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PEDIATRICS Vol. 108 No. 4 October 2001, pp. 949-955
From the * University of California, San Diego Medical Center,
San Diego, California; and Objective. There is little
information on the response to very low doses of inhaled nitric oxide
(iNO) in hypoxic near-term infants. The potential toxicities of iNO are
dose related; thus, the ability to use lower doses safely and
effectively may be advantageous. We hypothesized that there is no
difference in the acute improvement in oxygenation between treatment
with inhaled nitric oxide at 1 to 2 parts per million (ppm) or 10 to 20 ppm.
Methods. We randomized near-term and term infants with
hypoxic respiratory failure with oxygenation indices (OIs) of Results. Thirty minutes after the study gas was initiated,
PaO2 increased significantly overall in the
low-dose (90.7 ± 41 torr to 166.8 ± 95.6 torr) and
high-dose (76.2 ± 32.7 torr to 198.7 ± 142.8 torr) groups;
the maximal increase was seen in the infants who initially were treated
with 10 ppm. The OI also decreased significantly overall and also was
significant in the high-dose group (21.0 ± 13.7 to 11.4 ± 10.4; low-dose: 18.3 ± 7.1 to 13.2 ± 12.3). There was a
nonsignificant fall of PaCO2 with iNO treatment (low dose 35 ± 7.3 to 30 ± 8.5 torr vs high dose 35.2 ± 9.9 to 32.4 ± 10.7 torr). A sustained response (ie,
maintaining a PaO2 and OI gain greater than
20% for the duration of the study gas administration) was greater in
the high-dose group (53.3% vs 30.0%). In addition, dose increases
were required more often in the low-dose group than in the high-dose
group (80.0% vs 57.1%). Among patients who did not respond to the
initial iNO dose, 100.0% and 83.3% responded at higher doses of iNO
for the low- and high-dose groups, respectively. There were no
differences for death, need for extracorporeal membrane oxygenation, or
other outcomes between the groups.
Conclusions. We did not find any significant difference in
response to low- versus high-dose iNO. An initial exposure to low-dose
iNO does not compromise the response to higher doses if required and
may result in less toxicity.
Royal Victoria Hospital, Montreal,
Quebec, Canada.
ABSTRACT
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Abstract
Methods
Results
Discussion
Conclusion
References
10 and
PaO2 <100 on 2 separate blood gases taken at
least 30 minutes apart. Infants with congenital diaphragmatic hernia
were excluded. After parental consent was obtained, patients were
randomized to receive a starting nitric oxide (iNO) dose of either 1 to
2 ppm (low-dose group, n = 15) or 10 to 20 ppm
(high-dose group, n = 21). The response to iNO was
assessed according to the increase in arterial
PaO2 and decrease in OI 30 to 60 minutes after
exposure to the initial starting concentration. A response of <10%
increase on PaO2 and a <10% decrease in OI
resulted in a doubling of iNO within the dose range protocol (1, 2, 4, and 8 ppm for the low-dose group; 10, 20, 40, and 80 ppm for the
high-dose group).
Hypoxic respiratory failure in the term and near-term
neonate remains a clinically significant problem and the most common reason for referral for neonatal extracorporeal membrane oxygenation (ECMO). Such respiratory failure usually is caused by a limited number
of conditions that include meconium aspiration (MAS), pneumonia with or
without sepsis, congenital diaphragmatic hernia (CDH), and other causes
of pulmonary hypoplasia, usually in association with pulmonary
hypertension. These conditions share the common pathophysiology of
potentially reversible pulmonary hypertension that causes right-to-left
shunting and profound hypoxemia that is unresponsive to high
concentrations of inspired oxygen.1 Treatment strategies,
including alkalinization, hyperventilation, the use of systemic
vasodilators, sedation, and paralysis are aimed at lowering pulmonary
vascular resistance. However, they often are associated with adverse
effects and many times are not effective.2 A recent review
of the use of such therapies demonstrated that they are used
frequently, with wide variation in practice between units, and there is
no clear evidence for the effectiveness of many of these therapies in
such infants.3 Furthermore, although ECMO has improved
survival for neonates with severe refractory hypoxemia, it is an
invasive procedure that also is associated with serious complications.
