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Persistent pulmonary hypertension of the newborn
Journal of Neonatal Nursing (2012) 18, 63e71
www.elsevier.com/jneo
ORIGINAL ARTICLE
Persistent pulmonary hypertension of the newborn* Christine Niccolls * Neonatal unit, Liverpool Women’s NHS Foundation Trust, Liverpool, United Kingdom Available online 23 November 2010
KEYWORDS Persistent pulmonary hypertension; Nitric oxide; high frequency oscillation
Abstract To protect the identity of the neonate and her family, pseudonyms and fictitious dates have been used, so as to ensure confidentiality as directed by the Nursing Midwifery Council (NMC, 2004). This article explores the aetiology of persistent pulmonary hypertension (PPHN) in a term neonate and discusses nursing management and the management of neonates on high frequency oscillation and inhaled nitric oxide therapy. It is imperative that all staff nursing a neonate on high frequency oscillation and inhaled nitric oxide therapy has a knowledge of the concept, be aware of the problems that may arise and be capable of taking steps in avoiding their occurrence. ª 2010 Neonatal Nurses Association. Published by Elsevier Ltd. All rights reserved.
Case study Katie was born at 38 weeks and 5 days gestational age via an elective caesarean section at an outside hospital. She was born to a multiparous woman in view of previous caesarean sections. Apgars of eight at five and ten at 10 min were assigned. Clear amniotic fluid was noted when the membranes were ruptured at delivery. At 30 min of life, she was noted to have moderate respiratory distress with an intermittent grunt. She was taken to the neonatal unit for observation and intervention, at 4 h postnatal age. A septic screen was undertaken *
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and broad spectrum antibiotics started in the early treatment of her respiratory symptoms. She required an increasing oxygen requirement by head box, progressing to endotracheal intubation at 19 h of age. An umbilical arterial line and a double lumen umbilical venous catheter were placed. Sodium bicarbonate was given intravenously to correct a metabolic acidosis and intravenous fluids were commenced at 60 millitres per kilogram per day. Pre and post ductal saturations were measured and were noted to be 20 points lower postductally. After adequate volume administration dopamine hydrochloride was started at 5 micrograms per kilogram per minute with concurrent 15 micrograms per kilogram per minute of dobutamine hydrochloride because of a persistently low mean arterial pressure of 29 mmHg.
1355-1841/$ - see front matter ª 2010 Neonatal Nurses Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jnn.2010.10.001
64 Her chest X-ray depicted a uniform reticulogranular appearance in both lung fields and reduced lung volume. She received several dosages of artificial surfactant via her endotracheal tube. The main function of surfactant is to lower the surface tension within the alveolar and prevent alveolar collapse at the end of expiration and the loss of lung volume (Cifuentes and Carlo, 2007). The referring hospital obtained an echocardiogram with pulse doppler to rule out structural heart disease, identify PPHN and document cardiac function. Echocardiogram showed right ventricular enlargement with elevated ventricular pressures with right to left shunting at the level of the foramen ovale and the ductus arteriosus. In light of her clinical course and these findings it was determined that the most likely diagnosis was PPHN; synonymous with term neonates. Her arterial blood gases showed a persistent partial pressure of oxygen of less than 33 mm of mercury despite breathing 100% oxygen. Conventional ventilation techniques failed to maintain normal respiratory function therefore plans were made for Katie to be transported to a tertiary centre for high frequency oscillation and nitric oxide therapy due to an oxygen index of 30. On admission to the tertiary centre she was placed on high frequency oscillation with a mean airway pressure at 15 cm of water, amplitude at 53 cm of water, and a frequency of 10 Hz and inhaled nitric oxide at 20 parts per million.
Persistent pulmonary hypertension To appreciate the mechanism of PPHN, one has to be familiar with the fetal circulation and neonatal circulatory adaption. The fetal circulation is designed to deliver oxygenated blood from the placenta to the fetal brain and other major organs and to allow blood to be diverted away from the pulmonary circulation via fetal shunt pathways (DeBoer and Stephens, 1997). When the neonate takes its first breaths at delivery, the entrance of oxygen into the pulmonary circulation is the most important initiator of vasodilatation. The alveolar oxygen concentration rises and the pulmonary vascular bed dilates, pulmonary vascular resistance decreases and lung compliance increases (Prullage and Melichar, 1993). With the increase in pulmonary blood flow, the arterial oxygen concentration continues to rise, resulting in the closure of the ductus arteriosus. Subsequently there is an increase in blood return to the left atrium, resulting in an increase left arterial pressure. At the point when the left arterial pressure is greater than the right arterial pressure there is
C. Niccolls closure of the foramen ovale (DeBoer and Stephens, 1997). If, for any reason, right sided pressures remain higher to those on the left side, fetal circulation will persist through one or both of the fetal pathways. Therefore persistent pulmonary hypertension of the newborn is defined as: an increase or failure of the postnatal fall in pulmonary vascular resistance thereby resulting in right to left shunting of deoxygenated blood at atrial, ductal and pulmonary levels with consequent severe hypoxia (Boden and Bennett, 2004, pp 290). PPHN is an appropriate term for non-cardiac causes of cyanosis with elevated pulmonary vascular resistance in term or near term neonates (Ganesh-Konduri, 2004). The syndrome may be idiopathic or secondary to another disorder. Idiopathic PPHN commonly results from an abnormal remodelling of the pulmonary vascular bed with vascular wall thickening and hyperplasia of the smooth muscle (D’Cunha and Sankaran, 2001a). Secondary PPHN is most commonly seen in a neonate with another disorder such as meconium aspiration syndrome, congenital diaphragmatic hernia, respiratory distress syndrome, sepsis, asphyxia, polycythaemia or hypoglycaemia (Abman and Kinsella, 2003). The workup for the neonate suspected of having PPHN should include arterial blood gases to assess pH, partial pressure of oxygen and carbon dioxide. Arterial blood gases reveal severe hypoxia with a partial pressure of oxygen <100 mmHg in 100% oxygen (Boden and Bennett, 2004). The response of supplemental oxygen can help distinguish PPHN from primary lung disease as supplemental oxygen traditionally increases partial pressure of oxygen readily in lung disease than cyanotic heart disease or PPHN (Abman and Kinsella, 2003). Oxygenation should be assessed by differential oxygen saturation monitoring, with one saturation probe placed simultaneously on the right hand and one on either lower extremity. A significant higher saturation reading in the right hand suggests right to left shunting across a patent ductus arteriosus (Rohan and Golombek, 2009). However caution must be given as according to Rohan and Golombek (2009) as if the shunt is large across the foreman ovale, preductal saturation differences may be obscured or absent and therefore PPHN cannot be excluded when differential is absent. A chest X-ray can be helpful in determining the presence of underlying parenchymal lung disease or ruling out disorders such as congenital diaphragmatic hernia. Cardiomegaly and increased vascular markings are often visible in PPHN. In
pulmonary hypertension newborns with idiopathic PPHN, the lung fields appear clear with decreased vascular markings and the heart size is typically normal and therefore is often referred to clear-lung PPHN (Burst et al., 2009). Suspicion of PPHN should be considered when hypoxemia is out of proportion to the degree of parenchymal disease on the chest radiograph. When PPHN is suspected, an echocardiogram is essential to rule out the presence of congenital heart disease in the newborn with cyanosis and tachypnea. If the heart is deemed structurally normal, like in case study, and the echocardiogram shows high pulmonary artery pressures and right to left shunting through the patent ductus arteriosus, foreman ovale, or both, then PPHN can be presumptive diagnosis. Frequently, there is evidence of right heart failure because the pressures in the pulmonary artery are greater than the systemic pressure, resulting in the right ventricle inability to eject blood (Burst et al., 2009). Inhaled nitric oxide should not be administered to neonates with congenial heart disease who depend on right to left shunting or who have severe left heart failure (Williams et al., 2004). Levene et al (2000) suggest the following conditions should be present before a diagnosis of persistent pulmonary hypertension of the newborn can be made: Sustained systemic pulmonary artery pressure Profound hypoxemia with or without acidosis while breathing 100% oxygen Normal cardiac anatomy on echocardiography examination Evidence of right to left shunting of blood through either the ductus arteriosus or the foramen ovale (pp 200). An evaluation of the complete blood count may be significant for derangements that may cause or aggravate PPHN including polycythaemia, hypoglycaemia and hypocalcaemia; therefore levels should be kept within reference range Burst et al (2009). A white blood cell count and differential are helpful in determining whether an underlying sepsis or pneumonia exists. Broad spectrum antibiotics had been started in the early treatment of her respiratory symptoms. It is important to note, that the white out appearance of the chest X-ray cannot be differentiated from the appearance of neonatal pneumonia which is often caused by Group B Streptococcus therefore broad spectrum antibiotic cover should be given after blood cultures, to ensure that the respiratory distress is not caused by a bacterial pathogen (Jeenakeri and Drayton, 2009). Respiratory pathology was confirmed after blood cultures were negative after 72 h.
