Researchers from a consortium of hospitals including Children’s Hospital of Philadelphia (CHOP) have identified factors that make children with diabetic ketoacidosis more likely to experience acute kidney injury. Analyzing data from a large, multicenter clinical trial, the researchers also found that children who experience acute kidney injury are more likely to also experience subtle cognitive impairment and demonstrate lower IQ scores, suggesting a pattern of multiple organ injury.
The findings were published online today in JAMA Network Open.
Multiple recent studies have shown that organ injuries in children with diabetic ketoacidosis occur more frequently than previously thought.
One recent retrospective study found that acute kidney injury commonly occurs in these children. Earlier analysis of a large, multicenter study demonstrated cerebral injury commonly occurs in diabetic ketoacidosis.
Together, these studies raised the possibility of an underlying pathophysiology that connects these injuries across the body if the presence of these injuries were linked in patients.
“We wanted to look at these issues in a more prospective manner,” said Sage Myers, MD, an attending physician in the Emergency Department at CHOP and first author of the study. “With 13 participating emergency departments in the Pediatric Emergency Care Applied Research Network, we had the ability to not only study the frequency of acute kidney injury in these children, but also the underlying factors associated with injury and whether there is an association between the occurrence of acute kidney injury and cerebral injury, which would suggest a possible linkage between the mechanisms of injury underlying both.”
The researchers studied 1,359 episodes of diabetic ketoacidosis in children. Acute kidney injury occurred in 584 (43%) of those episodes, and 252 of those episodes (43%) were classified as either stage 2 or 3, representing more severe cases of kidney injury.
When assessing whether acute kidney injury was associated with cognitive issues, children with kidney injuries had lower scores on short-term memory tests during diabetic ketoacidosis, as well as lower IQ scores three to six months after recovering from the condition.
These differences persisted after adjusting for the severity of diabetic ketoacidosis and demographic factors like socioeconomic status.
“If we can identify the mechanisms of kidney injury after diabetic ketoacidosis, it can help in the development of new therapeutic and preventive strategies,” said Nathan Kuppermann, MD, professor and chair of emergency medicine at UC Davis Health, and senior author and co-principal investigator of the study.
“We’re also hoping to focus future research on how diabetic ketoacidosis causes simultaneous, multi-organ injuries such as what we demonstrated in this study.”
Diabetic ketoacidosis (DKA) represents a profound insulin-deficient state characterized by hyperglycemia (>200 mg/dL [11.1 mmol/L]) and acidosis (serum pH <7.3, bicarbon- ate <15 mEq/L [15 mmol/L]), along with evidence of an accumulation of ketoacids in the blood (measurable serum or urine ketones, increased anion gap).
Dehydration, electrolyte loss, and hyperosmolarity contribute to the presentation and potential compli- cations. DKA is the most common cause of death in children who have type 1 diabetes. Therefore, the best treatment of DKA is prevention through early recognition and diagnosis of diabetes in a child who has polydipsia and polyuria and through careful attention to the treatment of children who have known diabetes, particularly during
Patients who have DKA generally present with nausea and vomiting. In individuals who have no previous diagnosis of diabetes mellitus, a preceding history of polyuria, polydipsia, and weight loss usually can be elicited. With significant ketosis, patients may have a fruity breath. As the DKA becomes more severe, patients develop lethargy due to the acidosis and hyperosmolarity; in severe DKA, they may present with coma.
Acidosis and ketosis cause an ileus that can lead to abdominal pain severe enough to raise concern for an acutely inflamed abdomen, and the elevation of the stress hormones epinephrine and cortisol in DKA can lead to an elevation in the white blood cell count, suggesting infection.
Thus, leukocytosis during DKA is not a reliable indicator of infection. On the other hand, infection can be a precipitant of DKA. Therefore, careful evaluation is important, with early treatment of any infection.
