PEDIATRICS Vol. 109 No. 5 May 2002, pp. 852-856
Efficacy and Safety of Tolazoline for Treatment of Severe Hypoxemia in Extremely Preterm Infants
* Department of Pediatrics, Mahidol University, Bangkok, Thailand
Departments of Pediatrics and Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, Tennessee
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Objective. To determine the efficacy of tolazoline as a rescue treatment for hypoxemia in preterm infants with respiratory distress syndrome.
Methods. Retrospective chart review on case series of infants weighing <750 g at birth who received tolazoline during a severe hypoxemic episode while receiving maximal ventilator support for respiratory distress syndrome. A slow bolus infusion of low dose tolazoline (0.5 mg–2 mg/kg) mixed with plasmanate or normal saline (10 mL/kg) was administered. Outcome measures evaluated included an increase in PaO2 
20 mm Hg from pretreatment value and an increase in oxygen saturation to 90%.
Results. Forty-three infants with a mean gestational age and birth weight of 24 weeks and 581 g, respectively, received tolazoline. All infants were mechanically ventilated and required a fraction of inspired oxygen of 1.0. Oxygenation improved in 72% (31/43) of infants with a tolazoline dose of 0.5 to 1.0 mg/kg. Of those who responded, PaO2 values (mean ± standard deviation) pretolazoline and posttolazoline were 32 ± 7.5 mm Hg and 156 ± 114.9 mm Hg, respectively. In all responders, oxygen saturation increased to 90% within 30 minutes of tolazoline administration. Improvement in pH, pCO2, oxygenation index, and mean airway pressure was also noted. Among nonresponders, pH decreased and pCO2 increased after tolazoline. Minimal change in blood pressure was noted in both responders and nonresponders. Heart rate decreased by 19 beats per minute among nonresponders compared with an increase of 3 beats per minute in those who responded to tolazoline.
Conclusion. Tolazoline is an effective treatment of severe resistant hypoxemia in preterm infants who are already on vigorous ventilatory support.
Key Words: respiratory distress syndrome • pulmonary hypertension • hypoxemia • premature • newborn
Abbreviations: OI, oxygenation index • IVH, intraventricular hemorrhage • PVL, periventricular leukomalacia • RDS, respiratory distress syndrome
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INTRODUCTION |
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Tolazoline, an imidazoline derivative, was described pharmacologically as early as 1947.1 Korones and Eyal2 were the first investigators to report on the successful use of tolazoline in the treatment of persistent pulmonary hypertension in term infants. Since then it has been used mainly for treatment of this condition. Reported incidence of adverse effects associated with tolazoline use has varied from 30% to 82%; these side effects were dependent on the dose and the methods of administration.3–5 Higher doses seemed to produce more side effects, and the serious adverse effects reported were mostly associated with high-dose continuous infusion.5–7
In the clinical setting, the very preterm or extremely low birth weight infant may manifest severe hypoxemia, even after initial improvement following endotracheal surfactant instillation. This hypoxemia often can be prolonged and unresponsive to conventional medical treatment and/or increasing respiratory support. Persistent pulmonary hypertension may be a possible explanation; this leads to a significant decrease in pulmonary blood flow and an increase in right-to-left shunting. Prolonged elevated pulmonary artery pressure in very preterm infants has been reported by many investigators, and pulmonary artery vasospasm has been demonstrated to occur in this group of preterm infants.8–11 For several years we have used tolazoline to treat hypoxemia that was likely attributable to pulmonary hypertension in extremely low birth weight and ventilated infants. We, therefore, reviewed our experience with the use of tolazoline in extremely preterm infants to determine the efficacy and safety of this drug. We assessed our use of slow bolus, low-dose infusions of tolazoline and its impact on oxygenation of hypoxemic, preterm infants.
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METHODS |
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This was a retrospective study that was approved by the University of Tennessee Health Science Center Institutional Review Board. Records of infants born between 1994 and 1998 who received tolazoline were reviewed. Additional criteria for case series selection included birth weight <750 g, need for mechanical ventilation for respiratory insufficiency or failure, and severe hypoxemia in the absence of air leak syndromes or acute cardiovascular failure. Infants with major congenital anomalies were excluded. All infants received care in the neonatal intensive care unit, had continuous blood pressure and heart rate recorded through an umbilical artery catheter or radial artery catheter, and had interval blood gas determination.