65
High frequency oscillation and nursing management The maintenance of adequate oxygenation is the primary goal in the management of PPHN and mechanical ventilation is one of the therapies to achieve this goal. One of the early strategies in conventilational mechanical ventilation was hyperventilation as it is known that the pulmonary vascular bed responds to acidosis with constriction, therefore treatment is aimed at reversing that effect (Ostrea et al., 2006). Inducing a respiratory alkalosis and increasing pH will thereby interrupt the cycle of hypoxia and acidosis permitting relaxation of the constricted pulmonary vascular bed. However this method has to be employed with caution since hypocarbia may result in ischaemia and subsequent neurodevelopment mental deficits (Ostrea et al., 2006; D’Cunha and Sankaran, 2001a); use of alkalinizing agents such as sodium bicarbonate has become commonplace (Hagedorn-Enzman et al., 2006), as hyperventilation is not evidence based practice (Engle, 2007). High frequency oscillation is an alternative mode of ventilatory support in neonates. The goal of high frequency oscillation is to optimise lung expansion and functional residual capacity to avoid over distension of the lung parenchyma. Over distension can predispose the neonate to significant barotrauma and elevation of pulmonary vascular resistance, thereby worsening the PPHN (Ostrea et al., 2006). High frequency oscillatory ventilation maintains gas exchange at lower mean airway pressures and peak inspiratory pressures; it is used to recruit atelectatic alveoli and sustain lung volumes in cases of severe respiratory failure (Miller, 1995). Surfactant combination with high frequency oscillation reduces alveolar oedema and improves oxygenation (Lotze et al., 1993) and reduces the need for extracorporeal membrane oxygenation (Jackson et al., 1994). Assessment of the neonate while he or she is receiving high frequency ventilation is frequent and extensive and it differs from routine assessment on conventional ventilation. It is not possible to auscultate the chest for either breath sounds or apical pulse while on high frequency oscillation and the skill is in assessing the “bounce” of the chest, evaluating lung expansion on chest radiographs and monitoring a continuous ECG tracing. Chest vibration provides an assessment of the adequacy of ventilation, and learning to detect changes in the vibratory pressure amplitude of the chest is important because small changes may
66 affect carbon dioxide elimination (Levin and Morris, 1997). For example, endotracheal tube displacement, pulmonary secretions, lung over inflation and pneumothoraces are common complications that may be discovered when assessing chest vibration (Levin and Morris, 1997). Pneumothoraces may result as a consequence of hyperventilation but also occur as a consequence of ventilation on damaged parenchymal tissue. Consequently, we must always have equipment for chest drain insertion close to hand. It is possible to interrupt or pause the ventilator briefly during the assessment process to auscultate breaths sounds and listen for heart murmurs; however this can destabilise the neonate (Wylie et al., 2004). If the neonate is removed from the ventricular circuit, the bag utilised to supply breaths must be connected to the inhaled nitric oxide and oxygen supply (Williams et al., 2004). As disconnection should be avoided, a closed system approach to endotracheal suctioning needs to be performed, as this will prevent the loss of lung volume due to alveolar collapse. Auscultation of the chest due to the continuous vibration of the chest is difficult therefore indications of endotracheal suctioning will be a reduction in chest wall vibration and/or deterioration in the arterial blood gases with an increase in carbon dioxide (Hunt and Milner, 1999). However according to Levin and Morris (1997) even though the aspect of chest auscultation is affected by the loud rapid vibratory sounds, they highlight the importance of the clinician acquiring an appreciation for the vibratory breath sounds; these may be characterised by bright, dull or squeaky. Serial chest X-rays were obtained, with the first taken within 30 min after starting high frequency oscillation on Katie, this was to determine the efficacy of alveoli recruitment and lung expansion and therefore allowing the ventilation to be adjusted accordingly. The diaphragm should be at the level of the ninth rib (Cameron and Haines, 2000). If the diaphragm is lower the mean arterial pressure will need to be reduced, as the lungs are overinflated and this will reduce cardiac output and increase the risk of intravenous haemorrhage. If the diaphragm is higher the mean arterial pressure will need to be increased (Cameron and Haines, 2000). Alterations in ventilation may be made frequently when commencing high frequency oscillation therefore as the neonatal nurse we must record ventilation changes as they occur as well as on a routine basis. Amplitude, MAP, fi02, inspiratory time and frequency should be observed and documented and on some oscillators it is also necessary to note
C. Niccolls the position of the piston in the oscillator, with the nurse centring the piston if it drifts from the midline. Excellent humidification is essential with such high flow oscillators, as necrotizing tracheobronchitis has been reported with high frequency jet and oscillator ventilation (Levin and Morris, 1997); this problem appears to relate to a combination of dry gas and high inspiratory flow. The neonatal nurse must therefore ensure that airway temperature is maintained at 37 degrees and the fluid level in the humidification chamber is checked and refilled.
Nitric oxide and nursing management Pulmonary vasodilatation with multiple drugs have being evaluated for treatment of PPHN, but none recommended for clinical use accept inhaled nitric oxide (Ostrea et al., 2006). Endogenous or exogenously delivered nitric oxide causes relaxation of the vascular smooth muscle by a normal occurring mechanism (Williams et al., 2004). Because it is a short lived molecule it relaxes the pulmonary vascular smooth muscle when inhaled but does not enter the systemic vasculature. For inhaled nitric oxide to work optimally, it has to be delivered effectively to the terminal air spaces. Hence it is important to achieve adequate alveolar recruitment prior to inhaled nitric oxide therapy. In a large randomised controlled trial of mature neonates with severe respiratory failure, the combination of high frequency oscillation and inhaled nitric oxide was more effective in improving short-term oxygenation than either treatment alone (Kinsella et al., 1997). In accordance with the Cochrane review by Finer and Barrington (2006) they state that starting inhaled nitric oxide therapy in term neonates when the oxygenation index is greater than 25 or when partial pressure of oxygen is <100 mmHg when receiving 100% oxygen is consistent with published evidence. An oxygenation index (OI ¼ mean airway pressure FiO2 100/PaO2) was established as the entry criterion for trials, with the mean upon initiation being 38. The oxygenation index has been used to define severity of illness in neonates with respiratory failure, but a given oxygenation index might not predict successful treatment with inhaled nitric oxide, largely because the oxygenation index calculation does not consider the cause of hypoxemia (Williams et al., 2004). Some studies (Schreiber, 2003) have shown equal efficacy in preterm neonates but a recent multicentre randomised controlled trial could not
pulmonary hypertension support this group (Van Meurs et al., 2005). With the evidence presently available, Finer and Barrington (2006) state that near term or term infants without a diaphragmatic hernia should have a trial of inhaled nitric oxide. This therapy is very effective in reducing the need for EMCO, with a need to treat ratio of 5e3. Nursing care of the newborn receiving inhaled nitric oxide therapy includes careful monitoring of the gas administration because nitric oxide has a high affinity for haemoglobin. Once nitric oxide combines with haemoglobin, then a chemical inactivation occurs resulting in the formation of methaemoglobin. Once it combines with haemoglobin, this prevents oxygen from binding with the haem and therefore reduces the oxygen-transporting ability of the blood (Williams et al., 2004). Consequently methaemoglobin levels need to be monitored during inhaled nitric oxide therapy (Williams et al., 2004). Exposure to inhaled nitric oxide concentrations greater than 20 parts per million can be associated with methaemoglobinemia (Williams et al., 2004), therefore in our nursing practices side effects are kept minimal at the recommended 5e20 parts per million (Guthrie et al., 2004). In addition because nitric oxide and oxygen can react to produce toxic by-products such as nitrogen dioxide, the delivered amount must be closely monitored. Extremely high levels of nitrogen dioxide can be toxic to parenchymal lung tissue and cause severe pulmonary oedema (Miller, 1995). It is now widely acknowledged toxic nitrogen dioxide, can suppress platelet adhesion and aggregation and as such plays an important role in vascular haemostasis (Hagaman et al., 1993; Kairamkonda, 2009). The nurse should be alert to the neonates increased susceptibility to bleeding. The Neonatal Inhaled Nitric Oxide Study (1997) was the first controlled clinical trial demonstrating that inhaled nitric oxide therapy reduced the need for ECMO in neonates with hypoxic respiratory failure without significant toxicity and demonstrated that inhaled nitric oxide therapy could improve oxygenation in neonates with severe hypoxic respiratory failure. Subsequent research by Clark and Kueser (2000) also demonstrated a reduction for EMCO therapy. The Neonatal Inhaled Nitric Oxide Study Group (2000), including the neurodevelopmental component, demonstrated the safety and efficacy of inhaled nitric oxide therapy for severe hypoxic respiratory failure. However, the follow- up study revealed that survivors of severe hypoxic respiratory failure experience significant morbidities
67 regardless of whether inhaled nitric oxide or ECMO therapies were utilised.
