On Friday evening after my late afternoon rounds, a new patient arrived in ICU. That time was about 15 minutes to 6 pm. My medical officer told me the diagnosis is diabetic ketoacidosis. She is a young lady, known type 1 diabetes mellitus since she was twelve-year old. There was no appropriate handover since the intern who accompanied the patient only functioned as a 'medical' porter and didn't know what was going on except that his patient has a diagnosis of DKA. This place is very strange and the system is not right. I still not really impressed with the department of emergency in my hospital.
She has a pink cannula (20G) in her right arm. After scrutinizing the case notes (no attached intravenous fluid chart), we concluded that she received the appropriate IV fluid replacement therapy. From the ABG, she had a high AG metabolic acidosis, pH of 7.15. Urine ketone was positive, blood sugar level on admission was 41mmol/l, serum Na 125 and K 4.5. We also noted that IV NaHCO3 was given by medical medical officer to treat the acidosis. Ten units of IV insulin was given but the sliding scale has not been started.
The question is "Is Na bicarbonate therapy is indicated to treat high anion gap acidosis in DKA?"
Let me start with the major effects of metabolic acidosis on the body
Respiratory effects:
1. Hyperventilation (Kussmaul respirations) - as compensatory response
2. Shift of ODC to the right
3. Decreased 2,3 DPG in the red cells (shift the ODC back to the left)
Cardiovascular effects:
1. Depression of myocardial contractility
2. Sympathetic overactivity (include tachycardia, vasoconstriction, decreased arrythmia threshold)
3. Resistance to the effects of catecholamines
4. Peripheral arteriolar vasodilation
5. Venoconstriction of peripheral veins
6. Vasoconstriction of pulmonary arteries
7. Effects of hyperkalemia on heart
The cardiac stimulatory effects of sympathetic activity and release of cathecolamines usually counteract the direct myocardial depression while plasma pH remains above 7.2. At systemic pH values less than this the direct depression of contractility usually predominates. The direct vasodilation is offset by the indirect sympathetically mediated vasoconstriction and cardiac stimulation during a mild acidosis. The venoconstriction shifts blood centrally and this causes pulmonary congestion. Pulmonary artery pressure usually rises during acidosis.
Other effects:
1. Increased bone resorption (chronic acidosis only)
2. Shift of K out of cells causing hyperkalaemia
The effect on K level is variable and indirect effects due to the type of acidosis present are much more important. e.g. hyperkalaemia in renal failure is due to uraemic acidosis rather than the acidosis. In DKA, singnificant K loss due to osmotic diuresis, therefore the K level at presentation is variable although total body K stores are invariably depleted. Treatment with fluid and insulin can cause a prompt and marked fall in plasma K. Hypokalaemia may be than a problem.
Bicarbonate is an anion and cannot be given alone. Its therapeutic use is as a solution of Na bicarbonate. An 8.4% solution is a molar solution ( i.e. contains 1 mmol of HCO3 per ml). Thi solution is very hypertonic and its osmolality is 2,000 mOsm/kg.
The main goal of alkali therapy
1. to counteract the extracellular acidemia with the aim of reversing or avoiding the adverse clinical effects of the acidosis (esp adverse CVS effects).
2. Emergency management of hyperkalemia
3. To promote alkaline diuresis (e.g. to hasten salicylate excretion)
Undesirable effects of bicarbonate administration:
1. Hypernatremia
2. Hyperosmolality
3. Volume overload
4. Rebound or overshoot alkalosis
5. Hypokalaemia
6. Impaired oxygen unloading due to left shift of the ODC
7. Acceleration of lactate production by removal of acidotic inhibition of glycolysis
8. CSF acidosis
9. Hypercapnia
Important points about bicarbonate:
1. Ventilation must be adequate to eliminate the CO2 produced from bicarbonate. If hypercapnia occurs, CO2 crosses the cell membranes easily and intracellular pH may decrease even further with further deterioration of cellular function.
