1090 m MEDICAL INTELLIGENCE ARTICLE Dennis M. Fisher, M.D., Editor Anesthesiology 1999; 91:1090–121 © 1999 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Inhaled Nitric Oxide Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/91/4/1090/398065/0000542-199910000-00030.pdf by guest on 30 September 2021 Basic Biology and Clinical Applications Wolfgang Steudel, M.D.,* William E. Hurford, M.D.,† Warren M. Zapol, M.D.‡ A REMARKABLY exciting field of research has developed applicability of inhaled NO. In subgroups of severely ill since nitric oxide (NO) was identified in 1987 as a key and hypoxic children and adults, inhaled NO improves endothelium-derived relaxing factor (EDRF).1,2 The arterial oxygenation and selectively decreases pulmo- awarding of the 1998 Nobel prize in physiology or med- nary arterial hypertension (PAH). NO inhalation therapy, icine to three seminal researchers in the field of NO in combination with conventional6,7 or high-frequency biology provided the most recent evidence for the oscillatory ventilation,8 can reduce the need for extra- emerging prominence of this area of study.3 The under- corporeal membrane oxygenation (ECMO), an expen- standing of the roles of NO in the cardiovascular, im- sive and invasive procedure in newborn patients with mune, and nervous systems; the isolation and localiza- hypoxic respiratory failure.6,7 However, it remains un- tion of NO synthases (NOS); the manipulation of the certain whether NO inhalation improves survival rates in genes for NOS, including their cloning and selective adults or children with severe lung injury. transfer or knock-out; and the therapeutic use of inhaled New applications for NO inhalation have been discov- NO gas have revolutionized many fields of physiologic ered. Recent studies indicate that inhaled NO may de- research and are influencing clinical therapy. crease intestinal ischemia–reperfusion injury9 and may Many insights into the mechanisms of action of NO be useful to treat thrombotic disorders.10,11 By increas- have been gained. Since the reported applications of ing the oxygen affinity of sickle cell hemoglobin,12 in- inhaled NO in the laboratory4 and in adult patients with haled NO may prevent or treat sickle cell crisis. This primary pulmonary hypertension in 1991,5 hundreds of article reviews the relevant physiologic effects, thera- studies have been conducted to determine the clinical peutic uses, side-effects, and toxicity of NO inhalation. The first portion of this article concentrates on the chemistry, biochemistry, toxicology, and biology of NO; * Research Fellow in Anaesthesia and Critical Care. the second portion summarizes the results of NO inha- † Associate Professor of Anaesthesia; Director, Critical Care. lation studies to date in experimental settings and the ‡ Reginald Jenney Professor of Anaesthesia, Anesthetist-in-Chief. results of clinical studies in newborns, children, and adults. Received from the Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Mas- sachusetts. Submitted for publication June 9, 1998. Accepted for pub- Chemistry, Biochemistry, and Toxicology of lication May 4, 1999. Supported by grant no. HL-42397 from the United Nitric Oxide States Public Health Service, Bethesda, Maryland (Dr. Zapol and Dr. Nitric oxide is a colorless, almost odorless gas that is Hurford), and by grant no. STE 835/1-2 from the Deutsche Forschungs- 13 gemeinschaft, Bonn, Germany (German Research Association; Dr. Steu- slightly soluble in water (2 or 3 mM). Environmental del). The Massachusetts General Hospital has licensed a patent cover- NO arises from combustion processes (e.g., fossil fuel ing the use of nitric oxide inhalation to AGA Inc., Stockholm, Sweden, combustion and tobacco smoke) and lightning.14 Atmo- and the authors have rights to receive royalties. spheric concentrations of NO usually range between 10 Address reprint requests to Dr. Zapol: Department of Anesthesia and and 500 parts per billion (ppb), but can exceed 1.5 parts Critical Care, Massachusetts General Hospital, Harvard Medical School, per million (ppm) in areas of heavy traffic.15 Concentra- 32 Fruit Street, Boston, Massachusetts 02114. Address electronic mail to: [email protected] tions of NO produced in the hot cone of a glowing 16 Key words: Adult respiratory distress syndrome; lung; primary pul- cigarette can reach 1,000 ppm in a 40-ml puff. The monary hypertension of the newborn; pulmonary hypertension; re- Occupational Safety and Health Administration has set view. 8-h time-weighted average exposure limits in the work- Anesthesiology, V 91, No 4, Oct 1999 1091 NITRIC OXIDE INHALATION place at 25 ppm for NO breathing and at 5 ppm for tant molecules (e.g., lipids, proteins, DNA; for review 17 31,32 nitrogen dioxide (NO2). Commercially, NO is manufac- articles see Szabo et al. ). The cytotoxic effects of tured from the reaction of sulfur dioxide with nitric acid, 2OONO provide protective functions if they are di- from the reaction of sodium nitrite and sulfuric acid, or rected by inflammatory cells against invading microor- by the oxidation of ammonia over a platinum catalyst at ganisms or tumor cells. a high temperature (. 