Successful treatment of dumping syndrome with diazoxide in an infant with hypoplastic left heart syndrome

in Endocrinology, Diabetes & Metabolism Case Reports
Authors:
Khalifah A Aldawsari Department of Pediatrics, Nicklaus Children’s Hospital, Miami, Florida, USA

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Claudia Mattos Department of Pediatrics, Nicklaus Children’s Hospital, Miami, Florida, USA

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Danyal M Khan The Heart Institute, Nicklaus Children’s Hospital, Miami, Florida, USA

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Omar Beckett Department of Endocrinology, Nicklaus Children’s Hospital, Miami, Florida, USA

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Pedro Pagan Department of Endocrinology, Nicklaus Children’s Hospital, Miami, Florida, USA

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Correspondence should be addressed to K A Aldawsari: Khalifah.aldawsari@nicklaushealth.org
Open access

Summary

Dumping syndrome is a rare but potentially serious condition that causes inappropriate postprandial hyperinsulinemia leading to hypoglycemia in children following gastrointestinal surgeries. While dietary modifications are often the first line of treatment, severe cases may require pharmacological intervention to prevent severe hypoglycemia. We present a case of successful treatment of dumping syndrome with diazoxide. A 2-month-old infant with left hypoplastic heart syndrome who underwent single ventricle palliation pathway and developed feeding intolerance that required Nissen fundoplication. Postprandial hypoglycemia was detected following the procedure, with glucose level down to 12 mg/dL, and the diagnosis of dumping syndrome was established. The patient was successfully managed with diazoxide, which effectively resolved postprandial hypoglycemia without any major adverse events. The patient was eventfully weaned off the medication at the age of 5 months. This case highlights the potential role of diazoxide in the management of pediatric patients with postprandial hyperinsulinemic hypoglycemia secondary to dumping syndrome.

Learning points

  • Dumping syndrome is a possible complication of gastrointestinal surgeries and should be suspected in children with abnormal glucose levels.

  • Postprandial hyperglycemia should be monitored closely for significant subsequent hypoglycemia.

  • Diazoxide might be considered as part of the treatment plan for dumping syndrome.

Abstract

Summary

Dumping syndrome is a rare but potentially serious condition that causes inappropriate postprandial hyperinsulinemia leading to hypoglycemia in children following gastrointestinal surgeries. While dietary modifications are often the first line of treatment, severe cases may require pharmacological intervention to prevent severe hypoglycemia. We present a case of successful treatment of dumping syndrome with diazoxide. A 2-month-old infant with left hypoplastic heart syndrome who underwent single ventricle palliation pathway and developed feeding intolerance that required Nissen fundoplication. Postprandial hypoglycemia was detected following the procedure, with glucose level down to 12 mg/dL, and the diagnosis of dumping syndrome was established. The patient was successfully managed with diazoxide, which effectively resolved postprandial hypoglycemia without any major adverse events. The patient was eventfully weaned off the medication at the age of 5 months. This case highlights the potential role of diazoxide in the management of pediatric patients with postprandial hyperinsulinemic hypoglycemia secondary to dumping syndrome.

Learning points

  • Dumping syndrome is a possible complication of gastrointestinal surgeries and should be suspected in children with abnormal glucose levels.

  • Postprandial hyperglycemia should be monitored closely for significant subsequent hypoglycemia.

  • Diazoxide might be considered as part of the treatment plan for dumping syndrome.

Introduction

Hyperinsulinemic hypoglycemia (HH) is characterized by abnormally elevated insulin levels leading to hypoglycemia. HH can be secondary to various factors, such as medications, genetic syndromes, and malignancies (1). Postprandial HH due to dumping syndrome (DS) is a recognized complication following gastrointestinal surgery, with an incidence of 9% following fundoplication in one study, while another study reported a higher incidence rate up to 30% (1, 2). Therefore, it is important to consider the possibility of DS-induced HH when managing patients with hypoglycemia, especially in children with a history of gastrointestinal surgeries. The literature on the use of diazoxide in the treatment of pediatric patients with DS is exceedingly limited. This case describes hyperinsulinemic hypoglycemia consistent with DS in an infant with complex congenital heart disease, managed with diazoxide. We also reviewed the current literature pertaining to the clinical outcomes of diazoxide in children with DS.

