Common indications for sodium bicarbonate administration \200 Severe inorganic metabolic acidosis, pH <7.1 and when the precipitating pathophysiology is unlikely to reverse spontaneously, e.g. renal failure or sudden ischaemia of a major organ. Forced alkaline diuresis. Patients who develop meta- bolic acidosis following salicylate o verdose can bene \201 t from accelerated renal salicylate excretion by promoting an alkali ne diuresis. Typically 1l of isotonic (1.26%) sodium bicarbonate is given in the \201 rst hour, followed by 500ml of 5% dextrose, 500ml of saline and 500ml of 1.26% sodium bicarbon ate at hourly intervals. Ef \201 cacy of alkalinization is monitored by measuring urine pH , and dosing is altered to achieve values \211 7 and relating this to the need by observin g the fall in blood salicylate. Organic metabolic acidosis associated with hypopefu- sion w hether cardiogenic or hypovolaemic (blood loss or sepsis) in origin should be corrected wit h speci \201 c resuscitative measures prior to consideration of bicar- bonate. Diabetic ke toacidosis usually does not need bicarbonate unless pH is <7.0. Management of hyperkalaemia or tricyclic antide- pressant overdosage in the context of cardiac arrest. Sodium bicarbon ate helps reduce the sensation of dysp- neoa and restores plasma [H+] towards concentration s at which enzyme activity is usually most ef \201 cient. Sodium bicarbonate preparations Sodium bicarbonate can be given as an oral preparation; thi s is common for patients with chronic acidotic states such as chronic renal failure or rena l tubular acidosis. It is available as a 600mg tablet providing 7mmol Na and bicarbonate, or 500mg capsules providing 6mmol. Daily dosage depends on the degree of acidosis. IV solut ions are commonly available as the iso-osmolar \200\223 /l) or the 1.26% (150mmol Na+ and 150mmol HCO3 hyperosmolar 8.4% preparation (1000mmol Na+ and \200\223 /l or 1mmol/ml. The latter is corrosive to veins and HCO3 should be administered through a central line. Isoton ic bicarbonate is a convenient solution for restoring buffer base when hypovolaemia is sign i \201 cant. Sodium bicarbonate in dialysate \202 uids Bicarbonate-containing dialysate \202 uids ha ve now replaced acetate for intermittent dialysis. Acetate, together with lactate and citra te, are buffers which with a normal functioning liver are converted to bicarbonate. However , acetate dialysate proved to be problematic with respect to haemodynamic stability and bio compatibility. Lactate, hitherto the most common buffer for continuous dialysis systems, ha s been replaced by bicarbonate solutions. This is primarily because hyperlactataemia which is commonly observed with lactate dialysate confuses management even though there is effect ive buffering of acids. However, in those with hepatic dysfunction, it is not metabolized t o bicarbonate suf \201 ciently to be an effective buffer. Buffers are needed in dialysis f luid to deal with the 100mmol of \201 xed acid protons generated by metabolism each day b y normal adults. Kidney failure results in pro- gressive depletion of buffers because proto ns are instanta- neously buffered. Consequently, proton concentrations are extremely low an d are not effectively removed by dialysis. However, to avoid development of acidosis, buffe rs need repletion. Modern bicarbonate dialysate solutions contain between 30 and 40mmol/l, and not 25mmol/l as might be expected. This is in order that bicarbonate not only moves ef \201 ciently down a concentration gradient but also replen- ishes buffer de \201 cit. If lower concentrations were used, the plasma bicarbonate concentration 25mmol/l would be achi eved slowly. This would be a problem with the time Potential and theoretical dangers of sodium bicarbonate administration \200 Hypokalaemia through acid \200\223base changes and precipita- tion of dysrhythmias. Sodium load/hyperosmolar load. Overtreatment decreases ionized calcium, causing impaired myocardia l contractility and possible dysrhyth- mias and hypotension. Leftward shift oxygen dissocia tion and decreased tissue oxygen release. Intracellular acidosis due to dissolved CO2 movin g across the cellular membrane (relatively impermeable to bicarbonate anion) potentially