-173,1974. 33. Fulop, M., Tannenbaum, H., and Dreyer, N.: Ketotic hyperosmolar coma. Lancet, 2:635-639,1976. 34. Fulop, M., Rosenblatt, A., Kreitzer, S. M., et al.: Hyperosmolar nature of diabetic coma. Diabetes, 24:594-599, 1975. 35. Gault, M. H., Dixon, M. E., Doyle, M., et al.: Hypernatremia, azotemia, and dehydration due to high-protein tube feeding. Ann. Intern. Med., 68:778-791,1968. 36. Gennari, F. J., and Kassirer, J. P.: Osmotic diuresis. New Engl. J. Med., 291 :714-720, 1974. 37. Genuth, S.: Diabetic ketoacidosis: Low dose or conventional insulin therapy? In Podolsky, S., ed.: Clinical Diabetes: Modern Management. New York, Appleton-Century-Crofts, in press, 1978. 38. Gerich, J. E., Lorenzi, M., Bier, D. M., et al.: Prevention of diabetic ketoacidosis by somatostatin.. New Engl. J. Med., 292:985-989, 1975. 39. Gerich, J. E., Martin, M. M., and Recant, L.: Clinical and metabolic characteristics of hyperosmolar nonketotic coma. Diabetes, 20:228-238, 1971. 40. Ginsburg-Fellner, F., and Primack, W. A.: Recurrent hyperosmolar nonketotic episodes in a young diabetic. Amer. J. Dis. Child., 129:240-243, 1975. 41. Goldberg, E. M. and Sanbar, S. S.: Hyperglycemic, nonketotic coma following administration of Dilantin (diphenylhydantoin). Diabetes, 18:101-106, 1969. 42. Guisado, R., and Arieff, A. I.: Neurological manifestations of diabetic comas: Correlation with biochemical alterations in the brain. Metabolism, 24:665-679, 1975. 43. Henry, D. P., 2nd, and Bressler, R.: Serum insulin levels in nonketotic hyperosmotic diabetes mellitus. Amer. J. Med. Sci., 256:150-154, 1968. 44. Hockaday, T. D. R., and Alberti, K. G. M. M.: Diabetic coma. Clin. Endocrinol. Metab., 1 :751-788,1972. 45. Ionescu-Tirgoviste, C., and Mincu, I.: Classification of diabetic ketoacidosis. Rev. Roum. Med., 13:227-234, 1975. 46. Jackson, W. P. U., and Forman, R.: Hyperosmolar non ketotic diabetic coma. Diabetes, 15:714-722, 1966. 47. Joffe, B. I., Goldberg, R. B., Krut, L. H .. , et al.: Pathogenesis of nonketotic hyperosmolar diabetic coma. Lancet, 1 :1069-1071,1975. 48. Joffe, B. I., Seftel, H. C., Goldberg, R., et al.: Factors in the pathogenesis of experimental nonketotic and ketoacidotic diabetic stupor. Diabetes, 22:653-657, 1973. 49. Kitchabi, A. E., Ayyagari, V., Guerra, S. M. 0., et al.: The efficacy of low-dose versus conventional therapy of insulin for treatment of diabetic ketoacidosis. Ann. Intern. Med., 84:633-638, 1976. 50. Knowles, H. C., Jr.: Syrupy blood. Diabetes, 15:760-761, 1966. 51. Kolin, M.: A third diabetic shock syndrome: Hyperosmolar hyperglycemic nonketotic coma. JEN, 3:15-17,1977. 52. Kwaan, N. C., Colwell, J. A., and Suwanuela, N.: Disseminated intravascular coagulation in diabetes mellitus with reference to the role of platelet aggregation. Diabetes, 21 :108-113, 1972.
