Department of Anaesthesia, Division of Surgery and Anaesthetics, Faculty of Medicine, Imperial College London, Department of Anaesthetics, Royal Brompton and Harefield NHS Trust, Harefield Hospital, Middlesex UB9 6JH, UK E-mail: n.marczin{at}imperial.ac.uk
History repeats itself, first as tragedy, second as farce 38153. Marx, Karl. The Columbia World of Quotations. 1996.
Reading the work of Hess and colleagues in this issue of the British Journal of Anaesthesia1 reminds me of the familiar line History repeats itself. An Internet search traces the origins of this quotation to Hegel. However, I came across the above extension by Marx, which seems quite applicable to the story of inhaled nitric oxide and anaesthesia, and particularly to the topic of contamination of nitrous oxide with nitric oxide. Certainly, the story starts as the tragedy reported by J. Clutton-Brock,2 who described two cases of fatal poisoning by contamination of nitrous oxide with apparently toxic concentrations of higher oxides of nitrogen during anaesthesia. The toxic effects culminated in massive lung injury and were most likely a result of manufacturing problems. This toxic potential created immediate anxiety among anaesthetists, and the entire 39th volume of the British Journal of Anaesthesia in 1967 was devoted to this issue by comprehensively reviewing manufacturing issues, original animal research, the clinical physiology, and therapy for poisoning as available at that time.
Although Murad's work a few years later demonstrating smooth muscle relaxation by nitro compounds and nitric oxide with involvement of cGMPthat was later acknowledged with a Nobel Prizeindicated the pharmacological significance of nitric oxide in the lung,3 the condemnation of nitric oxide as a biologically and clinically hazardous entity perhaps delayed any recognition of endogenous nitric oxide as an ubiquitous physiological regulator. A series of milestone discoveries including the demonstration by Furchgott of the endothelium derived relaxing factor, its identification as nitric oxide, and the elucidation of its characteristics as a selective pulmonary vasodilator,48 then resulted in a complete turn of fate for inhaled nitric oxide in the anaesthetic and critical care community. At that time, we advocated inhaled nitric oxide as the wonder drug of the decade, and the magic bullet for many conditions. Somewhat ironically, inhaled nitric oxide was promoted as a therapy for adult respiratory distress syndrome (ARDS), a feared complication of its recognized toxicity.911
Although the wheels have turned again because of the relative failures of the multicentre clinical trials in ARDS and inhaled nitric oxide being labelled as only cosmetic therapy and the wrong bullet for the wrong target,12 13 inhaled nitric oxide has been proven effective at least in some forms of paediatric hypoxic respiratory failure. It has been approved as a new drug for this application by the FDA in the newborn. In addition, we continue to use this form of rather costly therapy in many off-licence applications including rescue therapy for refractory hypoxaemia in ARDS and many forms of right ventricular failure. Furthermore, international consensus is emerging regarding the use of inhaled nitric oxide both in children and adults.14
The article of Hess and co-workers, and our own experience15 (Fig. 1), however, highlight that rather inadvertently we are regularly using a much cheaper form of inhaled nitric oxide therapy whenever we administer an anaesthetic with nitrous oxide or compressed medical air. The authors from Hamburg found a range of 1.322.3 parts per billion (ppb) nitric oxide in the inspiratory limb of their patient ventilators when using nitrous oxide 65%. On the basis of the well-known positive effects of inhaled nitric oxide in the parts per million (ppm) concentration range, and the startling findings by the Pittsburgh group demonstrating clinical effects of environmental nitric oxide contamination (in the hundred ppb range) in compressed medical air in critically ill patients,16 Hess tested the intriguing hypothesis that the observed very low level contamination of anaesthetic gases by nitric oxide (<5 ppb) also influences oxygenation in patients undergoing general anaesthesia for cardiac surgery. In a predominantly female patient population, they found that ventilation with nitrous oxide not only shared a similar inspired nitric oxide fraction with compressed medical air but these protocols were associated with a higher oxygenation index, and lower levels of alveolo-arterial difference of oxygen partial pressure and venous admixture when compared with ventilation with synthetic medical air containing less nitric oxide. In contrast, mixed venous and pulmonary haemodynamics were similar in these three conditions. Thus, the authors concluded that very low concentrations of nitric oxide contamination increases arterial oxygen partial pressure by an effect on the lung microcirculation involving ventilationperfusion matching.