The most common cause for DKA in a patient who has known diabetes is omission of insulin doses. Such action can result from failure of an insulin pump, prolonged discon- nection from an insulin pump without appropriate monitoring, and improper discontin- uation of insulin during an illness associated with poor oral intake.
For an older child who has the responsibility for managing his or her diabetes without adult oversight, DKA most often is caused by the child forgetting to administer insulin doses. Recurrent DKA almost always is caused by intentional omission of insulin. Improved oversight of diabetes management can eliminate this cause of DKA, but adherence can be a challenge for older teens developing independence from their parents.
Intercurrent illnesses can increase insulin requirements, and a failure to meet the increased requirement can lead to ketoacidosis in a child who has diabetes. However, careful monitoring during illnesses should identify ketosis early so proper management canbe provided to prevent deterioration to DKA or to identify DKA at an early, mild stage, when treatment can lower the risk of morbidity and mortality.
Treatment of DKA is aimed at correcting the metabolic abnormalities while avoiding complications that can oc- cur during correction. Therapy consists of fluid and electrolyte replacement, insulin administration, and care- ful ongoing monitoring of clinical and laboratory factors (Figure).
Fluid and Electrolyte Replacement
The osmotic diuresis produced by glucosuria results in large water and electrolyte losses, exacerbated by com- promised intake due to nausea and vomiting. Intrave- nous fluid replacement is begun as soon as the diagnosis of DKA is established. Initial fluid resuscitation begins with 10 mL/kg of isotonic fluid, either 0.9% saline or lactated Ringer solution, administered over 1 hour. For more critically ill children, for whom there is concern over impending cardiovascular collapse, additional resus- citation fluid should be administered more rapidly.
After the initial fluid resuscitation, the remainder of
the fluid deficit is replaced evenly over 48 hours. Most patients who have DKA are approximately 6% dehy- drated (10% for children <2 years). For patients present- ing with more severe DKA (serum glucose >600 to 800 mg/dL [33.3 to 44.4 mmol/L] and pH <7.1), fluid losses are approximately 9% of body weight (15% for children <2 years).
Maintenance fluid requirements are added to this deficit replacement to provide the total fluid requirements, which rarely exceed 1.5 to 2 times the usual daily fluid requirement. Urine losses generally are not replaced to avoid excessively rapid fluid delivery.
However, careful attention to the fluid balance during treatment is necessary to identify the patients who will need additional fluid. The 0.9% saline (with added potas- sium) is continued as the hydration fluid until the blood glucose value declines to less than 300 mg/dL (16.7 mmol/L).
At that time, our practice is to change the fluid to D5 0.45% saline (with added potassium). The American Diabetes Association recommendation is that deficit replacement fluids contain at least 0.45% saline with added potassium. If the blood glucose concentration declines below 150 mg/dL (8.3 mmol/L), the dextrose content may need to be increased to 10% or even 12.5%.
Patients who have DKA may present with high, normal, or low serum potassium values. However, all affected patients have total body potassium depletion. Both insulin treatment of DKA and correction of the acidosis cause potassium to move intracellularly.
Because of this effect, hypokalemia is a potentially fatal complication during treatment of DKA. Unless the patient exhib- its hyperkalemia or anuria, potassium should be added to the intravenous fluids at the beginning of the second hour of therapy. Otherwise, potassium is added as soon as urine output is established or the hyperkalemia abates.
If the patient presents with hypokalemia, potassium re- placement is initiated immediately. Most patients require 30 to 40 mEq/L of potassium in the replacement fluids, with adjustment based on serum potassium concentra- tions that are measured every 1 to 2 hours.
DKA results in significant phosphate depletion, and serum phosphate values decrease during treatment. Hy- pophosphatemia may cause metabolic disturbances.
However, clinical studies have not shown benefit from phosphate replacement during the treatment of DKA, although phosphate replacement should be given if the values decrease below 1 mg/dL.