Tolazoline was administered slowly intravenously as a bolus mixture of tolazoline, 0.5 mg/kg to 2.0 mg/kg in 10 mL/kg of plasmanate or normal saline. The mixture was infused at a rate of 1 to 2 mL of the mixture over 1 minute while monitoring oxygen saturation. The infusion was discontinued if oxygen saturation increased and maintained above 90%. Administration was discontinued in the absence of a response after 1 mg/kg of tolazoline had been infused or if blood pressure dropped significantly. During tolazoline administration, blood pressure and heart rate were monitored continuously with the oxygen saturation. Ventilator settings were also recorded. Arterial blood gases were obtained before and 30 to 60 minutes after termination of tolazoline infusion. A successful response to tolazoline treatment was defined as an increase in PaO2 20 mm Hg from baseline. Those infants who demonstrated a successful response were called responders.
As part of the neonatal intensive care management of these infants, they had serial cranial ultrasound performed, with the first procedure done during the first 3 days of life and repeated at 7 to 10 days after the first study.
Statistical Analysis
Data were presented as means and standard deviation. Variables between responders and nonresponders to tolazoline administration were compared as well as variables pretreatment and posttreatment. Continuous variables were analyzed by unpaired Student’s t test, and dichotomous variables were analyzed by 
2 test or Fisher exact test. A P value 
.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Between 1994 and 1998, a total of 46 preterm infants whose birth weights were <750 g received tolazoline infusion because of severe hypoxemia that resisted vigorous ventilatory support. Three infants were excluded from analysis because they received tolazoline when they were at the terminal stage of their illness. Thus, the results presented are from 43 infants. Mean ± standard deviation gestational age and birth weight were 24 ± 2 weeks (range: 22–34 weeks) and 581 ± 103 g (range: 370–741 g). Thirty-two infants received surfactant therapy before receiving tolazoline. All infants were mechanically ventilated with a fraction of inspired oxygen of 1.0 and with a mean airway pressure of 10.5 ± 2.3 cm H2O. Despite maximal respiratory support, all infants developed severe hypoxemia with a mean PaO2 of 32.8 ± 9.5 mm Hg and a mean oxygenation index (OI) of 34.5 ± 14.3. Fourteen infants required vasopressor agents (dopamine and dobutamine), and 2 infants also received hydrocortisone. The dose of tolazoline ranged from 0.25 to 2 mg/kg/dose. No infant received more than 2 mg/kg/dose, primarily because such a high dose was avoided because of the potential for hypotension. Only 3 infants received a dose of 2 mg/kg. Thirty-one infants (74%) responded to tolazoline infusion; 52% of these infants exhibited a dramatic response within 5 minutes as indicated by abrupt increase in oyxgen saturation, and almost all (97%) were able to maintain oxygen saturation above 90% by 30 minutes after tolazoline treatment.
Responders and nonresponders are compared in Table 1. No differences were observed between responders and nonresponders as to gestational age, birth weight, Apgar scores, admission pH, and pretreatment pH and PaO2. Although not statistically significant, responders received tolazoline earlier at a mean postnatal age of 7.7 ± 4.4 hours, as compared with a mean postnatal age of 18.3 ± 26 hours in nonresponders. Nonresponders required higher mean airway pressure and had higher pretreatment PaCO2 than responders.
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In Table 2 the blood gases, OI, and mean airway pressure are compared between responders and nonresponders at pretreatment and posttreatment with tolazoline. Among responders, PaO2 increased markedly from a mean pretreatment PaO2 of 32.1 ± 7.5 mm Hg to a mean posttreatment PaO2 of 156.1 ± 114.9 mm Hg (range: 45–476 mm Hg; P < .001). OI was also reduced significantly following tolazoline administration, with mean pretreatment OI of 33.3 ± 13.9 compared with posttreatment OI of 9.6 ± 6.3. Mean airway pressure changed minimally from 9.7 cm H2O to 9.6 cm H2O. The average dose of tolazoline administered to responders was 0.8 mg/kg, with a range of 0.25 to 1 mg/kg/dose. Nine infants (29%) required repeat doses (2–5 doses) 40 minutes to 14 hours (mean 6.3 ± 4.8 hours) after the first dose. In nonresponders, there was no significant change in PaO2 after tolazoline infusion.
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Table 3 shows the changes in physiologic variables and complications noted in responders and nonresponders. No significant change in blood pressure was observed both in responders and nonresponders. Mean changes from baseline of mean blood pressure were -1.0 mm Hg and -1.4 mm Hg in responders and nonresponders, respectively. Only 1 nonresponder showed significant alteration of blood pressure, a decrease in mean blood pressure of 6 mm Hg and subsequently required volume expander (plasmanate) and vasopressor after tolazoline administration; this infant was the only 1 who survived in the nonresponder group. Also among nonresponders, there was a significant alteration in heart rate as a result of treatment; mean heart rate decreased 19 beats per minute compared with an increase of a mean of 3 beats per minute among responders.