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To lessen this overall enthusiasm, we should also recognize the limitations of the study. Some of these include the relatively small sample size and heterogenous patient population with variable pulmonary haemodynamics. Furthermore, one of the strongest criticisms may be the observed small magnitude of the oxygenation effects. It is highly unlikely that the difference in arterial of 17.5 vs 14.9 kPa with and without nitrous oxide would concern any clinician In this regard, we should remember the teachings of the Hungarian physicist and biophysicist Leo Szilard, who commented on his 1939 Columbia University experiment that confirmed atoms could be split, making possible the use of atomic power: A scientist's aim in a discussion, with his colleagues is not to persuade, but to clarify.18 Moreover, it is interesting to note the individual variability in the oxygenation responses to the different ventilation protocols. It appears that some patient's oxygenation improved by nearly 10 kPa when ventilated with a nitric oxide-containing gas mixture. This effect may even be greater in other patient populations, particularly those exhibiting lung disease and high intrapulmonary shunts. In contrast, as there is a non-responder population to inhaled nitric oxide therapy in the ppm range, it is likely that a significant fraction of patients will also be resistant to low ppb concentrations of nitric oxide contamination during anaesthesia. Further studies are required to explore these areas.
However, before we fully accept the fascinating concept presented by the authors, further assurances are needed so that the theory does not present as a farce. There is currently no proof that the observed responses are a result of nitric oxide-related contamination itself. One might argue that the improved oxygenation is a result of nitrous oxide-related vasoconstrictor effects potentiating hypoxic pulmonary vasoconstriction in relatively less ventilated lung regions during anaesthesia. Alternatively, compressed medical air might contain vasodilators other than nitric oxide. For instance, ambient air may contain variable but considerable ppm concentrations of carbon monoxide, a substance that appears to mimic many effects of nitric oxide. The best way to demonstrate that the effects are truly a result of nitric oxide contamination would be through using nitric oxide scrubs after a biological change is established with the contaminated gas. In addition, more detailed physiological assessment should be made to elucidate the exact mechanisms of improved oxygenation by the gas mixtures with nitric oxide contamination.
The authors also appear to suggest a relationship between inhaled and exhaled concentrations of nitric oxide. In their experience, 726% of inspired nitric oxide was represented in the expired air. Surely, this is an overly simplistic view of consumption, uptake, and binding to haemoglobin of inhaled nitric oxide, and of intrapulmonary generation, partition, diffusion, and exhalation of endogenous nitric oxide. In particular, the capacity of the human lung to take up nitric oxide is much higher than suggested in this paper. Kharitonov and colleagues demonstrated that inhalation of 800 ppb nitric oxide did not change exhaled nitric oxide after 15 seconds of breath-holding in two healthy subjects, suggesting that inspired nitric oxide must disappear from the respiratory tract within 15 seconds.19 We have also presented data in the British Journal of Anaesthesia regarding characteristics of endogenous nitric oxide during breath-holding and mechanical ventilation.20 Thirty seconds of breath-holding alone produced nitric oxide accumulation in the airways in the 50100 ppb range. The nitric oxide profile of the first exhalation, however, was not different from prior breath-holding suggesting that autoinhalation of these concentrations of endogenous nitric oxide is complete in a single inhalation and does not significantly contribute to exhaled nitric oxide in intubated and ventilated patients.20
