EDITOR'S COLUMN
Diabetic ketoacidosis-the bicarbonate controversy
IN 1967, YOUNG AND BRADLEY 1 of the Joslin Clinic reported the unexpected deaths with cerebral edema of two children 9 and 14 years of age, respectively, who were under treatment for diabetic ketoacidosis and apparently progressing satisfactorily. This article stimulated a reappraisal of treatment regimens and led to further investigation of the pathogenesis of this important disorder. Increased attention has been given to the possible role of rapid changes in extracellular fluid osmolality in the development of cerebral edema, since hyperglucosemia is corrected with insulin therapy. The molecular weight of glucose is 180 gm; an elevation of 180 m g / d l in blood glucose concentration 0,800 mg/1) is equivalent to an increase of l0 mOsm/1. Therefore a blood glucose concentration of 540 mg/dl above the normal range results in an increase in osmolality of plasma and extraceUular fluid of 30 mOsm/1. As the blood glucose concentration is lowered with insulin treatment, a shift of water from the extra- to the intracellular compartment occurs which may result in the development of cerebral edema. Among the factors proposed as contributing to this complication of treatment are the generation and retention of increased concentrations of osmotically active metabolites within brain cells as a consequence of diabetic hyperglycemia. Increased blood levels of the polyol sorbitol and fructose have been demonstrated and considered of significance in this regard. 2 Increased production of the cyclic hexose myoinositol in brain during hyperglycemia has also been described? Arieff and Kleeman 4 have demonstrated an increased brain content of Na +, K +, and water after the administration of insulin to hyperglycemic rabbits. They have attributed less importance to the increase in carbohydrate metabolites and have emphasized that electrolyte changes coupled with rapid lowering of glucose are the major factors in the development of cerebral edema during treatment of diabetic ketoacidosis. They point out that, in their experiments and in clinical experience with nonketotic coma, cerebral edema does not occur until plasma glucose has fallen to 14 mM (252 mg/dl). The therapeutic implications of this sequence are clear. Overly rapid reduction of the elevated osmolality of the extracellular fluid should be avoided by gradual reduction 156
The Journal o f P E D I A T R I C S VoL 87, No. 1, pp. 156-159
of hyperglucosemia and by the early administration of isotonic or near-isotonic rather than hypotonic electrolyte solutions and by infusion of glucose, when its concentration has been reduced to approximately 250 mg/dl. A number of reports have dealt with the unfavorable effects of abrupt increases in blood pH in the course of treatment of the patient with ketoacidosis. Among these are impaired delivery of O2 to the tissues and increasing central nervous system acidosis as the pH of the blood and extracellular fluid rises toward normal. The impact of these observations has been so strong that there has been, in many quarters, an interdiction of the use of bicarbonate in the treatment of diabetic ketoacidosis. There now exists the real possibility that bicarbonate may be withheld from patients who may be in critical need of rapid partial correction of a potentially lethal degree of acidosis. Abbreviations used 2,3-DPG: 2,3-diphosphoglycerate ATP: adeonosine triphosphate It is the primary purpose of this communication to review the major untoward effects of rapid correction of severe metabolic acidosis and to emphasize circumstances under which a low pH may in itself constitute a threat to life and thereby provide a rational basis for the use or nonuse of bicarbonate in the treatment of diabetic ketoacidosis. The major anions which accumulate in the late stages of diabetic ketoacidosis are beta hydroxybutyrate and acetoacetate. These compounds are generated as strong acids which are neutralized by the blood buffers with a consequent reduction in serum bicarbonate concentra'tion. With the administration of insulin to facilitate metabolism of glucose, the ketone bodies are oxidized in the Krebs cycle to carbon dioxide and water and thus regenerate bicarbonate. Because of this endogenous source of bicarbonate, it has long been recognized that there is relatively less need for the provision of exogenous bicarbonate in diabetic ketoacidosis than in comparable states of metabolic acidosis of other origins. Recognition of these facts underlies an appropriate conservatism in administration of bicarbonate in diabetic ketoacidosis
