1 Department of Medical Cell Biology, Section of Integrative Physiology, Uppsala University, Box 571,SE-751 23 Uppsala, Sweden. 2 Datex-Ohmeda Research Unit, Helsinki, Finland
Corresponding author. E-mail: erkki.heinonen@datex-ohmeda.com
Accepted for publication: October 16, 2002
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Abstract |
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Methods. Nitric oxide was delivered in four different pulse volumes synchronously with inspiration. The delivery was monitored with a fast responding high sensitivity nitric oxide monitor and nitric oxide uptake was calculated. Pulse delivery dose range, accuracy of the delivered dose, and stability of successive doses were analysed in a laboratory setting.
Results. Uptake of the delivered nitric oxide was 8792%. Measured nitric oxide pulse concentration was 1.6-fold the delivery concentration, calculated as the ratio of nitric oxide flow to inspiration flow. Dose accuracy and stability were both 5% or 3 nmol in the validated range of 31000 nmol.
Conclusion. With pulsed administration nitric oxide therapy can be directed to well-ventilated lung regions. Avoiding administration to the anatomic dead space eliminates nitric oxide exhalation effectively, which makes the method optimal for nitric oxide therapy in a rebreathing circuit. The required dose range from paediatric to adult is covered by the delivery device with a single nitric oxide gas supply.
Br J Anaesth 2003; 90: 33842
Keywords: pharmacology, nitric oxide; ventilation, artificial
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Introduction |
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After demonstration of this therapeutic effect of nitric oxide, the technique for optimal administration has progressed in several steps.24 In the first approach a nitric oxide/nitrogen mixture was infused at constant rate into various sites of the inspiratory limb.5 6 This method produces high nitric oxide peaks at certain phases of the breathing cycle, which is regarded as problematic in nitric oxide inhalation therapy.5 Nitric oxide peaks were avoided with a delivery system producing constant breathing gas nitric oxide concentration over the entire inhalation phase.7 With this method a 120 p.p.m. concentration is considered as optimal.811 Nitric oxide administered in short pulses of 5170 nmol dose synchronously with early inspiration has been effective in relieving pulmonary hypertension in spontaneously breathing patients and in artificially ventilated pigs.1214 Pulsed administration also redirected the perfusion from atelectatic to well ventilated lung regions during equine anaesthesia, and reduced nitric oxide expiration, which improves safety when the therapy is used in a rebreathing circuit.13 15 16
Nitric oxide administered as a pulse into the early inspiration imitates natural breathing where nitric oxide is carried to the ventilated lung regions from nasal sinus cavities, where nitric oxide is produced in substantial amounts.17 For this to succeed the nitric oxide should be infused as near the patient airway as possible. Design, construction and clinical use of the device developed for pulsed administration of nitric oxide is described, and the device performance is evaluated in both an animal model and a laboratory test.
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Methods |
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The delivery device uses carrier gas to boost the speed of dose transport through a delivery line to the administration point. The carrier gas is suctioned from the inspiratory limb to retain the breathing gas mixture, and loaded in a 100-ml carrier gas container. The container overpressure at the beginning of the pulse is typically 50 kPa. A carrier flow of the order of 50 ml s1 is activated at the beginning of the pulse flushing the nitric oxide to the administration point in less than 100 ms. This enables accurate administration timing even against increasing breathing circuit pressure during inspiration. The flushing is continued 200500 ms after closing the pulse to flush the delivery line from nitric oxide. With this method no control equipment is needed near the patient, and nitrogen dioxide formation in the delivery line is prevented.
The device control program runs with 25 Hz frequency in a laptop computer equipped with an interface board DAC-card 1200 (National Instruments, Austin, TX, USA). The control software is written on a LabVIEWTM (National Instruments) programming platform.
In vivo evaluation
The local ethics committee for animal experimentation approved a study of a 30-kg pig ventilated in constant flow ventilation given nitric oxide therapy in an open breathing circuit. Nitric oxide was administered in 5, 10, 40, and 80 nmol doses during the first 30% of the inspiration period. Average inspiratory nitric oxide fraction during the pulse (FINOpulse) was calculated as ratio of the nitric oxide flow (pulse volume divided by pulse duration) to the inspiratory gas flow (tidal volume (Vt) divided by inspiration time (ti)).
Nitric oxide delivery was monitored with a chemiluminescence nitric oxide analyser (a prototype made by Datex-Ohmeda) having a 200-ms response time and connected to measure breath-by-breath inspired and expired nitric oxide (Fig. 1). Peak inspired nitric oxide fraction (FINOpeak) and end-tidal nitric oxide fraction (FE'NO) were determined from the recording. Linear regression analysis (Statistica/5.0 software, StatSoft Inc., Tulsa, OK, USA) was used to test the correlation between FINOpulse and FINOpeak. Ventilatory frequency and Vt were monitored with the D-liteTM flow sensor. Nitric oxide uptake was defined as the proportion of the delivered nitric oxide remaining in the body. This was done by measuring the amount of nitric oxide not taken up by integrating the product of nitric oxide fraction and flow during expiration.