2. Bicarbonate may cause clinical deterioration if tissue hypoxia is present. This is due to increased lactate production (removal of acidotic inhibition of glycolysis) and the impairment of tissue oxygen unloading (left shift of ODC due to increased pH). This means that with lactic acidosis or cardiac arrest then bicarbonate therapy may be dangerous.
3. Bicarbonate is probably not useful in most cases of high anion gap acidosis.
4. The preferred management of metabolic acidosis is to correct the primary cause and to use specific treatment for any potentially dangerous complications.
5. Bicarbonate therapy may be useful for correction of acidemia due to non-organic or mineral acidosis (i.e. normal anion gap acidosis).
Diabetes Ketoacidosis - summary of events in pathophysiology of DKA:
1. A precipitating event occurs which results in insulin deficiency (absolute or relative) and usually an excess of stress hormones (particularly glucagon)
2. Hyperglycemia occurs due to decreased gluconse uptake in fat and muscle cells due to insulin deficiency
3. Lipolysis in fat cells now occurs promoted by the insulin deficiency releasing FFA into the blood
4. Elevated FFA levels provide substrate to the liver
5. A switch in hepatic lipid metabolism occurs due to the insulin deficiency and glucagon excess, so the excess FFA is metabolised resulting in excess production of acetyl CoA
6. The excess hepatic acetyl CoA is converted to acetoacetate which is released into the blood
7. Ketoacidosis and hyperglycemia both occur due to the lack of insulin and the increase in glucagon and most of the clinical effects follow from these two factors
8. Other acid-base and electrolyte disorders may develop as a consequence and complicate the clinical condition.
Oher acid base disorders may be present: Possible complicating acid base disorders are
1. Lactic acidosis due to hypoperfusion and anaerobic muscle metabolism
2. Metabolic alkalosis secondary to excessive vomiting
3. Respiratory alkalosis with sepsis
4. Respiratory acidosis due to pneumonia or mental obtundation
5. Renal tubular acidosis type 4 - the syndrome known as hyporeninemic hypoaldosteronism occurs in some elderly diabetics who have pre-existing moderate renal insufficiency by is not a common problem in acute DKA.
Correction of acidosis in DKA
This occurs more slowly than the correction of blood glucose but the use of bicarbonate in DKA remains controversial (Viallon CCM 1999) . In most studies the use of bicarbonate fails to provide any hemodynamic benefit that could not be attributed purely to osmotic load of sodium administered (Cooper ICM 1994). Therefore the evidence of benefits are lacking (Latif KA Diabetes care 2002). In a randomized trial of 24 DKA patients with admission arterial pH between 6.9 and 7.4 bicarbonate therapy did not change morbidity of mortality (Morris LR Ann inter med 1986). The study was small, limited to arterial pH 6.9 and above. There was no difference in the rate of rise in the arterial pH and serum bicarbonate and placebo groups. No prospective trial in DKA with pH values less than 6.9. Below pH 6.9 most authorities would recommend the use of bicarbonate to correct the pH partially.
There is no doubt that blood pH can be improved, but at the expense of worsening intracellular acidosis (Forsythe Chest 2000). Neurologic deterioration has been reported due to paradoxical fall in cerebral pH (Narins RG Ann Intern Med 1987). Other side effects of bicarbonate are listed above.
In the context of DKA, sodium bicarbonate also delays the clearance of ketones and may further enhance hepatic production even when insulin and glucose are being delivered (Okuda J Clin Endocrinol Metab 1996). This may slow the rate of recovery of the ketosis. At pH of > 7.0 insulin will block lipolysis and ketoacid production.
Selected patients who may benefit from cautious alkali therapy (Narins RG Ann Intern Med 1987):
1. Patients with an arterial pH of 7.0 in whom decreased cardiac contractality and vasodilation can further impair tissue perfusion. At an arterial pH above 7.00 most experts agree that bicarbonate thrapy is not necessary since insulin therapy alone will result in resolution of most of the metabolic acidosis.
2. Patiens with potentially life threatening hyperkalemia, since bicarbonate therapy in acidemic patients drives potassium into cells, thereby lowering the serum potassium concentration.