Volume 87 Number i
Editor's column
which has been reinforced by the recent recognition of potentially undesirable effects of its use. In addition, the administration of insulin effectively inhibits lipolysis and thus limits further ketone production. State of consciousness correlates more closely with spinal fluid pH than with blood pH. Posner and Plum 6 have emphasized that patients with severe respiratory acidosis, in which there is primary elevation of carbon dioxide tension ( P c o ) , are characteristically obtunded. In contrast the subject with comparable reduction in blood pH on the basis of metabolic acidosis is usually alert. This difference can be understood in terms of the greater permeability of the blood-brain barrier and the cells of the central nervous system to carbon dioxide than to the anion bicarbonate. Therefore, with respiratory insufficiency and elevation of systemic Pco2, there is rapid transfer of the retained CO2 to the cerebrospinal fluid and a fall in pH as defined by the Henderson-Hasselbalch equation,
HCO~ pH = 6.10 + log
0.03 Pco 2
Metabolic acidosis, in contrast, involves primary reduction of HCO3 as a consequence of the neutralization of H § generated during the development of the disorder. The pH of the central nervous system, as reflected in the spinal fluid pH, is better maintained than that of the systemic circulation, because the reduced permeability of the blood-brain barrier to the movement of HCO~ results in its relative conservation. This confers partial protection to the central nervous system from sharing the full burden of the systemic acidosis. The relative differences in permeability of the blood-brain barrier to CO2 and HCO~ constitute an important defense mechanism which provides protection to brain function during the development of metabolic acidosis. During the correction of metabolic acidosis the differential permeability of the blood-brain barrier and central nervous system cells to CO2 and HCO~ is responsible for a further decline in pH of the cerebrospinal fluid and probably of the brain cells as t h e systemic pH rises. This apparent paradoxical change results from the decrease in respiratory minute volume and in the accompanying increase in Pco2 as pH rises toward normal levels. The increased Pco2 of the extracellular fluid is rapidly reflected in a comparable rise in the spinal fluid. On the other hand, the increase in extracellular H C O ; concentration does not lead to a commensurate increment in the concentration of this anion in the cerebrospinal fluid. Thus, while the extracellular pH rises the cerebrospinal fluid pH falls. This paradoxical change may lead to a worsening of the state of consciousness in spite of an
t decPH~ t '
D E A L Y E D/
15 7
D 3 -2 ,P G] decrease
increaseI OXYGEN AFFINITY decrease
I iogose
D E A L Y E D~ D 3 ? -increase _ P ,Gj
Fig. 1. Diagrammatic representation of the effect of pH changes on hemoglobin affinity of oxygen. (Reproduced with permission from Bellingham A J, Detter JC, and Lenfant C: Trans Assoc Am Physicians 83:113, 1970.
"improvement" in extracellular pH and HCO~ concentration. These changes are not limited to the cells o f the central nervous system but are experienced by the cells of the body as a whole, which also exhibit the same differential permeability of CO2 and HCO~ and will therefore experience a fall in intraceliular pH as the systemic pH rises. These changes are properly viewed as the superimposition of a respiratory acidosis (relative increase in Pc02 in relation to HCO~ concentration) upon a metabolic acidosis (relative decrease in HCOa concentration in relation to Pco2)It should be pointed out that the sequence described above is minimized by an altered sensitivity o f the respiratory center to pH during correction of metabolic acidosis. Kety and associates6 document continued hyperventilation in patients under treatment for diabetic ketoacidosis in spite of a rise in serum HCO~ concentration. This has the effect o f diminishing the expected rise in Pc02 and exaggerating the increment in pH o f the extracellular fluid consequent to a given increase in serum HCO3 concentration. The altered response of the respiratory center in which hyperventilati0n continues in spite of a rising serum pH serves to limit the extent of the central nervous system and general intracellular acidosis, while exaggerating the rise in pH of the extracellular fluid as HCO~ concentration increases with insulin treatment with or without added alkali therapy. An additional reason for conservatism in the administration of HCO; in the treatment of diabetic ketoacidosis is based on a beneficial "shift to the fight" of the hemoglobin-O~ dissociation curve which accompanies the acidotic state. 7 The shift in the hemoglobin-O2 dissociation curve favoring enhanced release of O2 constitutes a