Nursing management Neonates with PPHN have continued high pulmonary resistance that impedes pulmonary flow, leading to hypoxia, metabolic acidosis and decreased lung compliance. As hypoxia continues further pulmonary vasoconstriction ensues, therefore hypoxia creates and maintains a negative feedback system (DeBoer and Stephens, 1997). Therefore interventions are aimed at increasing pulmonary flow by decreasing pulmonary resistance or increasing systemic resistance, thus impeding right to left shunting (DeBoer and Stephens, 1997). The goal of nursing care must be to optimise oxygenation and minimise hypoxia and acidosis, thus preventing the cyclical pattern and progression. Providing a neutral thermal environment and clustering care is key in decreasing oxygen requirements. Katie’s own heat e regulating system was inefficient as evidence from her poor flexion. Neuromuscular block agents inhibit a neonate’s ability to maintain a flexed position increasing exposed surface area and heat loss (Woods-Blake and Murray, 2006). Following transfer she was nursed in an incubator as a means of controlling thermoregulation and for closer observation and assessment of her general condition. Evaluation of care was measured by the fact Katie remained normothermic and monitoring did not show any signs of hypoglycaemia. Strategies to eliminate stress must be individualised to the neonate and appropriate to the level of illness. Labiality in her oxygenation persisted with handling therefore minimal stimulation techniques were instituted. Care requirements of Katie were to be undertaken twelve hourly to facilitate minimal handling and energy conservation which is of extreme importance to enable the most beneficial utilization of calories and moreover, disturbing a sick neonate can cause her condition to deteriorate, usually by making her hypoxic; hypoxia is a major reason for pulmonary vascular resistance failing to fall (HagedornEnzman et al., 2006; Boden and Bennett, 2004). The role of the neonatal nurse is to effectively anticipate, prevent and managed pain in all neonates regardless of their gestational age or severity of illness, having used an appropriate pain assessment tool (Boyd, 2002; Findlay, 2004). Katie was nursed on a continuous infusion of 40 mcg/kg/h morphine. Even though she was receiving vecuronum 50 mcg/kg/h, a muscle paralytic, she still required concurrent use of
68 morphine because muscle paralytics do not alter the infant’s pain threshold (DeBoer and Stephens, 1997). Eye care is important when infants are receiving muscle paralytic, as the blink reflex will be suppressed by the muscle depolarising agents; therefore hypromellose eye drops are used to keep the corneas moist and prevent corneal abrasions (DeBoer and Stephens, 1997). Ventilated neonates breathing in asynchrony with the ventilator are potentially exposed to more severe barotrauma and are at risk for complications such as pneumothorax or intraventricular haemorrhage (DeBoer and Stephens, 1997; Cools and Offringa, 2005). These neonates usually only have marginal respiratory gas exchange that is further compromised by agitation and asynchronising ventilation (Pettett et al., 2006). Neuromuscular paralysis, which eliminates the spontaneous breathing efforts of the neonate, creates complete synchronization with the ventilator and may minimise these risks. However induced paralysis is controversial. There have been some isolated reports in the literature of increased mortality with the use of pancuronium bromide, promotion of atelectasis of dependent lung regions and ventilation perfusion mismatch (Asad and Bhat, 2008). Therefore routine use of pancuronium or any other neuromuscular blocking agent in ventilated preterm newborn infants cannot be recommended based on current evidence as uncertainty remains regarding the long-term pulmonary and neurologic effects and the safety of prolonged use of neuromuscular blocking agents in ventilated newborn infants (Cools and Offringa, 2005). Of note there is no data available from randomised controlled trials with term ventilated neonates. Neonates at risk of skin injury include those on high frequency oscillisation because they are more difficult to move. Hypotension leading to peripheral tissue hypoperfusion is another factor predisposing these neonates, as well oedema in critically ill neonates who have leaking capillaries or require excessive fluids and blood products to maintain blood pressure (Wylie et al., 2004). Paralysing agents or infants on high levels of sedation creates poor muscle tone and decreased movement increasing risk of skin breakdown (Wylie et al., 2004). Neonates with PPHN will require monitoring of their vital signs. Continuous monitoring will provide information regarding their cardiac performance and respiratory status. A complete clinical assessment of cardiac function must include heart rate, blood pressure, capillary refill, urine output and acid base balance. Because of the inability to auscultate the cardiac sounds, heart
C. Niccolls rate is obtained from ECG monitoring. Delayed capillary refill, hypotension, metabolic acidosis, tachycardia and oliguria may all be signs of cardiac dysfunction. Although they may have pulmonary hypertension, the systemic blood pressure may be low because of the impaired cardiac output. This means the neonate is at risk of renal failure. Urine output should be monitored and intake adjusted accordingly (Beresford and Boxwell, 2006). Another consideration for the neonatal nurse is it is estimated that approximately 70% of inhaled nitric oxide is excreted within 48 h as nitrate in the urine. Nitrate itself is not toxic to the body however excess quantities can promote the conversion of nitrate to nitrite which can in turn result in increased production of both methaemoglobin and ammonia (Wendel and Nathan, 2006). If ammonia cannot be excreted in the urine excess quantities can lead to hepatic and central nervous system toxicity (Wendel and Nathan, 2006). Therefore as the bedside nurse we must ensure adequacy of urine output in our neonates on inhaled nitric oxide therapy. Umbilical arterial and umbilical venous catheters were placed under sterile conditions. As Katie, was likely to need ventilator support for some time, an umbilical artery catheter line was inserted for easily obtaining of blood samples and for continuous recording of her blood pressure. Intraarterial blood monitoring is essential once high frequency oscillation is commenced because oxygenation can change dramatically and hypoxia can develop rapidly if the neonate is not monitored in a meticulous fashion (Kemp, 1997). High frequency oscillation can produce high intrathoraic pressure causing cardiac compression and possible hypotension (Hunt and Milner, 1999). Mean systemic blood pressure should be maintained in the high normal range with the use of volume expansion and inotropes if required. Use of inotropic support ideally increases myocardial contractility and cardiac output thereby increasing systemic vascular resistance above the pulmonary pressure (Hagedorn-Enzman et al., 2006; D’Cunha and Sankaran, 2001b). Nursing concerns include an understanding of the dosage, calculation and administration of these drugs. For instance, dopamine at low doses combined with high dosage dobutamine is commonly used and the nurse should be alert to the fact dopamine at high doses acts as an alphaadrenergic stimulator which actually increases pulmonary vascular resistance and results in a negative outcome (D’Cunha and Sankaran, 2001b). After adequate volume administration, Dobutamine hydrochloride was initiated and
pulmonary hypertension titrated up to 15 micrograms per kilogram per minute concurrent with Dopamine hydrochloride at 5 micrograms per kilogram per minute for management of her hypotension. Often neonates with pulmonary hypertension have a low ventricular output because the reduced pulmonary perfusion leads to a lower pulmonary venous return and therefore a decreased left ventricular preload. By contrast the right ventricle is overloaded with a high afterload. Myocardial function may also be reduced due to hypoxia, hypercarbia and acidosis (Boden and Bennett, 2004). Blood products were administered to Katie with an aim to improve systemic pressure and optimise the oxygen carrying ability of her blood.
Family support While managing an unstable neonate, the nurse must also support the infant’s family members, who are frequently frightened by the amount of equipment and expertise needed to care for their baby (Williams et al., 2004). When faced with a NICU admission, parents struggle with the unknown in the unfamiliar and potentially threatening environment of an intensive care unit. An explanation of the environment surrounding the infant is important including type of monitoring and explaining the temporary but necessary effects of the muscle paralytics (Wylie et al., 2004). These parents often encounter challenges to the development of their parenting roles (Lupton and Fenwick, 2001), therefore the neonatal nurse identified tasks that Katie’s parents were comfortable with; both parents were shown how to perform hygiene and skin care and assisted with these on visiting the ward. The author provided advice regarding procedures for collecting and storing her breast milk in accordance with UNICEF international protocol (UNICEF Baby friendly initiative, 2007) and supported the mother in her efforts as many mothers view their providing of milk as an important personal contribution to their infant’s care. Good nursing practice and ethical conscience requires that parents be kept informed of their infant’s progress and treatments (Emery, 2000). Ethical and legal theorists suggests consent should be informed, where the focus is on autonomy as opposed to beneficence and the giving of informed consent becomes a ‘matter of self determination’ (Mason and Mccall, 1994). However, according to Cooke (2005) consent in the neonatal unit is often presumed to be implied by the parents agreeing verbally to their child being admitted to an intensive care unit after birth. While it is clearly
69 impractical, and probably needlessly distressful according to Cooke (2005), to seek individualised informed consent for each procedure at the time, he suggests that parental autonomy with regard to decision making about their child can be protected to some extent by an information-giving discussion with parents during early labour, or even a short tour around the intensive care unit prior to delivery. Unfortunately, such methods cannot help when the delivery is sudden or unexpectedly abnormal. Many neonatal units do not seek explicitly informed consent for ventilation, total parenteral nutrition, exchange transfusion or for newer technologies such as high frequency oscillation or nitric oxide therapy (Cooke, 2005). Shenoy et al. (2003) publication and the associated editorial criticised neonatologists for this, however according to Cooke (2005) the publication seemed to ignore the fact that many of the interventions discussed were emergency procedures. Parental autonomy can be, again protected to some extent with regular updates, therefore the health care team provided an environment that fostered open dialogue. The plan was to support the parents by ensuring they were kept up to date with Katie’s management with regular family meetings with the consultant and daily cot-side updates. Frequent family meetings were held as according to Mok and Leung (2005) parents are in a state of shock and cannot process large amounts of information all at once and particularly during a doctor’s round. Nurses might act as a buffer to fill in the gap or transcribe medical terminology into laymen’s terminology after the doctor’s visit. On day five of life, Katie was transferred on to conventional mechanical ventilation with her oxygen requirement as low as 30 per cent. Inhaled nitric oxide therapy was successfully discontinued on day 5 of life too. The process of weaning Katie from inhaled nitric oxide therapy was a gradual process to avoid sudden severe pulmonary vasoconstriction and arterial desaturation (Miller, 1995). Research provided by Davidson et al. (1999) reported minimizing inhaled nitric oxide dose to 1 ppm before discontinuation, was associated with least deterioration. Katie was transferred back to the outside hospital at 12 days old, where she was self ventilating in air. The case demonstrates the ability to successfully treat a neonate with severe PPHN. Caring for this neonate demanded skills, knowledge, diligence and collaborative management amongst the multidisciplinary health professionals. Due to the diverse nature of conditions complicating PPHN there is no single approach to treatment. Care should be individualised and based on the neonate’s response.
70 Nursing staff are integral to ensuring seamless coordination of this care and play a critical role in the success of any initiated therapy. Reflective practice enabled me to identify a lack of knowledge and therefore encouraged me to perform a literature review to address this imbalance. The process of reflection has encouraged me to reflect on my day to day practice, to examine the rationale behind my practice, to make further enquires and to ensure that all aspect of care are up to date and research based. The literature review reassuringly supported our management of the neonate.
Acknowledgements Thanking Debbie Webster and Ginny Wallace for their continued support and advice.