The conclusion is administering bicarbonate therapy is recommended if the pH is less than 6.9. Give 100mls of 8.4% of Na bicarbonate (can be added into 400mls of D5%) together with 20mmol of KCl if the serum K is less than 5.3 mmol/l and administered over two hours.
She has a pink cannula (20G) in her right arm. After scrutinizing the case notes (no attached intravenous fluid chart), we concluded that she received the appropriate IV fluid replacement therapy. From the ABG, she had a high AG metabolic acidosis, pH of 7.15. Urine ketone was positive, blood sugar level on admission was 41mmol/l, serum Na 125 and K 4.5. We also noted that IV NaHCO3 was given by medical medical officer to treat the acidosis. Ten units of IV insulin was given but the sliding scale has not been started.
The question is "Is Na bicarbonate therapy is indicated to treat high anion gap acidosis in DKA?"
Let me start with the major effects of metabolic acidosis on the body
Respiratory effects:
1. Hyperventilation (Kussmaul respirations) - as compensatory response
2. Shift of ODC to the right
3. Decreased 2,3 DPG in the red cells (shift the ODC back to the left)
Cardiovascular effects:
1. Depression of myocardial contractility
2. Sympathetic overactivity (include tachycardia, vasoconstriction, decreased arrythmia threshold)
3. Resistance to the effects of catecholamines
4. Peripheral arteriolar vasodilation
5. Venoconstriction of peripheral veins
6. Vasoconstriction of pulmonary arteries
7. Effects of hyperkalemia on heart
The cardiac stimulatory effects of sympathetic activity and release of cathecolamines usually counteract the direct myocardial depression while plasma pH remains above 7.2. At systemic pH values less than this the direct depression of contractility usually predominates. The direct vasodilation is offset by the indirect sympathetically mediated vasoconstriction and cardiac stimulation during a mild acidosis. The venoconstriction shifts blood centrally and this causes pulmonary congestion. Pulmonary artery pressure usually rises during acidosis.
Other effects:
1. Increased bone resorption (chronic acidosis only)
2. Shift of K out of cells causing hyperkalaemia
The effect on K level is variable and indirect effects due to the type of acidosis present are much more important. e.g. hyperkalaemia in renal failure is due to uraemic acidosis rather than the acidosis. In DKA, singnificant K loss due to osmotic diuresis, therefore the K level at presentation is variable although total body K stores are invariably depleted. Treatment with fluid and insulin can cause a prompt and marked fall in plasma K. Hypokalaemia may be than a problem.
Bicarbonate is an anion and cannot be given alone. Its therapeutic use is as a solution of Na bicarbonate. An 8.4% solution is a molar solution ( i.e. contains 1 mmol of HCO3 per ml). Thi solution is very hypertonic and its osmolality is 2,000 mOsm/kg.
The main goal of alkali therapy
1. to counteract the extracellular acidemia with the aim of reversing or avoiding the adverse clinical effects of the acidosis (esp adverse CVS effects).
2. Emergency management of hyperkalemia
3. To promote alkaline diuresis (e.g. to hasten salicylate excretion)
Undesirable effects of bicarbonate administration:
1. Hypernatremia
2. Hyperosmolality
3. Volume overload
4. Rebound or overshoot alkalosis
5. Hypokalaemia
6. Impaired oxygen unloading due to left shift of the ODC
7. Acceleration of lactate production by removal of acidotic inhibition of glycolysis
8. CSF acidosis
9. Hypercapnia
Important points about bicarbonate:
1. Ventilation must be adequate to eliminate the CO2 produced from bicarbonate. If hypercapnia occurs, CO2 crosses the cell membranes easily and intracellular pH may decrease even further with further deterioration of cellular function.
2. Bicarbonate may cause clinical deterioration if tissue hypoxia is present. This is due to increased lactate production (removal of acidotic inhibition of glycolysis) and the impairment of tissue oxygen unloading (left shift of ODC due to increased pH). This means that with lactic acidosis or cardiac arrest then bicarbonate therapy may be dangerous.