15 8
Editor's column
The Journal of Pediatrics July 1975
RESP, MIN.VOL. LIT./MIN. 4O X
30
/ 9/
9 \
2o/x
\
6.8 7.0 ARTERIAL pH
Z2
7.4
Fig. 2. The relationship between respiratory minute volume and arterial pH. (Reproduced with permission from Katy SS, Polls BD, Nadler CS, and Schmidt CF: J Clin Invest 27:500, 1948. valuable compensatory mechanism which is of particular importance in diabetic ketoacidosis in which hypovolemia and decreased perfusion resulting from dehydration impair tissue oxygenation. Rapid correction of blood pH prior to restoring blood volume and an adequate peripheral circulation deprive the patient of this adjustment. This undesirable effect is further compounded as acidosis is associated with reduced concentrations of 2,3-diphosphoglycerate and adenosine triphosphate which lead to decreased release of O5 to the tissues-a "shift to the left" of the hemoglobin-O~ dissociation curve. These effects on O~ release are in opposite directions and tend to offset each other in the untreated patient. Rapid correction of blood pH places the patient at a disadvantage because there is a lag in restoring 2,3-DPG and ATP concentrations to normal. Both the continued reduction in red cell organic phosphorous Compounds and the restoration of normal or near normal blood pH additively displace the hemoglobin-O~ dissociation curve to the left, decreasing the release of O2 to the tissues (Fig. 1). Munk and associates~ found equal "left shifts" in the hemogtobin-O2 dissociation curves of juvenile diabetics with ketoacidosis whether or not they were treated with exogenous bicarbonate. Since this potentially undesirable effect occurred in both groups, the authors concluded that bicarbonate therapy does not affect oxygen transport adversely and, therefore, the possibility of such an effect
does not support the omission of bicarbonate from the treatment plan. The validity of the assessment by these authors of the potential hazards of bicarbonate therapy in this regard is minimized by the fact that their control group was less acidotic at the start of treatment, and, with one exception, the treated patients received small quantities of bicarbonate (0.9-1.7 mEq/kg). Thus far the evidence presented favors restriction in the use of bicarbonate therapy in the treatment of diabetic ketoacidosis. What, if any, are the indications for its use? In this regard, one m a y cite the reduced sensitivity to insulin in the acidotic state demonstrated by Mackler and associates2 Of greater importance are the adverse effects of very low pH on the respiratory center described by Kety and associates6 (Fig. 2), as well as the effects of low pH on myocardial contractility ..... described below and an increased risk of cardiac arrhythmias. 12 There is only minimal stimulation of respiratory minute volume as arterial pH declines from normal to 7.2. With further fall in pH, there is a marked increase in ventilation, which then decreases at pH levels Of approximately 7.1 and below as shown in Fig. 2. The fall in minute volume reduces the effectiveness of the respiratory component of the compensatory mechanisms involved in adjusting to metabolic acidosis and may lead to a potentially lethal increase in the severity of acidosis. The adverse effects of low pH on myocardial function are important to recognize in an analysis of the role of bicarbonate in the therapy of diabetic ketoacidosis. Opie TM observed that the contractility of the is 9 left ventricle is unaffected over the pH range of 7.4 to 8.0, but is significantly impaired when pH fell to levels of 7.1 or less. Ng and associates 11 observed decreased left ventricular systolic pressure with low pH. The above considerations strongly suggest a therapeutic role for exogenous administration of bicarbonate to ketoacidotic patients with extreme depression of arterial pH. There is no good documentation, however, by clinical studies of superior results in relation to its use. King and associates, 1~ who treated a series of ketoacidotic patients without bicarbonate, documented a slow return of acidbase status toward normal which was not complete in 24 hours. Their conclusion as to the role of bicarbonate in therapy was, "In most it will not be required, but where, after several hours treatment, the arterial pH remains below 7.1 an infusion of bicarbonate seems a sensible precaution." In a similar vein, Assal and associates ~ ~ompared a bicarbonate-treated group of ketoacidotic patients with a control group treated earlier without bicarbonate at the same clinic by Ohman and associates. 14 No significant differences were noted between the groups except for a significantly smaller decrease in cerebrospinal
