1Department of Medical Cell Biology, Section of Integrative Physiology, Uppsala University, Box 571, SE-75123 Uppsala, Sweden. 2Department of Large Animal Clinical Sciences, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden. 3Datex-Ohmeda Research Department, Helsinki, Finland*Corresponding author
Accepted for publication: November 9, 2001
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Abstract |
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Methods. We administered NO as a pulse and varied the pulse timing during inspiration in equine anaesthesia, where atelectasis develops regularly. Six spontaneously breathing standard breed trotters were studied under isoflurane anaesthesia in lateral recumbency. NO pulsed into the first 30% of inspiration (group NOp1) was assumed to affect open lung areas. To cover more open lung areas NO was then pulsed into the first 60% of inspiration (group NOp2). In a third group, administration between 50 and 80% of inspiration was aimed at the intermittently opening lung areas (group NOp3).
Results. With NOp1, venous admixture decreased by 8 (2)% (mean (SEM), P=0.045) and with NOp2 by 10 (1)% (P=0.01). With NOp3, venous admixture reduction was insignificant.
Conclusions. Pulsed administration of NO in early inspiration is optimal in reducing right to left vascular shunt in atelectatic equine lung. This reduction is positively correlated with the magnitude of the initial shunt. With administration in early inspiration, NO is mostly taken up by the lung. This prevents NO accumulation and NO2 formation in rebreathing circuits. These findings may be important in humans when atelectasis occurs increasingly with overweight and age during anaesthesia, but also in postoperative intensive care and in ARDS.
Br J Anaesth 2002; 88: 3948
Keywords: pharmacology, nitric oxide; lung, atelectasis; anaesthesia, equine; horse
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Introduction |
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In horses, atelectasis and ventilationperfusion mismatch develop regularly during anaesthesia.12 We therefore used equine anaesthesia to study the effect of NO delivered to various lung areas, in reducing shunt.
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Material and methods |
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Procedure and NO delivery
One hour after
induction of anaesthesia, a period used for catheterization and to achieve
stable anaesthesia, the first baseline readings were recorded and then NO
was administered during the first 30% of inspiration (NOp1). Fifteen
minutes after cessation of NOp1, a further baseline was recorded and NO was
administered during the first 60% of inspiration (NOp2). After
completion of NOp2, there was another 15-min resting period, followed
by a new baseline recording. NO was then administered during
5080% of inspiration (NOp3) to reach poorly ventilated areas
of the lung. The response was recorded after 5 min of NO delivery in all
delivery modes. As NOp3 involved a risk of a severe increase in shunt and
hypoxaemia, no randomization of the order of administration of NO was
performed.
NO was injected with a pulsed delivery device developed by Datex-Ohmeda Research Department, Helsinki, Finland. The device generates a NO pulse by regulating the flow of the NO-containing gas mixture for the required period. For the flow regulation, the device has a proportionally adjustable valve and a dose flow sensor. The NO pulse was injected during inspiration (NOp1, NOp2, or NOp3). A D-liteTM (Datex-Ohmeda) type flow sensor, dimensioned appropriately for the monitoring of horse ventilation, was used to synchronize the dose with breathing. The pulse was injected at the beginning of the tracheal tube to allow selective administration to different parts of the lungs. The NO supply was 2000 µl litre1 NO in N2 (AGA AB, Lidingö, Sweden).
Anaesthesia
During
the12 h preceding anaesthesia, the horses were allowed to drink only water.
Acepromazine 0.05 mg kg1 was given intramuscularly
approximately 30 min before induction of anaesthesia. An i.v. infusion of
7.5% guaifenesin was given until the horse became ataxic. Then
anaesthesia was induced by the i.v. injection of thiopental 5 mg
kg1. The trachea was intubated and the horses were
positioned in lateral recumbency, and connected to a large-animal
breathing circuit. Anaesthesia was maintained with spontaneous breathing of
isoflurane in oxygen with a fresh gas flow of 56 litre
min1. The end-tidal isoflurane fraction was
1.31.7%, adjusted for stable anaesthesia.
A thermodilution catheter (7F, Swan-Ganz) was inserted with an introducer kit (Arrow Int. Inc., Reading, PA, USA) through a right jugular vein to the pulmonary artery. This catheter was used for pulmonary artery pressure (PAP) and cardiac output (Q·t) measurement, and mixed venous blood sampling. A pigtail, multi-hole catheter (Cook Europe A/S, Söborg, Denmark) was inserted with a similar technique into the same jugular vein, advanced to the right ventricle, and retracted into the right atrium. This catheter was used as an injection port for Q·t measurement. A catheter to measure mean arterial pressure (MAP) and to sample arterial blood was introduced percutaneously into the facial artery (Insyte-W, 18GA, Becton-Dickson, Ohmeda, Helsingborg, Sweden). The catheters were positioned under pressure-tracing guidance with simultaneous ECG monitoring and locked in position with a Luer-lock adaptor.
Monitoring
Expired NO was monitored with
a chemiluminesence analyser prototype (Datex-Ohmeda) connected between
the Y-piece and the point of NO administration. The analyser was
calibrated with the mixture 100 µl litre1 NO in
N2 (AGA AB) and with room air depleted of NO with a charcoal
absorber. The signal rise time of the analyser was 200 ms, which allowed
analysis of the expired breath pattern. The monitor was used to determine
the end-tidal and peak expired NO fractions.
MAP and PAP were measured by pressure transducers positioned at the level of the sternal manubrium, which was considered to correspond to the level of the right atrium. These pressures, and also the inspired (FIO2) and expired (FEO2) gas oxygen fractions, respiratory rate (RR), tidal volume (VT), end-tidal carbon dioxide and oxygen fractions, and isoflurane fractions, were recorded on an AS/3 AMTM (Datex-Ohmeda) anaesthesia monitor.