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There were only 30 infants, 24 responders and 6 nonresponders, who survived to have a cranial ultrasound evaluation; the overall incidence of severe intraventricular hemorrhage (IVH) was 23%. There was no significant difference in proportion of infants with severe IVH between groups (5 responders and 2 nonresponders). Because of early deaths among nonresponders, the incidence of periventricular leukomalacia (PVL) cannot be assessed. In responders, the 16 infants who survived did not show evidence of PVL. Of nonresponders, 11 of 12 infants died. Nine deaths (75%) occurred in the first week of life and were attributed to severe respiratory failure and pulmonary interstitial emphysema. There were 9 deaths in the first week of life among the 31 responders (29%), a significantly lower proportion compared with nonresponders (P < .01). Among responders, there were 9 additional deaths between the end of the first postnatal week and before discharge. Therefore, the mortality of all responders was 58.0% (18 of 31 infants). Overall, during the study period, we admitted to the neonatal intensive care unit 255 infants whose birth weights were <750 g. Whether or not they were treated with tolazoline, their mortality was 41.5%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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This report describes our experience with the use of tolazoline as a rescue therapy for severe hypoxemia in extremely low birth weight infants who were on maximal mechanical ventilatory support. Of the infants who received tolazoline, oxygenation improved in 72%. Of those who responded to treatment, 1 out of 2 showed dramatic improvement in oxygenation within 5 minutes of initiating tolazoline administration, as indicated by improvement in oxygen saturation and OI. Such a dramatic response facilitated the weaning of these infants from vigorous ventilatory support, thus diminishing barotrauma and the hazard of pulmonary air leak syndrome. Air leak syndrome was the major cause of death in nonresponders. As a rescue therapy for severe hypoxemia that was resistant to vigorous ventilatory support in extremely low birth weight infants, it seemed to be associated with lower mortality in the first week of life and no difference in short-term morbidity among survivors. Valid comparison of responders to nonresponders is difficult because this is a retrospective observational study.
The pharmacologic effects of tolazoline are complex and unclear. Studies have indicated diverse pharmacological properties attributable to the 2-benzyl-2-imidazoline structure of tolazoline. Observed pharmacologic effects have been contradictory, including effects such as 
-adrenergic agonist and antagonist, cholinergic agonist and antagonist, and histaminergic (H1 and H2 receptor) agonist.12–16 In animal models and in adults, the cardiovascular effects of tolazoline may be either sympathomimetic or parasympathomimetic, resulting in an increase of heart rate and contractility. In adults, stimulation of H1 receptors causes vasoconstriction while stimulation of H2 receptors causes vasodilation. However, in the human fetus and newborn, histamine receptors (both H1 and H2) have been shown to be present in the pulmonary perivascular smooth muscle, and stimulation of receptors, either H1 or H2, could result in vasodilatation.15 Since the first report of successful use of tolazoline therapy in persistent fetal circulation in 1975,2 clinical uses of this drug have been mainly on infants with higher birth weight and with severe hypoxemia associated with pulmonary hypertension in various conditions, such as severe respiratory distress syndrome (RDS), meconium aspiration syndrome, sepsis, and idiopathic pulmonary hypertension.3–5 The use of tolazoline has been reported to show efficacy rates in newborns ranging from 30% to 80%, depending on the infant’s diagnosis and lung parenchymal diseases.14
Persistently elevated pulmonary pressure in preterm infants with RDS has been reported.8–11 Walther et al10 have demonstrated right-to-left shunting and persistent pulmonary hypertension documented by Doppler echocardiography in severe and fatal RDS in preterm infants weighing <1250 g at birth even after surfactant treatment. Furthermore, they demonstrated that pulmonary hypertension could occur as early as 4 to 8 hours after birth.
