Letters to the Editor
Treatment of Diabetic Ketoacidosis In their recent review of diabetic ketoacidosis (Diabetes Care I: 314, 1978), Clements and Vourganti have tried to base their therapeutic recommendations on considerations of pathophysiology. While I agree with most of their reasoning, I must disagree with some of their recommendations concerning oxygen and phosphate therapy (p. 322). It is not clear that "it makes sense to administer oxygen" during the treatment of ketoacidosis. Most patients with untreated ketoacidosis are not hypoxemic. In fact, in one recent series, mean arterial PO2 was elevated on admission, apparently owing to hyperventilation.1 Rather, the possibility of impaired tissue oxygenation arises from the finding of decreased erythrocytic 2,3-DPG, which will shift the oxyhemoglobin dissociation curve to the left.1'2 However, under conditions of hyperventilation coupled with increased affinity of hemoglobin for oxygen, one would expect hemoglobin to become fully saturated with oxygen in the pulmonary capillaries. The supranormal arterial PO2 produced by inhalation of oxygen in these circumstances will be a source of false reassurance to the physician, reflecting as it does primarily dissolved gas, which represents only a minor addition to the oxygen-carrying capacity of the blood. Moreover, even if one could load more oxygen into hemoglobin in the lungs, the maneuver will not help overcome a defect in oxyhemoglobin dissociation at the tissue level. Therefore, it does not seem rational to administer nasal oxygen to a patient with initially normal arterial PO2. My other disagreement is with the recommendation that "the initial 100 meq of potassium in the intravenous fluids should be in the form of buffered potassium phosphate." It should be remembered that serum phosphate in untreated ketoacidosis is often moderately elevated,3 presumably reflecting egress of phosphate from cells into the extracellular compartment. Moreover, as the authors themselves recognize, the intravascular volume of ketoacidotic patients is usually
highly contracted, a situation that favors renotubular reabsorption of filtered phosphate.4'5 Under these conditions, administration of intravenous phosphate can elevate the plasma phosphate to a degree where two serious consequences may occur. First, hypocalcemia may be produced. Second, elevating calcium X phosphorus product may lead to extravascular deposition of calcium in lungs, myocardium, or kidneys. This problem is well illustrated by a case I recently observed. The patient was a 41-yr-old man, whose presenting manifestation of diabetes was ketoacidosis. On admission, serum glucose was 1450 mg/dl, calculated osmolality 400 mosmol/kg, the anion gap 40 mM, serum ketones (nitroprusside reaction) were positive at Vi6, lactate 3.5 mM, creatinine 6.1 mg/dl, calcium 12.4 mg/dl, and phosphorus 3.6 mg/dl. He was treated with 220 mmol phosphate in the intravenous fluids over the first 24 h. Urine output fell to 100 ml/h by 6 h after admission. By 24 h after admission, the serum phosphate was 16 mg/dl and the calcium 8.2 mg/dl. Thereafter, despite discontinuation of intravenous phosphate, the phosphate level remained unchanged while the serum calcium fell to 4.5 mg/dl. The patient became oliguric and died of cardiac arrhythmias 91 h after admission. Admittedly, the phosphate was given without proper regard for the initial hypercalcemia and azotemia, and the dose was excessive. The point is that this situation arose because the man's physicians believed that it was important to give phosphate intravenously early in treatment. Perhaps it is time to reconsider phosphate therapy, bearing in mind that oxygen dissociation from hemoglobin is approximately normal in untreated ketoacidosis, becoming impaired only after the acidosis is corrected.1'2 Therefore, there seems to be little need for early phosphate replacement. On the other hand, there are genuine risks involved with phosphate administration to a volume-contracted individual, as illustrated by the case above. These considerations lead me to recommend that phosphate not be given until intravascular volume is restored, the patient is clearly making adequate amounts of urine, and the serum phosphate has actually fallen below the normal range. I recognize that there may be a
DIABETES CARE, VOL. 2 NO. 4, JULY-AUGUST 1979
385
LETTERS TO THE EDITOR
need to replete tissue and erythrocytic stores of phosphate. In many cases, this can safely be done orally after the patient has recovered from ketoacidosis. Oral administration of phosphate salts for a week or two does not run the risk of massive overload of the vascular compartment at a time when the ability of the kidneys to excrete excess phosphate is severely impaired. I hope these comments will be helpful and will lead to continued consideration by all of us of the proper treatment of diabetic ketoacidosis.