References Abman, S., Kinsella, J.P., 2003. Persistent pulmonary hypertension of the newborn. In: Greenough, A., Milner, A.D. (Eds.), Neonatal Respiratory Disorders, second ed. Arnold, London 2003. Asad, A., Bhat, R., 2008. Pharmacology for meconium aspiration. Journal of Perinatology 28, S72eS78. Beresford, D., Boxwell, G., 2006. Fluid and electrolyte balance Cited in. In: Boxwell, G. (Ed.), Neonatal Intensive Care Nursing. Routledge, London 2006. Boden, G., Bennett, C., 2004. The management of persistent pulmonary hypertension of the newborn. Current Paediatrics 14, 290e297. Boyd, S., 2002. Sucrose analgesia: a realistic alternative to conventional pharmacology for pain relief in neonates. Journal of Neonatal Nursing 8 (6), 184. Burst, P., Hamburger, M., Larkin, P., 2009. Transport of the neonatal patient with persistent pulmonary hypertension. Newborn and Infant Nursing Review 9 (4), 219e225. Cameron, J., Haines, J., 2000. Management of respiratory disorders Cited in. In: Boxwell, G. (Ed.), Neonatal Intensive Care Nursing. Routledge, London 2000. Cifuentes, J., Carlo, W.A., 2007. Respiratory system Cited in. In: Kenner, C., Wright-Lott, J. (Eds.), Comprehensive Neonatal Care e an Interdisciplinary Approach, fourth ed. Saunders Elsevier, St Louis 2007. Clark, V., Kueser, T.J., 2000. Low dose inhaled NO treatment of PPHN. New England Journal of Medicine 342, 469e474. Cooke, R.W.I., 2005. Good practice in consent. Seminars in Neonatology 10, 63e71. Cools, F., Offringa, M., 2005. Neuromuscular paralysis for newborn infants receiving mechanical ventilation. Cochrane Database of Systemic Reviews(2) OXFORD: Updated software. Davidson, D., Barefield, E.S., Kattwinkel, J., Dudell, G., Damask, M., Straube, R., Rhines, J., Chang, C.T., 1999. Safely withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics 104 (2), 231e236. D’Cunha, C.D., Sankaran, K., 2001a. Persistent pulmonary hypertension of the newborn (persistent fetal circulation). Neonatal Intensive Care e The Journal of PerinatologyNeonatology 14 (1), 14e20.
C. Niccolls D’Cunha, C., Sankaran, K., 2001b. Persistent fetal circulation. Paediatric Child. Health 6 (10), 744e750. DeBoer, S.L., Stephens, D., 1997. Persistent pulmonary hypertension of the newborn: case study and pathophysiology review. Neonatal Network 16 (1), 7e12. Emery, M., 2000. Informed consent: keeping parents in the picture. Journal of Neonatal Journal 6 (3), 90e92. Engle, W.A., 2007. Persistent pulmonary hypertension of the newborn Cited in. In: Polin, R.A., Yoder, M.C. (Eds.), Workbook in Practical Neonatology, fourth ed. Saunders Elsevier, USA 2007. Findlay, J., 2004. The gate control theory of pain e applying theory to practise. Journal of Neonatal Nursing 10 (2), 38. Finer, J., Barrington, K.J., 2006. Nitric oxide for respiratory failure in infants born near term or term (Cochrane Review). Cochrane Database of Systemic Reviews(4) OXFORD: updated software. Ganesh-Konduri, G., 2004. New approaches for persistent pulmonary hypertension of newborn. Clinics in Perinatology 31, 591e611. Guthrie, S.O., Walsh, W.F., Auten, K., Clark, R.H., 2004. Initial dosing of inhaled nitric oxide in infants with hypoxic respiratory failure. Journal of Perinatology 24, 290e294. Hagaman, M., Frostell, C., Arnberg, H., Hedenstierma, G., 1993. Bleeding time prolongation and NO inhalation. Lancet 341, 1664e1665. Hagedorn-Enzman, M.I., Gardner, S.L., Dickey, L.A., Abman, S. H., 2006. Respiratory diseases Cited in. In: Merestein, G.B., Gardner, S.L. (Eds.), Handbook of Neonatal Intensive Care, sixth ed. Mosby Elsevier, USA 2006. Hunt, A., Milner, A.D., 1999. High frequency oscillation. Journal of neonatal nursing 5 (3) supplement. Jackson, J.C., Truog, W.E., Standaert, T.A., Murphy, J.H., Juul, S.E., Chi, E.Y., Hildebrandt, J., Hodson, W.A., 1994. Reduction in lung injury after combined surfactant and high frequency ventilation. Am Journal Respiratory Critical care Med 150, 534e539. Jeenakeri, K., Drayton, M., 2009. Management of respiratory distress syndrome. Paediatric and Child Health 19 (4), 158. Kairamkonda, V., 2009. Respiratory difficulties and ventilator support in newborns Cited in. In: Meeks, M., Hallsworth, M., Yeo, H. (Eds.), Nursing the Neonate, second ed. Wiley Blackwell 2009. Kemp, J., 1997. Nursing care if the baby receiving high frequency oscillatory ventilation: the importance of familiarity with the technique. Journal of neonatal nursing;31e35. Kinsella, J.P., Truog, W.E., Walsh, W.F., 1997. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr 131, 55e62. Levene, M.I., Tudehope, D.I., Thearle, M.J., 2000. Essentials of neonatal medicine, third ed. Blackwell Science, Oxford. Levin, D.L., Morris, F.C., 1997. Essentials of Paediatric Intensive Care, second ed. Churchill Livingstone, New York. Lotze, A., Knight, G.R., Martin, G.R., Bulas, D.I., Hull, W.M., O’Donnell, R.M., Whitsett, J.A., Short, B.L., 1993. Improved pulmonary outcome after exogenous surfactant therapy in respiratory failure in term infants requiring extracorporeal membrane oxygenation. Journal of Pediatrics 122, 261e268. Lupton, D., Fenwick, J., 2001. “They’ve forgotten that I’m the mum’’ constructing and practicing motherhood in special care nurseries. Social Science and Medicine 53, 1011e1021. Mason, J.K., McCall, R.S., 1994. Law and Medical Ethics. Butterworth, London. Miller, C.L., 1995. Nitric oxide therapy for persistent pulmonary hypertension of the newborn. Neonatal Network 14 (8), 9e14. Mok, E., Leung, S., 2005. Nurses as providers of support for mothers of premature infants. Journal of Clinical Nursing 15, 726e734.
pulmonary hypertension
71
Nursing and Midwifery Council, 2004. The NMC Code of Professional Conduct: Standards for Conduct, Performance and Ethics. NMC, London. Ostrea, E.M., Villanueva-Uy, E.T., Natarajan, G., UY, H.G., 2006. Persistent pulmonary hypertension of the newborn. Pediatric Drugs 8 (3), 179e185. Pettett, G., Pallotto, E.K., Merestein, G.B., 2006. Perinatal transport Cited in. In: Merenstein, G.B., Gardner, S.L. (Eds.), Handbook of Neonatal Intensive Care, sixth ed. Mosby Elsevier, USA 2006. Prullage, S., Melichar, C., 1993. Stabilization and transportation of the infant with PPHN. Neonatal Network 12 (7), 45e50. Rohan, A.J., Golombek, S.G., 2009. Hypoxia in the term newborn: cardiopulmonary physiology and assessment. Maternal Child Health 34 (2), 106e112. Schreiber, M.D., 2003. Inhaled nitric oxide in preterm neonates with respiratory distress syndrome. The England Journal of Medicine 349 (22), 1061. Shenoy, S., Archdeacon, C., Kotecha, S., Elias-Jones, 2003. Current practice for obtaining consent in UK neonatal units. Bull Med Ethics 118, 17e19. The Neonatal Inhaled Oxide Study, 1997. Inhaled nitric oxide in term and near term infants with hypoxic respiratory failure. New England Journal of Medicine 336, 597e604. The Neonatal Inhaled Oxide Study, 2000. Inhaled nitric oxide in term and near term infants: neurodevelopmental follow up of the NINOS. Journal of Pediatrics 136, 611e617.
UNICEF Baby Friendly Intitiative, 2007. Off to the Breast Start (Online) UNICEF Available at. http://www.babyfriendly.org. uk/pdfs/otbs_leaflet.pdf (accessed 16th October 2009). Van Meurs, K.P., Wright, L.L., Ehrenkranz, R.A., 2005. Inhaled nitric oxide for premature infants with severe respiratory failure. New England Journal of Medicine 353, 13e22. Wendel, K.R., Nathan, A.T., 2006. Inhaled nitric oxide. Newborn and Infant Nursing Reviews 6 (2), 100e105. Williams, L.J., Shaffer, T.H., Greenspan, J.S., 2004. Inhaled nitric oxide therapy in the near term or term neonate with hypoxic respiratory failure. Neonatal Network 23 (1), 5e12. Woods-Blake, W., Murray, J.A., 2006. Heat balance Cited in. In: Merenstein, G.B., Gardner, S.L. (Eds.), Handbook of Neonatal Intensive Care, sixth ed. Mosby Elsevier, USA 2006. Wylie, J.P., Goldsmith, J.P., Karotkin, T.H., 2004. Assisted Ventilation of the Neonate, fourth ed. Saunders, Philadelphia.
Biblithography
Dakshinamurti, S., 2005. Pathophysiologic mechanisms of persistent pulmonary hypertension. Paediatric Pulmonary 39 (6), 492e503. Walsh, M.C., Stork, E.K., 2001. Persistent pulmonary hypertension of the newborn e Rational therapy based on pathophysiology. Clinics in Perinatology 28 (3), 609e627.
