AS A REFLECTION of insulinopenia, ketonuria is a potentially serious diabetic emergency that can rapidly progress to diabetic ketoacidosis. By definition, ketonuria is characterized by the appearance of ketone bodies in the urine, usually preceding diabetic ketoacidosis by at least several hours. The development of diabetic ketoacidosis, which is indicated by a blood pH of less than 7.30, accounts for 85% of hospitalizations and is the No. 1 cause of death in children with type 1 diabetes mellitus.1 It is well recognized that diabetic ketoacidosis is usually preventable in patients known to have diabetes if the ketonuria is recognized early and treated quickly and appropriately, and if the patients fully comply with prescribed insulin regimens.2
Currently, home management of ketonuria involves taking supplemental doses of regular insulin and increasing fluid intake. Although such practices have been shown to be efficacious,2 a new form of insulin with a rapid onset, insulin lispro (Humalog, Eli Lilly & Co, Indianapolis, Ind), has the potential to treat ketonuria more effectively. Insulin lispro is a quick-acting analog of human insulin that takes effect within 10 to 20 minutes, peaks within 30 to 90 minutes, and works for approximately 4 hours.3-7 The use of insulin lispro to treat ketonuria has not previously been documented in the medical literature.
The purpose of this study was to compare the use of insulin lispro with the use of regular insulin in the outpatient management via telephone of ketonuria in children with known diabetes.
METHODS
POPULATION
This prospective study analyzed the telephone records of children treated over the telephone by registered nurses, physicians, and physician assistants at the Barbara Davis Center for Childhood Diabetes, Denver, Colo. All patients in the study were children or adolescents (age range, 0-19 years) with type 1 diabetes mellitus whose parents called the center for assistance between November 1996 and March 1997 when their children experienced episodes of ketonuria. Because at least half of the 1700 children actively followed up at the center had switched regimens to receive insulin lispro, it was anticipated that parents of patients who were using either human regular insulin or insulin lispro would call the center when moderate or large ketonuria developed. When appropriate, the children were treated at home with the type of insulin they had already been receiving.
DATA COLLECTION
For the purposes of this study, health care providers were asked to document the exact time of all telephone calls related to ketonuria, the home blood glucose (HBG) concentration of the patients who called, the level of ketonuria, the usual insulin dose, the prescribed supplemental dosage, the likely cause of the ketonuria, the patient's caregiver, and any other factors related to the ketonuria incident. Long-acting insulin therapy was continued, although the amount was reduced for 14 of the patients (all of whom had vomited at least 1 time). In addition to supplemental short-acting insulin injections, fluid intake, for example, fruit juice or water, was strongly encouraged if the patient was not vomiting.
Once management had been established, the health care provider instructed the family to keep in touch via telephone every 3 hours. At the time of each telephone call, the family provided the health care worker with updated urine ketone and HBG levels. The telephone calls and monitoring of urine ketone levels and HBG measurements continued until the urine ketone levels decreased to small, trace, or negative amounts.
OUTCOME
Outcome was based on the number of successful home management episodes (ie, prevented hospitalizations), the amount of insulin required by the patients, and the time to resolution of small, moderate, or large ketonuria in patients receiving regular insulin compared with those receiving insulin lispro.
STATISTICAL ANALYSIS
Statistical tests were used to assess the null hypothesis that regular insulin and insulin lispro have different resolution times and require different dosages. Only the first episode of ketonuria in each patient was analyzed to prevent undue influence from any 1 patient in a group. Due to differences in sample size, for all comparisons both the Mann-Whitney and the Student t test for uneven groups were applied to both the time until resolution of ketonuria and the insulin dose needed. Calculations for the Student t test were performed using Microsoft Excel version 5.0 (Microsoft, Seattle, Wash).
RESULTS
The staff (H.P.C. and those listed in the Acknowledgments) managed a total of 79 episodes of ketonuria in 75 patients in their homes during the 5-month course of observation. Of these episodes, 57 met the criteria for data analysis. Twelve episodes were excluded from data analysis because the patient's family did not report back to the health care provider after theinitial telephone contact. Four other episodes were excluded because of repeat episodes of ketonuria, of which only the first was included. Two patients had 2 episodes and 1 patient had 3 episodes. The latter patient had an emergency department visit; however, hospitalization was not required for any of the patients who had repeat episodes. Six patients who received mixtures of regular insulin and insulin lispro were eliminated from the study. The 57 patients in the study were divided into 2 groups, depending on whether they were receiving insulin lispro or regular insulin.