Even in the absence of severe hypophosphatemia, however, many clinicians elect to provide phosphate in intravenous fluids, typically by giving half of the potas- sium replacement as potassium phosphate. This practice decreases chloride delivery to the patient, minimizing the hyperchloremic metabolic acidosis that occurs in most patients.
he hyperchloremia generally is of no clinical significance, although it can confound the clinician’s interpretation of DKA resolution. Administration of potassium acetate to provide the other half of the potassium replacement further decreases the chloride load. The serum calcium concentration must be monitored if phos- phorus is given, due to the risk of hypocalcemia. If hypocalcemia develops, phosphate administration should be stopped.
Bicarbonate losses are large in DKA. However, during the treatment of DKA, the patient can produce substan- tial bicarbonate as insulin stimulates the generation of bicarbonate from the metabolism of ketones. Consistent with this, clinical trials have failed to show any benefit of bicarbonate administration during the treatment of DKA.
Potential risks of bicarbonate therapy include para- doxic central nervous system acidosis and exacerbation of hypokalemia. Bicarbonate treatment also has been asso- ciated with cerebral edema, the most common cause of mortality for children who have DKA.
Therefore, bicarbonate treatment should be considered only in cases of extreme acidosis, such as for the patient whose pH is <6.9, when the acidosis may impair cardiovascular stability, or as treatment of life-threatening hyperkalemia.
If bicarbonate administration is believed to be necessary, 1 to 2 mmol/kg (added to 0.45% saline) should be provided over 1 to 2 hours.
Insulin treatment is begun after the initial fluid resuscitation; that is, at the beginning of the second hour of therapy (beginning insulin treatment at the same time as fluid resuscitation increases the risks of severe hypokalemia and of rapidly and excessively decreasing the serum osmolarity). Insulin is administered as a continuous in- travenous infusion of regular insulin at a rate of 0.1 units/kg per hour; a bolus should not be given at the start of therapy.
The infusion tubing should be prepared by running 30 to 50 mL of the insulin solution through the tube to saturate binding sites on the tube lining. If intravenous administration of insulin is not possible, short- or rapid-acting insulin injected intramuscularly or subcutaneously every 1 or 2 hours can be effective.
Resolution of the acidosis in DKA invariably takes longer than the time to achieve a normal blood glucose concentration. The temptation to decrease the rate of insulin administration based on glucose values should be resisted because this practice delays resolution of the acidosis.
The dose of insulin should remain at 0.1 units/kg per hour until the acidosis resolves (pH >7.3, bicarbonate >15 mEq/L [15 mmol/L]). The insulin dose should be decreased only if hypoglycemia or a decrease in serum glucose persists despite administra- tion of maximal dextrose concentrations in the intrave- nous fluid. If the acidosis is not resolving, the insulin dose should be increased to 0.15 or 0.20 units/kg per hour.
The initial assessment of a patient who has DKA involves evaluation of vital signs and the physical examination, including mental status and a neurologic evaluation. Such baseline assessments, along with results of laboratory testing, serve to determine if appropriate treatment for infection is necessary and to adjust fluid resuscitation based on the more in-depth evaluation of the cardiovas- cular status and the degree of the patient’s dehydration. In addition, if the patient is markedly obtunded, a naso- gastric tube should be placed to decrease the risk of aspiration.
Over the ensuing hours, vital signs and mental status are monitored at least every hour, and the balance of total fluid intake and fluid output is calculated each hour. The goal of monitoring is to ascertain that the patient shows signs of rehydration and improving mental status over time along with biochemical resolution of the DKA.
Serum glucose, electrolytes (including blood urea nitrogen and creatinine), and pH and urine ketones should be measured at presentation. Subsequently, serum glucose and pH should be measured hourly, with serum electrolytes and urine ketones assessed every 2 to 3 hours.
