Long-term, Continuous SC Octreotide for Hyperinsulinism
Long-term, Continuous SC Octreotide for Hyperinsulinism
Fifteen Japanese patients with diazoxide-unresponsive KATP CHI who were treated with continuous subcutaneous octreotide infusion for 4 months to 5·9 years were included in the study. At presentation, all patients showed blood glucose below 2·5 mmol/l (45·05 mg/dl) and insulin level greater than 25 pmol/l (3·6 μU/ml). The patients first underwent molecular diagnosis at Osaka City General Hospital while blood glucose levels were maintained by continuous glucose infusion. Then, the patients who were suspected with a possible focal KATP CHI, because a paternally inherited monoallelic mutation was found in either ABCC8 or KCNJ11, were further assessed by 18F-DOPA PET scan at Kizawa Memorial Hospital. The patients showing diffuse uptake or focal uptake in the head of the pancreas, which could be difficult to enucleate, were preferentially enrolled into the long-term octreotide treatment.
Mutational Analysis Mutational analysis of the KATP-channel genes, KCNJ11 and ABCC8, was performed as described previously. All exons and exon–intron boundaries were amplified from genomic DNA and directly sequenced. Deletion mutations that might not have been detected by the PCR-sequencing strategy were analysed by multiple ligation-dependent probe amplification (MLPA) of all 39 exons of the ABCC8 gene. The analyses were performed using SALSA MLPA kit P117 (MRC Holland, Amsterdam) as recommended by the manufacturer.
18F-DOPA PET 18F-DOPA PET studies were performed at the PET facility of Kizawa Memorial Hospital, as described previously. The scan results were fused with those of a CT scan performed at the same time to localise the focal lesion more accurately.
Octreotide Treatment The patients were treated with continuous, subcutaneous octreotide infusion using an insulin pump to maintain blood glucose levels higher than 3·33 mmol/l (60 mg/dl). Starting at a lower dose, the amount of octreotide was titrated up to 25 μg/kg/day to minimize the amount of IV glucose. Blood glucose was measured at least eight times a day at the initiation of the treatment by using a portable glucometer, and 1–4 times a day at home after the patient was discharged. The age of the patients at the initiation of octreotide was 11 day to 12 month. In four patients (patients 4, 11, 13, 14), octreotide was first initiated by multiple daily injections to confirm its effectiveness and then switched to continuous infusion within 4 weeks. Other treatments immediately before and after the initiation of octreotide are shown in Table 1 . After the initial stabilization of blood glucose and after the age of 4 months, most infants who did not undergo pancreatectomy were fed cornstarch up to 2 g/kg at bedtime to help reduce the required dosage of octreotide. Additional treatments (IV glucose, glucagon or enteral feeding) were administered as needed to maintain normoglycaemia. The study was conducted in accordance with the Declaration of Helsinki (British Medical Journal, 1964, ii, 177) after obtaining informed consent from the guardians, and the protocols for molecular diagnosis, 18F-DOPA PET and octreotide treatment were approved by the institutional review boards of each participating hospital.
Clinical and Laboratory Data Collection Clinical and laboratory data, which were collected from the medical record of each patient, included gestational age; birth weight; blood glucose and insulin at diagnosis; details of octreotide treatment and any additional treatment required to achieve euglycaemia; laboratory results including complete blood counts, blood chemicals (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, total protein, albumin, urea nitrogen, creatinine, total cholesterol, triglyceride), electrolytes, thyroid function tests and abdominal ultrasound; reports of short-term adverse effects such as abdominal symptoms; and long-term neurological and growth outcomes when applicable.
Subjects and Methods
Subjects
Fifteen Japanese patients with diazoxide-unresponsive KATP CHI who were treated with continuous subcutaneous octreotide infusion for 4 months to 5·9 years were included in the study. At presentation, all patients showed blood glucose below 2·5 mmol/l (45·05 mg/dl) and insulin level greater than 25 pmol/l (3·6 μU/ml). The patients first underwent molecular diagnosis at Osaka City General Hospital while blood glucose levels were maintained by continuous glucose infusion. Then, the patients who were suspected with a possible focal KATP CHI, because a paternally inherited monoallelic mutation was found in either ABCC8 or KCNJ11, were further assessed by 18F-DOPA PET scan at Kizawa Memorial Hospital. The patients showing diffuse uptake or focal uptake in the head of the pancreas, which could be difficult to enucleate, were preferentially enrolled into the long-term octreotide treatment.
Methods
Mutational Analysis Mutational analysis of the KATP-channel genes, KCNJ11 and ABCC8, was performed as described previously. All exons and exon–intron boundaries were amplified from genomic DNA and directly sequenced. Deletion mutations that might not have been detected by the PCR-sequencing strategy were analysed by multiple ligation-dependent probe amplification (MLPA) of all 39 exons of the ABCC8 gene. The analyses were performed using SALSA MLPA kit P117 (MRC Holland, Amsterdam) as recommended by the manufacturer.
18F-DOPA PET 18F-DOPA PET studies were performed at the PET facility of Kizawa Memorial Hospital, as described previously. The scan results were fused with those of a CT scan performed at the same time to localise the focal lesion more accurately.
Octreotide Treatment The patients were treated with continuous, subcutaneous octreotide infusion using an insulin pump to maintain blood glucose levels higher than 3·33 mmol/l (60 mg/dl). Starting at a lower dose, the amount of octreotide was titrated up to 25 μg/kg/day to minimize the amount of IV glucose. Blood glucose was measured at least eight times a day at the initiation of the treatment by using a portable glucometer, and 1–4 times a day at home after the patient was discharged. The age of the patients at the initiation of octreotide was 11 day to 12 month. In four patients (patients 4, 11, 13, 14), octreotide was first initiated by multiple daily injections to confirm its effectiveness and then switched to continuous infusion within 4 weeks. Other treatments immediately before and after the initiation of octreotide are shown in Table 1 . After the initial stabilization of blood glucose and after the age of 4 months, most infants who did not undergo pancreatectomy were fed cornstarch up to 2 g/kg at bedtime to help reduce the required dosage of octreotide. Additional treatments (IV glucose, glucagon or enteral feeding) were administered as needed to maintain normoglycaemia. The study was conducted in accordance with the Declaration of Helsinki (British Medical Journal, 1964, ii, 177) after obtaining informed consent from the guardians, and the protocols for molecular diagnosis, 18F-DOPA PET and octreotide treatment were approved by the institutional review boards of each participating hospital.
Clinical and Laboratory Data Collection Clinical and laboratory data, which were collected from the medical record of each patient, included gestational age; birth weight; blood glucose and insulin at diagnosis; details of octreotide treatment and any additional treatment required to achieve euglycaemia; laboratory results including complete blood counts, blood chemicals (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, total protein, albumin, urea nitrogen, creatinine, total cholesterol, triglyceride), electrolytes, thyroid function tests and abdominal ultrasound; reports of short-term adverse effects such as abdominal symptoms; and long-term neurological and growth outcomes when applicable.