Case presentation

A 2-month-old female infant was born at full term with a prenatal diagnosis of hypoplastic left heart syndrome to a healthy 39-year-old mother who developed gestational hypertension during the prenatal period. The patient was born with weight of 2.85 kg through spontaneous vaginal delivery and underwent echocardiography, which showed double-outlet right ventricle with inlet ventricular septal defect, mitral valve atresia, severe hypoplastic left ventricle, and moderate hypoplasia of the transverse aortic arch. The patient was admitted to the neonatal intensive care unit (NICU) for the management of congenital heart disease and hyperbilirubinemia, which was treated with phototherapy.

Given the echocardiographic findings, along with oxygen saturation at 80% while in room air, the patient was selected to undergo single ventricle palliation route. The patient underwent the Norwood procedure at 12 days of life (atrial septostomy, aortic arch reconstruction, central shunt with patent ductus arteriosus ligation). The patient developed feeding difficulty at 2 months of age and was diagnosed with gastroesophageal reflux disease (GERD) based on an upper gastrointestinal study. Subsequently, the patient underwent hiatal hernia repair with Nissen fundoplication and gastrostomy tube placement. Since the procedure, the patient was on bolus feeding 65 mL through the gastrostomy tube every 3 h with 24 kcal/oz formula, given over 1 h. The patient gained approximately 0.5 kg over a 20-day period while on this regimen.

Twenty days after the procedure, the patient began experiencing frequent hypoglycemic episodes, with a nadir point-of-care (POC) serum glucose level of 12 mg/dL. The Endocrinology service was consulted, and a critical sample was obtained 3.5 h after the last feed that demonstrated the presence of an elevated insulin level of 15.2 µIU, a glucose level <20 mg/dL, and an adequate response to hypoglycemia with a cortisol level of 55.1 µg/dL. Further endocrine evaluation, including thyroid function testing and genetic studies (Invitae Hypoglycemia Panel), yielded negative results. Based on these findings, the patient was diagnosed with hyperinsulinemic hypoglycemia. To further evaluate the hypothesis of DS, a formula tolerance test was performed, which involved monitoring the patient's glucose levels before and after feeding. During the test, the patient received 70 mL of Enfamil Gentlease formula (24 kcal/oz) over 60 min. The results showed a brisk increase in glucose levels from 62 to 189 mg/dL after 1 h of feeding, followed by a drop to 12 mg/dL within 5 h. These findings were consistent with DS, which occurs when there is rapid emptying of the stomach, resulting in an exaggerated insulin response that leads to immediate postprandial hyperglycemia followed by severe hypoglycemia. Additionally, stress-induced hyperinsulinemic hypoglycemia is another differential diagnosis to consider. However, the patient was hospitalized at our institution from the second day of life until 2 months of age. During this period, the patient experienced only one episode of mild hypoglycemia with glucose of 42 mg/dL on the second day of life while being NPO and receiving a starter TPN (with a glucose infusion rate of 4.3 mg/kg/min). Other than this instance, the patient remained normoglycemic until the fundoplication procedure. The frequency of glucose checks during that period was inconsistent, driven more by the clinical picture, as it was usually obtained as part of the blood gas, independent of the feeding status. These observations suggest that stress-induced HH is less likely to be the primary etiology in this case. Nevertheless, due to the severity of the cardiac disease, the possibility of concurrent stress-induced hyperinsulinism hypoglycemia cannot be entirely excluded.