any increase in the amount of dissolved oxygen would tend to alleviate tissue hypoxia. For this reason, we maintain that the slight increase in available dissolved oxygen provided for by oxygen administration to the patient in ketoacidosis would not be harmful, but might be of some benefit. It should also be pointed out that this speculation concerning the potential benefit of oxygen administration has not, as yet, been studied in patients with diabetic ketoacidosis. We do not believe that many physicians would be sufficiently naive as to be lulled into a false sense of security concerning the adequacy of tissue oxygenation in a VICTOR R. LA VIS ketoacidotic patient whose arterial PO2 has been elevated HOUSTON, TEXAS by oxygen administration. REFERENCES With regard to the danger inherent in the administration of 1 Ditzel, J., and Standl, E.: The oxygen transport system of red phosphate to patients with renal failure, we agree with his blood cells during diabetic ketoacidosis and recovery. Diabetologia caveat. A careful reading of our review will reveal that we 11: 255-60, 1975. recognized this hazard when we stated that "In those 2 Alberti, K. G. M. M., Darley, J. H., Emerson, P. M., and patients whose serum potassium is elevated, we delay the Hockaday, T. D. R.: 2,3-Diphosphoglycerate and tissue oxygenation administration of potassium until the urine output has been in uncontrolled diabetes mellitus. Lancet 2: 391-95, 1972. reestablished . . . and the initial 100 meq of potassium in 3 Piters, K. M., Kumar, D., Pei, E., and Bessman, A. N.: Comshould be in the form of buffered parison of continuous and intermittent intravenous insulin therapies the intravenous fluids 2 If the administration of both potassium potassium phosphate. for diabetic ketoacidosis. Diabetologia 13: 317-21, 1977. 4 Massry, S. G., Coburn, J. W., and Kleeman, C. R.: The and phosphate is delayed until the patient has demonstrated influence of extracellular volume expansion on renal phosphate an adequate renal function, catastrophes such as the one he describes can be avoided. reabsorption in the dog. J. Clin. Invest. 48: 1237-45, 1969. 5 Steele, T. H.: Increased urinary phosphate excretion following However, the fear of inducing hyperphosphatemia in the volume expansion in normal man. Metabolism 19: 129-39, 1970. uncommon patient with renal failure should not overshadow the importance of administering phosphate to the patient whose renal function is intact. Numerous studies have revealed that the serum phosphate falls precipitously following initiation of treatment of ketoacidosis.3"6 The hypophosphatemia seen in these patients is sufficient to cause seizures, Dr. Lavis raises some important points concerning the use acute respiratory failure, and impaired leukocyte and platelet 7 of oxygen and phosphate in the treatment of patients with function, as well as gastrointestinal bleeding. It has recently diabetic ketoacidosis. He is correct in stating that in the been observed that the addition of 25 mmol of phosphate absence of an abnormal pulmonary diffusion capacity, the to each liter of administered fluid during the initial 24 h of partial pressure of oxygen in the arterial blood of the therapy of ketoacidosis will maintain the serum phosphate patient in ketoacidosis is usually elevated at the outset. Under at the lower limit of normal and that such treatment will 6 normal circumstances the majority of the oxygen present in not provoke hypocalcemia. Furthermore, intravenous phosarterial blood (about 20 vol %) is associated with hemoglobin phate therapy will rapidly increase the erythrocyte 2,3-DPG and a small fraction (about 0.3 vol %) is dissolved in the concentration and prevent the decrease of P50 that is plasma.1 Whereas an increase in the oxygen content within consistently observed in patients who do not receive 6 the alveoli will not increase the amount of hemoglobin- phosphate. Thus, it appears that maintaining serum phosassociated oxygen, it can increase the amount of dissolved phate concentrations within normal limits during the early oxygen to a maximum of about 2 vol %. Assuming a tissue phase of treatment of diabetic ketoacidosis should be listed oxygen tension of 40 mm Hg, the normal patient will extract among our major therapeutic objectives. Such therapy will about 4 - 5 vol % of oxygen from each 100 ml of arterial certainly increase tissue oxygenation by maintaining a normal blood. In contrast, the patient whose oxyhemoglobin P50, and will thereby render an increased cardiac output dissociation curve is shifted to the left during the treatment unnecessary. Awareness of the potential hazards of intraof diabetic ketoacidosis will only be able to extract 3 vol % venous phosphate administration should not prevent the from the same amount of blood. To compensate for this physician from providing the benefit of such therapy to all defect, the cardiac output must be increased. Such an increase patients in ketoacidosis whose renal function is normal. may not be possible for the dehydrated, maximally vasoconREX S. CLEMENTS, JR. BIRMINGHAM, ALABAMA stricted patient in ketoacidosis. Under such circumstances,
