Tolazoline

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome associated with various neonatal cardiopulmonary diseases. It occasionally presents as a relatively isolated pathophysiologic disturbance marked by severe pulmonary hypertension and altered pulmonary vasoreactivity without concomitant lung disease (idiopathic PPHN, "PFC").[1] However, PPHN is more commonly associated with variable degrees of pulmonary parenchymal disease (eg, meconium aspiration, pneumonia, surfactant deficiency, etc.) Therefore, the therapeutic approach to PPHN requires attention to both the pulmonary vascular component of this syndrome as well as the accompanying alveolar disease.

We have previously reported acute improvement in oxygenation in severe PPHN using inhalational nitric oxide (NO) therapy at doses as low as 10 ppm,[2] and sustained improvement with prolonged treatment up to 72 h at 6 ppm NO.[3] Moreover, we have observed that conventional mechanical ventilation alone is often ineffective when PPHN occurs in association with severe pulmonary disease. In PPHN complicated by parenchymal lung disease (particularly homogenous lung disease with underinflation), high frequency oscillatory ventilation (HFOV) is an important adjunctive treatment, allowing adequate lung inflation and potentially improving the efficacy of inhalational NO therapy.[3]

In this report, we summarize the results of a pilot study in 15 consecutive patients with refractory PPHN, emphasizing the roles of selective pulmonary vasodilation with inhaled NO and optimal pulmonary management with HFOV.

METHODS

Fifteen consecutive patients with severe PPHN who were candidates for extracorporeal membrane oxygenation (ECMO) were enrolled in this study. Patients were eligible if they had severe respiratory failure, echocardiographic evidence of PPHN, and met criteria for extracorporeal membrane oxygenation (ECMO) therapy. The study was approved by the Institutional Review Board of the Children's Hospital, and by the United States Food and Drug Administration under an investigator-initiated Investigational New Drug exemption. Patients were enrolled after informed consent was obtained from the parents.

Patients with significant parenchymal lung disease or pulmonary hypoplasia were offered a trial of HFOV before enrollment in the NO protocol. At enrollment, baseline echocardiographic measurements and postductal arterial blood samples were drawn for determination of pH, blood gas tensions, and methemoglobin saturation immediately prior to NO treatment. The diagnosis of pulmonary hypertension was based on standard echocardiographic criteria.[4] The NO was initially administered at 20 ppm for 4 h; the dose was decreased to 6 ppm for the following 20 h. At 24 h, NO therapy was discontinued. If adequate oxygenation was not sustained following discontinuation of NO (a/A ratio [less than]0.10), then NO was restarted for another 24-h period.

[TABULAR DATA OMITTED]

Study variables were analyzed using one-way or two-way analysis of variance for repeated measures, where appropriate. Fisher's least significant difference test was employed for post-hoc comparisons. Paired measurements of continuous variables were analyzed using the paired Student's t test. The level of statistical significance was set at p [less than]0.05. Data are expressed as mean [+ or -] SEM.

RESULTS

Each newborn had severe hypoxemia and echocardiographic evidence of pulmonary hypertension despite aggressive treatment with mechanical ventilation and 100 percent inspired [O.sub.2] at enrollment. Mean gestational age and birth weight were 39 [+ or -] 1 weeks and 3,334 [+ or -] 160 g, respectively. In addition to severe PPHN, associated diagnoses included meconium aspiration syndrome (6 patients), sepsis (5), idiopathic (3), and congenital diaphragmatic hernia (2). Eight patients were initially treated with HFOV (Sensormedics 3100A) and showed transient improvement in oxygenation, but subsequently met ECMO criteria and were candidates for NO treatment.

Marked improvements in oxygenation occurred with the onset of NO inhalation, and this improvement was sustained for the entire 24-h period without causing systemic hypotension (Table 1). Nine patients had adequate resolution of PPHN and sustained improvement in oxygenation after only 24 h of low-dose NO therapy. Nitric oxide therapy was required for 48 h in two patients and for 72 h in two patients. However, two patients had severe sepsis associated with progressive deterioration of left ventricular performance. Despite initial improvement in oxygenation with inhaled NO, these patients required ECMO for cardiac support.

To assess the need for continued treatment with NO, NO was discontinued at 24 h in all patients. In four patients, PPHN persisted as evidenced by acute deterioration in oxygenation upon discontinuation of NO (oxygen index [OI] increased from 21.3 [+ or -] 7.4 to 38.9 [+ or -] 10.5 over 10 to 15 min, p = 0.02). When NO was restarted, oxygenation rapidly improved with OI returning to the baseline level (19.5 [+ or -] 6.9, p = 0.02). In nine patients who required only 24 h of NO therapy, OI increased when NO was discontinued (9.5 [+ or -] 1.6 vs 14.3 [+ or -] 2.4, p = 0.01), but this change was clinically insignificant.