DEMOGRAPHIC DATA
The patient population consisted of 32 boys and 25 girls with similar male-female distributions in the insulin lispro and regular insulin groups (Table 1). The ages of the patients ranged from 1 to 18 years. Their weight ranged from 8.0 to 90.9 kg, with similar means for the 2 groups. The mean duration of diabetes was similar in the insulin lispro group (5.0 years) and the regular insulin group (5.5 years). Most (46 [81%]) telephone calls received by the health care workers were from concerned parents who were the caregivers. Illness was the most common cause (42 [74%]) of ketonuria.
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Table 1. Patient Characteristics
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BLOOD GLUCOSE AND KETONE LEVELS
There were 34 patients in the insulin lispro group and 23 patients in the regular insulin group. Twenty-two patients presented with moderate urine ketone values, 31 presented with large values, and 4 presented with small values (Table 2). Because we do not instruct families to call for assistance if urine ketone measurements are small (unless there are other problems, eg, vomiting) only 4 families reported small ketonuria.
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Table 2. Initial Home Blood Glucose (HBG) and Urine Ketone Measurements
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The average blood glucose value (Table 2) for the insulin lispro group was based on a total of 30 patients, since measurement values were unknown for 2 patients and blood glucose levels of 2 patients exceeded the measurement capacity of 27.75 mmol/L (500 mg/dL) on the glucose meter. In the regular insulin group, average blood glucose values were based on 21 patients, since blood glucose values of 2 patients exceeded the measurement capacity of the glucose meter.
INSULIN DOSAGE
The average extra total dose (range) of short-acting insulin above the usual dosage was 5.7 U (0-32 U) or 0.15 U/kg (0-0.78 U/kg) for the insulin lispro group from the first telephone call to the resolution of large ketonuria (Table 3). The comparable dose for the regular insulin group was 5.2 U (0-32 U) or 0.15 U/kg (0.04-0.48 U/kg) (P>.05). For patients presenting with moderate urine ketone values, the average insulin dose (range) was 5.7 U (0-22 U) or 0.2 U/kg (0-0.89 U/kg) for the insulin lispro group compared with 3.8 U (0-0.16 U) or 0.07 U/kg (0-0.16 U/kg) for the regular insulin group (P>.05).
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Table 3. Supplemental Insulin Dose Requirement and Time Until Resolution of Ketonuria*
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The long-acting insulin dosage was reduced for 6 patients treated with insulin lispro and for 8 patients treated with regular insulin. All 14 patients had vomited at least 1 time before calling in for an insulin dose. The mean reduction was 3.5 U per patient for insulin lispro and 4.8 U per patient for regular insulin. The other 28 patients in the insulin lispro group and 15 patients in the regular insulin group continued to receive their usual dosages of long-acting insulin.
DURATION
The time until resolution of ketonuria was comparable in the insulin lispro and the regular insulin groups for patients with both moderate and large urine ketone values (Table 3). For moderate ketone measurements, the average duration (range) was 4.0 hours (1-16 hours) in the insulin lispro group, compared with 4.2 hours (2-8 hours) for the regular insulin group (P>.05). For large ketone measurements, the average duration (range) was 4.6 hours (1.6-24 hours) for the insulin lispro group, compared with 4.3 hours (2-8 hours) for the regular insulin group (P>.05).
ADVERSE EFFECTS
Hypoglycemia, which is characterized by a blood glucose concentration of less than 3.25 mmol/L (<60 mg/dL), occurred in 3 of 34 patients in the insulin lispro group, compared with 1 of 23 patients in the regular insulin group. No severe insulin reactions, such as loss of consciousness or seizures, occurred in either group, and no other adverse effects were observed.
OUTCOME
No patients for whom treatment was attempted by telephone required hospitalization in this study. A visit to the emergency department was also not required for 59 (94%) of the 63 patients managed for ketonuria by telephone. For large ketonuria, a visit to the emergency department was required for 1 patient who received insulin lispro and for 3 patients who received regular insulin. No other patients required visits to the hospital.