A dietary modification was established by extending the feeding duration to 90 min and was in conjunction with the initiation of diazoxide at a dose of 7.5 mg/kg/day. Subsequently, there was a partial improvement in glucose levels, with a nadir of 51 mg/dL observed 2 h post feeding. Consequently, the dose of diazoxide was titrated up to 10 mg/kg/day, which led to an overall enhancement in glucose levels, as evidenced by a pre-prandial glucose level of 75 mg/dL and a postprandial level of 139 mg/dL at 4 h, without any significant hypoglycemic events. The patient was discharged home with the same dose of diazoxide (10 mg/kg/day) and several cardiac medications, including sotalol (3 mg t.i.d.), digoxin (15 µg b.i.d.), enalapril (0.4 mg b.i.d.), famotidine (4 mg b.i.d.), and subcutaneous enoxaparin (6 mg b.i.d.) for nonocclusive arterial thrombi. The standard diuretic therapy with Chlorothiazide was not started in lieu of furosemide (5 mg t.i.d.) that was added to the regimen for cardiac issues. The patient's weight upon discharge was 4.35 kg. The patient was monitored in the outpatient setting with blood glucose levels remaining above 60 mg/dL at home, thus maintaining the same dose of diazoxide and allowing gradually weaning through progressive weight gain. At 5 months of age, the patient was admitted for stage II palliative surgery, that included superior cavopulmonary anastomosis, atrial septectomy, and central shunt takedown. Diazoxide was discontinued perioperatively during the second hospitalization and was not resumed in the setting of consistent normoglycemia. Following an uneventful 12-day hospitalization, the patient was discharged with a blood glucose level that remained above 65. A fasting glucose test was not performed prior to discharge.

Discussion

The phenomena of DS can be subdivided into either early or late onset. Early DS occurs within 10–30 min postprandially and is due to a rapid shift of osmotic fluid from the stomach to the small intestine. This osmotic shift causes vasomotor symptoms such as flushing, tachycardia, and hypotension, as shown in Fig. 1. Late-onset DS occurs 1 h after a meal and is primarily caused by the rapid absorption of glucose into the bloodstream. This rapid absorption leads to hyperglycemia, followed by hyperinsulinemia and reactive hypoglycemia (3).

Figure 1
Figure 1

Illustration of DS.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 1; 10.1530/EDM-23-0137

In our patient, delayed onset DS was observed at the 5-h mark after feeding. This highlights the concern regarding the development of significant hypoglycemia despite the presence of normal to high levels of postprandial glucose. This phenomenon may be easily overlooked in young children or children with significant comorbidities, where the typical clinical symptoms of hypoglycemia are not apparent. Furthermore, the diagnosis of DS can be confirmed through a glucose tolerance test (2). The initial management strategy for DS involves dietary modifications, which include the consumption of small, frequent meals supplemented with fiber and starch (4). While octreotide is a viable treatment option, due to its ability to reduce insulin secretion and prevent reactive hypoglycemia, it is not the preferred pharmacotherapy. Its use requires subcutaneous injection prior to each meal, which may impact patient compliance, it may result in steatorrhea due to the inhibition of other pancreatic exocrine hormones, and it carries a dose related risk of necrotizing enterocolitis (NEC) (5, 6). Acarbose is an alpha-glycosidase inhibitor that delays carbohydrate absorption from ingested food, thus minimizing postprandial hyperglycemia. However, its use is limited by gastrointestinal side effects, mainly bloating (4).

Diazoxide is a potential treatment option that has both antihypertensive and antihypoglycemic properties. It functions by activating potassium channels in the beta cells of the pancreas, thereby reducing insulin secretion. Diazoxide has been widely used in the pediatric population for the treatment of congenital HH, with a favorable safety profile and good tolerability (7). Notable side effects of diazoxide include hypertrichosis and fluid retention, which may require concurrent diuretic therapy. Pulmonary hypertension represents a particularly concerning complication. The efficacy of diazoxide for the treatment of postprandial hypoglycemia secondary to DS has been demonstrated in three adult patients (8). Our case report describes the first case of diazoxide being used as a treatment for DS in a pediatric patient with complex congenital heart disease.

Careful monitoring of patients for potential side effects is essential during diazoxide therapy. Particular attention should be given to patients with congenital heart disease, as diazoxide-induced fluid retention may precipitate heart failure. Our patient was diagnosed with HLHS and underwent single ventricle palliation. However, no major adverse effects were observed with a diazoxide dose of 10 mg/kg/day and diuretic therapy with Furosemide. A comprehensive literature search of the PubMed database, utilizing the search term ‘dumping syndrome’ ‘postprandial hyperinsulinemic hypoglycemia’ with age criteria ranging from birth to 18 years, from inception to December 2023, yielded 224 results. The majority of the published studies were focused on the prevalence of DS as a complication of Nissen fundoplication. Upon review, only three studies examined diazoxide as a therapeutic option, summarized in Table 1. The total included patients were 3 with an age range from 2 years to 6 years. Notably, these studies utilized a combination of diazoxide and dietary modifications. Only one patient with complex gastrointestinal history and prematurity responded well to diazoxide with dose of 5 mg/kg/day (9).

