Diazoxide, utilised in hyperinsulinism since the 1960s,¹ is the recommended first-line pharmacological therapy for children with hyperinsulinism.² It blocks the sulfonylurea receptor 1 (SUR1) subunit of K_ATP-channel on pancreatic beta cells, increasing the permeability to potassium ions leading to hyperpolarization of the cells and inhibition of calcium-dependent insulin secretion.³

The recently published International Guidelines for the Diagnosis and Management of Hyperinsulinism² recommends therapeutic diazoxide doses of 5–15 mg/kg/day aiming for plasma glucose concentration targets of 3.9–5.6 mmol/L (70–100 mg/dl). A lower hypoglycaemia threshold (3.5 mmol/L or 63 mg/dl) may be acceptable in children with severe forms of hyperinsulinism—where the recommended plasma glucose concentration targets may be difficult to achieve - depending on the severity and frequency of hypoglycemia and the availability other therapeutic options.²

Malhotra et al. and Ng et al. advocate for a shift to this paradigm, presenting their experience with the initial use of low-dose diazoxide (2–5 mg/kg/day) - escalating the dose if necessary—and adopting a plasma glucose concentration threshold for treatment of 3.5 mmol/L (63 mg/dl) as standard practice. These consensus parameters have been adopted in the UK.⁴ This sola dosis facit venenum approach aims to utilise the smallest effective dose to minimise the likelihood of adverse diazoxide-related side effects.

Ng et al. reported that diazoxide doses of ≤5 mg/kg/day was sufficient to achieve therapeutic goals in preterm and term 34 neonates regardless of whether they were born small-for-gestational age (SGA). They reported 6 (17.6%) neonates having documented non-symptomatic hypoglycemia—the lowest being 3.3 mmol/L—with minimal adverse effects.

In a larger cohort of 73 neonates, Malhotra et al. initiated low-dose diazoxide (2, 3 or 5 mg/kg/day) based on weight when commenced at a median age of 11 days (range 3–43) for a median duration of 4 months. They were able to achieve glycaemic stability in 65% of neonates without dose escalation, although 60% of those on 2 mg/kg/day (the 1000–2000 g cohort) required increased doses. Oedema (12%) and hyponatraemia (5%) were the most common adverse events but two neonates did develop necrotizing enterocolitis.

The studies by Malhotra et al. and Ng et al investigating the effectiveness and safety of low-dose diazoxide for the management of hyperinsulinism in children adds to the literature first published by Chandran et al. who reported successful management of neonates born SGA with doses of diazoxide <5 mg/kg/day.⁵

Reports of the incidence rates of diazoxide-related adverse events vary, with the rate of pulmonary hypertension occurring in 2.4%–4.8% of infants with risk factors including being prematurity, and co-existing respiratory failure or structural heart defects.^{6, 7} Other reported rates of adverse events included oedema (18%), neutropenia (15.6%), thrombocytopenia (4.7%), and hyperuricemia (5.0%) (ref.11). A recent meta-analysis found similar rates of diazoxide-related adverse events.⁸ The rate of diazoxide-related necrotizing enterocolitis in preterm infants (33–37 weeks of gestation) is estimated to 4.4%, and 0.1%–0.7% in term infants.⁹ The rates of diazoxide-related adverse events reported by both Malhotra et al and Ng et al. were generally more favourable than the published literature.

Although the factors associated with hyperinsulinism in neonates are well established, there are limited useful clinical or biochemical indicators allowing for the differentiation of transient vs persistent disease. A birth weight greater than the 90th percentile has been found to be associated with an eightfold increased risk of having a persistent form of HI (OR 8.8, 95% CI 2.5–30) and a 21-fold increased risk of being diazoxide unresponsive (OR 21.1, 95% CI 4.9–91.8).¹⁰ More research is required to allow for the accurate identification of children with transient forms of hyperinsulinism responsive to lower doses of diazoxide.

The studies by Ng et al. and Malhotra et al. provide supplementary support for the safe initial use of low-dose diazoxide in hyperinsulinism. A lower hypoglycemia threshold is also an important feature of the suggested practice but must be predicated on adequate blood glucose monitoring, and prompt appropriate management of hypoglycemia. Long-term neurodevelopmental outcome data is lacking. The United Kingdom consensus standardising this practice⁴ will hopefully provide important additional information which may ultimately lead to a wider adoption.