Volume 87 Number 1
fluid osmolality and a greater fall in cerebrospinal fluid pH in the bicarbonated treated patients. They concluded, 18 "It appears that supplemental bicarbonate therapy does not materially improve the clinical course of patients with diabetic ketoacidosis. However, its use would seem to be indicated, if not mandatory, when metabolic acidosis itseff impairs or embarrasses already compromised circulatory or ventilatory function." It would therefore be good practice to protect, by the administration of HCO'2, the patient whose blood pH has fallen to the range of 7.1 to 7.15 from the dangers of impaired ventilatory response and myocardial function which may accompany this degree of acidosis. Diabetic patients with lesser degrees of acidosis will be adequately served by permitting endogenously generated HCO-~ to restore blood pH toward normal. As current methods of estimating base deficit in diabetic ketoacidosis tend, to over-estimate its magnitude by approximately 100%, 15 it is recommended that in estimating the amount of exogenous bicarbonate to be administered somewhat less than half of the estimated deficit be corrected. It is our practice to infuse an arbitrary dosage of 2.0-2.5 mEq/kg of NaHCO3 to patients manifesting a need for this agent. Guidelines for bicarbonate dosage in adults have been presented recently and are in reasonable agreement with that given above for pediatric patients. Zimmet and associates 15 recommended the administration of 44 to 88 mEq to patients whose arterial pH is in the range of 7.17.2 and 110-176 mEq to those with a pH value of less than 7.1. In the event that the pH failed to respond satisfactorily in one to two hours, additional alkali is given but is discontinued when the pH rises above 7.25. Felig TM states that infusing bicarbonate in a quantity sufficient to restore only 50% of the calculated base deficit (estimated on multiplying the reduction in serum bicarbonate by 50% of body weigh0 often results in a mild metabolic alkalosis. He suggests restricting bicarbonate treatment to patients with severe metabolic acidosis indicated by an arterial pH of 7.1 or less or a bicarbonate concentration of less than 5 mEq/1. He recommends 88 mEq (132 mEq, if pH is less than 7.0) as an initial bicarbonate dosage. Additional quantities are given according to the criteria of Zimmet described above. The controversy over the use of bicarbonate in diabetic ketoacidosis may be resolved both by an understanding of its potential dangers a n d also by recognition of circumstances in which the risk factors attendant on its use may be outweighed by the greater danger of withholding it from the patient threatened by respiratory and myocardial depression secondary to severe acidosis. The bicarbonate controversy in the treatment of diabetic ketoaci-
Editor's column
159
dosis appears to resemble many similar therapeutic dilemmas and is resolved not by "yes" or "no" but by asking the questions "when" and "how much."
Robert Kaye, M.D. Department of Pediatrics Hahnemann Medical College and Hospital 230 N. Broad St. Philadelphia, Pa. 19102
REFERENCES
1. Young E, and Bradley RF: Cerebral edema with irreversible coma in severe diabetic ketoacidosis, N Engl J Med 276:665, 1967. 2. Clements RS Jr, Blumenthal SA, Morrison AD, and Winegrad AI: Increased cerebrospinal-fluid pressure during treatment of diabetic ketosis, Lancet 2:671, 1971. 3. Prockop LD: Hyperglycemia, polyol accumulation and increased intracranial pressure, Arch Neurol 25:126, 1971. 4. Arieff AI, and Kleeman CR: Studies on mechanisms of cerebral edema in diabetic comas: Effects of hyperglycemia and rapid lowering of plasma glucose in normal rabbits, J Clin Invest 52:571, 1973. 5. Posner JB, and Plum F: Spinal fluid pH and neurologic symptoms in systemic acidosis, N Engl J Med 277:605, 1967. 6. Kety SS, Polis BD, Nadler CS, and Schmidt CF: The blood flow and oxygen ~consumption of the human brain in diabetic acidosis and coma, J Clin Invest 27:500, 1948. 