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53. Lampe, E. W., 2nd, Ruiz, J. 0., Simmons, R L., et al.: Hyperglycemic non ketotic coma after renal transplantation. Amer. J. Surg., 127: 342-344, 1974. 54. Larcan, A., Lambert, H., Laprevote-Heully, M. C., et al.: Coagulopathie de consommation et etats d'acidose chez le diabetique. Diab. Metab., 2:33-40,1976. 55. Lavender, S., and McGill, M. B.: Nonketotic hyperosmolar coma and furosemide therapy. Diabetes, 23:247-248,1974. 56. Limas, C. J., Samad, A., and Seef, D.: Hyperglycemic nonketotic coma as a complication of steroid therapy. NY State J. Med., 71 :1542-1543,1971. 57. Lindsey, C. A., Faloona, C. R, and Unger, R.: Plasma glucagon in nonketotic hyperosmolar coma. J.A.M.A., 229:1771-1773,1974. 58. Loeb, J. N.: Current concepts: The hyperosmolar state. New Engl. J. Med., 290:11841187,1974. 59. Maccario, M.: Neurological dysfunction associated with non ketotic hyperglycemia. Arch. Neurol., 19:525-534, 1968. 60. Madison, L. L.: Low dose insulin: A plea for caution. New Engl. J. Med., 294:393-394, 1976. 61. Manzano, F., and Kozak, G. P.: Acute quadriplegia in diabetic hyperosmotic coma with hypokalemia. J.A.M.A., 207:2278-2281,1969. 62. Marks, L., Steinke, J., Podolsky, S., et al.: Hypoglycemia associated with neoplasia. Ann. NY Acad. Sci., 230:147-160,1974. 63. Martin, M. M., Gaboardi, F., Podolsky, S., et al.: Intermittent steroid therapy: Its effect on hypothalamic-pituitary-adrenal function and the response of plasma growth hormone and insulin to stimulation. New Engl. J. Med., 279:273-278, 1968. 64. McConnell, J. B., Chaturvedi, N. C., and Logan, J. S.: Hyperglycemic nonketotic coma in diabetes occasioned by a concentrated carbohydrate drink. Ulster Med. J., 38:150156,1969. 65. McCurdy, D. K.: Hyperosmolar hyperglycemic nonketotic diabetic coma. MED. CLIN. N. AMER., 54:683-699, 1970. 66. Nicholson, G., and Tomkin, G. H.: Successful treatment of disseminated intravascular coagulopathy complicating diabetic coma. Brit. Med. J., 4:450, 1974. 67. Nobis, H., Bruneder, H., Falkensammer, C., et al.: Untersuchungen der Blutgerinnung in Coma diabeticum. Intensivmed., 12:52-60, 1975. 68. Orosz, S.: Hyperosmolar aglycosurial diabetic coma without ketoacidosis. NY State J. Med., 75:611-613, 1975. 69. Podolsky, S.: Hyperosmolar nonketotic diabetic coma: Underdiagnosed and undertreated. In Podolsky, S., ed.: Clinical Diabetes: Modern Management. New York, Appleton-Century-Crofts, 1978 (in press). 70. Podolsky, S., and Burrows, B. A.: Severity of potassium depletion in hyperosmolar nonketotic diabetic coma. The Gerontologist, 17:108,1977. 71. Podolsky, S., and Burrows, B. A.: Development of abnormal glucose tolerance and impaired insulin secretion with hepatic decompensation and reduced body potassium. Diabetes, 26:411,1977. 72. Podolsky S., and Melby. J. C.: Improvement of growth hormone response to stimulation in primary aldosteronism with correction of potassium deficiency. Metabolism, 25:1027-1032, 1976. 73. Podolsky, S., and Sclar, E.: Changing patterns of outpatient clinic utilization by diabetic veterans. Diabetes, 25:381, 1976. 74. Podolsky, S., and Burney, S. W.: Development of hyperglycemia in healthy subjects followed longitudinally. Diabetes, 24:402, 1975. 75. Podolsky, S., Melissinos, C., and Burrows, B. A.: Potassium depletion in fatal diabetic ketoacidosis: High serum potassium with low body potassium and similar skeletal and myocardial potassium values. Diabetes, 23:381,1974. 76. Podolsky, S., and Emerson, K., Jr.: Potassium depletion in diabetic ketoacidosis and in hyperosmolar nonketotic coma. Diabetes, 22:299, 1973. 77. Podolsky, S., and Pattavina, C. G.: Hyperosmolar nonketotic diabetic coma. A complication of propranolol therapy. Metabolism, 22:685-693, 1973. 78. Podolsky, S., Zimmerman, H. J., Burrows, B. A., et al.: Potassium depletion in hepatic cirrhosis: A reversible cause of impaired growth hormone and insulin response to stimulation. New Engl. J. Med., 288:644-648,1973. 79. Podolsky, S., and Sivaprasad, R: Assessment of growth hormone reserve: Comparison of intravenous arginine and subcutaneous glucagon stimulation tests. J. Clin. Endocrinol. Metab., 35:580-584, 1972. 80. Podolsky, S.: Lipoatrophic diabetes and miscellaneous conditions related to diabetes mellitus. In Marble, A., White, P., Bradley, R. F., et al., eds.: Joslin's Diabetes Mellitus. Philadelphia, Lea & Febiger, 11th ed., 1971, pp. 722-766. 81. Podolsky, S.: A possible role of propranolol in recurrent nonketotic hyperosmolar diabetic coma. Diabetes, 19:398, 1970.
