An international survey on persistent pulmonary hypertension of the newborn: A need for an evidence-based management

Abstract

OBJECTIVE: To assess the current practice preferences in diagnosis and management of persistent hypertension of the newborn (PPHN) of neonatologists or pediatricians with expertise in neonatal care.

STUDY DESIGN: Investigators identified potential participants worldwide through a literature search. They were emailed the URL of an online 25-item questionnaire through the web survey site SurveyMonkey^®. Additional respondents were also acquired through a professional online discussion group. The survey was conducted during July - September 2015.

RESULTS: Overall, there were 200 respondents from 51 different countries. Of these, the average 2014 mortality rate of the 90 respondents who completed this section of the questionnaire was 8.3% (interquartile range (IQR): 0-20.3). Echocardiography together with pre-to-post ductal oxygen pulse oximetry (SpO₂) gradient was the most common PPHN diagnostic method. The most frequent first-line pulmonary vasodilator was inhaled nitric oxide (155/199, 77.9%). Oral sildenafil was most commonly used as second-line adjunctive therapy by 46.3% (81/175). Dopamine (139/198, 70.2%) was chosen to be the initial inotropic agent and normal saline (191/199, 96.0%) was the preferred initial fluid resuscitation for hypotension. Sedation and analgesia were routinely used for PPHN treatment. Twenty-one percent (42/199) of respondents also used muscle relaxants to control respiratory distress. The most commonly used targets for partial pressure of oxygen, partial pressure of carbon dioxide, SpO₂ and hemoglobin were 71–80 mmHg (60/197, 30.4%), 36–45 mmHg (100/199, 50.2%), 91–95% (111/199, 55.8%), and 13–15 gm/dL (156/196, 79.6%), respectively.

CONCLUSIONS: This survey shows that the management of PPHN varies widely around the world. The major PPHN diagnostic method is echocardiography together with bedside SpO₂ monitoring. The study numbers show the main differences are between developed and developing countries. Further studies exploring evidence-based principles of diagnosis and management in PPHN are warranted.

Keywords

Persistent pulmonary hypertension of the newborn international survey newborn nitric oxide PPHN

1 Introduction

Persistent pulmonary hypertension of the newborn (PPHN) is one of the most serious neonatal respiratory diseases. Although the mortality rate has been decreasing in developed countries, it is still a serious cause of mortality in developing countries [1 –4].A recent review of the evidence base of PPHN treatment options found relatively few clinical trials and overall low quality of the available evidence [5]. For this reason, management of PPHN in all settings largely depends on the individual neonatologist’s preferences and skills. In addition, although echocardiography is a well-established tool for the diagnosis of PPHN and guide for the assessment of severity, the availability of this procedure or a qualified pediatric cardiologist to use it, is often limited, particularly in developing countries [6–7]. Treatment of PPHN can vary widely depending on the factors noted above, but mainly involves high frequency oscillatory ventilation (HFOV) [8], inhaled nitric oxide (iNO) [9], and extracorporal membrane oxygenation (ECMO) [10], the best current treatments to improve the survival of infants with PPHN with intractable respiratory failure.

Currently there is widespread variation for management of PPHN, a situation which is not helped by the sparsity of recent prospective clinical trial studies [11]. In order to gain some better insights into “best modern practices” concerning diagnosis and optimal treatment for PPHN, we decided a worldwide survey of leading neonatologists concerning this topic would be of use and interest to pediatricians involved with neonatal care.

2 Method

A prospective cross-sectional survey was conducted from July to September 2015. The study was approved by the Ethics Committee of Hat Yai Hospital. A web-based email survey request via SurveyMonkey^® was emailed to 606 neonatologists and pediatricians known for their expertise in neonatal care through having published at least one article in the area of neonatal disease found through a PubMed, Scopus, and Embase search. The questionnaire contained 25 questions eliciting basic information of the respondents, and information about their PPHN patients, notably the number of PPHN infants they treated yearly and the number of these who died in 2014, their method of diagnosing PPHN, preferred pulmonary vasodilator, inotropic agent and volume expander, and target blood chemistries. Reminder emails were sent to non-respondents after 7 and 14 days. One respondent suggested placing a notification in a neonatologists’ Yahoo discussion list, which was done, resulting in a further 98 responses.