Available online at www.sciencedirect.com
www.elsevier.com/jneo
ORIGINAL ARTICLE
Persistent pulmonary hypertension of the newborn* Christine Niccolls * Neonatal unit, Liverpool Women’s NHS Foundation Trust, Liverpool, United Kingdom Available online 23 November 2010
KEYWORDS Persistent pulmonary hypertension; Nitric oxide; high frequency oscillation
Abstract To protect the identity of the neonate and her family, pseudonyms and fictitious dates have been used, so as to ensure confidentiality as directed by the Nursing Midwifery Council (NMC, 2004). This article explores the aetiology of persistent pulmonary hypertension (PPHN) in a term neonate and discusses nursing management and the management of neonates on high frequency oscillation and inhaled nitric oxide therapy. It is imperative that all staff nursing a neonate on high frequency oscillation and inhaled nitric oxide therapy has a knowledge of the concept, be aware of the problems that may arise and be capable of taking steps in avoiding their occurrence. ª 2010 Neonatal Nurses Association. Published by Elsevier Ltd. All rights reserved.
Case study Katie was born at 38 weeks and 5 days gestational age via an elective caesarean section at an outside hospital. She was born to a multiparous woman in view of previous caesarean sections. Apgars of eight at five and ten at 10 min were assigned. Clear amniotic fluid was noted when the membranes were ruptured at delivery. At 30 min of life, she was noted to have moderate respiratory distress with an intermittent grunt. She was taken to the neonatal unit for observation and intervention, at 4 h postnatal age. A septic screen was undertaken *
No support in the form of funding/equipment. * Tel.: þ151 708 9988. E-mail address: [email protected].
and broad spectrum antibiotics started in the early treatment of her respiratory symptoms. She required an increasing oxygen requirement by head box, progressing to endotracheal intubation at 19 h of age. An umbilical arterial line and a double lumen umbilical venous catheter were placed. Sodium bicarbonate was given intravenously to correct a metabolic acidosis and intravenous fluids were commenced at 60 millitres per kilogram per day. Pre and post ductal saturations were measured and were noted to be 20 points lower postductally. After adequate volume administration dopamine hydrochloride was started at 5 micrograms per kilogram per minute with concurrent 15 micrograms per kilogram per minute of dobutamine hydrochloride because of a persistently low mean arterial pressure of 29 mmHg.
1355-1841/$ - see front matter ª 2010 Neonatal Nurses Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jnn.2010.10.001
64 Her chest X-ray depicted a uniform reticulogranular appearance in both lung fields and reduced lung volume. She received several dosages of artificial surfactant via her endotracheal tube. The main function of surfactant is to lower the surface tension within the alveolar and prevent alveolar collapse at the end of expiration and the loss of lung volume (Cifuentes and Carlo, 2007). The referring hospital obtained an echocardiogram with pulse doppler to rule out structural heart disease, identify PPHN and document cardiac function. Echocardiogram showed right ventricular enlargement with elevated ventricular pressures with right to left shunting at the level of the foramen ovale and the ductus arteriosus. In light of her clinical course and these findings it was determined that the most likely diagnosis was PPHN; synonymous with term neonates. Her arterial blood gases showed a persistent partial pressure of oxygen of less than 33 mm of mercury despite breathing 100% oxygen. Conventional ventilation techniques failed to maintain normal respiratory function therefore plans were made for Katie to be transported to a tertiary centre for high frequency oscillation and nitric oxide therapy due to an oxygen index of 30. On admission to the tertiary centre she was placed on high frequency oscillation with a mean airway pressure at 15 cm of water, amplitude at 53 cm of water, and a frequency of 10 Hz and inhaled nitric oxide at 20 parts per million.
Persistent pulmonary hypertension To appreciate the mechanism of PPHN, one has to be familiar with the fetal circulation and neonatal circulatory adaption. The fetal circulation is designed to deliver oxygenated blood from the placenta to the fetal brain and other major organs and to allow blood to be diverted away from the pulmonary circulation via fetal shunt pathways (DeBoer and Stephens, 1997). When the neonate takes its first breaths at delivery, the entrance of oxygen into the pulmonary circulation is the most important initiator of vasodilatation. The alveolar oxygen concentration rises and the pulmonary vascular bed dilates, pulmonary vascular resistance decreases and lung compliance increases (Prullage and Melichar, 1993). With the increase in pulmonary blood flow, the arterial oxygen concentration continues to rise, resulting in the closure of the ductus arteriosus. Subsequently there is an increase in blood return to the left atrium, resulting in an increase left arterial pressure. At the point when the left arterial pressure is greater than the right arterial pressure there is
C. Niccolls closure of the foramen ovale (DeBoer and Stephens, 1997). If, for any reason, right sided pressures remain higher to those on the left side, fetal circulation will persist through one or both of the fetal pathways. Therefore persistent pulmonary hypertension of the newborn is defined as: an increase or failure of the postnatal fall in pulmonary vascular resistance thereby resulting in right to left shunting of deoxygenated blood at atrial, ductal and pulmonary levels with consequent severe hypoxia (Boden and Bennett, 2004, pp 290). PPHN is an appropriate term for non-cardiac causes of cyanosis with elevated pulmonary vascular resistance in term or near term neonates (Ganesh-Konduri, 2004). The syndrome may be idiopathic or secondary to another disorder. Idiopathic PPHN commonly results from an abnormal remodelling of the pulmonary vascular bed with vascular wall thickening and hyperplasia of the smooth muscle (D’Cunha and Sankaran, 2001a). Secondary PPHN is most commonly seen in a neonate with another disorder such as meconium aspiration syndrome, congenital diaphragmatic hernia, respiratory distress syndrome, sepsis, asphyxia, polycythaemia or hypoglycaemia (Abman and Kinsella, 2003). The workup for the neonate suspected of having PPHN should include arterial blood gases to assess pH, partial pressure of oxygen and carbon dioxide. Arterial blood gases reveal severe hypoxia with a partial pressure of oxygen <100 mmHg in 100% oxygen (Boden and Bennett, 2004). The response of supplemental oxygen can help distinguish PPHN from primary lung disease as supplemental oxygen traditionally increases partial pressure of oxygen readily in lung disease than cyanotic heart disease or PPHN (Abman and Kinsella, 2003). Oxygenation should be assessed by differential oxygen saturation monitoring, with one saturation probe placed simultaneously on the right hand and one on either lower extremity. A significant higher saturation reading in the right hand suggests right to left shunting across a patent ductus arteriosus (Rohan and Golombek, 2009). However caution must be given as according to Rohan and Golombek (2009) as if the shunt is large across the foreman ovale, preductal saturation differences may be obscured or absent and therefore PPHN cannot be excluded when differential is absent. A chest X-ray can be helpful in determining the presence of underlying parenchymal lung disease or ruling out disorders such as congenital diaphragmatic hernia. Cardiomegaly and increased vascular markings are often visible in PPHN. In
pulmonary hypertension newborns with idiopathic PPHN, the lung fields appear clear with decreased vascular markings and the heart size is typically normal and therefore is often referred to clear-lung PPHN (Burst et al., 2009). Suspicion of PPHN should be considered when hypoxemia is out of proportion to the degree of parenchymal disease on the chest radiograph. When PPHN is suspected, an echocardiogram is essential to rule out the presence of congenital heart disease in the newborn with cyanosis and tachypnea. If the heart is deemed structurally normal, like in case study, and the echocardiogram shows high pulmonary artery pressures and right to left shunting through the patent ductus arteriosus, foreman ovale, or both, then PPHN can be presumptive diagnosis. Frequently, there is evidence of right heart failure because the pressures in the pulmonary artery are greater than the systemic pressure, resulting in the right ventricle inability to eject blood (Burst et al., 2009). Inhaled nitric oxide should not be administered to neonates with congenial heart disease who depend on right to left shunting or who have severe left heart failure (Williams et al., 2004). Levene et al (2000) suggest the following conditions should be present before a diagnosis of persistent pulmonary hypertension of the newborn can be made: Sustained systemic pulmonary artery pressure Profound hypoxemia with or without acidosis while breathing 100% oxygen Normal cardiac anatomy on echocardiography examination Evidence of right to left shunting of blood through either the ductus arteriosus or the foramen ovale (pp 200). An evaluation of the complete blood count may be significant for derangements that may cause or aggravate PPHN including polycythaemia, hypoglycaemia and hypocalcaemia; therefore levels should be kept within reference range Burst et al (2009). A white blood cell count and differential are helpful in determining whether an underlying sepsis or pneumonia exists. Broad spectrum antibiotics had been started in the early treatment of her respiratory symptoms. It is important to note, that the white out appearance of the chest X-ray cannot be differentiated from the appearance of neonatal pneumonia which is often caused by Group B Streptococcus therefore broad spectrum antibiotic cover should be given after blood cultures, to ensure that the respiratory distress is not caused by a bacterial pathogen (Jeenakeri and Drayton, 2009). Respiratory pathology was confirmed after blood cultures were negative after 72 h.