im pairing myocardial con- tractility. The effect of bicarbonate administration on haemodynami c function has been debated vigorously. The evidence would suggest no detrimental effect on haemodynamics if given at a rate which does not rapidly change ionized calcium. Doses of 1 00mmol over 40 min appear to be clinically safe. Hypercarbia in ventilated patients if vent ilation is not temporarily increased during administration. \200 Quanti \201 cation of dosage Various formulations for correcting base de \201 cit have be en proposed. The bicarbonate concentration in extracellular \202 uid is twice that in int racellular \202 uid. Replacement in the \201 rst instance should match the extracellula r base de \201 cit. This is calcaulated on the basis that extracellular \202 uid is 20% body weight. 148 M PALAZZO limits imposed by intermittent dialysis or prove to be less effective with the slower \202 ow of continuous dialysis tech- niques. It is notable that dialysis often leaves patie nt very slightly alkalotic. It should also be noted that convection during haemo \201 ltra - tion removes buffer base; therefore, the replacement buffer solutions have to not only re place the corrected buffer removed but also provide additional buffer to replenish the orig inal buffer de \201 cit more rapidly. Cooper DJ, Walley KR, Wiggs BR, et al. Bicarbonate does not improve hemodynamics in critica lly ill patients who have lactic acidosis. A prospective, controlled clinical study. Ann In tern Med 1990; 112: 492 \200\2238. Kaehny WD, Anderson RJ. Bicarbonate therapy of metabolic acido- sis. Crit Care Med 1994; 22: 1525 \200\2237. Kellum JA. Determinants of blood pH in health and disease. Crit Care 2000; 4: 6 \200\22314. Mathieu D, Neviere R, Billard V, et al. Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical stu dy. Crit Care Med 1991; 19: 1352 \200\2236. Further reading Bersin RM, Chatterjee K, Arieff AI. Metabolic and hemodynamic consequences of sodium bicarbonate administration in patients with heart disease. Am J Med 1989; 87: 7 \200\22314. Stewart PA. Modern quantitative acid \200\223base chemistry. Can J Physiol Pharmacol 1983; 61: 1444 \200\22361. This page intentionally left blank 150 D THOMAS Blood Whole blood transfusion is rare, and usually blood compo- nents are given, targeted to the speci \201 c requirements of patients. The recognition of virally transmitted infection, t he apparent detrimental effect of transfusion of stored blood and supply problems have led to a far more objec- tive use of blood products. 1 Red blood cells are usually recommended when there is a percived need to correct hemoglobin/oxygen delivery. 2 Component use should be limited to correction of known de \201 ciencies as highlighted by either laboratory or near patient testing. patient testing results. As a general rule, a Hb level of 7 \200\2239g/ dl would be deemed adequate in all stable ICU patients. Patients with severe chronic cardiorespratory disease may bene \201 t from a haematocrit of between 28 and 33%, equiva- lent to a Hb of between 9 and 10g/dl. In younger patients without cardiorespiratory disease, a level of 70g/l would be suf \201 cient. Platelet count In bleeding patients, maintain platelets at 75 x 109/l, while in brain injur y of traumatic of haemorrhagic origin this will need to be 100 x 109/l. In stable non-bleed ing ICU patients, 10 x 109/l would seem to be an adequate level, unless some invasive proce dure is planned which may then trigger the need for platelet trans- fusion. 3 In an unstable patient with suspected massive haemor- rhage, clinical assessment and empi rical transfusion therapy is justi \201 ed, but a process of repeated coagula- tion testin g needs to be used to con \201 rm diagnosis and guide further treatment. 