Table 1

Summary of studies that evaluated diazoxide in children with DS.

Study Pts, n Age Medical/Surgical history Type of feeding Other PCT Diazoxide, dosage Side effects Comments
Mejia-Otero et al. (9) 1 6 years Prematurity, gastroschisis, jejunal atresia, short bowel resection, transplantation of liver, small bowel and pancreas at 1 year of age GT Loperamide failed Started at 3 mg/kg/day increased to 5 mg/kg/day None Successful control of glucose level
Rivkees & Crawford (10) 1 36 months GERD, underwent Nissen fundoplication Oral None 8 mg/kg/day None Failed to control glucose and insulin level
Musthaffa et al. (11) 1 4 years Congenital central hypoventilation Oral None 10 mg/kg/day Improved hypoglycemic episodes but worsening hyperglycemia readings

PCT, pharmacological treatments; Pts, patients.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent for publication was obtained from the parent of the patient.

Author contribution statement

All the authors have accepted responsibility for the entire content of the submitted manuscript and approved the submission.

References

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    Gϋemes M, Rahman SA, Kapoor RR, Flanagan S, Houghton JAL, Misra S, Oliver N, Dattani MT, & Shah P. Hyperinsulinemic hypoglycemia in children and adolescents: recent advances in understanding of pathophysiology and management. Reviews in Endocrine and Metabolic Disorders 2020 21 577597. (https://doi.org/10.1007/s11154-020-09548-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Samuk I, Afriat R, Horne T, Bistritzer T, Barr J, & Vinograd I. Dumping syndrome following Nissen fundoplication, diagnosis, and treatment. Journal of Pediatric Gastroenterology and Nutrition 1996 23 235240. (https://doi.org/10.1097/00005176-199610000-00006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Tack J, Arts J, Caenepeel P, De Wulf D, & Bisschops R. Pathophysiology, diagnosis and management of postoperative dumping syndrome. Nature Reviews Gastroenterology and Hepatology 2009 6 583590. (https://doi.org/10.1038/nrgastro.2009.148)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Scarpellini E, Arts J, Karamanolis G, Laurenius A, Siquini W, Suzuki H, Ukleja A, Van Beek A, Vanuytsel T, Bor S, et al.International consensus on the diagnosis and management of dumping syndrome. Nature Reviews Endocrinology 2020 16 448466. (https://doi.org/10.1038/s41574-020-0357-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Arts J, Caenepeel P, Bisschops R, Dewulf D, Holvoet L, Piessevaux H, Bourgeois S, Sifrim D, Janssens J, & Tack J. Efficacy of the long-acting repeatable formulation of the somatostatin analogue octreotide in postoperative dumping. Clinical Gastroenterology and Hepatology 2009 7 432437. (https://doi.org/10.1016/j.cgh.2008.11.025)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Laje P, Halaby L, Adzick NS, & Stanley CA. Necrotizing enterocolitis in neonates receiving octreotide for the management of congenital hyperinsulinism. Pediatric Diabetes 2010 11 142147. (https://doi.org/10.1111/j.1399-5448.2009.00547.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Arnoux J-B, Verkarre V, Saint-Martin C, Montravers F, Brassier A, Valayannopoulos V, Brunelle F, Fournet J-C, Robert J-J, Aigrain Y, et al.Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet Journal of Rare Diseases 2011 6 63. (https://doi.org/10.1186/1750-1172-6-63)

    • PubMed
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    • Export Citation
  • 8

    Thondam SK, Nair S, Wile D, & Gill GV. Diazoxide for the treatment of hypoglycaemic dumping syndrome. QJM 2011 106 855858. (https://doi.org/10.1093/qjmed/hcr234)