2.1 Database and statistical analysis

The survey responses were extracted from the SurveyMonkey^® database, and the results summarized with descriptive statistics, using counts and percentages for categorical data and median and interquartile range (IQR: 25th –75th percentiles) for continuous data. Pearson Chi square test was used for comparisons regarding oxygen index (OI) for initiating iNO, starting dose and maximum dose of iNO, between respondents who had or did not have ECMO availability. Statistical significance was set at ap value of 0.05. Data analyses were performed using SPSS 19.0 (SPSS Inc, Chicago, IL).

3 Results

3.1 Study population

Of the 606 doctors sent invitations, 102 (16.9%) responded to the survey, 14 (2.3%) emails bounced, 8 respondents (1.3%) opted out, and 481 addressees (79.5%) did not respond. Another 98 neonatologists from the NICU-Net Yahoo Group accessed the SurveyMonkey^® site and completed the survey questionnaire, giving, finally, a total of 200 participants from 51 different countries whose responses to the questionnaire were finally analyzed in the study. Table 1 shows the basic characteristics of the survey respondents. The area with the most respondents was Europe and Central Asia with 65 (32.5%) and two-thirds of the respondents were from high income countries (as determined by the World Bank classification of countries). Of the 200 respondents, 191 (95.5%) indicated ‘neonatologist’ as their specialty, with most (182/200, 91.0%) indicating a level III neonatal intensive care unit (NICU) as their major working place and 72/200 (36.0%) working at a university hospital. Most were in the 35–44 and 45–54 years age groups, each with 31.0%, and most (114/199, 57.3%) had worked in an NICU >15 years. Most indicated their hospitals had HFOV and iNO available (192/200 (96.0%) and 166/200 (83.0%), respectively), while ECMO availability was confirmed by only one-third of respondents (65/200, 32.5%).

3.2 Estimated mortality rate

Only 90 of the 200 respondents (45.0%) completed the questions concerning the total number of PPHN infants and the number of these who died in 2014. The overall average estimated mortality rate from this survey was 8.3% (IQR: 0–20.3). The lowest estimated mortality rate was found in North America with 4.0% (IQR: 0–9.3), whereas South Asia, and Latin America and the Caribbean having the highest estimated mortality rates with 20.0% (IQR: 0–37.0) and 19.9% (IQR: 17.0–30.5), respectively.Examining our findings by country income, the group of high income countries had the lowest estimated mortality rate at 2.0% (IQR: 0–13.5) while the lower middle income and upper middle income countries had much higher rates (20.0% (IQR: 4.0–35.0) and 16.7% (IQR: 10.0–33.0), respectively).

3.3 PPHN diagnostic method

Most respondents indicated they primarily used echocardiography as the basis of their diagnosis of PPHN (191/200, 95.5%) as presented in Table 2; some also used pre-to-postductal partial pressure of oxygen (PaO₂) and/or oxygen pulse oximetry (SpO₂) gradient to help establish a diagnosis.

3.4 Inhaled nitric oxide and other pulmonary vasodilators

Seventy-seven percent of the respondents reported that iNO was used as the first-line pulmonary vasodilator for PPHN treatment in their hospital. The most common OI for initiating iNO was 20–24 with 38.4% of respondents (56/146). The most common initiating and maximum doses of iNO reported were 20 ppm with 69.3% and 65.9% of the respondents, respectively, as presented in Table 3. There were no statistically significant differences in OI level for initiating iNO or maximum dose of iNO between respondents who had or did not have ECHO in their hospital. Oral sildenafil was the most common second-line adjunctive therapy with a pulmonary vasodilator. Intravenous milrinone and magnesium sulphate were also used in second and third-line treatments (Table 3).

3.5 Sedation, analgesia and muscle relaxation

All respondents reported using sedation and/or analgesia as routine treatment for PPHN. Midazolam was used by 52.5% of respondents. Fentanyl and morphine were also used by 57.0% and 36.5% of respondents, respectively. Only 21.1% of respondents used muscle paralysis during PPHN treatment.