4 In the long-stay ICU patient, strategies to minimize trans- fusion should be employed. Bl ood sampling can be mini- mized and will decrease the volume of blood discarded. Iron suppl ements, oral or IV (non-septic patient), and potentially the use of recombinant erythropoie tin can reduce transfusion need. Folate and iron de \201 ciency Folate replacement has become routine on most ICUs, whereas there is an increasing trend to test iron status in long-stay patients. The interpretation of such tests is fraught with dif \201 culty in such patients as ferritin is an acute pha se protein. The use of oral and IV iron supplementation and the use of recombinant erythrop oietin can be consid- ered. Current practice Red blood cells Transfusion should be decided on an individual basis takin g into consideration the stability of the patient, co-morbidi- ties and age, as well as cur rent physiological status. The study by Herbert suggested withholding transfusion in sta- b le patients, resulted in a better outcome, although this was with non-leucoreduced blood. A ll blood in the UK now undergoes a 4-log reduction in white cells (99.99% white blood cells (WBCs) removed) before storage. There are two categories of ICU patient: stable and unstab le. Unstable patients who have overt or covert hemorrhage need to be aggressively resuscita ted. Massively bleeding patients can bleed to death, and prompt resuscitation and transfusi on can save life. Uncontrolled bleeding usually needs surgical correction or at least local control, i.e. simple pressure. Resuscitation is targeted at maintaining an adequate circul ating volume, but with lower blood pressure than normal. This prevents dislodging clots on bleeding, severed vessels after vasos- pasm, and platelet plugging. Overenthusiastic resusc itation will promote bleeding, increase the size of haematoma, increase the need for more \202 uid and blood components, and eventually lead to dilutional coagulation problems in a ddition to the coagulopathy caused by the initial hemorrhage. Coagulation tests may alter u nexpectedly in such dynamic situations, with non-linear changes in test results. Platelet c ounts may decline rapidly, for example, therefore early and anticipated transfusion of plat elets and FFP is made on an empirical clinical basis. Caution is also needed in withholding red cell transfusion in those patients who have suffered obvious severe trauma and who may be hypovolaemic but still have misleading normal or high hemoglobin values. Stable non-acu te patients do not justify empirical transfusion therapy, and transfusion may be minimized using laboratory or near Laboratory testing for coagulopathy FBC and platelet count The Coulter counter measures pla telet counts and corpus- cular size, which may hint at other de \201 ciencies leading to a bnormal red cell shape. This is a count, and provides no information about red cell or plat elet function. Near patient testing is extremely useful in dynamic unsta- ble situations, b ut such machines need similar quality con- trol and maintenance to the laboratory machines in use. Spurious results are dangerous, but may occur if sampling procedures have not been followed accurately, e.g. the testing of dilute samples giving falsely low readings, etc. Tests of coagulation A problem in assessing coagulation abnormalities is the non-speci \201 c nature of the tests and the time to obtain results in clinical practice. Most decisi ons will need to be made on the more basic available tests conducted by your coagulation an d hematology laboratory, these include: \200 Prothrombin time (PT). A normal result would be 10 \200\22314s and is a measure of extrinsi c and common coagulation pathways. Factor VII and factors common to both path- ways are eva luated. The test is conducted by adding tis- sue thromboplastin and calcium ions to plasma. Activated partial thromboplastin time (aPTT). A time of 30 \200\22340s would be considered normal. It is a measure of the intrinsic pathway. The test involves adding Kaolin, a surfa ce activator, phospholipids and calcium ions to plasma. Failure to correct both PT and aPTT with nor- mal plasma when tested in the laboratory would indi- cate the presence of inhibi tors, e.g. heparinoids or \201 brinogen degradation products (FDPs). Thrombin time. If pr olonged, normal being 10 \200\22312s, \201 bri- nolyis due to reduced \201 brinogen (wh ich may also be measured and needs to be >1g/dl) is suspected. Thrombin time is assayed by adding thrombin to plasma and observing the time to \201 brin formation 151 CHAPTER 9.4 Blood Treatment If these tests are abnormal for the patient tested, correc- tion towards a normal value can be obtained by treating with