Laboratory evaluation
The delivered dose volume was evaluated by collecting two to 20 successive nitrogen pulses into a 1, 10, or 50 ml measuring chamber. The volume accuracy was evaluated with selected combinations of dose volumes (3, 10, 33, 100, 330, 1000 nmol) and pulse durations (0.2, 0.3, 0.6, 1.2 s). The dose accuracy was determined as the average of the measured volume and the stability of the delivery was evaluated by calculation the standard deviation for successive doses, with pulses of different duration.
All statistical analysis was performed with Statistica/5.0 software (StatSoft Inc.).
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Results |
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Discussion |
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In healthy humans nitric oxide uptake is 90% in perfused alveoli and 55% when nitric oxide is delivered throughout the whole inspiration.19 In this study uptake for the nitric oxide delivery to the first 30% of inspiration was 8793% (Table 1). Although potentially slightly overestimated because of a slow nitric oxide analyser response time, the results suggest administration to the perfused alveolar lung region only.
As calculated for 1001000 ml alveolar tidal volumes the optimal delivery range of 120 p.p.m. in human therapies corresponds with 4.5890 nmol per inspiration, and HPV is relieved with pulsed administration of 5170 nmol per inspiration. Thus, the 31000 nmol per inspiration delivery range validated in the laboratory covers the therapeutic range from paediatric to adult patients. In neonatal patients the alveolar tidal volume can, however, be less than 100 ml. Under these circumstances the differences between administration modes disappear and lung recruitment strategies are useful in improving the efficacy of the therapy.20 With an I:E ratio of 1:1, the dose can be administered to the first 30% of inspiration when the respiration rate is below 40 bpm.
A nitric oxide analyser connected at the patient limb distal to the administration point is very useful in guiding pulsed administration (Fig. 2). The characteristic nitric oxide fraction chart for successful administration contains the phases A, B, and C whereas their absence, or the presence of phases D or E, indicates a problem. Measures to correct the problem include the use of a shorter administration pulse or longer lung filling time to fill the dead spaces with nitric oxide free gas after the pulse.
The relatively slow response time of the nitric oxide analyser compared with the nitric oxide pulse duration was a potential source of damping in measuring the inspiratory dose delivery spike. Despite this damping, the (FINOpeak) was high compared with the (FINOpulse). This is because of incomplete mixing caused by the short distance between administration and sampling points, and the FINOpeak may vary depending on the relative locations of the administration and measurement ports. Therefore, the analyser cannot be used to monitor administration volumes. An independent safety monitor measuring the volume of the delivered dose should preferably be incorporated as part of the delivery device.
When nitric oxide is delivered in a continuous flow to improve oxygenation, maximal improvement is achieved when the oxygenation failure is caused by a true shunt.21 The effectiveness of the therapy decreases with the presence of low ventilated lung regions.22 These observations in animal models could explain the inconsistent oxygenation response to nitric oxide inhalation of acute respiratory distress syndrome (ARDS) when nitric oxide is administered at a constant inspired concentration.23 With pulsed administration oxygenation can effectively be improved even when lung ventilation is dispersed.1416 24 25 This method has been used successfully in pigs and during equine anaesthesia.13 15 16
In humans, oxygenation failure as a result of perfusion of low ventilated lung regions may be present also during anaesthesia especially in obese patients.26 27 In these circumstances pulsed administration of nitric oxide could be used to redirect the perfusion from the collapsed lung regions towards well ventilated regions. The delivery method would be optimal for anaesthesia applications in rebreathing circuits because of low nitric oxide expiration. This reduces nitric oxide rebreathing, which has been identified as a problem with constant inspired concentration delivery.7 However, even with pulsed administration circuit nitric oxide fraction has to be monitored since large alveolar dead space or reduced nitric oxide diffusion may increase nitric oxide expiration. A concomitant increase in the circuit nitric oxide fraction contributes to increased nitrogen dioxide formation and disturbs selective administration to the perfused alveoli. Nitric oxide accumulation can easily be resolved by enhancing the circuit ventilation with larger fresh gas flow. Otherwise the pulsed administration device described is inherently safe with respect to nitrogen dioxide formation because of to the minimal reaction time achieved by mixing nitric oxide with oxgen at the time of inspiration.
Pulsed delivery of nitric oxide at the early inspiration described here should not be confused with continuous flow administration where a bolus effect is well known.5 28 In that case the bolus is formed at the administration point during expiration when the inspiration flow is zero. The rationale for administering nitric oxide right at the ventilator outlet was to smooth out this bolus to enable reliable nitric oxide monitoring with slow response time electrochemical cells. However, the characteristic notches resulting from distant administration are still indirectly visible in breathing gas oxygen fraction charts.5 Depending on the breathing circuit volume between the administration point and the alveoli compared with the tidal volume, the bolus may reach, at worst, lung regions of low ventilation impairing oxygenation or even remain in the anatomic dead space from where it becomes directly expired.
In conclusion, pulsed administration of nitric oxide is technically feasible for use in ventilation therapy with the delivery concept and device presented here. Further studies in animal models and humans during anaesthesia and intensive care are needed to reveal if the pulsing of nitric oxide is more effective in improving oxygenation during nitric oxide therapy and whether the occurrence of non-responding patients is reduced compared with conventional administration modes.
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References |
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