Cardiac output was measured with the thermodilution technique (Cardiac Output Computer Model 9520 A, Edwards laboratory, Santa Ana, CA, USA); 20 ml 0°C 0.9% saline was injected into the right atrium through the pigtail catheter.
Arterial
and central venous blood was obtained and analysed with a standard
electrode technique (ABL 5, Radiometer, Copenhagen, Denmark). The arterial
and venous (PO2) oxygen partial pressures were measured at standard electrode temperature (37°C) and the oxygen saturations (SaO2 and SvO2, respectively) were calculated from the blood samples using the human P50 value 3.57 kPa, which is close to the equine value of 3.41 kPa.
To estimate the pulmonary shunt, venous admixture was calculated from the blood gas values using the method described by Berggren.13
Statistical analysis
Repeated measurement ANOVA was used to compare data within the group on different parts of the study. The Tukey honest significant difference test was used for post hoc comparisons and probability values were calculated. For all statistical calculations, the Statistica/w 5.0 software package (StatSoft Inc., Tulsa, OK, USA) was used. Results are given as mean values (SEM). In the analysis, the probability P<0.05 was considered as significant.
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Results |
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Discussion |
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When NO was delivered in early inspiration, the decrease in venous admixture was positively correlated with its baseline value. A similar correlation was observed in our previous study of five horses in dorsal recumbency, where NO was only delivered during the first half of inspiration in three different procedures.14 The venous admixture was reduced by 14% from a baseline of 37% when 9 µmol min1 of NO was delivered during spontaneous breathing (reduction predicted from the line of identity of Fig. 2 is 13%); a reduction of 10% from a baseline of 32% occurred when 17 µmol min1 of NO was delivered during spontaneous breathing (predicted value 10%) and a reduction of 7% from a baseline of 26% occurred when 30 µmol min1 of NO was delivered during mechanical ventilation (predicted value 7%).14 In another study of seven horses given NO at a constant 10 p.p.m. inspired concentration, the reduction in venous admixture fell below the line of identity with a baseline value of 21% and reduction of 1% (predicted value 4%).15 This is comparable with the NO delivery given in NOp3 with corresponding figures of 30% and 5%, respectively (predicted value 9%).
The reduction in venous admixture in human ARDS patients when NO is administered during the whole of inspiration is independent of the initial level,4 estimations derived from that data suggest reduction of only 5% from 40% (14% predicted from Fig. 2). The smaller reduction in venous admixture when NO is delivered during the whole of inspiration may be explained by NO affecting the border zone, dilating the vessels affected by local hypoxic vasoconstriction, which counteracts any reduction in shunt caused by NO in the ventilated lung areas.
The proposed mechanism for the decrease in venous admixture with NO inhalation is vasodilatation as a result of decreased pulmonary vascular resistance. Even though the venous admixture was reduced with NO delivery during early inspiration in the present study, NO did not alter PAP or Q·t. This surprising result may be because of vasoconstriction occurring in the zones not receiving NO. Perfusion redistribution without a change in PAP or Q·t has also been observed in humans when NO is administered to one lung only.16 This was associated with a significant increase in the pulmonary vascular resistance in the lung not receiving NO. Down-regulation of endogenous NO production in both lungs during unilateral administration of NO is proposed as one explanation of this finding. Another explanation involves vessel elasticity. Distension in regions receiving NO would allow the vessels to constrict elsewhere, because Q·t remains unaltered, thus preserving PAP.
The alveolar NO uptake determined experimentally in humans is 95100%.17 In simulation experiments, the uptake of NO administered in the first third of inspiration in pigs is 8090%.18 From the mean of the exhaled peak- and end-tidal fractions (Fig. 3), and the ventilation and NO delivery data in Table 1, the uptake in the NOp1 mode can be estimated at 92%, suggesting that NOp1 is delivered successfully to the alveolar region. When NO is delivered at a constant inspired concentration, the uptake rate decreases to 5619 or 5060%,18 because of the expiration of NO from the anatomical dead space. In a rebreathing circuit, the expired NO is recycled leading to administration of an uncontrollable dose. In this circuit, the NO also reacts with oxygen forming NO2. Hence in rebreathing circuits, NO should be delivered only in short pulses synchronous with early inspiration.
During human anaesthesia, the ventilationperfusion ratio is high in the uppermost regions and low at the base of the lungs, which are subject to atelectasis.20 Anaesthesia also induces at least a 70% increase in closing volume.21 This increase is positively correlated with age and body mass index.21 22 In morbidly obese patients, an observed 50% reduction in functional residual capacity compared with the pre-anaesthesia value has been found to be closely related to the development of atelectasis.23 24 During general anaesthesia with mechanical ventilation, 75% of the impairment of arterial oxygenation may be explained by atelectasis and airway closure.25 Common measures to compensate for the impairment are the use of a higher FIO2 or increasing the positive end-expiratory pressure (PEEP). The development of atelectasis correlates with a high FIO2, and PEEP may increase the shunt, leading to deteriorating oxygenation.25 26 Pulsed NO may provide a new method for maintenance of arterial oxygenation during anaesthesia, which could even reduce atelectasis formation by allowing a reduction in FIO2.
In conclusion, to reduce pulmonary shunt, NO delivered in pulses in early inspiration is the optimal method. With this type of administration, the degree of improvement correlates positively with the initial magnitude of the shunt. In rebreathing systems, NO should be delivered only in pulses to permit accurate dosing and to avoid NO2 formation in the breathing circuit.
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Acknowledgement |
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