Treatment of Diabetic Ketoacidosis—A Reply
386
DIABETES CARE, VOL. 2 NO. 4, JULY-AUGUST 1979
Treatment of Diabetic Ketoacidosis In their recent review of diabetic ketoacidosis (Diabetes Care I: 314, 1978), Clements and Vourganti have tried to base their therapeutic recommendations on considerations of pathophysiology. While I agree with most of their reasoning, I must disagree with some of their recommendations concerning oxygen and phosphate therapy (p. 322). It is not clear that "it makes sense to administer oxygen" during the treatment of ketoacidosis. Most patients with untreated ketoacidosis are not hypoxemic. In fact, in one recent series, mean arterial PO2 was elevated on admission, apparently owing to hyperventilation.1 Rather, the possibility of impaired tissue oxygenation arises from the finding of decreased erythrocytic 2,3-DPG, which will shift the oxyhemoglobin dissociation curve to the left.1'2 However, under conditions of hyperventilation coupled with increased affinity of hemoglobin for oxygen, one would expect hemoglobin to become fully saturated with oxygen in the pulmonary capillaries. The supranormal arterial PO2 produced by inhalation of oxygen in these circumstances will be a source of false reassurance to the physician, reflecting as it does primarily dissolved gas, which represents only a minor addition to the oxygen-carrying capacity of the blood. Moreover, even if one could load more oxygen into hemoglobin in the lungs, the maneuver will not help overcome a defect in oxyhemoglobin dissociation at the tissue level. Therefore, it does not seem rational to administer nasal oxygen to a patient with initially normal arterial PO2. My other disagreement is with the recommendation that "the initial 100 meq of potassium in the intravenous fluids should be in the form of buffered potassium phosphate." It should be remembered that serum phosphate in untreated ketoacidosis is often moderately elevated,3 presumably reflecting egress of phosphate from cells into the extracellular compartment. Moreover, as the authors themselves recognize, the intravascular volume of ketoacidotic patients is usually
highly contracted, a situation that favors renotubular reabsorption of filtered phosphate.4'5 Under these conditions, administration of intravenous phosphate can elevate the plasma phosphate to a degree where two serious consequences may occur. First, hypocalcemia may be produced. Second, elevating calcium X phosphorus product may lead to extravascular deposition of calcium in lungs, myocardium, or kidneys. This problem is well illustrated by a case I recently observed. The patient was a 41-yr-old man, whose presenting manifestation of diabetes was ketoacidosis. On admission, serum glucose was 1450 mg/dl, calculated osmolality 400 mosmol/kg, the anion gap 40 mM, serum ketones (nitroprusside reaction) were positive at Vi6, lactate 3.5 mM, creatinine 6.1 mg/dl, calcium 12.4 mg/dl, and phosphorus 3.6 mg/dl. He was treated with 220 mmol phosphate in the intravenous fluids over the first 24 h. Urine output fell to 100 ml/h by 6 h after admission. By 24 h after admission, the serum phosphate was 16 mg/dl and the calcium 8.2 mg/dl. Thereafter, despite discontinuation of intravenous phosphate, the phosphate level remained unchanged while the serum calcium fell to 4.5 mg/dl. The patient became oliguric and died of cardiac arrhythmias 91 h after admission. Admittedly, the phosphate was given without proper regard for the initial hypercalcemia and azotemia, and the dose was excessive. The point is that this situation arose because the man's physicians believed that it was important to give phosphate intravenously early in treatment. Perhaps it is time to reconsider phosphate therapy, bearing in mind that oxygen dissociation from hemoglobin is approximately normal in untreated ketoacidosis, becoming impaired only after the acidosis is corrected.1'2 Therefore, there seems to be little need for early phosphate replacement. On the other hand, there are genuine risks involved with phosphate administration to a volume-contracted individual, as illustrated by the case above. These considerations lead me to recommend that phosphate not be given until intravascular volume is restored, the patient is clearly making adequate amounts of urine, and the serum phosphate has actually fallen below the normal range. I recognize that there may be a
DIABETES CARE, VOL. 2 NO. 4, JULY-AUGUST 1979
385
LETTERS TO THE EDITOR
need to replete tissue and erythrocytic stores of phosphate. In many cases, this can safely be done orally after the patient has recovered from ketoacidosis. Oral administration of phosphate salts for a week or two does not run the risk of massive overload of the vascular compartment at a time when the ability of the kidneys to excrete excess phosphate is severely impaired. I hope these comments will be helpful and will lead to continued consideration by all of us of the proper treatment of diabetic ketoacidosis.