normal plasma usually provided in the form of thawe d FFP. It is recommended that thawed plasma can be kept at 4 C for 24h, and so should alwa ys be immediately available in large hospitals with a busy laboratory. Otherwise it can be thawed within 20 \200\22330min from frozen in a water bath. A low \201 brinogen is treate d with reconstituted cryoprecipi- tate providing no more FFP is indicated, as 3 packs of FF P contains similar amounts of \201 brinogen to 10 packs of cryo- precipitate. FFP Provided as packs of 300ml of plasma produced by cen- trifugation of whole blood from a previously tested donor and frozen to achieve factor VIII concentration of >0.7IU/ ml. Thr ee packs of FFP will provide 1.5 \200\2233.0g of \201 brinogen (VIIa needs \201 brinoge n to work). Usually given as a 4-pack dose Cost: $400 per 4-pack dose Cryoprecipitate This is provided as 20-40ml of cryoprecipitate rich in factor VIII, von Wil lebrand factor, factor XIII, \201 bronectin and \201 brinogen. Packs contain at least 1 50 \200\223300mg of \201 brinogen and 70IU of factor VIII. Thromboelastogram (TEG) Not all ICUs will have access to a TEG machine, but many hospitals with a cardiovascular or liver transplant unit or a vascular surgical unit may well be usin g such machines routinely. The information obtained from such machines is displayed graphic ally and can give useful information detecting subtle changes between coagulation \201 br inolysis and related hae- mostatic parameters. Cost of one unit 33 and of a 10-unit dose 330. Further reading BCSH. Guidelines for the use of fresh frozen plasma, cryoprecipi- tate and cryosupernatant. 2003. BCSH. Guidelines for the use of platelet transfusions. 2003. BCSH. Guidelines on the manage ment of massive blood loss. 2006. www.bcshguidelines.co.uk Blood Transfusion and the Anesthetist. Red cell transfusion 2001. Blood components commonly available in the UK Red blood cells All red blood cell concentrat es supplied are leucoreduced with 99.99% of the leucocytes removed before storage (4-log re duction). The concentrated red cells are resus- pended in 50 \200\22380ml of saline adenine glucose with mannitol (SAG-M), with a resultant haematocrit of 0.5 \200\2230.7. They are s tored for up to 35 days at 4 C. www.aagbi.org.uk Blood Transfusion and the Anesthetist. Blood component therapy. 2005. www.aagbi.org.uk Corwin HL. Erythropoietin and transfusions among critically ill patients. JAMA 2003; 289: 1512. Hebert PC, Wells G, Blajchman MA, et al. A multicenter rand- omized controlled trial of tra nsfusion requirements in critical care. N Engl J Med 1999; 340: 409 \200\22317. Cost: 135 per bag Platelets These are administered in adult bag equivalents. Each adult therapeutic bag can be expected to raise the platelet count by 20 x 109/l. Cost: 200 per adult dose This page intentionally left blank 153 Chapter 10 Respiratory drugs Chapter contents Bronchodilators 154 Nitric oxide 156 Mucolytics 158 Surfactant 160 Helium \200\223oxygen ga s mixtures 162 154 D LAU Bronchodilators Bronchodilators, as the name suggests, are used in airways disease, particularly in asthma and COPD, to produce a reversal of airway obstruction. An overview of the three main catego ries is provided here: b2 Agonists B2 agonists give the greatest bronchodilation amongst th e bronchodilators in asthma. They are classi \201 ed by length of action: \200 Long-acting 2 agonists (LABAs) were developed later and marked an important milestone in asthma management. The bronchodilator effect lasts >12h. This is particularly important in addressing nocturnal asthma symptoms. LABAs are considered in Step 3 of the BTS/ SIGN chron ic asthma guidelines. Formoterol is a full ago- nist compared with salmeterol, and so has a more rapid onset of action. This may make formoterol suitable for symptom relief, as well as symptom prevention in combi- nation with an inhaled corticosteroid. LABAs have been show n to improve asthma symptoms and the need for additional bronchodilator therapy, peak expir atory \202 ow and asthma-speci \201 c measures of quality of life. short \200\223intermediate acting, e.g. salbutamol, terbutaline, fenoterol long-acting, e.g . formoterol, salmeterol. Mode of action B2 Agonists directly stimulate the