二氮嗪自 20 世纪 60 年代起用于治疗高胰岛素血症，¹是推荐用于高胰岛素血症儿童的一线药物治疗。²_{它阻断胰腺 β 细胞上 K ATP}通道的磺酰脲受体 1 (SUR1) 亚基，增加钾离子的通透性，导致细胞超极化并抑制钙依赖性胰岛素分泌。³

最近发布的高胰岛素血症诊断和管理国际指南²建议二氮嗪治疗剂量为 5–15 mg/kg/天，目标血浆葡萄糖浓度目标为 3.9–5.6 mmol/L (70–100 mg/dl)。对于患有严重高胰岛素血症的儿童，较低的低血糖阈值（3.5 mmol/L 或 63 mg/dl）可能是可以接受的，其中推荐的血浆葡萄糖浓度目标可能难以实现 - 取决于低血糖的严重程度和频率以及可用性其他治疗选择。²

马尔霍特拉等人。和吴等人。倡导转向这种模式，介绍他们最初使用低剂量二氮嗪（2-5 mg/kg/天）的经验——必要时增加剂量——并采用 3.5 mmol/天的血浆葡萄糖浓度阈值进行治疗L (63 mg/dl) 作为标准做法。这些共识参数已在英国采用。⁴这种单独用药方法旨在利用最小的有效剂量来最大程度地减少二氮嗪相关副作用的可能性。

吴等人。据报道，≤5 mg/kg/天的二氮嗪剂量足以实现早产儿和足月 34 新生儿的治疗目标，无论他们是否出生小于胎龄 (SGA)。他们报告称，有 6 名（17.6%）新生儿出现无症状低血糖（最低为 3.3 mmol/L），且不良反应最小。

Malhotra 等人在一个由 73 名新生儿组成的更大队列中进行了研究。根据体重，在中位年龄 11 天（范围 3-43）开始使用低剂量二氮嗪（2、3 或 5 mg/kg/天），中位持续时间为 4 个月。他们能够在不增加剂量的情况下使 65% 的新生儿实现血糖稳定，尽管 60% 的 2 mg/kg/天（1000-2000 g 队列）的新生儿需要增加剂量。水肿（12%）和低钠血症（5%）是最常见的不良事件，但两名新生儿确实出现了坏死性小肠结肠炎。

Malhotra 等人的研究。和 Ng 等人研究低剂量二氮嗪治疗儿童高胰岛素血症的有效性和安全性，为 Chandran 等人首次发表的文献增添了内容。他们报道了使用剂量<5毫克/公斤/天的二氮嗪成功治疗新生儿出生的SGA。⁵

关于二氮嗪相关不良事件发生率的报告各不相同，有早产、合并呼吸衰竭或结构性心脏缺陷等危险因素的婴儿中，肺动脉高压的发生率为 2.4%–4.8%。^{6, 7}其他报告的不良事件发生率包括水肿 (18%)、中性粒细胞减少 (15.6%)、血小板减少 (4.7%) 和高尿酸血症 (5.0%)（参考文献 11）。最近的一项荟萃​​分析发现，二氮嗪相关不良事件的发生率相似。⁸早产儿（妊娠 33-37 周）中与二氮嗪相关的坏死性小肠结肠炎的发生率估计为 4.4%，足月儿中为 0.1%-0.7%。⁹ Malhotra 等人和 Ng 等人报告的二氮嗪相关不良事件发生率。通常比已发表的文献更受欢迎。

尽管与新生儿高胰岛素血症相关的因素已被充分确定，但能够区分短暂性疾病与持续性疾病的有用临床或生化指标有限。研究发现，出生体重大于第 90 个百分位时，持续性 HI 的风险增加 8 倍（OR 8.8，95% CI 2.5–30），二氮嗪无反应的风险增加 21 倍（OR 21.1，95% CI 4.9–91.8）。¹⁰需要进行更多研究才能准确识别对低剂量二氮嗪有反应的短暂性高胰岛素血症儿童。

Ng 等人的研究。和马尔霍特拉等人。为低剂量二氮嗪在高胰岛素血症中的安全初始使用提供补充支持。较低的低血糖阈值也是建议做法的一个重要特征，但必须以充分的血糖监测为基础，并及时对低血糖进行适当的管理。缺乏长期神经发育结果数据。英国标准化这一做法的共识⁴有望提供重要的附加信息，最终可能导致更广泛的采用。