There have been few reports on the use of tolazoline in preterm infants3,5,11,17,18 with a diagnosis of severe RDS with pulmonary hypertension. The first report of tolazoline administration in preterm infants with RDS indicated that tolazoline resulted in increase in functional residual capacity, increase in expired carbon dioxide production, decrease in PaCO2, and increase in PaO2.17 Golan et al11 also described pulmonary hypertension in infants who did not respond to surfactant but exhibited a dramatic response to a single dose of 1 mg/kg tolazoline infusion. To our knowledge there is no other report on the administration of tolazoline as a rescue treatment for hypoxemia in extremely premature infants weighing <750 g at birth. Although echocardiography was not performed in this study to demonstrate elevated pulmonary pressure in these very fragile and critically ill infants, the dramatic response to tolazoline infusion indicated by improved oxygenation based on oxygen saturation and PaO2 suggests diminution or elimination of right-to-left shunting and lowering of pulmonary arterial pressure. These changes may have resulted in improved pulmonary blood flow and a decrease in ventilation/perfusion mismatch. It was not surprising that some of our infants required as many as 5 doses of tolazoline. Investigators have reported that elevated pulmonary pressure has been reported to persist as long as 96 to 144 hours.9
It has always been our practice to administer tolazoline solely as a bolus infusion, regardless of infusion site. We start with a low dose of 0.5 mg to 1.0 mg/kg by mixing tolazoline in 10 mL/kg of plasmanate or normal saline. A slow infusion is discontinued when a response is observed. This practice has avoided high doses that apparently precipitate a drop in blood pressure. Moreover, an associated decrease in blood pressure is avoided by infusing tolazoline with a volume expander to minimize the effect of systemic vasodilation.
There are several reasons that slow, low-dose bolus of tolazoline is preferable to continuous infusion. Serious complications reported with tolazoline use, such as severe systemic hypotension, gastrointestinal hemorrhage, duodenal perforation and oliguria, were reported in studies using high doses given by continuous intravenous infusion. Such dosage has ranged from 2 mg/kg/h to 10 mg/kg/h.3–7 Newborn infants have a much higher volume of distribution and longer elimination half-life than adults. In neonates the half-life of tolazoline ranges from 1.5 to 41 hours19 and appears to be inversely proportional to urinary output. This inverse relationship between tolazoline plasma level and urine output is curvilinear, rendering a newborn at risk for drug toxicity. Glomerular filtration rates are low in preterm and sick neonates. In a study of tolazoline pharmacokinetics in newborn infants, the continuous infusion dose of 0.9 mg/kg/h to 3.8 mg/kg/h can result in plasma concentrations as high as 9.8 mg/L. The highest plasma concentration measured was 20.3 mg/L and near the lethal level of 21.8 mg/L in fetal lambs.19,20 Tolazoline plasma levels may accumulate at 6 to 12 hours after continuous infusion of 1 and 2 mg/kg/h but not with a low dose of 0.5 mg/kg/h. It has been suggested that a lower dose of 0.3 mg/kg/h may be used to achieve clinical response and avoid drug accumulation.21 The adverse effects of tolazoline are dose-related, and therapeutic response has never been demonstrated to be dose-dependent.22 The successful clinical use of low-dose bolus injection has been reported and showed no significant side effects.11,18 In this report, the infants who responded to tolazoline showed a marked increase in PaO2 after treatment with only an average dose of 0.8 mg/kg (0.25–1.0 mg/kg).
Serious complications related to tolazoline use were not observed in our patients. We found no significant alteration in blood pressure, except in 1 nonresponder. The overall proportion of infants with severe IVH was 23%, comparable with our previous report and other studies given this birth weight category and the infant’s critical condition.23–25 PVL, acute gastrointestinal hemorrhage, and perforation were not observed in our patients. The causes of death during the first week of life were respiratory failure and severe pulmonary interstitial emphysema, which may in part be explained by a later use of tolazoline in the nonresponders. There were no clinical variables that we found predictive of a positive response to tolazoline. We found no significant differences between responders and nonresponders, consistent with other reports.5,26 However, this lack of difference may also be explained by limiting our selection to only those extremely preterm infants. The nonresponders had higher pretreatment mean airway pressure and pretreatment PaCO2 and received tolazoline at a later age, which may imply that a better response would be expected if the drug is administered early in the course of disease.
It has been suggested that tolazoline would be effective under optimal acid-base condition; ie, no acidosis.22 However, we are unable to address this because the infants we studied had comparable pH values at pretreatment pH above 7.20. In the nonresponders, heart rate decreased significantly after tolazoline infusion, which may indicate that these infants were already in a fully compensated state and, therefore, could not tolerate additional alteration in cardiovascular status. It may be prudent to take this manifestation of unexpected decrease in heart rate with tolazoline infusion as an indicator that the infant will likely not respond to tolazoline.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Our experience indicates that a bolus of low-dose tolazoline mixed with a volume expander has been a useful rescue treatment in very preterm infants with severe resistant hypoxemia associated with severe respiratory distress in early postnatal life. The dramatic response with tolazoline administration seems to be associated with lower early mortality and morbidity, which may be largely related to minimized barotrauma/pulmonary air leak.
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FOOTNOTES |
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Received for publication Aug 13, 2001; Accepted Nov 27, 2001.
Reprint requests to (S.B.K.) Newborn Center, 853 Jefferson Ave, Memphis, TN 38163. Email: skorones{at}utmem.edu
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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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