Moreover, the overall message of the paper by Hess and others1 resonates well with evolving current concepts regarding the biological aerocrine roles of endogenously produced nitric oxide in the airways. The core tenet of this idea is that among other cell types, the nasal and bronchial epithelium continuously produce relatively large amounts of nitric oxide, which is released to the gas phase and delivered to the alveoli and pulmonary microcirculation by each breath.21 Advocates of this theory reason that, as with the results of Hess and colleagues,1 this airborne endogenous nitric oxide influences biological responses at the level of the microcirculation. This concept is attributed to Lundberg and co-workers who showed that nasally produced nitric oxide enhanced arterial oxygenation in intubated patients and healthy individuals, and decreased pulmonary vascular resistance during nasal breathing in patients following cardiac surgery.22 23
The aerocrine nitric oxide concept as a physiological correlate of inhaled nitric oxide therapy was taken further by Gustafsson and his colleagues. They showed that a number of important physiological processes regulate nitric oxide production and its release into the gas phase in the lower airways that might contribute to the differential bioavailability of nitric oxide and vascular tone in ventilated and hypoventilated lung units.2426 In particular, they suggest that optimal oxygen concentration and a variety of stretch mechanisms maximize nitric oxide availability in well ventilated regions, whereas tissue hypoxia, lack of tidal excursion, and hypercapnia may decrease nitric oxide in less ventilated areas.27 Thus, by explaining maximal nitric oxide-dependent vasodilation in ventilated regions as opposed to deficiency in local pulmonary nitric oxide production and possible enhancement of hypoxic pulmonary vasoconstriction in non-ventilated regions, Adding and Gustafsson have significantly advanced the aerocrine hypothesis and adapted the upper airway autoinhalation concept to the lower airways for nitric oxide-dependent regulation of ventilationperfusion matching.27
We have explored different aspects of this concept and adapted them for the acute setting of one lung ventilation. First, we have demonstrated that breath-holding results in accumulation of high concentrations of nitric oxide (and carbon monoxide, unpublished observations) in the main airways.15 20 We further suggested that despite the high concentrations in the main airways, alveolar concentrations remained low suggesting removal/uptake mechanisms in the alveoli. By investigating exhaled nitric oxide characteristics in rapidly changing pulmonary blood flow conditions, we have demonstrated that cessation of pulmonary blood flow at commencement of cardiopulmonary bypass increases exhaled nitric oxide in humans.15 28 We interpreted the data as direct evidence for the continuous delivery of aerocrine nitric oxide to the pulmonary microcirculation. The data, together with demonstrations that autoinhaled nitric oxide in the 1030 ppb range is physiologically active and that nitric oxide activates guanylate cyclase and produces vasodilation in lung tissue in the equivalent nanomolar range,27 lead us to believe that accumulation of endogenous nitric oxide may influence microvascular events in the non-dependent lung during the early (partial collapse) phase of one-lung anaesthesia. We speculate that under these conditions, alveolar collapse and hypoxic pulmonary vasoconstriction (HPV) occur with a considerable time delay. Similarly to breath-holding, nitric oxide (and carbon monoxide) accumulates during this period in the gas phase in the non-ventilated lung regions, providing 1050-fold nitric oxide (and carbon monoxide) concentration gradients in poorly ventilated areas over well ventilated areas. The delivery of accumulated nitric oxide to the pulmonary microvasculature during the early minutes of one-lung anaesthesia might oppose HPV and might play an important role in the development of ventilationperfusion mismatch, right to left pulmonary shunt and arterial hypoxaemia15 (Fig. 2).
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It seems appropriate to finish by another anonymous quotation: Every time history repeats itself the price goes up. Considering how expensive nitric oxide therapy has become, I would hope that this does not apply to contamination of nitrous oxide cylinders, compressed medical air, or to physician fees for inhaled nitric oxide therapy during one lung anaesthesia!
Declaration of interest
Dr Marczin is a salaried consultant to Inotherapeutics and serves on their Advisory Board.
References
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