any increase in the amount of dissolved oxygen would tend to alleviate tissue hypoxia. For this reason, we maintain that the slight increase in available dissolved oxygen provided for by oxygen administration to the patient in ketoacidosis would not be harmful, but might be of some benefit. It should also be pointed out that this speculation concerning the potential benefit of oxygen administration has not, as yet, been studied in patients with diabetic ketoacidosis. We do not believe that many physicians would be sufficiently naive as to be lulled into a false sense of security concerning the adequacy of tissue oxygenation in a VICTOR R. LA VIS ketoacidotic patient whose arterial PO2 has been elevated HOUSTON, TEXAS by oxygen administration. REFERENCES With regard to the danger inherent in the administration of 1 Ditzel, J., and Standl, E.: The oxygen transport system of red phosphate to patients with renal failure, we agree with his blood cells during diabetic ketoacidosis and recovery. Diabetologia caveat. A careful reading of our review will reveal that we 11: 255-60, 1975. recognized this hazard when we stated that "In those 2 Alberti, K. G. M. M., Darley, J. H., Emerson, P. M., and patients whose serum potassium is elevated, we delay the Hockaday, T. D. R.: 2,3-Diphosphoglycerate and tissue oxygenation administration of potassium until the urine output has been in uncontrolled diabetes mellitus. Lancet 2: 391-95, 1972. reestablished . . . and the initial 100 meq of potassium in 3 Piters, K. M., Kumar, D., Pei, E., and Bessman, A. N.: Comshould be in the form of buffered parison of continuous and intermittent intravenous insulin therapies the intravenous fluids 2 If the administration of both potassium potassium phosphate. for diabetic ketoacidosis. Diabetologia 13: 317-21, 1977. 4 Massry, S. G., Coburn, J. W., and Kleeman, C. R.: The and phosphate is delayed until the patient has demonstrated influence of extracellular volume expansion on renal phosphate an adequate renal function, catastrophes such as the one he describes can be avoided. reabsorption in the dog. J. Clin. Invest. 48: 1237-45, 1969. 5 Steele, T. H.: Increased urinary phosphate excretion following However, the fear of inducing hyperphosphatemia in the volume expansion in normal man. Metabolism 19: 129-39, 1970. uncommon patient with renal failure should not overshadow the importance of administering phosphate to the patient whose renal function is intact. Numerous studies have revealed that the serum phosphate falls precipitously following initiation of treatment of ketoacidosis.3"6 The hypophosphatemia seen in these patients is sufficient to cause seizures, Dr. Lavis raises some important points concerning the use acute respiratory failure, and impaired leukocyte and platelet 7 of oxygen and phosphate in the treatment of patients with function, as well as gastrointestinal bleeding. It has recently diabetic ketoacidosis. He is correct in stating that in the been observed that the addition of 25 mmol of phosphate absence of an abnormal pulmonary diffusion capacity, the to each liter of administered fluid during the initial 24 h of partial pressure of oxygen in the arterial blood of the therapy of ketoacidosis will maintain the serum phosphate patient in ketoacidosis is usually elevated at the outset. Under at the lower limit of normal and that such treatment will 6 normal circumstances the majority of the oxygen present in not provoke hypocalcemia. Furthermore, intravenous phosarterial blood (about 20 vol %) is associated with hemoglobin phate therapy will rapidly increase the erythrocyte 2,3-DPG and a small fraction (about 0.3 vol %) is dissolved in the concentration and prevent the decrease of P50 that is plasma.1 Whereas an increase in the oxygen content within consistently observed in patients who do not receive 6 the alveoli will not increase the amount of hemoglobin- phosphate. Thus, it appears that maintaining serum phosassociated oxygen, it can increase the amount of dissolved phate concentrations within normal limits during the early oxygen to a maximum of about 2 vol %. Assuming a tissue phase of treatment of diabetic ketoacidosis should be listed oxygen tension of 40 mm Hg, the normal patient will extract among our major therapeutic objectives. Such therapy will about 4 - 5 vol % of oxygen from each 100 ml of arterial certainly increase tissue oxygenation by maintaining a normal blood. In contrast, the patient whose oxyhemoglobin P50, and will thereby render an increased cardiac output dissociation curve is shifted to the left during the treatment unnecessary. Awareness of the potential hazards of intraof diabetic ketoacidosis will only be able to extract 3 vol % venous phosphate administration should not prevent the from the same amount of blood. To compensate for this physician from providing the benefit of such therapy to all defect, the cardiac output must be increased. Such an increase patients in ketoacidosis whose renal function is normal. may not be possible for the dehydrated, maximally vasoconREX S. CLEMENTS, JR. BIRMINGHAM, ALABAMA stricted patient in ketoacidosis. Under such circumstances,
Treatment of Diabetic Ketoacidosis—A Reply
386
DIABETES CARE, VOL. 2 NO. 4, JULY-AUGUST 1979
