Neonatal ICU protocol for the management of persistent pulmonary hypertension

General management principles were followed for all patients, including maintenance of normothermia, providing optimal nutritional support, avoidance of stress, maintaining a “low-noise” environment, gentle handling with sedation as needed, and maintenance of adequate intravascular volume and systemic blood pressure, optimising ventilator support for lung recruitment and alveolar ventilation. ^{Reference Fuloria and Aschner22,Reference Sweet, Carnielli and Greisen23} Specific treatments were applied according to the underlying diagnosis of each patient. Surfactant treatment was given according to European Consensus Guidelines on the Management of Respiratory Distress Syndrome-2019 Update. ^{Reference Sweet, Carnielli and Greisen23}

The primary treatment modality was inhaled nitric oxide after a diagnosis of persistent pulmonary hypertension was made in late preterm and term neonates. ^{Reference Barrington, Finer and Pennaforte3} Inhaled nitric oxide was initiated at an initial concentration of 20 ppm, and the dose was increased to 40 ppm (2 ppm every 30 minutes, while closely monitoring the patients for side effects) if the preductal venous oxygen saturation (SPO2) was <90%, although the fraction of inspired oxygen (FIO2) was 100% and the mean airway pressure (MAP) was adequate for optimal inflation of the lungs that was checked by chest X-ray. ^{Reference Barrington, Finer and Pennaforte3,Reference Kelly, Ohlsson and Shah24} Oral sildenafil, inhaled and intravenous iloprost treatment were initiated simultaneously for the treatment of inhaled nitric oxide resistant cases. Oral sildenafil was initiated at a dose of 1 mg/kg four times a day, and the dose was increased to a maximum dose of 2 mg/kg four times a day, if the patient did not respond to treatment after 24 hours. ^{Reference Kelly, Ohlsson and Shah24} Inhaled iloprost was given at a dose of 2 mcg, diluted with 1ml of isotonic sodium chloride, 12 times a day. Intravenous iloprost infusion was initiated at a dose of 4 ng/kg/min, and the dose was increased up to 20 ng/kg/min according to the response to treatment. ^{Reference Shivanna, Gowda, Welty, Barrington and Pammi2,Reference Mathew and Lakshminrusimha20,Reference Verma, Lumba and Kazmi25} The increments of the infusion rate were applied as 4 ng/kg/min every four hours.

For neonates <34 w, intravenous and inhaled iloprost were used for the treatment of persistent pulmonary hypertension. Inhaled iloprost was given at a dose of 1 mcg, diluted with 1ml of isotonic sodium chloride, 12 times a day. The intravenous dose was the same as it was used for late preterm and term neonates. Inhaled nitric oxide was not used for persistent pulmonary hypertension, since there was both a paucity of data on whether inhaled nitric oxide was effective and safe among this group of neonates, and inhaled nitric oxide treatment was very expensive for our resource-limited neonatal ICU. ^{Reference Barrington, Finer and Pennaforte3} Sildenafil was also not used for neonates <34 w, as it might be associated with worsening of retinopathy of prematurity. ^{Reference Aboudi, Swaminathan and Brumberg26}

After exclusion or correction of the major causes of the need for intense cardiopulmonary support (such as a displaced or blocked endotracheal tube, septicaemia, hypovolemia, pneumothorax) in neonates who received standard persistent pulmonary hypertension treatment, endotracheal iloprost was instilled as a rescue treatment for persistent pulmonary hypertension, if fraction of inspired oxygen was 100% and mean airway pressure was sufficient to ensure adequate inflation of the lungs (≥ eight ribs - ≤ nine ribs were counted on chest X-ray), but preductal oxygen saturation was still below 90%, plus systolic pulmonary artery pressure was suprasystemic. The preductal and postductal oxygen saturation were measured by pulse oxymeter.

Iloprost (Ilomedin®) was administered by endotracheal instillation through a catheter reaching the distal end of the endotracheal tube at the dose of 2 mcg for neonates ≥ 34 w and 1 mcg for neonates < 34 w, and the calculated doses were diluted with 1 ml of isotonic sodium chloride. To instill endotracheal iloprost, patients were disconnected from the ventilator, endotracheal iloprost was given, and then, positive pressure ventilation was performed with a self-inflating balloon 30 times per minute. Later, the patients were reconnected to the ventilator. The mean airway pressure, ventilation mode, applied oxygen fraction (fraction of inspired oxygen) and preductal and postductal oxygen saturation, heart rate, and blood pressure were monitored closely at least six hours after endotracheal iloprost instillation. The oxygen saturation index (OSI) was calculated as MAP × FIO2 × 100 / preductal sPO2 and was recorded before and after 30 minutes of endotracheal iloprost instillation. ^{Reference Aboudi, Swaminathan and Brumberg26} Oxygen saturation index was used instead of oxygenation index (OI), as oxygen saturation index was found to be strongly correlated with OI and a non-invasive method to assess oxygenation status of the patients continuously. ^{Reference Muniraman, Song and Ramanathan27} Systolic pulmonary arterial pressure, the degree of tricuspid regurgitation, OSI, MAP, FIO2, preductal and postductal SPO2, heart rate, systolic (SBP) and diastolic blood pressure (DBP), and mean arterial blood pressure (MABP) measurements were recorded before and after 30 minutes of endotracheal iloprost instillation. Blood pressure was measured non-invasively by using proper cuffs.

The aetiology of persistent pulmonary hypertension and postnatal hour of endotracheal iloprost instillation was recorded. All patients received continuous cardiorespiratory monitoring and continuous assessment of pulse oximetry. As all the treatment modalities used for persistent pulmonary hypertension were known to cause systemic hypotension, blood pressure of the neonates was followed closely and inotropic treatments were started as needed and titrated continuously to keep patients normotensive. ^{Reference Lai, Chu, Lakshminrusimha and Lin1} Transfontanel ultrasonography was performed for all patients before and after the treatment. All the adverse events after endotracheal iloprost instillation such as hypotension, haemorrhage, mortality were recorded for safety assessment.

Statistical analysis

The Statistical Package for Social Sciences version 21.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analyses. The data were assessed for normality using visual and analytic methods. Data were tested for normality with the Shapiro-Wilk test and expressed as a mean (standard deviations) or median (interquartile range) when appropriate. Qualitative variables were expressed as percentages and frequencies, normally distributed continuous variables as means (standard deviation), and non-normally distributed variables as medians (interquartile range, p25-p75). Differences between two paired groups were tested using paired samples t-test for parametric variables and Wilcoxon test for non-parametric variables. p values <0.05 were considered to be statistically significant.