Inhaled nitric oxide (iNO) is the only selective pulmonary vasodilator
that is not limited by serious hemodynamic side effects and now has
been shown to improve oxygenation and reduce the requirement for ECMO
in near-term and term infants in a number of prospective randomized
trials.4-8 Although these studies have shown the benefit
of iNO in improving such outcomes, few studies have evaluated the
minimally effective dose of iNO that is efficacious yet safe. We
previously reported no significant clinical differences in the
responses to doses of iNO from 5 to 80 parts per million (ppm) in a
group of hypoxic near-term neonates.9 Davidson et
al7 compared doses of 5, 20, and 80 ppm in their
prospective trial and also found no dose-related clinical benefits.
They did, however, note subsequently that discontinuation of iNO at
higher compared with lower doses resulted in greater deterioration.10 Inhaled NO is associated with potential side effects, including the production of methemoglobinemia,
NO2, peroxynitrite formation leading to possible
lung tissue injury, and impaired platelet aggregation and
adhesion.11 In view of such potential toxicities, it seems
advantageous to determine the lowest effective dose of iNO.
In adults with respiratory distress syndrome (RDS), the dose required
for 50% of the patients to improve oxygenation (mean effective dose
[ED50]) with iNO was found to be 100 parts per billion, and doses of >10 ppm were associated with decreases in oxygenation, whereas the ED50 for decreases in
pulmonary artery pressure was 2 ppm.12 In contrast to
these reports, Cornfield et al13 recently published a
trial that noted that infants who initially were treated with 2 ppm of
iNO failed to respond to this dose and to increased doses, suggesting
that exposure of neonates to such low doses may render them
unresponsive to subsequent higher doses of iNO. Although no specific
toxicities have been reported with doses from 10 to 20 ppm in term
infants, lower doses of iNO will lead to lower levels of
NO2, methemoglobin, and possibly peroxynitrites,
as well as other metabolites.
We therefore conducted a randomized prospective study to compare the
effects of very-low-dose (1-2 ppm) to the commonly used starting doses
of 10 to 20 ppm in term and near-term neonates with hypoxic respiratory
failure. We hypothesized that there is no difference in the acute
improvement in oxygenation with treatment with iNO at either 1 to 2 ppm
or 10 to 20 ppm.
Patient Entry Criteria
Infants were enrolled at the University of California, San
Diego, Medical Center Infant Special Care Center. The Institutional Review Board approved the study. Criteria for enrollment included neonates Study Design and Management
At the time of enrollment, all patients were ventilated with
either a time-cycled pressure-limited neonatal ventilator or a
high-frequency oscillatory ventilator. No attempt was made to control
the mode of ventilation. After parental consent was obtained, eligible
patients with 2 separate OIs of >10 were randomized to receive a
starting iNO dose of either 1 to 2 ppm (low-dose group) or 10 to 20 ppm
(high-dose group). The response to iNO was assessed according to the
increase in arterial PaO2 and
decrease in OI 30 to 60 minutes after exposure to the initial starting
concentration. During this interval, no changes were made to the
ventilator or to other therapies. A response of <10% increase on
PaO2 and a <10% decrease in OI
resulted in a doubling of iNO within the dose range protocol (1, 2, 4, and 8 ppm for the low-dose group; 10, 20, 40, and 80 ppm for the
high-dose group). A full response (>20% increase in
PaO2 and >20% decrease in OI)
resulted in a continuation at that treatment dose. For patients who
responded, an attempt was made every 12 ± 2 hours to decrease the
iNO concentration by 50%. When such a reduction was successful
(maintenance of PaO2 >125 torr),
further weaning toward discontinuation of gas was made every 6 to 12 hours. All discontinuation was performed from doses of 0.5 to 1 ppm.
When the response occurred at 40 ppm or greater, attempts were made
every 4 hours to halve the dose, until the infant was receiving 20 ppm.
When a low-dose group patient at 8 ppm did not have a full response
after 1 hour, they were tried on 20 ppm and increased as per the
high-dose protocol. When no sustained response was obtained, an attempt
was made to discontinue iNO. In such circumstances, when the patient
continued to deteriorate, iNO was continued and repeated attempts at
weaning were made every 4 to 8 hours.