COMMENT
This study shows that insulin lispro is at least as effective as regular insulin in treating ketonuria. The doses and the times until resolution of moderate or large urine ketone values were similar for both types of insulin. Insulin lispro is the first rapid-acting, short-lasting insulin. It begins to take effect within 10 to 20 minutes of administration, and works for approximately 4 hours.3, 7 In contrast, regular insulin acts within 30 to 90 minutes and works for 13 hours.5-6 The absorption of both types of insulin is likely delayed in patients who are dehydrated. Because insulin lispro is most effective within 2 hours of administration, future studies in which this shorter period is used between injections may demonstrate that insulin lispro is more effective than regular insulin in reversing ketonuria. As the quantities of liquids consumed by the patients in this study were not documented, varied intake could have affected the time to resolution of ketonuria.
All patients and families were educated regarding the early signs of ketonuria, how and when to test urine ketone levels, and the steps to take if ketonuria was detected. This was initially accomplished with an educational book8 and a videotape and was reinforced at subsequent clinic visits. The patient and the patient's family were instructed to test for ketonuria if the child felt ill, vomited 1 or more times, or if the patient's HBG test results were greater than 13.3 mmol/L (240 mg/dL). Patients were advised to call their diabetes care providers immediately if their urine ketone values were moderate or large.
Four of 63 patients who were initially managed over the telephone eventually required a visit to the emergency department. The 94% success rate in preventing hospitalization was similar to that reported in our previous study.2 All 4 patients sent to the emergency department had persistent vomiting, and 3 patients had suspected dehydration. The fourth patient, who was managed with regular insulin, was a girl whose HBG concentration was as low as 2.30 mmol/L (41 mg/dL). She was sent to the emergency department since further hypoglycemia was a concern.
The 100% success rate in preventing hospitalization for patients for whom home treatment was attempted was similar to that reported in our previous study.2 Patients were not treated at home by telephone for the following reasons: if they had Kussmaul respirations, excessive weakness, or dryness of the mouth, and if the patients or their families were not considered reliable. When patients were not treated at home, the families were instructed to go directly to the emergency department. In the current study, outpatient management was not attempted for 2 patients who called the center during the 5-month study period. In 1 patient, obvious Kussmaul respirations, which were correctly diagnosed over the telephone, led to direct hospitalization. The other patient did not require hospitalization, but was considered unreliable, so he was taken directly to his local physician for evaluation and then treated as an outpatient. For all 79 episodes documented in our study, including the 16 episodes excluded in the final analysis, 1 child (1.3%) was hospitalized and 6 children (7.6%) went to the emergency department. Thus, including the episodes that were excluded in the final analysis, hospitalization was avoided 99% of the time and visits to the emergency department were avoided 92% of the time.
In the 17 years that our center has been open, no patient who has been actively followed up (seen within 12 months) has ever died from ketoacidosis at the center. The availability of a physician and/or diabetologist on call 24 h/d and of support staff to handle calls from sick patients during clinic hours are the most likely reasons for this success. It is essential that physicians and other health care workers make themselves available to care for patients in their homes, particularly if the patient is vomiting. In conclusion, the use of insulin lispro appears to be an effective option for the management of ketonuria in the outpatient setting.
| Editor's Note: Physicians now have 2 options for managing patients with ketonuria in the outpatient setting. I hope the authors or others will now do the study to see which, if either, option is more effective.—Catherine D. DeAngelis, MD
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Accepted for publication February 24, 1998.
This study was supported by grant M01 RR00069 from the General Clinical Research Centers Program, National Centers for Research Resources, National Institutes of Health, Bethesda, Md, and by the Children's Diabetes Foundation, Denver, Colo.
We thank the following staff members at the Barbara Davis Center for Childhood Diabetes for their assistance with managing patients: Leslie Nobbe, RN, Sandy Hoops, CHA, Paul Jensen, RN, Susie Owen, RN, Cathy Johnson, RN, Carolyn Banion, RN, and Philippe Walravens, MD.
Reprints: H. Peter Chase, MD, 4200 E Ninth Ave, B140, Denver, CO 80262.