3.6 Inotropic drugs

High variation was seen in the use of inotropic agents. Dopamine was the most common first-line treatment for hypotension (139/198, 70.2%), followed by add-on therapy with dobutamine (103/187, 55.1%) and the most common third-line drug was epinephrine (72/129, 55.8%), as presented in Table 2.

3.7 Volume expanders

Normal saline was the most common choice for a volume expander by the respondents (191/199, 96.0%), while fresh frozen plasma was the second-line treatment to correct hypotension with 37.1% of respondents, as presented in Table 2.

3.8 Target blood chemistries

Target values of the respondents for PaO₂, partial pressure of carbon dioxide (PaCO₂), and SpO₂ are presented in Table 3. The most common target range of PaO₂ was 51–70 mmHg (92/197, 46.7%), while the range of targeted SpO₂ was 91–95% (111/199, 55.8%). The targeted PaCO₂ range of 50.3% of respondents was 36–45 mmHg, while 13–15 g/dL was the most common target range for haemoglobin level with 79.6% (156/196) of the respondents.

4 Discussion

To our knowledge, this is the first worldwide survey to comprehensively undertake to determine the estimated mortality rates, the preferred methods of diagnosis, and the current management practices in PPHN. The results indicate that: first, the most common method currently in use to diagnose PPHN is echocardiography with bedside SpO₂ monitoring; second, iNO and HFOV appear to be broadly available in hospitals worldwide; and thirdly, sedation and analgesia are the preferred methods for treatment in neonates with PPHN, while muscle relaxants are a distant third option.

Echocardiography is the gold standard for definite diagnosis of PPHN [6, 7], used by 95% of the survey respondents. Usually, infants diagnosed with PPHN develop severe respiratory distress with refractory hypoxia within 6 hours after birth, therefore rapid echocardiography should be performed to aid definite diagnosis and exclude cyanotic heart disease.

Oxygen is a potent pulmonary vasodilator and the process of post-natal physiological adaptation needs oxygen to facilitate pulmonary vasodilation [12, 13]. Although oxygen is the best pulmonary vasodilator for PPHN treatment, oxygen supplementation must be closely monitored, as hyperoxemia can occur if too much oxygen is given, leading to increased oxidative stress and reactive oxygen species formation, enhancing vasoconstrictive effects in the pathogenesis of PPHN [14 –16]. Our results showed that 47% of the respondents reported a target PaO₂ of 51–70 mmHg, and 55.8% said their acceptable SpO₂ level was 91–95%. Eighty-three percent of the respondents had iNO available as a standard treatment for PPHN and one-third had ECMO in their hospital, making these PaO₂ and SpO₂ targets easy to achieve and maintain. In developing countries, however, where iNO and ECMO are often limited due to both high costs and limited availability of physicians trained in their use, optimal PaO₂ and SpO₂ levels may be more difficult to attain, and inadequate PaO₂ and SpO₂ levels can lead to tissue hypoxia and generate lactic acidosis resulting in increased pulmonary vascular resistance (PVR) [17]. Thus, further research to find better strategies for achieving optimal PaO₂ and SpO₂ levels, especially in low-resource situations, remains an important need.

Low systemic vascular resistance (SVR) due to increased right-to-left shunt via patent ductus arteriosus and/or atrial septum can be a cause of PPHN [18]. Hence neonates with PPHN may need special attention to maintaining SVR above normal values to prevent the right-to-left shunt leading to hypoxemia and tissue hypoxia. Fluid administration is one of the most common interventions to treat critically ill neonates with hypotension, although the most appropriate type of fluid to be used remains controversial [19]. Oca et al. [20] have reported that crystalloid solutions, primarily normal saline, seem to be the most efficacious fluids for initial resuscitation of hypotension in neonates, and this practice was the current treatment of most of the neonatologists in this study.