Oxygen saturation, ventilator settings, and blood pressure were
recorded every 15 minutes after a change in the concentration of iNO.
An arterial blood gas was obtained 1 hour after a change in iNO and as
deemed necessary by the clinical team. Methemoglobin analysis was
performed before iNO administration and at 6 hours and every 8 hours
during iNO administration. The study gas was weaned by 50% for a
methemoglobin concentration of >5%, and for an
NO2 level of >3.5 ppm. Inhaled NO was
discontinued for a systemic mean arterial pressure drop of >30% from
baseline associated with iNO initiation or dose increase and
unresponsive to dose decreases, a
PaO2 drop of >25% from baseline or
an oxygen saturation fall of >10% associated with initiation or dose
increases and unresponsive to dose decreases, a methemoglobin level of
>8% despite decreases in iNO concentration, and any
NO2 concentration of >3.5 ppm despite decreases
of the iNO concentration. Treatment failure was defined as death or the
need for ECMO.
iNO Delivery System
Purified iNO in a concentration of 800 ppm mixed in nitrogen was
blended with nitrogen by a Bird blender (Bird Products Corporation, Palm Springs, CA) to achieve an iNO concentration ranging from 0 to 80 ppm. The NO mixture was blended into the ventilator circuit with oxygen
and clinical air to achieve the desired fraction of inspired oxygen.
The concentration of NO was analyzed continuously in the inspiratory
limb of the ventilator circuit by a chemiluminescence iNO analyzer
(Model 200; Advanced Pollution Instrument, Advanced Pollution
Instruments Incorporated, San Diego, CA), an Environmental Protection
Agency-approved device that measures iNO and
iNO2 or by using the INO Vent (Ohmeda Inc,
Madison, WI). The expired gas as well as ambient air was analyzed for
NO2 every 2 hours and at the beginning and end of
every study. Expired gas was removed from the exhalation port by wall
vacuum.
Sample Size and Data Analysis
We designed the current study to test the null hypothesis that
there was no difference in the improvements in oxygenation or outcome
between low-dose versus high-dose iNO. Previous studies suggested that
iNO reduced the OI by 20%; thus, we postulated that a >10%
difference in the reduction of OI would be clinically important and
therefore powered the study to detect such a difference with a power of
70% and an Data are presented as mean ± SD for normally distributed
variables. To test for differences in baseline and after treatment and
compare between groups, we performed a 2-way analysis of variance with
post hoc testing using a Tukey analysis using Sigma Stat (SPSS Inc, Chicago, IL). The Cochrane-Mantel-Haenszel
Baseline Characteristics
We analyzed the results of this trial after 36 patients had been
enrolled, as the study had been in progress for more than 2 years and
enrollments were decreasing. Fifteen infants were enrolled in the
low-dose group, and 21 were enrolled in the high-dose group. There were
no statistically significant differences in the baseline
characteristics between the 2 groups in terms of birth weight,
gestational age, gender, age at start of study gas, 1- and 5-minute
Apgar scores, and whether they were born outside the treating facility
(Table 1). In addition, baseline oxygenation and ventilation parameters, including
PaO2, OI,
PCO2, blood pH, mean airway pressure,
mean arterial pressure, ventilator rate, peak inspiratory pressure
(PIP), positive end-expiratory pressure (PEEP), and heart rate, were
similar in the 2 groups. The variables that came closest to
significance were PIP and PEEP (P = .091 and
P = .087, respectively; Table
2). There was no significant difference
in the number of infants in the low- and high-dose groups who had
echocardiographic evidence of PPHN (10 of 16 [62.5%] in the low-dose
group compared with 10 of 22 [45%] in the high-dose group).