7. Bellingham AJ, Detter JC, and Lenfant C: The role of hemoglobin affinity for oxygen and red cell 2,3-diphosphoglycerate in the management of diabetic ketoacidosis, Trans Assoc Am Physicians 83:113, 1970. 8. Munk P, Freedman MH, Levison H, and Ehrlich RM: Effect of bicarbonate on oxygen transport in .juvenile diabetic ketoacidosis, J PEDIATR84:510, 1974. 9. Mackler B, Lichenstein H, and Guest GM: Effects of ammonium chloride acidosis on the action of insulin in dogs, Am J Physiol 166:191, 1951. 10. Opie LH: Effect of extracellular pH on function and metabolism of isolated perfused rat heart, Am J Physiol 209:1075, 1965. ll. Ng ML, Levy MN, and Zieske HA: Effects of changes of pH and of carbon dioxide tension on left ventricular performances, Am J Physiol 213:115, 1967. 12. King AJ, Cooke NJ, McCuish A, Cherke BF, and Kirby BJ: Acid-base changes during treatment of diabetic ketoacidosis, Lancet 1:478, 1974. 13. Assal J, Aoki TI', Manzano FM, and Kozak GP: Metabolic effects of sodium bicarbonate in management of diabetic ketoacidosis, Diabetes 23:405, 1974. 14. Ohman JL Jr, Marliss EB, Oaki TT, Munichoodappo CS, Khanna VV, and Kozak GP: The cerebrospinal fluid in diabetic ketoacidosis, N Engl J Med 284:283, 1971. 15. Zimmet PA, Taft P, Ennis GC, and Sheath J: Acid production in diabetic acidosis; a more rational approach to alkali replacement, Br Med J 3:610, 1970. 16. Felig P: Current concepts, diabetic ketoacidosis, N Engl J Med 290:1360, 1974.
Diabetic ketoacidosis-the bicarbonate controversy
IN 1967, YOUNG AND BRADLEY 1 of the Joslin Clinic reported the unexpected deaths with cerebral edema of two children 9 and 14 years of age, respectively, who were under treatment for diabetic ketoacidosis and apparently progressing satisfactorily. This article stimulated a reappraisal of treatment regimens and led to further investigation of the pathogenesis of this important disorder. Increased attention has been given to the possible role of rapid changes in extracellular fluid osmolality in the development of cerebral edema, since hyperglucosemia is corrected with insulin therapy. The molecular weight of glucose is 180 gm; an elevation of 180 m g / d l in blood glucose concentration 0,800 mg/1) is equivalent to an increase of l0 mOsm/1. Therefore a blood glucose concentration of 540 mg/dl above the normal range results in an increase in osmolality of plasma and extraceUular fluid of 30 mOsm/1. As the blood glucose concentration is lowered with insulin treatment, a shift of water from the extra- to the intracellular compartment occurs which may result in the development of cerebral edema. Among the factors proposed as contributing to this complication of treatment are the generation and retention of increased concentrations of osmotically active metabolites within brain cells as a consequence of diabetic hyperglycemia. Increased blood levels of the polyol sorbitol and fructose have been demonstrated and considered of significance in this regard. 2 Increased production of the cyclic hexose myoinositol in brain during hyperglycemia has also been described? Arieff and Kleeman 4 have demonstrated an increased brain content of Na +, K +, and water after the administration of insulin to hyperglycemic rabbits. They have attributed less importance to the increase in carbohydrate metabolites and have emphasized that electrolyte changes coupled with rapid lowering of glucose are the major factors in the development of cerebral edema during treatment of diabetic ketoacidosis. They point out that, in their experiments and in clinical experience with nonketotic coma, cerebral edema does not occur until plasma glucose has fallen to 14 mM (252 mg/dl). The therapeutic implications of this sequence are clear. Overly rapid reduction of the elevated osmolality of the extracellular fluid should be avoided by gradual reduction 156
The Journal o f P E D I A T R I C S VoL 87, No. 1, pp. 156-159