65
High frequency oscillation and nursing management The maintenance of adequate oxygenation is the primary goal in the management of PPHN and mechanical ventilation is one of the therapies to achieve this goal. One of the early strategies in conventilational mechanical ventilation was hyperventilation as it is known that the pulmonary vascular bed responds to acidosis with constriction, therefore treatment is aimed at reversing that effect (Ostrea et al., 2006). Inducing a respiratory alkalosis and increasing pH will thereby interrupt the cycle of hypoxia and acidosis permitting relaxation of the constricted pulmonary vascular bed. However this method has to be employed with caution since hypocarbia may result in ischaemia and subsequent neurodevelopment mental deficits (Ostrea et al., 2006; D’Cunha and Sankaran, 2001a); use of alkalinizing agents such as sodium bicarbonate has become commonplace (Hagedorn-Enzman et al., 2006), as hyperventilation is not evidence based practice (Engle, 2007). High frequency oscillation is an alternative mode of ventilatory support in neonates. The goal of high frequency oscillation is to optimise lung expansion and functional residual capacity to avoid over distension of the lung parenchyma. Over distension can predispose the neonate to significant barotrauma and elevation of pulmonary vascular resistance, thereby worsening the PPHN (Ostrea et al., 2006). High frequency oscillatory ventilation maintains gas exchange at lower mean airway pressures and peak inspiratory pressures; it is used to recruit atelectatic alveoli and sustain lung volumes in cases of severe respiratory failure (Miller, 1995). Surfactant combination with high frequency oscillation reduces alveolar oedema and improves oxygenation (Lotze et al., 1993) and reduces the need for extracorporeal membrane oxygenation (Jackson et al., 1994). Assessment of the neonate while he or she is receiving high frequency ventilation is frequent and extensive and it differs from routine assessment on conventional ventilation. It is not possible to auscultate the chest for either breath sounds or apical pulse while on high frequency oscillation and the skill is in assessing the “bounce” of the chest, evaluating lung expansion on chest radiographs and monitoring a continuous ECG tracing. Chest vibration provides an assessment of the adequacy of ventilation, and learning to detect changes in the vibratory pressure amplitude of the chest is important because small changes may
66 affect carbon dioxide elimination (Levin and Morris, 1997). For example, endotracheal tube displacement, pulmonary secretions, lung over inflation and pneumothoraces are common complications that may be discovered when assessing chest vibration (Levin and Morris, 1997). Pneumothoraces may result as a consequence of hyperventilation but also occur as a consequence of ventilation on damaged parenchymal tissue. Consequently, we must always have equipment for chest drain insertion close to hand. It is possible to interrupt or pause the ventilator briefly during the assessment process to auscultate breaths sounds and listen for heart murmurs; however this can destabilise the neonate (Wylie et al., 2004). If the neonate is removed from the ventricular circuit, the bag utilised to supply breaths must be connected to the inhaled nitric oxide and oxygen supply (Williams et al., 2004). As disconnection should be avoided, a closed system approach to endotracheal suctioning needs to be performed, as this will prevent the loss of lung volume due to alveolar collapse. Auscultation of the chest due to the continuous vibration of the chest is difficult therefore indications of endotracheal suctioning will be a reduction in chest wall vibration and/or deterioration in the arterial blood gases with an increase in carbon dioxide (Hunt and Milner, 1999). However according to Levin and Morris (1997) even though the aspect of chest auscultation is affected by the loud rapid vibratory sounds, they highlight the importance of the clinician acquiring an appreciation for the vibratory breath sounds; these may be characterised by bright, dull or squeaky. Serial chest X-rays were obtained, with the first taken within 30 min after starting high frequency oscillation on Katie, this was to determine the efficacy of alveoli recruitment and lung expansion and therefore allowing the ventilation to be adjusted accordingly. The diaphragm should be at the level of the ninth rib (Cameron and Haines, 2000). If the diaphragm is lower the mean arterial pressure will need to be reduced, as the lungs are overinflated and this will reduce cardiac output and increase the risk of intravenous haemorrhage. If the diaphragm is higher the mean arterial pressure will need to be increased (Cameron and Haines, 2000). Alterations in ventilation may be made frequently when commencing high frequency oscillation therefore as the neonatal nurse we must record ventilation changes as they occur as well as on a routine basis. Amplitude, MAP, fi02, inspiratory time and frequency should be observed and documented and on some oscillators it is also necessary to note
C. Niccolls the position of the piston in the oscillator, with the nurse centring the piston if it drifts from the midline. Excellent humidification is essential with such high flow oscillators, as necrotizing tracheobronchitis has been reported with high frequency jet and oscillator ventilation (Levin and Morris, 1997); this problem appears to relate to a combination of dry gas and high inspiratory flow. The neonatal nurse must therefore ensure that airway temperature is maintained at 37 degrees and the fluid level in the humidification chamber is checked and refilled.
Nitric oxide and nursing management Pulmonary vasodilatation with multiple drugs have being evaluated for treatment of PPHN, but none recommended for clinical use accept inhaled nitric oxide (Ostrea et al., 2006). Endogenous or exogenously delivered nitric oxide causes relaxation of the vascular smooth muscle by a normal occurring mechanism (Williams et al., 2004). Because it is a short lived molecule it relaxes the pulmonary vascular smooth muscle when inhaled but does not enter the systemic vasculature. For inhaled nitric oxide to work optimally, it has to be delivered effectively to the terminal air spaces. Hence it is important to achieve adequate alveolar recruitment prior to inhaled nitric oxide therapy. In a large randomised controlled trial of mature neonates with severe respiratory failure, the combination of high frequency oscillation and inhaled nitric oxide was more effective in improving short-term oxygenation than either treatment alone (Kinsella et al., 1997). In accordance with the Cochrane review by Finer and Barrington (2006) they state that starting inhaled nitric oxide therapy in term neonates when the oxygenation index is greater than 25 or when partial pressure of oxygen is <100 mmHg when receiving 100% oxygen is consistent with published evidence. An oxygenation index (OI ¼ mean airway pressure FiO2 100/PaO2) was established as the entry criterion for trials, with the mean upon initiation being 38. The oxygenation index has been used to define severity of illness in neonates with respiratory failure, but a given oxygenation index might not predict successful treatment with inhaled nitric oxide, largely because the oxygenation index calculation does not consider the cause of hypoxemia (Williams et al., 2004). Some studies (Schreiber, 2003) have shown equal efficacy in preterm neonates but a recent multicentre randomised controlled trial could not
pulmonary hypertension support this group (Van Meurs et al., 2005). With the evidence presently available, Finer and Barrington (2006) state that near term or term infants without a diaphragmatic hernia should have a trial of inhaled nitric oxide. This therapy is very effective in reducing the need for EMCO, with a need to treat ratio of 5e3. Nursing care of the newborn receiving inhaled nitric oxide therapy includes careful monitoring of the gas administration because nitric oxide has a high affinity for haemoglobin. Once nitric oxide combines with haemoglobin, then a chemical inactivation occurs resulting in the formation of methaemoglobin. Once it combines with haemoglobin, this prevents oxygen from binding with the haem and therefore reduces the oxygen-transporting ability of the blood (Williams et al., 2004). Consequently methaemoglobin levels need to be monitored during inhaled nitric oxide therapy (Williams et al., 2004). Exposure to inhaled nitric oxide concentrations greater than 20 parts per million can be associated with methaemoglobinemia (Williams et al., 2004), therefore in our nursing practices side effects are kept minimal at the recommended 5e20 parts per million (Guthrie et al., 2004). In addition because nitric oxide and oxygen can react to produce toxic by-products such as nitrogen dioxide, the delivered amount must be closely monitored. Extremely high levels of nitrogen dioxide can be toxic to parenchymal lung tissue and cause severe pulmonary oedema (Miller, 1995). It is now widely acknowledged toxic nitrogen dioxide, can suppress platelet adhesion and aggregation and as such plays an important role in vascular haemostasis (Hagaman et al., 1993; Kairamkonda, 2009). The nurse should be alert to the neonates increased susceptibility to bleeding. The Neonatal Inhaled Nitric Oxide Study (1997) was the first controlled clinical trial demonstrating that inhaled nitric oxide therapy reduced the need for ECMO in neonates with hypoxic respiratory failure without significant toxicity and demonstrated that inhaled nitric oxide therapy could improve oxygenation in neonates with severe hypoxic respiratory failure. Subsequent research by Clark and Kueser (2000) also demonstrated a reduction for EMCO therapy. The Neonatal Inhaled Nitric Oxide Study Group (2000), including the neurodevelopmental component, demonstrated the safety and efficacy of inhaled nitric oxide therapy for severe hypoxic respiratory failure. However, the follow- up study revealed that survivors of severe hypoxic respiratory failure experience significant morbidities
67 regardless of whether inhaled nitric oxide or ECMO therapies were utilised.