B2-adrenergic receptor which is found in virtually all types of cells. The receptor is subclassi \201 ed as B1, B2 and B3. Although both B1 and B2 receptors are found in the lungs, bronchodilatory effects are predominantly a function of the B2 receptor. The receptor consists of a protein folded across the plasma membrane, and is linked to the stimulatory guanine nucleotide-binding protein (Gs). Occupa tion of the receptor activates the enzyme adenylate cyclase via the Gs protein, and this co n- verts ATP to cAMP, which is responsible for the physiological response, in this case, re laxation of airway smooth muscle. In addition, B2 agonists have non-direct bronchodilator a ctions which may contribute to their therapeutic function: \200 \200 \200 Side effects These are due to pharmacological actions on extrapulmo- nary B2 receptors. Sid e effects are uncommon with inhala- tion therapy, and more signi \201 cant in oral or IV t herapy. \200 Muscle tremor \200\224direct stimulation of skeletal muscle B2 receptors Tachycardia \200 \224direct effect on heart B2 receptors, and re \202 ex response to peripheral vasodilatat ion Metabolic \200\224hypokalaemia, hypomagnesaemia, hypergly- caemia Transient decrease in PaO2 \200\224increase of ventilation \200\223 perfusion mismatch by relaxation of compensa tory vasoconstriction in underventilated areas of lung Tolerance/subsensitivity/desensitiza tion \200\224occurs with regular use of B2 agonists and is clearly demon- strated for the n on-bronchodilatory responses (tremor, tachycardia and metabolic effects). The mechanism is thought to be due to uncoupling, internalization and/or downregulation of B2 receptors. Tol erance is not progressive and has not shown to be of clinical importance. enhancement of mucociliary clearance inhibition of cholinergic neurotransmission inhibiting the release of bronchoconstrictor mediators (e.g. leukotrienes, histamine, prostaglandins) from in \202 am- matory cells (e.g. mast cells) reducing microvascular leakage. There is no evidence however that B2 agonists have a sig- ni \201 cant inhibitory effect o n chronic in \202 ammation in asthma, hence they must not be used as alternative to inhale d ster- oids as anti-in \202 ammatory therapy. Anticholinergic agents Anticholinergics are one of the mainstays of treatment in COPD; they are also useful in the treatment of acute asthma exacerbation by nebulization, but are les s effective than B2 agonists. Mode of action Anticholinergics are antagonists of muscarinic receptors and inhibit cholinergic nerve re \202 exes which give airway smooth muscle its tone. As the airways in COPD are struc- turally narrowed, the bronchodilator effects of ant icholin- ergics are more signi \201 cantly marked compared with normal airways. Therapeutic use B2 agonists are most commonly administered via the inha- lation route; othe r routes include IV, subcutaneous (SC) and oral. B2 agonists may be inhaled in nebulized fo rm, or as metered-dose inhalation (MDI) in the form of propel- lant-generated aerosol or as a breath-propelled dry pow- der (e.g. \200\230turbohaler \200\231, \200\230accuhaler \200\231). Using the MDI optimally, 12% of the drug is delivered to the respiratory airway s; the remainder is deposited in the mouth, pharynx and lar- ynx. Nebulized doses need to b e 6 \200\22310 times that used in MDIs to produce the same level of bronchodilation. \200 Short-acting 2 agonists act rapidly and their duration of action lasts 3 \200\2234h. In a cute asthma, they are the bron- chodilators of choice. In this setting, it is common prac- tice to use nebulized B2 agonists, although studies have shown that supervised administrati on of B2 agonists by MDI with a spacer device in the emergency setting appears to be as eff ective as nebulizers in both adults and children. Short-acting B2 agonists are also useful in prevention of exercise-induced asthma, or other triggers including cold air and allergen s. In mild or stable asthma, short-acting B2 agonists should be used as required by symptom s, and not on a regular basis. Increased usage signals the need for step-up of anti-in \202 ammatory therapy. Therapeutic use Anticholinergics are most commonly administered in MDI. Short-acting agents (e.g. ipratropium bromide) have a max- imum effect 30 \200\22360min after use, and last fr om 4 to 6h, hence they are prescribed 4 times daily. The newer long- acting anticholinergic a (e.g. tiotropium) last up to 24h, and hence are used once a day. They have been shown to improve patient symptoms and spirometric parameters, and to reduce theexacerbation rate in COPD. Side effects Inhaled anticholinergics are minimally absorbed, so have relatively few side e ffects. Nebulized anticholinergics may rarely precipitate glaucoma in elderly patients by a direct effect on the eyes, hence a mouthpiece should be used as 155 CHAPTER 10.1 Bronchodilators an alternative to a mask. Other potential effects include dry mouth, blurred vision and uri nary retention. Theophylline can also be useful in stable COPD as an addi- tional bronchodilator, improving dyspnoea and reducing hyperin \202 ation. The drug is usually given in 2 divided doses at 12h intervals. In acute asthma, evidence for the ef \201 cacy of IV theophylline is con \202 icting; hence it should only be considered for patients with severe acute symptoms unr e- sponsive to other measures. Similarly, the bene \201 ts of add- ing theophylline in acu te exacerbation of COPD remain unclear, with a few randomized controlled trials showing no bene \201 t but with increased adverse effects. Doses giving peak serum concentrations bet ween 10 and 20mcg/ml are most effective in symptom prevention and reducing the need for res cue therapy in chronic asthma. Theophylline is predominantly eliminated by hepatic cyto- ch rome P450 isoenzymes. Many factors affect plasma clear- ance and hence plasma concentration : \200 Theophyllines Theophylline has been used in asthma treatment for >60yrs; it has seen its ro le change gradually with develop- ments in other classes of bronchodilators and anti-in \202 am- matory agents. Further developments included slow-release formulations which count ered the rapid absorption and elimination of theophylline, and rapid assays which made ther apeutic drug monitoring readily possible. Mode of action Although theophylline has traditionally been classi \201 ed as a bronchodil ator, its therapeutic effect in controlling asthma has always been disproportionately great er than is explained by its relatively small degree of bronchodilator ability. There is rec ognition that theophylline has, in addi- tion, anti-in \202 ammatory, immunomodulatory and broncho- protective effects that may contribute to its ef \201 cacy as preventive treatme nt for chronic asthma: \200 Increased plasma clearance \200\224enzyme induction by drugs (e/g. rifamipicin, antiepilept ics); cigarette and marijuana smoking, even passive; high-protein, low carbohydrate diet; i n children Decreased plasma clearance \200\224enzyme inhibition (e.g. ciprofloxacin, macrol ides, methotrexate, allopurinol, cimetidine, alcohol); liver disease; cardiac decompensa- t ion; septic shock; prolonged pyrexia; in the elderly. downregulation of the function of immune and in \202 am- matory cells (e.g. T lymphocytes, macrophages, mast cells) decrease of fatigue in diaphragmatic muscles decrease of airway m icrovascular leakage increasing mucociliary clearance central action to block decrease in v entilation which occurs with sustained hypoxia. \200 \200 \200 Side effects Ef \201 cacy and toxicity of theophylline are closely associated with serum d rug concentration. Side effects include nausea and vomiting, diarrhea, headaches, irritabil ity and insom- nia. Even higher serum concentrations can cause seizures, toxic encephalopat hy, hyperthermia, cardiac arrhythmias and death. These \201 ndings suggest, but do not establish, its non-bron- chodilator ef \201 cacy, and some of these actions give a ration- ale for added therapy in acute asthma unresponsive to B2 agonists and systemic steroids, as well as its use in stable COPD. On a molecular le vel, two modes of action are known to occur at clinically relevant drug concentrations: \200 Further reading Barnes PJ. Drugs for airway diseases. Medicine 1999; 27: 37 \200\22345. Bar nes PJ. Asthma and COPD: basic mechanisms and clinical man- agement. Academic Press, 2002. Inhibition of phosphodiesterases \200\224intracellular cAMP, essential for