of hyperglucosemia and by the early administration of isotonic or near-isotonic rather than hypotonic electrolyte solutions and by infusion of glucose, when its concentration has been reduced to approximately 250 mg/dl. A number of reports have dealt with the unfavorable effects of abrupt increases in blood pH in the course of treatment of the patient with ketoacidosis. Among these are impaired delivery of O2 to the tissues and increasing central nervous system acidosis as the pH of the blood and extracellular fluid rises toward normal. The impact of these observations has been so strong that there has been, in many quarters, an interdiction of the use of bicarbonate in the treatment of diabetic ketoacidosis. There now exists the real possibility that bicarbonate may be withheld from patients who may be in critical need of rapid partial correction of a potentially lethal degree of acidosis. Abbreviations used 2,3-DPG: 2,3-diphosphoglycerate ATP: adeonosine triphosphate It is the primary purpose of this communication to review the major untoward effects of rapid correction of severe metabolic acidosis and to emphasize circumstances under which a low pH may in itself constitute a threat to life and thereby provide a rational basis for the use or nonuse of bicarbonate in the treatment of diabetic ketoacidosis. The major anions which accumulate in the late stages of diabetic ketoacidosis are beta hydroxybutyrate and acetoacetate. These compounds are generated as strong acids which are neutralized by the blood buffers with a consequent reduction in serum bicarbonate concentra'tion. With the administration of insulin to facilitate metabolism of glucose, the ketone bodies are oxidized in the Krebs cycle to carbon dioxide and water and thus regenerate bicarbonate. Because of this endogenous source of bicarbonate, it has long been recognized that there is relatively less need for the provision of exogenous bicarbonate in diabetic ketoacidosis than in comparable states of metabolic acidosis of other origins. Recognition of these facts underlies an appropriate conservatism in administration of bicarbonate in diabetic ketoacidosis
Volume 87 Number i
Editor's column
which has been reinforced by the recent recognition of potentially undesirable effects of its use. In addition, the administration of insulin effectively inhibits lipolysis and thus limits further ketone production. State of consciousness correlates more closely with spinal fluid pH than with blood pH. Posner and Plum 6 have emphasized that patients with severe respiratory acidosis, in which there is primary elevation of carbon dioxide tension ( P c o ) , are characteristically obtunded. In contrast the subject with comparable reduction in blood pH on the basis of metabolic acidosis is usually alert. This difference can be understood in terms of the greater permeability of the blood-brain barrier and the cells of the central nervous system to carbon dioxide than to the anion bicarbonate. Therefore, with respiratory insufficiency and elevation of systemic Pco2, there is rapid transfer of the retained CO2 to the cerebrospinal fluid and a fall in pH as defined by the Henderson-Hasselbalch equation,
HCO~ pH = 6.10 + log
0.03 Pco 2
Metabolic acidosis, in contrast, involves primary reduction of HCO3 as a consequence of the neutralization of H § generated during the development of the disorder. The pH of the central nervous system, as reflected in the spinal fluid pH, is better maintained than that of the systemic circulation, because the reduced permeability of the blood-brain barrier to the movement of HCO~ results in its relative conservation. This confers partial protection to the central nervous system from sharing the full burden of the systemic acidosis. The relative differences in permeability of the blood-brain barrier to CO2 and HCO~ constitute an important defense mechanism which provides protection to brain function during the development of metabolic acidosis. During the correction of metabolic acidosis the differential permeability of the blood-brain barrier and central nervous system cells to CO2 and HCO~ is responsible for a further decline in pH of the cerebrospinal fluid and probably of the brain cells as t h e systemic pH rises. This apparent paradoxical change results from the decrease in respiratory minute volume and in the accompanying increase in Pco2 as pH rises toward normal levels. The increased Pco2 of the extracellular fluid is rapidly reflected in a comparable rise in the spinal fluid. On the other hand, the increase in extracellular H C O ; concentration does not lead to a commensurate increment in the concentration of this anion in the cerebrospinal fluid. Thus, while the extracellular pH rises the cerebrospinal fluid pH falls. This paradoxical change may lead to a worsening of the state of consciousness in spite of an
t decPH~ t '
D E A L Y E D/
15 7
D 3 -2 ,P G] decrease
increaseI OXYGEN AFFINITY decrease
I iogose
D E A L Y E D~ D 3 ? -increase _ P ,Gj
Fig. 1. Diagrammatic representation of the effect of pH changes on hemoglobin affinity of oxygen. (Reproduced with permission from Bellingham A J, Detter JC, and Lenfant C: Trans Assoc Am Physicians 83:113, 1970.
