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Persistent Pulmonary Hypertension of the Newborn

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Infants with Persistent Pulmonary Hypertension of the Newborn (PPHN) are exceptionally unstable and difficult to manage. After initial resuscitation the management should always be discussed with the consultant on call.

Pulmonary hypertension of the newborn occurs in a variety of clinical situations.1 These include meconium aspiration syndrome, hypoplastic lungs, transient tachypnoea of the newborn, congenital pneumonia and hyaline membrane disease. Secondary disturbances such as polycythaemia and myocardial failure are contributory. There is frequently a history of chronic in utero hypoxia, but some cases remain idiopathic.

Pathogenesis

  • Pulmonary vasoconstriction is exacerbated by hypoxia and acidosis. Meconium may trigger a vasoactive process to exacerbate this.
  • Structural lung abnormalities (e.g. Congenital Diaphragmatic Hernia, Congenital Pulmonary Airway Malformations, Alveolar Capillary Dysplasia) are frequently associated with PPHN.
  • Group B streptococcal sepsis via Strep polysaccharide toxins.
  • Polycythaemia, hyaline membrane disease, hypocalcaemia and hypoglycaemia may contribute similarly.
  • Some maternal medications e.g. NSAIDs, SSRIs2

Diagnosis

This is essentially one of exclusion of significant cyanotic congenital heart disease and severe parenchymal lung disease. However, PPHN may coexist with significant parenchymal lung disease. Have a high index of suspicion for the '"at risk' group" in a term baby with respiratory distress and cyanosis, particularly if there has been a history of intrauterine hypoxia and meconium exposure or birth asphyxia.

Investigations

Necessary investigations include:

  • Serial arterial blood gases (simultaneous pre- and post-ductal samples may be helpful)
  • Full blood count
  • Blood cultures
  • Blood glucose
  • Calcium
  • Chest radiograph
  • Echocardiogram. This is crucial to exclude cyanotic congenital heart disease (particularly transposition of the great arteries, and totally anomalous pulmonary venous return). In the presence of significant parenchymal lung disease, cardiac assessment is less urgent.
    Echocardiography is also useful to assess myocardial function, which is often severely affected, assess the severity of PPHN, and assess responses to treatment:
    - Tricuspid regurgitation - allows indirect measurement of the RV pressure and therefore severity
    - Ductual shunting
    - Shunting through the foramen ovale
    Click here to see echocardiographic images of PPHN
  • The hyperoxic test may play a role in diagnosis if 2D echocardiography is not available. However, severe PPHN is likely to produce a similar result to cyanotic CHD.

Aims of management

  1. Lower pulmonary vascular resistance.
  2. Maintain systemic blood pressure.
  3. Reverse right-to-left shunting.
  4. Improve arteriolar oxygen saturation and oxygen delivery to the tissues.
  5. Minimise barotrauma.

Specific therapies

  Oxygen and ventilation 100% O2





Always start with 100% oxygen and reduce the FiO2, rather than starting on 25% and increasing. In the short term there is no risk to a term baby using such measures.
Normo-ventilation i.e. pO2 7-12 kpa is acceptable if baby stable
pCO2 5-7 kpa if this can be achieved
Use of HFOV, particularly in combination with inhaled Nitric Oxide, has been shown to reduce the need for ECMO.
  Pulmonary vasodilators











Inhaled nitric oxide (iNO) is the vasodilator of choice.
iNO should be started at 20ppm and reduced to 5ppm as able, according to response and to stability.
Methaemoglobin levels should be monitored (these are measured automatically on blood gases).
Nitrogen dioxide (NO2) levels should be monitored and kept below 1ppm.
Sildenafil has been reported to reduce mortality where in centres where iNO/ECMO is not available. It improves oxygenation and may be helpful in the prevention of rebound pulmonary hypertension.4,5
Milrinone has inotropic and vasodilator effects and is used in neonatal patients post cardiac surgery. Two small case reports reported improved oxygenation.6.7 (It is rarely used in ACH.)
Magnesium sulphate may be used in refractory cases. The use of MgSO4 is controversial but may be indicated in selected instances.
Prostacyclin may also be used in severe and refractory cases, although it is difficult to obtain and its use is controversial.
Tolazoline is no longer used at ACH. It is a non-registered medication. It has an unpredictable effect and frequently results in systemic hypotension and collapse.
  Normotension