Systemic hypotension is associated with increased mortality and morbidity [21]. To deal with this condition, the next step after a volume expander is inotropic therapy. Seventy percent of the survey respondents said that dopamine was the drug most often used to correct hypotension, and the participants used dobutamine as the most common second-line inotropic drug. A recent Cochrane review confirmed that dopamine is more effective than dobutamine in raising blood pressure [22]. Epinephrine is known to have potent vasoconstriction effects via all adrenoceptors, and this was the third-line agent in resistant hypotension in PPHN indicated by 56% of the respondents [23, 24]. This was an important finding from this survey, showing that many current practitioners still regard using inotropic agents in PPHN still controversial, and there is a wide variation in practice among neonatologists, which is likely due to the lack of evidence showing positive results from using inotropic agents for PPHN. Further clinical trial studies are needed to provide reliable data on thistopic.

Our study found that most of the respondents (79.6%) preferred a hemoglobin level of 13-15 g/dL in their practice, as higher hemoglobin can prevent tissue hypoxia, which can lead to lactic acidosis and increased PVR [17]. Almost all respondents reported using sedation and analgesics for pain control during treatment of PPHN, most commonly midazolam and fentanyl, respectively. Only 21.1% of the respondents occasionally used neuromuscular paralysis in PPHN infants to stop the spontaneous breathing efforts of the infants. Recently, it has been recommended that neuromuscular paralysis should be avoided in ventilated neonates for a number of reasons, such as decreased functional residual capacity and oxygenation, associated tachycardia, or an increased risk of intraventricular hemorrhage [25].

In modern practice, iNO is generally regarded as the first-line treatment for PPHN, and 80% of the survey respondents had iNO available in their hospital. Meta-analysis studies have found that iNO treatment for PPHN reduced the incidence of death or need for ECMO (relative risk (RR): 0.65 (95% confidence interval (CI): 0.55–0.76) [9]. Our survey found that the indication for beginning iNO depended on the judgment of the individual neonatologist and the clinical symptoms of the particular patient. Sildenafil is the primary second-line pulmonary vasodilator for PPHN. A study by Shah et al. [26] found that it significantly reduced mortality in PPHN infants (RR 0.20) (95% CI: 0.07–0.57). Their meta-analysis concluded that sildenafil was a potential pulmonary vasodilator in resource limited settings due to being easier to use and less expensive, but future studies are needed to assess its efficacy and safety [26].

During the treatment of PPHN the physician must be continually monitoring the infant for the appearance of metabolic disturbances such as metabolic acidosis or respiratory acidosis. Rudolph and Yaun previously reported that the level of PaO₂ and H+ ions could effect pulmonary vascular response with lower PaO₂ and higher H+ ions leading to lower PVR [17]. In addition, blood pH could also be an important factor, and the level of CO₂ effects pH. In our study, of 199 respondents, 100 (50.3%) used 36–45 mmHg as a PaCO₂ target level.

There are several limitations within this study. It is a survey and it is therefore possibly influenced by the fact that there might have been bias in selecting the participants, that some of the answering options might not have corresponded exactly to the practice of each participants. The response rate is lower that desired, which may be related to the availability of the survey in English only and limited availability of computer/internet access in some countries in particular Africa region. Despite these limitations, although many participants did not completely fill in the questionnaire, the most interesting questions were answered by almost all participants, notably the first and second-line pulmonary vasodilators used, the first-line inotropes, and the first-line volume expanders.

In conclusion, although there was wide agreement for many of the treatment options, there was also considerable variation in some areas, and we believe our study shows that some efforts made towards developing an “evidence-based” model for PPHN diagnosis and management would be very useful in reducing worldwide mortality rates of this seriousdisease.

Funding

None.

Competing interests

None of the authors have any conflicts of interest.

Contributors

NN wrote the first draft of this paper. Both authors contributed to the intellectual content and approved the final version.

Footnotes

Acknowledgments

The authors thank Mr. David Patterson for English assistance with the manuscript.

References

Walsh-Sukys

, Tyson

, Wright

, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: Practice variation and outcomes. Pediatrics 2000;105:14–20.

Nakwan

, Nakwan

, Wannaro

. Predicting mortality outcome in infants with persistent pulmonary hypertension of the newborn with the Score for Neonatal Acute Physiology-Version II (SNAP-II) in Thai neonates. J Perinat Med 2011;39:311–5.