3. Bicarbonate is probably not useful in most cases of high anion gap acidosis.
4. The preferred management of metabolic acidosis is to correct the primary cause and to use specific treatment for any potentially dangerous complications.
5. Bicarbonate therapy may be useful for correction of acidemia due to non-organic or mineral acidosis (i.e. normal anion gap acidosis).
Diabetes Ketoacidosis - summary of events in pathophysiology of DKA:
1. A precipitating event occurs which results in insulin deficiency (absolute or relative) and usually an excess of stress hormones (particularly glucagon)
2. Hyperglycemia occurs due to decreased gluconse uptake in fat and muscle cells due to insulin deficiency
3. Lipolysis in fat cells now occurs promoted by the insulin deficiency releasing FFA into the blood
4. Elevated FFA levels provide substrate to the liver
5. A switch in hepatic lipid metabolism occurs due to the insulin deficiency and glucagon excess, so the excess FFA is metabolised resulting in excess production of acetyl CoA
6. The excess hepatic acetyl CoA is converted to acetoacetate which is released into the blood
7. Ketoacidosis and hyperglycemia both occur due to the lack of insulin and the increase in glucagon and most of the clinical effects follow from these two factors
8. Other acid-base and electrolyte disorders may develop as a consequence and complicate the clinical condition.
Oher acid base disorders may be present: Possible complicating acid base disorders are
1. Lactic acidosis due to hypoperfusion and anaerobic muscle metabolism
2. Metabolic alkalosis secondary to excessive vomiting
3. Respiratory alkalosis with sepsis
4. Respiratory acidosis due to pneumonia or mental obtundation
5. Renal tubular acidosis type 4 - the syndrome known as hyporeninemic hypoaldosteronism occurs in some elderly diabetics who have pre-existing moderate renal insufficiency by is not a common problem in acute DKA.
Correction of acidosis in DKA
This occurs more slowly than the correction of blood glucose but the use of bicarbonate in DKA remains controversial (Viallon CCM 1999) . In most studies the use of bicarbonate fails to provide any hemodynamic benefit that could not be attributed purely to osmotic load of sodium administered (Cooper ICM 1994). Therefore the evidence of benefits are lacking (Latif KA Diabetes care 2002). In a randomized trial of 24 DKA patients with admission arterial pH between 6.9 and 7.4 bicarbonate therapy did not change morbidity of mortality (Morris LR Ann inter med 1986). The study was small, limited to arterial pH 6.9 and above. There was no difference in the rate of rise in the arterial pH and serum bicarbonate and placebo groups. No prospective trial in DKA with pH values less than 6.9. Below pH 6.9 most authorities would recommend the use of bicarbonate to correct the pH partially.
There is no doubt that blood pH can be improved, but at the expense of worsening intracellular acidosis (Forsythe Chest 2000). Neurologic deterioration has been reported due to paradoxical fall in cerebral pH (Narins RG Ann Intern Med 1987). Other side effects of bicarbonate are listed above.
In the context of DKA, sodium bicarbonate also delays the clearance of ketones and may further enhance hepatic production even when insulin and glucose are being delivered (Okuda J Clin Endocrinol Metab 1996). This may slow the rate of recovery of the ketosis. At pH of > 7.0 insulin will block lipolysis and ketoacid production.
Selected patients who may benefit from cautious alkali therapy (Narins RG Ann Intern Med 1987):
1. Patients with an arterial pH of 7.0 in whom decreased cardiac contractality and vasodilation can further impair tissue perfusion. At an arterial pH above 7.00 most experts agree that bicarbonate thrapy is not necessary since insulin therapy alone will result in resolution of most of the metabolic acidosis.
2. Patiens with potentially life threatening hyperkalemia, since bicarbonate therapy in acidemic patients drives potassium into cells, thereby lowering the serum potassium concentration.
The conclusion is administering bicarbonate therapy is recommended if the pH is less than 6.9. Give 100mls of 8.4% of Na bicarbonate (can be added into 400mls of D5%) together with 20mmol of KCl if the serum K is less than 5.3 mmol/l and administered over two hours.
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