If phosphate is administered, serum calcium concentrations must be monitored. The goal for correc- tion of hyperglycemia is to induce a 100-mg/dL (5.6- mmol/L) per hour decrease in the serum glucose value. The persistence of severe hyperglycemia suggests inade- quate rehydration (or incorrect mixing of the insulin).
Too rapid a decrease, however, may indicate too rapid a rate of rehydration. After the first hour, the pH should increase at least 0.03 units per hour. A slower rise sug- gests a need for a higher insulin dose or for increased hydration.
Hyperglycemia causes the osmotic shift of water into the intravascular compartment, causing dilutional hypo- natremia. The calculation for the corrected sodium con- centration accounts for this effect:
Both the measured and the corrected serum sodium values should increase as the serum glucose concentration decreases during treatment of DKA. A failure of the corrected sodium value to rise or, even more signifi- cantly, a fall in either sodium value suggests overly rapid rehydration.
Cerebral edema is responsible for most of the deaths due to DKA in children, and significant neurologic morbidity persists in many survivors. Although cerebral edema typ- ically presents 4 to 12 hours after treatment has begun, it can present later or earlier, including before treatment is initiated. The cause of cerebral edema in DKA is not known, although a number of mechanisms have been proposed.
These theories include cerebral ischemia and hypoxia, fluid shifts due to inequalities in osmolarity between the extravascular and intravascular intracranial compartments, increased cerebral blood flow, and al- tered membrane ion transport. Risk factors that have been identified for the development of cerebral edema include young age, DKA in a child who has undiagnosed diabetes, factors indicating a more severe presentation (pH <7.2 and lower serum bicarbonate concentration, higher serum glucose concentration, higher blood urea nitrogen concentration, a calculated serum sodium concentration in the hypernatremic range, and hypocapnia), a lack of rise of the corrected sodium concentration during rehydration, and treatment with bicarbonate.
Earlier uncontrolled studies had suggested that a higher rate of rehydration increased the risk of cerebral edema. Although subsequent controlled studies have not found the rate of fluid administration to be a factor for cerebral edema, current recommendations for more gradual, even fluid replacement during the treatment of DKA are re- lated to the concern that a higher rate of rehydration may increase the risk for cerebral edema.
The signs and symptoms of cerebral edema include severe headache, sudden deterioration in mental status, bradycardia (or a sudden, persistent drop in heart rate not attributable to improved hydration), hypertension, cranial nerve dysfunction, and incontinence. If sus- pected, immediate treatment should be initiated with 0.25 to 1.0 g/kg of intravenous mannitol. If the patient requires intubation, hyperventilation should be avoided because it has been shown to be associated with worse outcomes.
When the ketoacidosis has resolved, the patient may be weaned from intravenous fluids and intravenous insulin to oral intake and subcutaneous insulin. Criteria for this transition include a normal sensorium and normal vital signs, an ability to tolerate oral intake, and resolution of the acidosis, reflected by a normal pH, a serum bicarbon- ate value greater than 18 mEq/L (18 mmol/L), and a normal anion gap.
Because of excess chloride delivered with intravenous fluids during the treatment of DKA, many patients develop a hyperchloremic metabolic aci- dosis. In these patients, the pH and serum bicarbonate concentrations do not normalize completely in spite of the resolving ketoacidosis. When such patients achieve a normal anion gap, they should be “transitioned” from intravenous fluids and insulin to oral nutrition and sub- cutaneous insulin.
The action of intravenous insulin dissipates in min- utes. Therefore, intravenous insulin should not be dis- continued until a dose of insulin is administered subcu- taneously. When using rapid-acting insulin analogs, subcutaneous insulin can be given just before the intravenous infusion is stopped.
When administering regular insulin, the subcutaneous injection should be given 30 minutes before the infusion is stopped. It is best to make the transition from intravenous insulin to subcuta- neous insulin at the time of a meal. Details on the subsequent management of diabetes mellitus can be found in our previously published article (Cooke, 2008).