Nakwan

, Pithaklimnuwong

. Acute kidney injury and pneumothorax are risk factors for mortality in persistent pulmonary hypertension of the newborn in Thai neonates. J Matern Fetal Neonatal Med 2016;29:1741–6.

Khorana

, Yookaseam

, Layangool

, Kanjanapattanakul

, Paradeevisut

. Outcome of oral sildenafil therapy on persistent pulmonary hypertension of the newborn at Queen Sirikit National Institute of Child Health. J Med Assoc ThaiS 2011;94:64–73.

Lakshminrusimha

, Keszler

. Persistent pulmonary hypertension of the newborn. Neoreviewse 2015;16:680–92.

Peterson

, Deatsman

, Frommelt

, Mussatto

, Frommelt

. Correlation of echocardiographic markers and therapy in persistent pulmonary hypertension of the newborn. Pediatr Cardiol 2009;30:160–5.

Malowitz

, Forsha

, Smith

, Cotten

, Barker

, Tatum

. Right ventricular echocardiographic indices predict poor outcomes in infants with persistent pulmonary hypertension of the newborn. Eur Heart J Cardiovasc Imaging 2015;16:1124–31.

Carter

, Gerstmann

, Clark

, et al. High-frequency oscillatory ventilation and extracorporeal membrane oxygenation for the treatment of acute neonatal respiratory failure. Pediatrics 1990;85:159–64.

Finer

, Barrington

. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006;4:CD000399.

10.

UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. Lancet 1996;348:75–82.

11.

Shivananda

, Ahliwahlia

, Kluckow

, Luc

, Jankov

, McNamara

. Variation in the management of persistent pulmonary hypertension of the newborn: A survey of physicians in Canada, Australia, and New Zealand. Am J Perinatol 2012;29:519–26.

12.

Lakshminrusimha

, Steinhorn

. Pulmonary vascular biology during neonatal transition. Clin Perinatol 1999;26:601–19.

13.

Morin

, Egan

, Ferguson

, Lundgren

CEl

. Development of pulmonary vascular response to oxygen. Am J Physiol 1988;254:H542–6.

14.

Farrow

, Groh

, Schumacker

, et al. Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. Circ Res 2008;102:226–33.

15.

Farrow

, Lakshminrusimha

, Reda

, et al. Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2008;295:L979–87.

16.

Lakshminrusimha

, Swartz

, Gugino

, et al. Oxygen concentration and pulmonary hemodynamics in newborn lambs with pulmonary hypertension. Pediatr Res 2009;66:539–44.

17.

Rudolph

, Yuan

. Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes. J Clin Invest 1966;45:399–411.

18.

Kinsella

, Abman

. Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn. J Pediatr 1995;126:853–64.

19.

Fanaroff

, Fanaroff

. Blood pressure disorders in the neonate: Hypotension and hypertension. Semin Fetal Neonatal Med 2006;11:174–81.

20.

Oca

, Nelson

, Donn

. Randomized trial of normal saline versus 5% albumin for the treatment of neonatal hypotension. J Perinatol 2003;23:473–6.

21.

Barrington

. Hypotension and shock in the preterm infant. Semin Fetal Neonatal Med 2008;13:16–23.

22.

Subhedar

, Shaw

. Dopamine versus dobutamine for hypotensive preterm infants. Cochrane Database Syst Rev 2003;3:CD001242.

23.

Barrington

, Finer

, Chan

. A blind, randomized comparison of the circulatory effects of dopamine and epinephrine infusions in the newborn piglet during normoxia and hypoxia. Crit Care Med 1995;23:740–8.

24.

Barrington

, Chan

Wky

. The circulatory effects of epinephrine infusion in the anesthesized piglet. Pediatr Res 1993;33:190–4.

25.

Levene

, Quinn

. Use of sedatives and muscle relaxants in newborn babies receiving mechanical ventilation. Arch Dis Child 1992;67:870–3.

26.

Shah

, Ohlsson

. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev 2011;8:CD005494.