relaxation of ai rway smooth muscle, is hydrolysed by phosphodiesterase. Thus its inhibition by theophylline increases cAMP concentration, leading to bronchodilation. Anti-in \202 ammatory effects m ay be due to action on the isoenzyme via cAMP in in \202 ammatory cells. Antagonism of ade nosine receptors \200\224this appears to be the mechanism by which theophylline stimulates ventila- tion in hypoxia, decreases fatigue in diaphragmatic mus- cles and inhibits release of certain mediators from mast cells. British Guideline to the Management of Asthma Update. BTS/SIGN 2007. http://www.brit-thoracic.org.uk. COPD guidelines. National Institute of Clinical Excellence (NICE) 2004. http://www.nice.org.uk. Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) 2 007. http://www.ginasthma. org. Nelson HS. Beta-adrenergic bronchodilators. N Engl J Med 1995; 333: 499 \200\223506. O \200\231Byrne P, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medica- tion in asthma. Am J Respir Crit Care Med 2005; 17 1: 129 \200\22336. Turner MO, Patel A, Ginsburg S, et al. Bronchodilator delivery in acute air \202 ow obstru ction. A meta-analysis. Arch Intern Med 1997; 157: 1736 \200\22344. Therapeutic use Theophylline is considered in Step 4 of the BTS/SIGN chronic asthma treatme nt guidelines, if asthma is still uncontrolled with inhaled corticosteroids and LABAs. Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996; 334: 1380 \200\2238. 156 A BRAME & M GRIFFITHS Nitric oxide History Nitric oxide (NO) was identi \201 ed as an endogenous vasodi- lator (endothelial-d erived relaxing factor) in 1987. It is now known to be a mediator of intracellular signalin g and numer- ous physiological functions, including: neurotransmission, inhibition of plate let and leucocyte adhesion, gastrointestinal motility and host defense. The physiological r ole of endog- enous NO was \201 rst demonstrated in healthy volunteers by evaluating the systemic and pulmonary pressor response to an infusion of an unselective inhibitor of NO sy nthase (NOS). It is a colorless, odorless gas, which is relatively insoluble in water. Envi ronmental NO arises from fossil fuel combustion, cigarette smoke and lightning. Atmospheric concentrations usually range between 10 and 500 parts per billion (ppb), but can be higher in heavy traf \201 c. augments hypoxic pulmonary vasoconstriction by selec- tively vasodilating vessels associate d with ventilated alveoli; because the gas is delivered by inhalation the blood supply to u nventilated lung units is unaffected. iNO improves indexes of oxygenation in 2/3 of patien ts with ALI; how- ever, there is no evidence from multiple randomized placebo-controlled tr ials that NO improves mortality or shortens the duration of mechanical ventilation. Therefo re, the role of iNO is as a rescue treatment in cases where oxygenation is dangerously low despite optimal ventilation. Right ventricular failure The right ventricle is exquisitely sensitive to increased afterlo ad. Therefore, iNO can markedly improve RV func- tion, cardiac output and oxygen delivery b y reducing pul- monary vascular resistance. The advantages of iNO over other vasodilators a re that oxygenation tends to be improved and systemic pressures are maintained. However, in patients with left heart failure, iNO may increase pulmo- nary blood \202 ow and left at rial pressure, causing an exacer- bation of pulmonary oedema. Despite a lack of evidence fr om randomized trials, iNO is most commonly used in this context to support patients after c ardiac surgery. There are also reports of haemodynamic bene \201 t in cases of acute massi ve PE. Biochemistry NO is synthesized from L-arginine by NOS. There are three isoforms: one is ind ucible (NOS II), and two are con- stitutively expressed, neuronal (NOS I) and endothelial ( NOS III). The inducible form NOS II is expressed in response to various stimuli, including proin \202 ammatory cytokines. Relatively large quantities of NO are produced continuously by inducible NOS II in blood vessel walls dur- ing an in \202 ammatory response, suggesti ng that this pathway contributes to the vasculopathy of sepsis. Under physiolog- ical condi tions, NO is produced in a highly regulated man- ner by NOS III, and controls