"improvement" in extracellular pH and HCO~ concentration. These changes are not limited to the cells o f the central nervous system but are experienced by the cells of the body as a whole, which also exhibit the same differential permeability of CO2 and HCO~ and will therefore experience a fall in intraceliular pH as the systemic pH rises. These changes are properly viewed as the superimposition of a respiratory acidosis (relative increase in Pc02 in relation to HCO~ concentration) upon a metabolic acidosis (relative decrease in HCOa concentration in relation to Pco2)It should be pointed out that the sequence described above is minimized by an altered sensitivity o f the respiratory center to pH during correction of metabolic acidosis. Kety and associates6 document continued hyperventilation in patients under treatment for diabetic ketoacidosis in spite of a rise in serum HCO~ concentration. This has the effect o f diminishing the expected rise in Pc02 and exaggerating the increment in pH o f the extracellular fluid consequent to a given increase in serum HCO3 concentration. The altered response of the respiratory center in which hyperventilati0n continues in spite of a rising serum pH serves to limit the extent of the central nervous system and general intracellular acidosis, while exaggerating the rise in pH of the extracellular fluid as HCO~ concentration increases with insulin treatment with or without added alkali therapy. An additional reason for conservatism in the administration of HCO; in the treatment of diabetic ketoacidosis is based on a beneficial "shift to the fight" of the hemoglobin-O~ dissociation curve which accompanies the acidotic state. 7 The shift in the hemoglobin-O2 dissociation curve favoring enhanced release of O2 constitutes a
15 8
Editor's column
The Journal of Pediatrics July 1975
RESP, MIN.VOL. LIT./MIN. 4O X
30
/ 9/
9 \
2o/x
\
6.8 7.0 ARTERIAL pH
Z2
7.4
Fig. 2. The relationship between respiratory minute volume and arterial pH. (Reproduced with permission from Katy SS, Polls BD, Nadler CS, and Schmidt CF: J Clin Invest 27:500, 1948. valuable compensatory mechanism which is of particular importance in diabetic ketoacidosis in which hypovolemia and decreased perfusion resulting from dehydration impair tissue oxygenation. Rapid correction of blood pH prior to restoring blood volume and an adequate peripheral circulation deprive the patient of this adjustment. This undesirable effect is further compounded as acidosis is associated with reduced concentrations of 2,3-diphosphoglycerate and adenosine triphosphate which lead to decreased release of O5 to the tissues-a "shift to the left" of the hemoglobin-O~ dissociation curve. These effects on O~ release are in opposite directions and tend to offset each other in the untreated patient. Rapid correction of blood pH places the patient at a disadvantage because there is a lag in restoring 2,3-DPG and ATP concentrations to normal. Both the continued reduction in red cell organic phosphorous Compounds and the restoration of normal or near normal blood pH additively displace the hemoglobin-O~ dissociation curve to the left, decreasing the release of O2 to the tissues (Fig. 1). Munk and associates~ found equal "left shifts" in the hemogtobin-O2 dissociation curves of juvenile diabetics with ketoacidosis whether or not they were treated with exogenous bicarbonate. Since this potentially undesirable effect occurred in both groups, the authors concluded that bicarbonate therapy does not affect oxygen transport adversely and, therefore, the possibility of such an effect
does not support the omission of bicarbonate from the treatment plan. The validity of the assessment by these authors of the potential hazards of bicarbonate therapy in this regard is minimized by the fact that their control group was less acidotic at the start of treatment, and, with one exception, the treated patients received small quantities of bicarbonate (0.9-1.7 mEq/kg). Thus far the evidence presented favors restriction in the use of bicarbonate therapy in the treatment of diabetic ketoacidosis. What, if any, are the indications for its use? In this regard, one m a y cite the reduced sensitivity to insulin in the acidotic state demonstrated by Mackler and associates2 Of greater importance are the adverse effects of very low pH on the respiratory center described by Kety and associates6 (Fig. 2), as well as the effects of low pH on myocardial contractility ..... described below and an increased risk of cardiac arrhythmias. 