Nursing management Neonates with PPHN have continued high pulmonary resistance that impedes pulmonary flow, leading to hypoxia, metabolic acidosis and decreased lung compliance. As hypoxia continues further pulmonary vasoconstriction ensues, therefore hypoxia creates and maintains a negative feedback system (DeBoer and Stephens, 1997). Therefore interventions are aimed at increasing pulmonary flow by decreasing pulmonary resistance or increasing systemic resistance, thus impeding right to left shunting (DeBoer and Stephens, 1997). The goal of nursing care must be to optimise oxygenation and minimise hypoxia and acidosis, thus preventing the cyclical pattern and progression. Providing a neutral thermal environment and clustering care is key in decreasing oxygen requirements. Katie’s own heat e regulating system was inefficient as evidence from her poor flexion. Neuromuscular block agents inhibit a neonate’s ability to maintain a flexed position increasing exposed surface area and heat loss (Woods-Blake and Murray, 2006). Following transfer she was nursed in an incubator as a means of controlling thermoregulation and for closer observation and assessment of her general condition. Evaluation of care was measured by the fact Katie remained normothermic and monitoring did not show any signs of hypoglycaemia. Strategies to eliminate stress must be individualised to the neonate and appropriate to the level of illness. Labiality in her oxygenation persisted with handling therefore minimal stimulation techniques were instituted. Care requirements of Katie were to be undertaken twelve hourly to facilitate minimal handling and energy conservation which is of extreme importance to enable the most beneficial utilization of calories and moreover, disturbing a sick neonate can cause her condition to deteriorate, usually by making her hypoxic; hypoxia is a major reason for pulmonary vascular resistance failing to fall (HagedornEnzman et al., 2006; Boden and Bennett, 2004). The role of the neonatal nurse is to effectively anticipate, prevent and managed pain in all neonates regardless of their gestational age or severity of illness, having used an appropriate pain assessment tool (Boyd, 2002; Findlay, 2004). Katie was nursed on a continuous infusion of 40 mcg/kg/h morphine. Even though she was receiving vecuronum 50 mcg/kg/h, a muscle paralytic, she still required concurrent use of
68 morphine because muscle paralytics do not alter the infant’s pain threshold (DeBoer and Stephens, 1997). Eye care is important when infants are receiving muscle paralytic, as the blink reflex will be suppressed by the muscle depolarising agents; therefore hypromellose eye drops are used to keep the corneas moist and prevent corneal abrasions (DeBoer and Stephens, 1997). Ventilated neonates breathing in asynchrony with the ventilator are potentially exposed to more severe barotrauma and are at risk for complications such as pneumothorax or intraventricular haemorrhage (DeBoer and Stephens, 1997; Cools and Offringa, 2005). These neonates usually only have marginal respiratory gas exchange that is further compromised by agitation and asynchronising ventilation (Pettett et al., 2006). Neuromuscular paralysis, which eliminates the spontaneous breathing efforts of the neonate, creates complete synchronization with the ventilator and may minimise these risks. However induced paralysis is controversial. There have been some isolated reports in the literature of increased mortality with the use of pancuronium bromide, promotion of atelectasis of dependent lung regions and ventilation perfusion mismatch (Asad and Bhat, 2008). Therefore routine use of pancuronium or any other neuromuscular blocking agent in ventilated preterm newborn infants cannot be recommended based on current evidence as uncertainty remains regarding the long-term pulmonary and neurologic effects and the safety of prolonged use of neuromuscular blocking agents in ventilated newborn infants (Cools and Offringa, 2005). Of note there is no data available from randomised controlled trials with term ventilated neonates. Neonates at risk of skin injury include those on high frequency oscillisation because they are more difficult to move. Hypotension leading to peripheral tissue hypoperfusion is another factor predisposing these neonates, as well oedema in critically ill neonates who have leaking capillaries or require excessive fluids and blood products to maintain blood pressure (Wylie et al., 2004). Paralysing agents or infants on high levels of sedation creates poor muscle tone and decreased movement increasing risk of skin breakdown (Wylie et al., 2004). Neonates with PPHN will require monitoring of their vital signs. Continuous monitoring will provide information regarding their cardiac performance and respiratory status. A complete clinical assessment of cardiac function must include heart rate, blood pressure, capillary refill, urine output and acid base balance. Because of the inability to auscultate the cardiac sounds, heart
C. Niccolls rate is obtained from ECG monitoring. Delayed capillary refill, hypotension, metabolic acidosis, tachycardia and oliguria may all be signs of cardiac dysfunction. Although they may have pulmonary hypertension, the systemic blood pressure may be low because of the impaired cardiac output. This means the neonate is at risk of renal failure. Urine output should be monitored and intake adjusted accordingly (Beresford and Boxwell, 2006). Another consideration for the neonatal nurse is it is estimated that approximately 70% of inhaled nitric oxide is excreted within 48 h as nitrate in the urine. Nitrate itself is not toxic to the body however excess quantities can promote the conversion of nitrate to nitrite which can in turn result in increased production of both methaemoglobin and ammonia (Wendel and Nathan, 2006). If ammonia cannot be excreted in the urine excess quantities can lead to hepatic and central nervous system toxicity (Wendel and Nathan, 2006). Therefore as the bedside nurse we must ensure adequacy of urine output in our neonates on inhaled nitric oxide therapy. Umbilical arterial and umbilical venous catheters were placed under sterile conditions. As Katie, was likely to need ventilator support for some time, an umbilical artery catheter line was inserted for easily obtaining of blood samples and for continuous recording of her blood pressure. Intraarterial blood monitoring is essential once high frequency oscillation is commenced because oxygenation can change dramatically and hypoxia can develop rapidly if the neonate is not monitored in a meticulous fashion (Kemp, 1997). High frequency oscillation can produce high intrathoraic pressure causing cardiac compression and possible hypotension (Hunt and Milner, 1999). Mean systemic blood pressure should be maintained in the high normal range with the use of volume expansion and inotropes if required. Use of inotropic support ideally increases myocardial contractility and cardiac output thereby increasing systemic vascular resistance above the pulmonary pressure (Hagedorn-Enzman et al., 2006; D’Cunha and Sankaran, 2001b). Nursing concerns include an understanding of the dosage, calculation and administration of these drugs. For instance, dopamine at low doses combined with high dosage dobutamine is commonly used and the nurse should be alert to the fact dopamine at high doses acts as an alphaadrenergic stimulator which actually increases pulmonary vascular resistance and results in a negative outcome (D’Cunha and Sankaran, 2001b). After adequate volume administration, Dobutamine hydrochloride was initiated and
pulmonary hypertension titrated up to 15 micrograms per kilogram per minute concurrent with Dopamine hydrochloride at 5 micrograms per kilogram per minute for management of her hypotension. Often neonates with pulmonary hypertension have a low ventricular output because the reduced pulmonary perfusion leads to a lower pulmonary venous return and therefore a decreased left ventricular preload. By contrast the right ventricle is overloaded with a high afterload. Myocardial function may also be reduced due to hypoxia, hypercarbia and acidosis (Boden and Bennett, 2004). Blood products were administered to Katie with an aim to improve systemic pressure and optimise the oxygen carrying ability of her blood.
Family support While managing an unstable neonate, the nurse must also support the infant’s family members, who are frequently frightened by the amount of equipment and expertise needed to care for their baby (Williams et al., 2004). When faced with a NICU admission, parents struggle with the unknown in the unfamiliar and potentially threatening environment of an intensive care unit. An explanation of the environment surrounding the infant is important including type of monitoring and explaining the temporary but necessary effects of the muscle paralytics (Wylie et al., 2004). These parents often encounter challenges to the development of their parenting roles (Lupton and Fenwick, 2001), therefore the neonatal nurse identified tasks that Katie’s parents were comfortable with; both parents were shown how to perform hygiene and skin care and assisted with these on visiting the ward. The author provided advice regarding procedures for collecting and storing her breast milk in accordance with UNICEF international protocol (UNICEF Baby friendly initiative, 2007) and supported the mother in her efforts as many mothers view their providing of milk as an important personal contribution to their infant’s care. Good nursing practice and ethical conscience requires that parents be kept informed of their infant’s progress and treatments (Emery, 2000). Ethical and legal theorists suggests consent should be informed, where the focus is on autonomy as opposed to beneficence and the giving of informed consent becomes a ‘matter of self determination’ (Mason and Mccall, 1994). However, according to Cooke (2005) consent in the neonatal unit is often presumed to be implied by the parents agreeing verbally to their child being admitted to an intensive care unit after birth. While it is clearly
69 impractical, and probably needlessly distressful according to Cooke (2005), to seek individualised informed consent for each procedure at the time, he suggests that parental autonomy with regard to decision making about their child can be protected to some extent by an information-giving discussion with parents during early labour, or even a short tour around the intensive care unit prior to delivery. Unfortunately, such methods cannot help when the delivery is sudden or unexpectedly abnormal. Many neonatal units do not seek explicitly informed consent for ventilation, total parenteral nutrition, exchange transfusion or for newer technologies such as high frequency oscillation or nitric oxide therapy (Cooke, 2005). Shenoy et al. (2003) publication and the associated editorial criticised neonatologists for this, however according to Cooke (2005) the publication seemed to ignore the fact that many of the interventions discussed were emergency procedures. Parental autonomy can be, again protected to some extent with regular updates, therefore the health care team provided an environment that fostered open dialogue. The plan was to support the parents by ensuring they were kept up to date with Katie’s management with regular family meetings with the consultant and daily cot-side updates. Frequent family meetings were held as according to Mok and Leung (2005) parents are in a state of shock and cannot process large amounts of information all at once and particularly during a doctor’s round. Nurses might act as a buffer to fill in the gap or transcribe medical terminology into laymen’s terminology after the doctor’s visit. On day five of life, Katie was transferred on to conventional mechanical ventilation with her oxygen requirement as low as 30 per cent. Inhaled nitric oxide therapy was successfully discontinued on day 5 of life too. The process of weaning Katie from inhaled nitric oxide therapy was a gradual process to avoid sudden severe pulmonary vasoconstriction and arterial desaturation (Miller, 1995). Research provided by Davidson et al. (1999) reported minimizing inhaled nitric oxide dose to 1 ppm before discontinuation, was associated with least deterioration. Katie was transferred back to the outside hospital at 12 days old, where she was self ventilating in air. The case demonstrates the ability to successfully treat a neonate with severe PPHN. Caring for this neonate demanded skills, knowledge, diligence and collaborative management amongst the multidisciplinary health professionals. Due to the diverse nature of conditions complicating PPHN there is no single approach to treatment. Care should be individualised and based on the neonate’s response.
70 Nursing staff are integral to ensuring seamless coordination of this care and play a critical role in the success of any initiated therapy. Reflective practice enabled me to identify a lack of knowledge and therefore encouraged me to perform a literature review to address this imbalance. The process of reflection has encouraged me to reflect on my day to day practice, to examine the rationale behind my practice, to make further enquires and to ensure that all aspect of care are up to date and research based. The literature review reassuringly supported our management of the neonate.
Acknowledgements Thanking Debbie Webster and Ginny Wallace for their continued support and advice.