500°C).18 In an anaerobic envi- An important example of a reaction caused by 2OONO ronment (i.e., in highly purified nitrogen), NO can be is the nitration of tyrosine. Tyrosine nitration inhibits Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/91/4/1090/398065/0000542-199910000-00030.pdf by guest on 30 September 2021 stored for several years. tyrosine phosphorylation, alters the dynamics of assem- bly and disassembly of cytoskeletal proteins, and inhibits Reaction of Nitric Oxide with Oxygen tyrosine hydroxylase, thereby reducing dopamine pro- In the gaseous phase, NO reacts with molecular oxy- duction by neurons and inhibiting cytoskeletal move- gen to form NO2. The conversion rate of NO to NO2 can ments of endothelial cells.31 Nitrotyrosine has been de- be described by the relation tected in lung tissue sections from patients with lung injury,33,34 in atherosclerotic lesions,35,36 and in lungs 2 d@NO#/dt5k z @NO# z @O2#19,20 2 after ischemia–reperfusion injury.37 where k is the rate constant for conversion of NO to Exposure of surfactant to high concentrations of 2 38 NO2. The rate constant has been reported to be between OONO in vitro reduced its minimum surface tension. 0.79 3 1029 to 2.26 3 1029 z ppm22 z min21, dependent Peroxynitrite exposure impaired pulmonary surfactant on experimental conditions.19 Approximately half of a function, because of peroxidation of surfactant lipids, 10,000-ppm NO mixture in air is converted into NO2 and decreased the ability of the major hydrophilic sur- within 24 s, whereas 50% of a 10-ppm NO mixture in air factant, protein A, to aggregate lipids and act synergisti- 21 is converted into NO2 within7hat20°C. In aqueous cally with other surfactant proteins to reduce the mini- 39,40 solution, NO2 decomposes to give equal amounts of mum surface tension. These changes of surfactant 2 2 13 nitrite (NO2 ) and nitrate (NO3 ). protein A were associated with nitrotyrosine forma- 39 The pathologic effects of NO2 inhalation have been tion. A mixture of surfactant proteins B and C exposed studied in various animal species. High levels of inhaled to 2OONO was incapable of reducing phospholipid min- . 41 NO2 ( 10 ppm) induce pulmonary edema, alveolar imum surface tension during dynamic compression. hemorrhage, changes in the surface tension activities of Peroxynitrite can cause cell apoptosis by DNA strand surfactant, hyperplasia of type 2 alveolar epithelial cells, breakage, activation of poly-adenosine-diphosphate-ribo- intrapulmonary accumulation of fibrin, neutrophils, and syltransferase and by inhibition of mitochondrial respi- 22,23 31,32 macrophages, and death. Lower inhaled NO2 con- ratory enzymes. Peroxynitrite rapidly reacts with centrations (, 2 ppm) can alter surfactant function, carbon dioxide to form an adduct that participates in produce alveolar cell hyperplasia, and alter the epithe- nitration and oxidation reactions.42 Interestingly, in a 24 lium of the terminal bronchioles. Inhalation of 2 ppm model of thrombin or hydrogen peroxide (H2O2)–in- 25 NO2 in humans increases alveolar permeability and duced vascular injury of the rat mesenteric endothelium 26–28 airway reactivity. Inhalation of 0.5–1.5 ppm NO2 for and in an ischemia–reperfusion model of the rat heart, 9 weeks caused focal degeneration of pulmonary inter- infusion of 2OONO significantly reduced neutrophil ad- stitial cells, with mild emphysematous changes, in rats.29 hesion to the endothelium and expression of adhesion molecules, suggesting that 2OONO exerts inhibitory ef- Reaction of Nitric Oxide with Superoxide fects on neutrophil adhesion in inflammatory processes.43 2 2 Nitric oxide and superoxide (O2 ) readily react to In summary, OONO is more cytotoxic than NO in a form peroxynitrite (2OONO) at nearly a diffusion-lim- variety of experimental systems,32 and the balance of 13 2 2 2 2 ited rate. During physiologic conditions, O2 is scav- NO, O2 , and O2 – OONO scavenging systems deter- 2 2 enged by endogenous O2 scavengers (e.g., superoxide mines whether biologically relevant OONO concentra- dismutase) and formation of 2OONO is minimal. During tions will occur in tissues.30 pathologic conditions, such as in the presence of in- 2 2 creased concentrations of O2 or after O2 scavengers Reaction of Nitric Oxide with Heme Proteins and are exhausted, significant concentrations of 2OONO Metals may be produced.30 Peroxynitrite directly causes oxida- Nitric oxide binds to intracellular iron and heme-con- tion, peroxidation, and nitration of biologically impor- taining proteins. Examples of heme proteins that are Anesthesiology, V 91, No 4, Oct 1999 1092 STEUDEL ET AL. directly affected by NO are oxyhemoglobin, soluble Such localized release of NO permits vasodilation and guanylate cyclase (sGC), cyclooxygenase, and cyto- increased oxygen delivery to occur in tissues with re- 57 chrome p450.