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82. Podolsky, S., and Ferguson, B. D.: Fatal systemic candidiasis following treatment of Addisonian crisis in a juvenile diabetic. Diabetes, 19:438-444, 1970. 83. Podolsky, S.: Special needs of the diabetic undergoing surgery. Postgrad. Med., 45: 128-131,1969. 84. Potter, D. J.: Death as a result of hyperglycemia without ketosis-a complication of hemodialysis. Ann. Intern. Med., 64:399-402, 1966. 85. Quibrera, R, Nava, M., de Leon, E. D., et al.: Treatment of diabetic ketoacidosis, hyperosmolar coma and severe diabetes with low intravenous intermittent doses of insulin. Rev. Invest. Clin. 28: 1-6, 1976. 86. Rademacher, C. A.: Hyperosmolar non ketotic diabetic coma. J. Amer. Osteopath. Assoc., 76:365-369, 1977. 87. Root, H. F.: The use of insulin and abuse of glucose in the treatment of diabetic coma. J.A.M.A., 127:557-564, 1945. 88. Rosenberg, S. A., Brief, D. K., Kinnery, J. M., et aL: The syndrome of dehydration, coma and severe hyperglycemia without ketosis in patients convalescing from burns. New Engl. J. Med., 272:931-938, 1965. 89. Sagel, J., Colwell, J. A., Crook, L., et al.: Increased platelet aggregation in early diabetes mellitus. Ann. Intern. Med., 82:733-738, 1975. 90. Sament, S., and Schwartz, M. D.: Severe diabetic stupor without ketosis. S. Afr. Med. J., 31 :893-894,1957. 91. Schade, D. S., and Eaton, R. P.: Dose response to insulin in man: Differential effects on glucose and ketone body regulation. J. Clin. Endocrinol. Metab., 44:1038-1052, 1977. 92. Sclar, E., and Podolsky, S.: Diabetic outpatient care: Implications for national health policy. Presented at the 30th annual meeting of the Gerontological Society, San Francisco, California, November 22, 1977. The Gerontologist, 17: 30, 1977. 93. Seltzer, H. S., and Harris, J. L.: Exhaustion of insulinogenic reserve in maturity-onset diabetes mellitus during prolonged and continuous hyperglycemic stress. Diabetes, 13:6-13,1964. 94. Shin, B., and Joseph, S. I.: Hyperglycemic hyperosmolar nonketotic coma following diazoxide, anesthesia and operation. Anesth. Analg. (Cleve.) 56:506-508, 1977. 95. Siebenmann, R, and Reutter, F.: Disseminierte intravasale gerinnung mit anurie bei coma diabeticum. Schweiz. Med. Wochen., 100:69-72, 1970. 96. Simpson, RD., Hockaday, T. D. R, and Bouillin, D. J.: Studies of platelet aggregation in diabetic coma. Clin. Sci. Molec. Med., 49: 19, 1975. 97. Soler, N. G., Bennett, M. A., Fitzgerald, M. G., et al.: Electrocardiogram as a guide to potassium replacement in diabetic ketoacidosis. Diabetes, 23:610-615, 1974. 98. Spenney, J. G., Eure, C. A., and Kreisberg, R. A.: Hyperglycemic, hyperosmolar, nonketoacidotic diabetes. A complication of steroid and immunosuppressive therapy. Diabetes, 18:107-110, 1969. 99. Tasker, P. R, and Mitchell-Heggs, P. F.: Non-ketotic diabetic precoma associated with lIi.l(h-dosc furosemide therapv. Brit. \1ed. J. 1 :626-627, HJ7b. 100. Tchertkoff, V., Nayak, S. V., Kamath, C., et al.: Hyperosmolar nonketotic diabetic coma: Vascular complications. J. Amer. Geriatr. Soc., 22:462-466, 1974. 101. Timperly, W. R, Preston, F. E., and Ward, J. D.: Cerebral intravascular coagulation in diabetic ketoacidosis. Lancet, 2:952-956, 1974. 102. Tyler, F. R: Hyperosmolar coma. Editorial. Amer. J. Med. Sci., 45:485-487,1968. 103. Weber, A. B.: Treatment of disseminated intravascular coagulation complicating diabetic coma. Brit., Med. J., 1 :96, 1975. 104. Weisenfeld, S., Podolsky, S., Goldsmith, L., et al.: Adsorption of insulin to infusion bottles and tubing. Diabetes, 17:766-771, 1968. 105. Whang, R J.: Hyperglycemic nonketotic coma induced by peritoneal dialysis. J. Lancet, 87:453-456, 1967. 106. Whelton, M. J., Walde, D., and Harvard, C. W. R: Hyperosmolar non-ketotic diabetic coma: With particular reference to vascular complications. Brit. Med. J., 1 :85-86, 1971. 107. Whitecar, J. P., Jr., Bodey, G. P., Hill, C. S., Jr., et al.: The effects of L-asparaginase on carbohydrate metabolism. Metabolism, 19:581-586, 1970. 108. Whitehouse, F. W.: Two minutes with diabetes: "My patient is not responding and is very dehydrated." Med. Times, 101 :35-37,1973. 109. Young, E., and Bradley, R F.: Cerebral edema with irreversible coma in severe diabetic ketoacidosis. New Engl. J. Med., 276:665-669, 1967. Endocrinology and Metabolism Section Boston VA Outpatient Clinic 17 Court Street Boston, Massachusetts 02108