TABLE 1 TABLE 2
METHODS
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Abstract
Methods
Results
Discussion
Conclusion
References
34 weeks' gestation, infants <30 days of age at the time
of enrollment, and severe respiratory failure requiring mechanical ventilation with an oxygenation index (OI) of 10 and
PaO2 <100 on 2 separate blood gases
taken at least 30 minutes apart within a 2-hour period. Infants whose
diagnoses were pneumonia, sepsis, primary pulmonary hypertension of the
newborn (PPHN), MAS, and RDS were included in the study. Infants with
CDH were excluded in view of the previous results showing that such
infants did not show a favorable response to iNO.8,14 An attempt was made to obtain cardiac and head ultrasounds before inclusion, but this was not always possible. PPHN was diagnosed when
there was echocardiographic evidence of bidirectional or right-to-left
shunt at the level of the ductus arteriosus and the presence of
tricuspid regurgitation in the absence of other cardiac anomalies.
Exclusion criteria included infants with congenital heart disease
except for a patent ductus arteriosus or a small ventricular septal
defect, intraventricular hemorrhage (IVH) of grade 2 or worse,
platelets <100 000, and infants for whom the decision had been made
not to provide full medical treatment.
of 0.05, which required 50 patients in each group.
2 test was used to compare categorical or
discrete data such as PPHN major sequelae (death, ECMO, neurologic
sequelae, bronchopulmonary dysplesia, or composite).
RESULTS
Top
Abstract
Methods
Results
Discussion
Conclusion
References
Baseline Characteristics
Baseline Cardiopulmonary Parameters
Admission diagnoses were somewhat variable between the 2 groups. RDS was diagnosed in 3 infants in each group, and sepsis was diagnosed in 1 low-dose infant and 2 high-dose infants. The greatest differences noted were in the incidence of MAS (26.7% vs 47.6%; not significant) and the diagnosis of pneumonia (26.7% vs 0.0%; P = .023) for the low- and high-dose groups, respectively.
Use of Other Treatment Modalities
There were no significant differences between the treatment modalities between the 2 groups except for the rate of use of high-frequency ventilation before the start of the study gas. This intervention was used more frequently in the low-dose group than in the high-dose group (26.7% vs 0.0%; P = .023; Table 3).
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Thirty minutes after the study gas was initiated, PaO2 significantly increased overall and in both the low-dose (90.7 ± 41.2 to 166.8 ± 95.6; P = .028) and high-dose (76.4 ± 34.1 to 198.7 ± 142.8; P < .001) groups. The OI also significantly decreased overall (P = .008). However, by post hoc testing, the change was significant only in the high-dose group (21.0 ± 13.7 to 11.4 ± 10.4 [P = .008]; low-dose: 18.3 ± 7.1 to 13.2 ± 12.3 [not significant]). The decreases in PaCO2 before and after treatment were not statistically significant in either the low-dose group (35 ± 7.3 to 30 ± 8.5 torr) or the high-dose group (35.2 ± 9.9 to 32.4 ± 10.7 torr; Table 4). The magnitude of changes in the other cardiopulmonary parameters (heart rate, mean arterial pressure) and ventilatory parameters (PIP, PEEP, mean airway pressure, ventilator rate) were insignificant.
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The analysis of the response by individual initial doses revealed that the improvement in oxygenation was significant by post hoc testing only in the 10-ppm group (91.7-252.1 torr; P < .001). The 20-ppm group comprised the "sickest" group of patients (OI: 24.9 ± 18.5; lowest PaO2: 56.9 ± 17.7) relative to the 1-, 2-, and 10-ppm groups, which had baseline PaO2s of 94.3, 96.4, and 91.8 and OIs of 18.7, 17.2, and 17.0, respectively. The 20-ppm group was the only subgroup to demonstrate a significant decrease in OI (24.9 to 12.6; P = .042; Table 5).
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Overall Response Profile
There were no differences for the duration of time that patients in the low-dose versus high-dose group were on iNO (91.2 ± 67.9 vs 90.5 ± 67.3 hours), the durations of assisted ventilation (150.2 ± 54 vs 205.6 ± 209.4 hours), or the duration of the need for supplemental oxygen (240.6 ± 126.6 vs 287.1 ± 156.7 hours).