Myocardial function is frequently poor, despite reasonable blood pressures.
Aim to keep the mean arterial pressures above 50mm Hg in term infants or higher if RV pressure calculated to be greater than this.
Use volume (initially normal saline) and inotropic support: dopamine and / or dobutamine, both starting at 5-10 mcg/kg/min. If the systemic pressure increases and pulmonary pressure stays the same, R-L shunt will diminish.
Adrenaline infusions may be indicated if there is severe myocardial dysfunction
  Sedation


Many babies are very unstable requiring early use of narcotic infusions.
A 'minimal handling' approach should also be used.1
  Muscle relaxation




This may be necessary to gain initial control in very vigorous babies who are not adequately sedated with narcotics and are fighting the ventilator to their detriment.
Use pancuronium 100micrograms/kg/dose PRN preferably for 24 hours or less.
Monitor for possible associated systemic hypotension; some babies may require additional fluid volume support.
Avoid polycythaemia
Aim to keep the PCV between 0.40 and 0.45.
  Alkalosis



Establish the critical pH- preferably 7.45 but may be higher. If there is no dramatic improvement in PaO2 at a pH >7.6, the infant can be deemed to be "pH unresponsive".
Use small boluses of bicarbonate (1-2 mmol/kg) or a continuous infusion (0.5mmol/kg/hour initially). Liberal bicarbonate use may result in hypernatraemia and hypokalaemia.
Hyperventilation
Inducing alkalosis by hyperventilation often creates as many problems as it solves and is no longer advocated.1
  ECMO
This is essentially prolonged cardio-pulmonary bypass and is provided via PICU at Starship Hospital.
Usual criteria are infants who have an Oxygenation Index (OI) >30.
It is appropriate to discuss infants who may potentially require ECMO with the PICU specialist early, rather than when ECMO or death are imminent. This will be done specialist-to-specialist. The neurological status of the infant may be an important factor in determining if ECMO is offered.

OI = MAP x100     x  FiO2 
     PaO2 (mmHg)

where MAP is Mean Airway Pressure,
PaO2 is the arterial oxygen tension in mmHg (1kPa = 7.5mmHg), and
FiO2 is the fraction of inspired oxygen (100% = 1.0, air = 0.21)

Click here to open the OI calculator
  Other



Pay careful attention to maintaining normal electrolyte, blood glucose and calcium concentrations and to baby's nutritional needs.1
In meconium aspiration syndrome associated PPHN some babies may benefit from surfactant bolus or intravenous steroids.
In babies on long term ventilation, particularly if they are growth restricted from the outset, intravenous nutrition may be required.
Weaning
Weaning such babies is invariably difficult. Steps should be taken one at a time and by small increments once lability appears to have stabilised.

References

  1. Roberton's Textbook of Neonatology. Ed JM Rennie. Elsevier, 2005. ISBN 0-44307-355-4.
  2. Kieler H, Artama M, Engeland A et al Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ. 2012 Jan 12;344:d8012. doi: 10.1136/bmj.d8012.
  3. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD000399
  4. Steinhorn RH, Kinsella JP, Pierce C,et al.. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr. 2009 Dec;155(6):841-847
  5. Baquero H, Soliz A, Neira F, et al. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. 2006 Apr;117(4):1077-83.
  6. Bassler D, Choong K, McNamara P, Kirpalani H. Neonatal persistent pulmonary hypertension treated with milrinone: four case reports. Biol Neonate. 2006;89(1):1-5
  7. McNamara PJ, Laique F, Muang-In S, Whyte HE. Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn.J Crit Care. 2006 Jun;21(2):217-22.

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Document Control

  • Date last published: 31 December 2013
  • Document type: Clinical Guideline
  • Services responsible: Neonatology
  • Owner: Newborn Services Clinical Practice Committee
  • Editor: Sarah Bellhouse
  • Review frequency: 2 years