Saving Tiny Limbs: Successful Use of Nitroglycerin Ointment in a Preterm Infant

Tissue ischaemia, necrosis and gangrene are uncommon but well-described complications of arterial catheterization in the neonate. Treatment options for progressive tissue necrosis following arterial embolization and/or vasospasm are limited in these patients secondary to unpredictable pharmacokinetics and risks associated with systemic anticoagulation or vasodilatation in newborns. We report a case of the application of topical 0.4% nitroglycerin ointment for reversing severe tissue ischaemia following arterial umbilical catheter placement. A female infant was born at 26 + 1 weeks of gestation to a gravida 3, para 2 woman who experienced preterm premature rupture of membranes (pPROM) 2 weeks before delivery. She received antibiotics and two doses of betamethasone. Delivery occurred via emergency caesarean section due to placental abruption. Pregnancy was complicated by anidramnios, pPROM and threat of preterm labour at 24 + 1 weeks of gestational age. Apgar scores were 1, 5 and 8 at 1, 5 and 10 min, respectively and birth weight was 890 g. At birth the baby underwent primary resuscitation with endotracheal intubation. Both umbilical venous and arterial catheter (3.5 Fr) were placed shortly after birth. Arterial catheter was immediately removed due to malposition. After a few hours, a dark bluish discoloration was noted over the first, second, third and fourth toes of the left foot (shown in Figure 1A). Diagnosis of peripheral tissue ischaemia secondary to vasospasm was made. Tissue ischaemia worsened despite physical treatment (heating the opposite limb for reflex vasodilatation) and at 8 h of life, treatment was started with the off-label topical galenic ointment of 0.4% nitroglycerin (TNG). It was applied every 12 h over the affected area. In the following days, the peripheral lesions developed vesicles over the gangrenous parts, but necrosis was limited to the distal parts of toes (shown in Figure 1B). The treatment was discontinued in the forth day of life, after seven applications. The heart rate, blood pressure and methemoglobin level were monitored and no adverse effects due to ointment application were noted. The maximum methemoglobin level was 1.7% in the third day of treatment and was within the normal range. The lesions did not expand any further and became dry (shown in Figure 2A); autoamputation of dry gangrene occurred on the following days. The final outcome of the lesions, thanks to the early treatment, was more than acceptable (shown in Figures 2B and 3). Peripheral tissue ischaemia is a well-described complication of central venous or arterial catheter placement, caused by peripheral vasospasm and thromboembolism. Treatment options for progressive tissue necrosis are limited in these patients, and data on different management strategies and the efficacy and safety of specific therapeutic agents in the neonatal population are limited. Due to risk of bleeding, anticoagulation and fibrinolytic therapy are only considered as a treatment option for severe life-threatening thrombosis when the benefits of the treatment outweigh the risk of bleeding [1]. Nitroglycerin is a well-known vasodilator drug, which acts on both veins and arteries. The first metabolic products, dinitrates, also share a weak vasodilator effect. The use of topical nitroglycerin as a salvage therapy for peripheral tissue injuries in neonates was first described in 1989. In the case report, treatment with nitroglycerin ointment was used for a newborn with ischaemia caused by dopamine extravasation [2]. In a systematic review, Mosalli et al. [3] reported that full resolution of ischaemic tissue injuries was obtained among extremely preterm, very preterm and late preterm/term infants, in 62.5% (10/16), 66.7% (4/6) and 83% (10/12) respectively. The median birth weight of the patient population was 1281 g (500–3600). In the majority of reports, the most commonly used formulation is the ointment with 4 mg/1 g of nitroglycerin, while in a few cases, patches, spray or a combination of both plus the ointment have been used. The review by Sushko et al. [4] confirms the good safety profile of topical treatment. It analyses 23 cases involving 37 neonates, showing that TNG ointment is effective for ischaemic tissue injuries, with a 76% full recovery rate. Additionally, the authors suggest that the ointment is the preferred option compared to patches, which have less precise dosage control and a higher risk of side effects due to overdosing or underdosing. The reports show a good safety profile. Despite the low weight of treated infants, the review by Mosalli [2] mostly reports hypotensive events without cerebral consequences, two cases of pathological methemoglobinemia, and one case of intraventricular haemorrhage (IVH). In the case of IVH, it is difficult to establish a cause–effect relationship, as it is a known complication in preterm infants. The main side effects reported by Sushko et al. [4] are low blood pressure and increased heart rate, mainly in patients already receiving inotropic treatment. Nitroglycerin can cause an increase in methemoglobin levels in a dose-dependent manner. This occurs because nitroglycerin's metabolic derivatives oxidise the iron in haemoglobin from the ferrous (Fe2+) to the ferric (Fe3+) form, resulting in methemoglobin. Methemoglobin, unlike regular haemoglobin, cannot bind oxygen effectively, causing a decrease in oxygen delivery to tissues. Normal levels of methemoglobin are usually between 0% and 2%. In newborns, the higher concentration of foetal haemoglobin enhances the risk of methemoglobinemia, as this type of haemoglobin is more prone to oxidation. This mechanism is even more pronounced in premature infants, who naturally tend to have higher methemoglobin levels than adults [5]. In the case of our patient, no adverse effects were observed, neither hemodynamic compromise nor increased levels of methemoglobin. Topical nitroglycerine is a good treatment option for peripheral tissue ischaemia with the benefit of a non-invasive and easy administration profile. Currently, only data from case reports and case series are available, and further studies and evaluations are required, but topical nitroglycerine is apparently a safe treatment with only a few mild adverse events reported also in very low birth weight infants. Irene Malni: wrote original draft. Meta Starc: provided images, critically revised the manuscript for relevant intellectual content. Francesca Marrazzo, Ursula Manzon, Davide Zanon, Laura Travan: contributed to revision. The authors have nothing to report. Written informed consent was obtained from the patient's legal guardian for publication of this case report and any accompanying images. The authors declare no conflicts of interest.