The percentage of patients in each group who responded to the initial dose of NO administered was not significantly different (66.7% for low-dose and 71.4% for high-dose). Subdividing each group according to the actual initial dose used (1 or 2 ppm for low-dose vs 10 or 20 ppm for high-dose) reveals an initial response rate of 50.0% for 1 ppm, 85.7% for 2 ppm, 71.4% for 10 ppm, and 75.0% for 20 ppm. The rate of sustained response (ie, maintaining a PaO2 and OI gain >20% for the duration of the iNO administration) was greater in the high-dose group (53.3% vs 30.0%). In addition, dose increases were required more often in the low-dose group than the high-dose group (80.0% vs 57.1%), regardless of whether there was an initial response, even when only considered in the subgroup of patients who had responded initially (70.0% low-dose vs 46.7% high-dose). Eight of 15 infants in the low-dose group required an increase to at least 10 ppm, and 2 required an increase to either 40 or 60 ppm. In the high-dose group, 48% (10 of 21) infants required increased doses to as high as 40 to 60 ppm. Finally, among patients who did not respond to the initial iNO dose, 100.0% and 83.3% responded at higher doses of iNO for the low- and high-dose groups, respectively.
Outcomes and Adverse Events
There were 3 treatment failures in the high-dose group; 2 infants died (1 who initially responded to iNO died after withdrawal of support for severe hypoxic ischemic encephalopathy after cardiac surgery for a subsequently diagnosed coarctation of the aorta, and the other, who also responded to iNO, died after withdrawal of support for lung hypoplasia and confirmed bilateral renal dysplasia). One infant with proven group B streptococcal sepsis initially responded to iNO but eventually required ECMO for inadequate oxygenation and was discharged from the hospital without supplemental oxygen. There were no treatment failures in the low-dose group. Two infants in the low-dose group exhibited seizure activity with electroencephalogram changes, as did 1 patient in the high-dose group. None of the neonates in this study experienced an IVH, and no patient in either group was given a diagnosis of chronic lung disease defined as requiring supplemental oxygen at 28 days.
NO was not weaned or discontinued in any patient either because of methemoglobinemia or an elevated NO2, and there was no significant fall in mean arterial pressure or fall in PaO2 associated with initiation of iNO. The mean peak value of blood methemoglobin was 2.19 ± 1.66 for the high-dose group and 1.36 ± 1.13 for the low-dose group (P = .169).
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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We report that in term and near-term infants with hypoxic respiratory failure, treatment with NO at doses as low as 1 to 2 ppm is as efficacious initially as 10 or 20 ppm. The results of this study show that an initial dose of 1 to 2 ppm did not differ significantly from an initial dose of 10 to 20 ppm in terms of the level of improvement in PaO2, OI, and rate of response. Furthermore, the length of time that infants required NO did not differ by the initial dose. In fact, the high-dose group spent more time intubated and required supplemental oxygen for a longer period. However, it should be noted that more infants in the low-dose group required dose escalation compared with the high-dose group. There were only 2 deaths in this cohort, both of whom initially responded to iNO, and the cause of death was unrelated to the need for iNO. No infant in the low-dose group died or required ECMO. In addition, although a significant number of our infants had echocardiographic evidence of PPHN, this evaluation was not performed in all infants. Previous studies in adults12 and neonates9 demonstrated that iNO may improve gas exchange by decreasing ventilation perfusion mismatch.
This study is consistent with a previous study by Davidson et al,7 who showed that improvement in PaO2 and OI was similar between groups that received an iNO dose of either 5 ppm or 20 ppm. In addition, the group that received a starting dose of 80 ppm did not do significantly better and was associated with greater incidences of methemoglobinemia and elevated inspired NO2 levels. Finer et al9 also showed that the mean improvement in oxygenation was similar between groups that were randomized to doses of iNO from 5 to 80 ppm. This is the first study to show that a dose as low as 1 or 2 ppm can be as efficacious as 10 or 20 ppm.
A previous study by Schedin et al15 showed that term infants have peak concentrations of NO in their nasal passages of 2.7 ppm within 10 minutes after birth, increasing up to 3.8 ppm 4 to 7 days postnatally. In premature infants, the concentrations were lower (1-2 ppm) but increased significantly with postconceptional age.15 An intubated neonate may be unable to take full advantage of the physiologic NO that is manufactured in its nasal passages and upper airway, and thus the administration of iNO at very low doses may simply replace a physiologic concentration that facilitates adequate oxygenation.