12 There is only minimal stimulation of respiratory minute volume as arterial pH declines from normal to 7.2. With further fall in pH, there is a marked increase in ventilation, which then decreases at pH levels Of approximately 7.1 and below as shown in Fig. 2. The fall in minute volume reduces the effectiveness of the respiratory component of the compensatory mechanisms involved in adjusting to metabolic acidosis and may lead to a potentially lethal increase in the severity of acidosis. The adverse effects of low pH on myocardial function are important to recognize in an analysis of the role of bicarbonate in the therapy of diabetic ketoacidosis. Opie TM observed that the contractility of the is 9 left ventricle is unaffected over the pH range of 7.4 to 8.0, but is significantly impaired when pH fell to levels of 7.1 or less. Ng and associates 11 observed decreased left ventricular systolic pressure with low pH. The above considerations strongly suggest a therapeutic role for exogenous administration of bicarbonate to ketoacidotic patients with extreme depression of arterial pH. There is no good documentation, however, by clinical studies of superior results in relation to its use. King and associates, 1~ who treated a series of ketoacidotic patients without bicarbonate, documented a slow return of acidbase status toward normal which was not complete in 24 hours. Their conclusion as to the role of bicarbonate in therapy was, "In most it will not be required, but where, after several hours treatment, the arterial pH remains below 7.1 an infusion of bicarbonate seems a sensible precaution." In a similar vein, Assal and associates ~ ~ompared a bicarbonate-treated group of ketoacidotic patients with a control group treated earlier without bicarbonate at the same clinic by Ohman and associates. 14 No significant differences were noted between the groups except for a significantly smaller decrease in cerebrospinal
Volume 87 Number 1
fluid osmolality and a greater fall in cerebrospinal fluid pH in the bicarbonated treated patients. They concluded, 18 "It appears that supplemental bicarbonate therapy does not materially improve the clinical course of patients with diabetic ketoacidosis. However, its use would seem to be indicated, if not mandatory, when metabolic acidosis itseff impairs or embarrasses already compromised circulatory or ventilatory function." It would therefore be good practice to protect, by the administration of HCO'2, the patient whose blood pH has fallen to the range of 7.1 to 7.15 from the dangers of impaired ventilatory response and myocardial function which may accompany this degree of acidosis. Diabetic patients with lesser degrees of acidosis will be adequately served by permitting endogenously generated HCO-~ to restore blood pH toward normal. As current methods of estimating base deficit in diabetic ketoacidosis tend, to over-estimate its magnitude by approximately 100%, 15 it is recommended that in estimating the amount of exogenous bicarbonate to be administered somewhat less than half of the estimated deficit be corrected. It is our practice to infuse an arbitrary dosage of 2.0-2.5 mEq/kg of NaHCO3 to patients manifesting a need for this agent. Guidelines for bicarbonate dosage in adults have been presented recently and are in reasonable agreement with that given above for pediatric patients. Zimmet and associates 15 recommended the administration of 44 to 88 mEq to patients whose arterial pH is in the range of 7.17.2 and 110-176 mEq to those with a pH value of less than 7.1. In the event that the pH failed to respond satisfactorily in one to two hours, additional alkali is given but is discontinued when the pH rises above 7.25. Felig TM states that infusing bicarbonate in a quantity sufficient to restore only 50% of the calculated base deficit (estimated on multiplying the reduction in serum bicarbonate by 50% of body weigh0 often results in a mild metabolic alkalosis. He suggests restricting bicarbonate treatment to patients with severe metabolic acidosis indicated by an arterial pH of 7.1 or less or a bicarbonate concentration of less than 5 mEq/1. He recommends 88 mEq (132 mEq, if pH is less than 7.0) as an initial bicarbonate dosage. Additional quantities are given according to the criteria of Zimmet described above. The controversy over the use of bicarbonate in diabetic ketoacidosis may be resolved both by an understanding of its potential dangers a n d also by recognition of circumstances in which the risk factors attendant on its use may be outweighed by the greater danger of withholding it from the patient threatened by respiratory and myocardial depression secondary to severe acidosis. The bicarbonate controversy in the treatment of diabetic ketoaci-
Editor's column
159
dosis appears to resemble many similar therapeutic dilemmas and is resolved not by "yes" or "no" but by asking the questions "when" and "how much."
Robert Kaye, M.D. Department of Pediatrics Hahnemann Medical College and Hospital 230 N. Broad St. Philadelphia, Pa. 19102
REFERENCES
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