  • 9

    Mejia-Otero JD, Grishman EK, & Patni N. Diazoxide for the treatment of hypoglycemia resulting from dumping syndrome in a child. Journal of the Endocrine Society 2019 3 13571360. (https://doi.org/10.1210/js.2019-00120)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Rivkees SA, & Crawford JD. Hypoglycemia pathogenesis in children with dumping syndrome. Pediatrics 1987 80 937942. (https://doi.org/10.1542/peds.80.6.937)

  • 11

    Musthaffa YM, Goyal V, Harris MA, Kapur N, Leger J, & Harris M. Dysregulated glucose homeostasis in congenital central hypoventilation syndrome. Journal of Pediatric Endocrinology and Metabolism 2018 31 13251333. (https://doi.org/10.1515/jpem-2018-0086)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

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  • Expand
  • 1

    Gϋemes M, Rahman SA, Kapoor RR, Flanagan S, Houghton JAL, Misra S, Oliver N, Dattani MT, & Shah P. Hyperinsulinemic hypoglycemia in children and adolescents: recent advances in understanding of pathophysiology and management. Reviews in Endocrine and Metabolic Disorders 2020 21 577597. (https://doi.org/10.1007/s11154-020-09548-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Samuk I, Afriat R, Horne T, Bistritzer T, Barr J, & Vinograd I. Dumping syndrome following Nissen fundoplication, diagnosis, and treatment. Journal of Pediatric Gastroenterology and Nutrition 1996 23 235240. (https://doi.org/10.1097/00005176-199610000-00006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Tack J, Arts J, Caenepeel P, De Wulf D, & Bisschops R. Pathophysiology, diagnosis and management of postoperative dumping syndrome. Nature Reviews Gastroenterology and Hepatology 2009 6 583590. (https://doi.org/10.1038/nrgastro.2009.148)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Scarpellini E, Arts J, Karamanolis G, Laurenius A, Siquini W, Suzuki H, Ukleja A, Van Beek A, Vanuytsel T, Bor S, et al.International consensus on the diagnosis and management of dumping syndrome. Nature Reviews Endocrinology 2020 16 448466. (https://doi.org/10.1038/s41574-020-0357-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Arts J, Caenepeel P, Bisschops R, Dewulf D, Holvoet L, Piessevaux H, Bourgeois S, Sifrim D, Janssens J, & Tack J. Efficacy of the long-acting repeatable formulation of the somatostatin analogue octreotide in postoperative dumping. Clinical Gastroenterology and Hepatology 2009 7 432437. (https://doi.org/10.1016/j.cgh.2008.11.025)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Laje P, Halaby L, Adzick NS, & Stanley CA. Necrotizing enterocolitis in neonates receiving octreotide for the management of congenital hyperinsulinism. Pediatric Diabetes 2010 11 142147. (https://doi.org/10.1111/j.1399-5448.2009.00547.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Arnoux J-B, Verkarre V, Saint-Martin C, Montravers F, Brassier A, Valayannopoulos V, Brunelle F, Fournet J-C, Robert J-J, Aigrain Y, et al.Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet Journal of Rare Diseases 2011 6 63. (https://doi.org/10.1186/1750-1172-6-63)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Thondam SK, Nair S, Wile D, & Gill GV. Diazoxide for the treatment of hypoglycaemic dumping syndrome. QJM 2011 106 855858. (https://doi.org/10.1093/qjmed/hcr234)

  • 9

    Mejia-Otero JD, Grishman EK, & Patni N. Diazoxide for the treatment of hypoglycemia resulting from dumping syndrome in a child. Journal of the Endocrine Society 2019 3 13571360. (https://doi.org/10.1210/js.2019-00120)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Rivkees SA, & Crawford JD. Hypoglycemia pathogenesis in children with dumping syndrome. Pediatrics 1987 80 937942. (https://doi.org/10.1542/peds.80.6.937)

  • 11

    Musthaffa YM, Goyal V, Harris MA, Kapur N, Leger J, & Harris M. Dysregulated glucose homeostasis in congenital central hypoventilation syndrome. Journal of Pediatric Endocrinology and Metabolism 2018 31 13251333. (https://doi.org/10.1515/jpem-2018-0086)

    • PubMed
    • Search Google Scholar
    • Export Citation