Our results showed that the need for increasing dose(s) of NO was more frequent in the low-dose versus high-dose group, a difference that was not statistically significant. Approximately half (8 of 15) of the low-dose group required an increase to at least 10 ppm; 2 (13%) required a increase to either 40 or 60 ppm. This may reflect an attenuation of response to the initial concentrations of NO that occurs with prolonged treatment, or it may represent further clinical deterioration unrelated to NO, such as a loss of lung volume and thus poor absorption of the iNO. Although patients in the high-dose group had a lower rate of requiring increasing doses, 48% (10 of 21) of the patients in this group required increased doses to as high as 40 to 60 ppm.
A recent multicenter study by Cornfield et al13 concluded that initial treatment with iNO at 2 ppm does not result in acute improvements in oxygenation and actually may attenuate the subsequent responses to NO at 20 ppm. Our study, which is very similar in the number of patients per group, demonstrates that treatment at an initial concentration of 1 ppm does, in fact, significantly improve oxygenation almost as much as the high-dose group. Furthermore, all of our patients who initially did not respond at 1 or 2 ppm responded to increased doses of NO in direct contrast to the observations of Cornfield et al, who reported that the subsequent use of 20 ppm in infants who had received earlier treatment with 2 ppm did not result in an improvement in oxygenation or a change in OI (42.6-42). Adult studies in patients with acute RDS (ARDS) indicate that the ED50 of iNO for adults is 0.1 to 1.0 ppm of NO.12 Cornfield et al included infants with CDH, seen in 9 of their 38 infants, a group previously established to have a poor response to iNO.14 In addition, their initial randomization was between 2 ppm of iNO and no iNO, and their initial OIs were 34 to 37, substantially higher than the current study. Infants with OIs that exceeded 35 then were treated with 20 ppm of iNO. Their study found a greater fall in OI and improvement in oxygenation with later treatment with the higher dose of iNO. In addition, 5 of the 15 infants in their high-dose group required ECMO and 7 died, compared with 5 of 23 infants who required ECMO in their early low-dose arm with 2 deaths. Other differences between our study and that of Cornfield et al included our more frequent use of surfactant and possibly more frequent use of high-frequency ventilation, which was not specified in the trial of Cornfield et al. Our study was a single-center experience with the potential for more consistent treatment decisions.
Several other studies showed an effective response to low doses comparable to those used in the current study, including infants and children with ARDS and postoperative cardiac patients; one study reported that the optimal concentration was <4 ppm, with improvements noted with doses of <1 ppm, similar to the observations in adults by Gerlach and colleagues.12,16,17 Wood et al18 compared the use of an initial dose of 6 ppm with an initial dose of 20 ppm in neonates with hypoxic respiratory disease and reported no difference in outcome between these 2 groups. Okamoto et al16 also reported that the iNO-induced increase in PaO2 was greater with higher PaO2/fraction of inspired oxygen values, suggesting that the more severe the lung disease, the greater the dose of iNO required to achieve a response. This may explain some of the differences between our observations and those of Cornfield et al. Although there may be a mechanism by which low-dose iNO inhibits subsequent responses to higher doses, perhaps more commonly in infants with more severe lung disease, our study does not support such a conclusion.
Patients in the low-dose group did not have any negative outcomes in regard to need for ECMO, death, chronic lung disease, or IVH. Two patients in this group experienced seizures. Two patients in the high-dose group died, and 1 had a seizure. The infant in the high-dose group who required ECMO had a 146-torr increase in PaO2 with the initial iNO dose of 10 ppm and subsequently deteriorated. The higher sequelae rate in the high-dose group likely is the result of sicker patients' being randomized to the high-dose group. The pretreatment PaO2 was almost 20 torr lower and the OI 3 units greater compared with the low-dose infants, although these differences were not statistically significant (Table 5). Our 2 groups were similar in terms of initial cardiopulmonary parameters; the low-dose group more frequently received high-frequency ventilation before iNO. This may explain why the initial PaO2 and OI were more favorable for this group at initiation of study gas. The PIP and PEEP values also were higher in the low-dose group. Ultimately, these 2 groups likely are more similar than their initial PaO2 and OI suggest if the increased use of high-frequency ventilation were factored into the initial parameters. If indeed the 2 groups are comparable in terms of their level of acuity at the time of study gas initiation, then an argument could be made that the negative sequelae in the high-dose group may be related partially to the use of higher doses of NO. In fact, the methemoglobin level reached at least 3.0 in 35.7% of the high-dose group versus only 9.1% in the low-dose group. Nevertheless, the levels of methemoglobinemia and NO2 measured in inspired or expired air were not significant enough to cause the study gas to be terminated. We are concerned that lower doses may be safer for immature preterm infants and also that unmeasured molecules such as peroxynitrites may be formed at lesser levels if iNO is used at lower doses. Until these and other byproducts are measured routinely with iNO administration, we continue to believe that the lowest effective dose of iNO is also the safest dose.