References Abman, S., Kinsella, J.P., 2003. Persistent pulmonary hypertension of the newborn. In: Greenough, A., Milner, A.D. (Eds.), Neonatal Respiratory Disorders, second ed. Arnold, London 2003. Asad, A., Bhat, R., 2008. Pharmacology for meconium aspiration. Journal of Perinatology 28, S72eS78. Beresford, D., Boxwell, G., 2006. Fluid and electrolyte balance Cited in. In: Boxwell, G. (Ed.), Neonatal Intensive Care Nursing. Routledge, London 2006. Boden, G., Bennett, C., 2004. The management of persistent pulmonary hypertension of the newborn. Current Paediatrics 14, 290e297. Boyd, S., 2002. Sucrose analgesia: a realistic alternative to conventional pharmacology for pain relief in neonates. Journal of Neonatal Nursing 8 (6), 184. Burst, P., Hamburger, M., Larkin, P., 2009. Transport of the neonatal patient with persistent pulmonary hypertension. Newborn and Infant Nursing Review 9 (4), 219e225. Cameron, J., Haines, J., 2000. Management of respiratory disorders Cited in. In: Boxwell, G. (Ed.), Neonatal Intensive Care Nursing. Routledge, London 2000. Cifuentes, J., Carlo, W.A., 2007. Respiratory system Cited in. In: Kenner, C., Wright-Lott, J. (Eds.), Comprehensive Neonatal Care e an Interdisciplinary Approach, fourth ed. Saunders Elsevier, St Louis 2007. Clark, V., Kueser, T.J., 2000. Low dose inhaled NO treatment of PPHN. New England Journal of Medicine 342, 469e474. Cooke, R.W.I., 2005. Good practice in consent. Seminars in Neonatology 10, 63e71. Cools, F., Offringa, M., 2005. Neuromuscular paralysis for newborn infants receiving mechanical ventilation. Cochrane Database of Systemic Reviews(2) OXFORD: Updated software. Davidson, D., Barefield, E.S., Kattwinkel, J., Dudell, G., Damask, M., Straube, R., Rhines, J., Chang, C.T., 1999. Safely withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics 104 (2), 231e236. D’Cunha, C.D., Sankaran, K., 2001a. Persistent pulmonary hypertension of the newborn (persistent fetal circulation). Neonatal Intensive Care e The Journal of PerinatologyNeonatology 14 (1), 14e20.
C. Niccolls D’Cunha, C., Sankaran, K., 2001b. Persistent fetal circulation. Paediatric Child. Health 6 (10), 744e750. DeBoer, S.L., Stephens, D., 1997. Persistent pulmonary hypertension of the newborn: case study and pathophysiology review. Neonatal Network 16 (1), 7e12. Emery, M., 2000. Informed consent: keeping parents in the picture. Journal of Neonatal Journal 6 (3), 90e92. Engle, W.A., 2007. Persistent pulmonary hypertension of the newborn Cited in. In: Polin, R.A., Yoder, M.C. (Eds.), Workbook in Practical Neonatology, fourth ed. Saunders Elsevier, USA 2007. Findlay, J., 2004. The gate control theory of pain e applying theory to practise. Journal of Neonatal Nursing 10 (2), 38. Finer, J., Barrington, K.J., 2006. Nitric oxide for respiratory failure in infants born near term or term (Cochrane Review). Cochrane Database of Systemic Reviews(4) OXFORD: updated software. Ganesh-Konduri, G., 2004. New approaches for persistent pulmonary hypertension of newborn. Clinics in Perinatology 31, 591e611. Guthrie, S.O., Walsh, W.F., Auten, K., Clark, R.H., 2004. Initial dosing of inhaled nitric oxide in infants with hypoxic respiratory failure. Journal of Perinatology 24, 290e294. Hagaman, M., Frostell, C., Arnberg, H., Hedenstierma, G., 1993. Bleeding time prolongation and NO inhalation. Lancet 341, 1664e1665. Hagedorn-Enzman, M.I., Gardner, S.L., Dickey, L.A., Abman, S. H., 2006. Respiratory diseases Cited in. In: Merestein, G.B., Gardner, S.L. (Eds.), Handbook of Neonatal Intensive Care, sixth ed. Mosby Elsevier, USA 2006. Hunt, A., Milner, A.D., 1999. High frequency oscillation. Journal of neonatal nursing 5 (3) supplement. Jackson, J.C., Truog, W.E., Standaert, T.A., Murphy, J.H., Juul, S.E., Chi, E.Y., Hildebrandt, J., Hodson, W.A., 1994. Reduction in lung injury after combined surfactant and high frequency ventilation. Am Journal Respiratory Critical care Med 150, 534e539. Jeenakeri, K., Drayton, M., 2009. Management of respiratory distress syndrome. Paediatric and Child Health 19 (4), 158. Kairamkonda, V., 2009. Respiratory difficulties and ventilator support in newborns Cited in. In: Meeks, M., Hallsworth, M., Yeo, H. (Eds.), Nursing the Neonate, second ed. Wiley Blackwell 2009. Kemp, J., 1997. Nursing care if the baby receiving high frequency oscillatory ventilation: the importance of familiarity with the technique. Journal of neonatal nursing;31e35. Kinsella, J.P., Truog, W.E., Walsh, W.F., 1997. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr 131, 55e62. Levene, M.I., Tudehope, D.I., Thearle, M.J., 2000. Essentials of neonatal medicine, third ed. Blackwell Science, Oxford. Levin, D.L., Morris, F.C., 1997. Essentials of Paediatric Intensive Care, second ed. Churchill Livingstone, New York. Lotze, A., Knight, G.R., Martin, G.R., Bulas, D.I., Hull, W.M., O’Donnell, R.M., Whitsett, J.A., Short, B.L., 1993. Improved pulmonary outcome after exogenous surfactant therapy in respiratory failure in term infants requiring extracorporeal membrane oxygenation. Journal of Pediatrics 122, 261e268. Lupton, D., Fenwick, J., 2001. “They’ve forgotten that I’m the mum’’ constructing and practicing motherhood in special care nurseries. Social Science and Medicine 53, 1011e1021. Mason, J.K., McCall, R.S., 1994. Law and Medical Ethics. Butterworth, London. Miller, C.L., 1995. Nitric oxide therapy for persistent pulmonary hypertension of the newborn. Neonatal Network 14 (8), 9e14. Mok, E., Leung, S., 2005. Nurses as providers of support for mothers of premature infants. Journal of Clinical Nursing 15, 726e734.
pulmonary hypertension
71
Nursing and Midwifery Council, 2004. The NMC Code of Professional Conduct: Standards for Conduct, Performance and Ethics. NMC, London. Ostrea, E.M., Villanueva-Uy, E.T., Natarajan, G., UY, H.G., 2006. Persistent pulmonary hypertension of the newborn. Pediatric Drugs 8 (3), 179e185. Pettett, G., Pallotto, E.K., Merestein, G.B., 2006. Perinatal transport Cited in. In: Merenstein, G.B., Gardner, S.L. (Eds.), Handbook of Neonatal Intensive Care, sixth ed. Mosby Elsevier, USA 2006. Prullage, S., Melichar, C., 1993. Stabilization and transportation of the infant with PPHN. Neonatal Network 12 (7), 45e50. Rohan, A.J., Golombek, S.G., 2009. Hypoxia in the term newborn: cardiopulmonary physiology and assessment. Maternal Child Health 34 (2), 106e112. Schreiber, M.D., 2003. Inhaled nitric oxide in preterm neonates with respiratory distress syndrome. The England Journal of Medicine 349 (22), 1061. Shenoy, S., Archdeacon, C., Kotecha, S., Elias-Jones, 2003. Current practice for obtaining consent in UK neonatal units. Bull Med Ethics 118, 17e19. The Neonatal Inhaled Oxide Study, 1997. Inhaled nitric oxide in term and near term infants with hypoxic respiratory failure. New England Journal of Medicine 336, 597e604. The Neonatal Inhaled Oxide Study, 2000. Inhaled nitric oxide in term and near term infants: neurodevelopmental follow up of the NINOS. Journal of Pediatrics 136, 611e617.
UNICEF Baby Friendly Intitiative, 2007. Off to the Breast Start (Online) UNICEF Available at. http://www.babyfriendly.org. uk/pdfs/otbs_leaflet.pdf (accessed 16th October 2009). Van Meurs, K.P., Wright, L.L., Ehrenkranz, R.A., 2005. Inhaled nitric oxide for premature infants with severe respiratory failure. New England Journal of Medicine 353, 13e22. Wendel, K.R., Nathan, A.T., 2006. Inhaled nitric oxide. Newborn and Infant Nursing Reviews 6 (2), 100e105. Williams, L.J., Shaffer, T.H., Greenspan, J.S., 2004. Inhaled nitric oxide therapy in the near term or term neonate with hypoxic respiratory failure. Neonatal Network 23 (1), 5e12. Woods-Blake, W., Murray, J.A., 2006. Heat balance Cited in. In: Merenstein, G.B., Gardner, S.L. (Eds.), Handbook of Neonatal Intensive Care, sixth ed. Mosby Elsevier, USA 2006. Wylie, J.P., Goldsmith, J.P., Karotkin, T.H., 2004. Assisted Ventilation of the Neonate, fourth ed. Saunders, Philadelphia.
Biblithography
Dakshinamurti, S., 2005. Pathophysiologic mechanisms of persistent pulmonary hypertension. Paediatric Pulmonary 39 (6), 492e503. Walsh, M.C., Stork, E.K., 2001. Persistent pulmonary hypertension of the newborn e Rational therapy based on pathophysiology. Clinics in Perinatology 28 (3), 609e627.
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