Methemoglobin levels increased from baseline during the 4-h period of 20 ppm therapy, however, as the inhaled NO concentration was reduced, percent methemoglobin fell (Fig 1). Changes in methemoglobin levels over time were not different between patients receiving HFOV and intermittent mechanical ventilation (p = 0.67).

DISCUSSION

Treatment of PPHN has been limited because therapy to reduce pulmonary hypertension with vasodilator drugs often causes systemic hypotension and infrequently sustains pulmonary vasodilation.[5,6] However, recent reports support the potential role of inhaled nitric oxide in PPHN. Studies in animals have shown that endogenous NO formation contributes to the normal decline in pulmonary vascular resistance at birth,[7] and exogenous (inhaled) NO causes selective and sustained pulmonary vasodilation in the late gestation ovine fetus.[8] Roberts et al[9] found that brief exposure (30 min) to 80 ppm NO in newborns with PPHN increased arterial oxygen saturation, however, this response was not sustained when NO therapy was discontinued. We have previously reported that low-dose inhaled NO (6 ppm) caused sustained improvement in oxygenation in patients with PPHN. However, progressive loss of NO efficacy in PPHN is a potential problem that has received little attention.

One potential mechanism for loss of NO responsiveness is deterioration in cardiac performance. All patients treated with NO in this study showed marked improvement in oxygenation in response to very low doses of NO. However, two patients were treated with ECMO for cardiac support following progressive cardiac failure associated with overwhelming sepsis.

A second mechanism contributing to decreased efficacy of inhaled NO is reduced lung volume associated with progression of the pulmonary parenchymal disease which often complicates the course of patients with PPHN. Progressive atelectasis will decrease effective delivery of this inhalational agent to its site of action in terminal lung units. To optimize lung inflation and minimize lung injury from tidal volume mechanical breaths, we have used HFOV. In eight patients, we combined HFOV with inhalational NO therapy, due to failure of HFOV alone to sustain clinical improvement. When HFOV has been employed using a strategy designed to recruit atelectatic lung and sustain lung volume, marked improvements in oxygenation have been demonstrated in severe respiratory failure.[10,11] Although the optimal roles for HFOV and NO are unclear, some patients appear to benefit from combined treatment.

Finally, other mechanisms which could contribute to diminished inhalational NO responsiveness in pulmonary hypertension require further study. For example, circulating vasoconstrictor substances could potentially abate the vasodilatory effects of inhaled NO.[12] Moreover, both structural and functional (eg, decreased soluble guanylate cyclase activity) changes in the pulmonary vascular smooth muscle cell may alter responsiveness to exogenous NO.

In conclusion, inhaled NO causes sustained improvement in oxygenation in severe PPHN when clinical management includes meticulous attention to the nature of the underlying lung disease. In patients with severe PPHN and parenchymal lung disease or pulmonary hypoplasia, optimal management may include HFOV to recruit and maintain lung volume, thus promoting effective delivery of the inhalational vasodilator NO.

REFERENCES

[1] Gersony WM, Duc GV, Sinclair JD. "PFC" syndrome: persistence of the fetal circulation [abstract]. Circulation 1969; 40(suppl 3):87

[2] Kinsella JP, Neish SR, Shaffer E, et al. Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992; 340:819-20

[3] Kinsella JP, Neish SR, Ivy DD, et al. Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. J Pediatr 1993; 123:103-08

[4] Kinsella JP, McCurnin DC, Clark RH, et al. Cardiac performance in ECMO candidates: echocardiographic predictors for ECMO. J Pediatr Surg 1992; 27:44-7

[5] Stevenson DK, Kasting DS, Darnall RA, et al. Refractory hypoxemia associated with neonatal pulmonary disease: the use and limitations of tolazoline. J Pediatr 1979; 95:595-99

[6] Abman SH, Wilkening RB, Ward RM, et al. Adaptation of fetal pulmonary blood flow to the local infusion of tolazoline. Pediatr Res 1986; 20:1131-35

[7] Abman SH, Chatfield BA, Hall SL, et al. Role of EDRF during transition of pulmonary circulation at birth. Am J Physiol 1990; 259:H1921-27

[8] Kinsella JP, McQueston J, Rosenberg AA, et al. Hemodynamic effects of exogenous nitric oxide in ovine transitional pulmonary circulation. Am J Physiol (Heart Circ Physiol) 1992; 32:H875-80

[9] Roberts JD, Polaner DM, Lang P, et al. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992; 340:818-19

[10] Carter JM, Gerstmann DR, Clark RH, et al. High-frequency oscillatory ventilation and extracorporeal membrane oxygenation for the treatment of neonatal respiratory failure. Pediatrics 1990; 85:159-64

[11] Kinsella JP, Gerstmann DR, Clark RH, et al. HFOV vs IMV: early hemodynamic effects in the premature baboon with HMD. Pediatr Res 1991; 29:160-66

[12] Rosenberg AA, Kennaugh J, Koppenhafer SL, et al. Elevated immunoreactive endothelin-1 levels in newborns infants with persistent pulmonary hypertension. J Pediatr 1993; 123:109-14

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