We noted a nonsignificant decrease in PaCO2 associated with iNO, in agreement with previous observations.16,19 Puybasset et al20 noted that iNO can reverse pulmonary hypertension induced by permissive hypercapnia. They noted a decrease in alveolar dead space with iNO in adult patients with ARDS. Such decreases in PaCO2 probably occur secondary to reperfusion of previously nonperfused lung units, resulting in a fall of physiologic dead space. Okamoto et al16 noted greater decreases in PaCO2 in children with higher initial PaCO2 values, suggesting that iNO may be of additional value in such patients.
Limitations of this study include that the clinicians who were caring for the infants were aware of the assignment of the patients to either a low or high dose as well as subsequent NO concentration adjustments made during the clinical course. In addition, the numbers of infants in each arm were unbalanced as a result of larger blocks of randomization, and the total number of infants in this trial was small. This study did not have a placebo group, as its primary purpose was to compare the efficacy of 2 different ranges of doses of iNO, not to show the efficacy of iNO over placebo. In addition, the lower OI and level of illness of infants in this study compared with other studies that have been discussed and other interventions after the use of iNO raises the possibility that a number of infants may have improved over time, without the need for iNO.
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CONCLUSION |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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This study provides evidence that iNO at 1 to 2 ppm as an initial dose can be as effective as higher concentrations in infants with OIs of <25. Our study also shows clearly that exposure to an initial dose of 1 to 2 ppm does not attenuate responses to higher doses of iNO, including 20 ppm in this population. The use of such low doses may be especially useful in the premature infant, for whom concerns regarding platelet function and bleeding disorders21-24 may be somewhat alleviated by using the lowest effective dose. In our study, the largest increase in PaO2 was observed with an initial dose of 10 ppm, and the largest fall of OI was observed with 20 ppm, the sickest group in the present study. On the basis of the observed sustained responses, we recommend initiating iNO at 10 ppm in the near-term infant and then reducing the dose to the lowest that maintains an acceptable clinical response. Our data suggest that the initial use of lower doses may provide a wider safety margin for more fragile premature infants, without compromising their ability to respond to higher doses, if needed.
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FOOTNOTES |
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Received for publication Sep 18, 2000; accepted Jan 31, 2001.
Reprint requests to (N.N.F.) University of California, San Diego Medical Center, Department of Pediatrics, 200 W Arbor Dr, 8774, San Diego, CA 92103-8774. E-mail: nfiner{at}ucsd.edu
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ABBREVIATIONS |
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ECMO, extracorporeal membrane oxygenation; MAS, meconium aspiration; CDH, congenital diaphragmatic hernia; iNO, inhaled nitric oxide; ppm, parts per million; RDS, respiratory distress syndrome; ED50, mean effective dose; PPHN, primary pulmonary hypertension of the newborn; IVH, intraventricular hemorrhage; OI, oxygenation index; PIP, peak inspiratory pressure; PEEP, positive end-expiratory pressure; ARDS, acute respiratory distress syndrome.
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REFERENCES |
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This article has been cited by other articles:
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  M. Beghetti, C. Sparling, P. N. Cox, D. Stephens, and I. Adatia Inhaled NO inhibits platelet aggregation and elevates plasma but not intraplatelet cGMP in healthy human volunteers Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H637 - H642. [Abstract] [Full Text] [PDF]
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