local vascula r tone by diffusing from the vascular endothelium to act on smooth muscle cells. NO has a h igh af \201 nity for iron \200\223sulfur groups and haem, which accounts for its very shor t half-life in blood. In combination with oxyhaemoglobin, NO forms methaemo- globin and nit rate. Nitrate is excreted in urine, whilst most of the methaemoglobin is reduced to ferrous hemoglobin. NO also reacts very rapidly with superoxide species to produce peroxynitrite a nions, which may form highly reac- tive and toxic hydroxyl radicals. These so-called reacti ve nitrogen species are bene \201 cial when used by leucocytes to kill microbes, but can a lso cause local tissue damage. NOS inhibitors were proposed as adjuncts to cardiovascular s upport in patients with septic shock. Despite reports of suc- cessful cases, larger trials demonstrated increased mortality in patients with sepsis associated with the use of non-sel ec- tive NOS inhibitors, and these agents are not currently used. Neonatal hypoxic respiratory failure In hypoxaemic infants born after 35 weeks of gestation , iNO reduces the need for ECMO, but mortality is not reduced. Oxygenation improves in 50% of infants. Whether infants have evidence of persistent pulmonary hypertension of the newb orn (PPHN) does not affect out- come. Administration of iNO NO is most commonly administered to mechanically venti- lated patient s through an ETT, although it may also be given through a face mask or nasal cannulae. Inte rmittent \202 ow, co-incident with inspiration, reduces the production of nitrogen dioxid e by minimizing the mixing time of oxygen and NO. iNO should be administered at the lowest effec- tive dose for the shortest possible time because the toxic effects of iNO are largel y unknown, the physiological ben- e \201 t of continuous inhalation lasts no longer than 4 8h and it is very expensive. Dose \200\223response studies in patients with ARDS have demon strated that over 1 day of continuous inhalation the pulmonary vasculature becomes 10 times more sensitive to its effects. Before starting iNO, all other appropriate strategies to op timize pulmonary vascular resistance or oxygenation should have been deployed. The means of assessing effectiveness, PaO2:FiO2 ratio or car- diac output monitoring should also be ava ilable before iNO is administered. Reasonable starting doses are 5 and 10ppm to modify oxyg enation and pulmonary haemody- namics, respectively. Gradual up-titration every 30min to 20 ppm should be tried before concluding that there is no physiological response. Daily dose t itration against the rel- evant physiological parameter should be performed with the expect ation of a 10-fold decrease in dose each day and withdrawal after 48h or sooner if there is no longer physi- ological bene \201 t. If iNO has been administered for >12h, acute rebou nd pulmonary hypertension may develop on withdrawal, particularly in children. Incremental withdrawal with close haemodynamic monitoring is advised. Clinical use of inhaled nitric oxide (iNO) NO donors, including sodium nitroprusside and ni trates, have an established role in treating patients with hyperten- sive crises, angina an d acute heart failure. The objectives of using iNO are: reducing pulmonary vascular resista nce, reducing ventilation \200\223perfusion mismatch or replacing cir- culating NO stores. Endogenous NO activity is decreased after lung transplantation and in patients with sickle cell disease. iNO has been used effectively to support patients with ALI after lung transpl antation. However, despite encouraging initial reports, its prophylactic use is of no bene \201 t. High dose iNO may be bene \201 cial in treating sickle crises, but has not been a ssessed in a randomized trial. The most common clinical scenarios in which iNO is used are: Acute lung injury (ALI) Severe hypoxaemia caused by extensive ventilation \200\223 perfusio n mismatching is characteristic of ALI. iNO 157 CHAPTER 10.2 Nitric oxide Adverse effects of iNO Most of the adverse effects of iNO can be predicted from the physiol ogical effects and biochemical reactions of NO. There is a negligible risk of methaemoglobi naemia in adults receiving up to 40ppm iNO, although administration is contraindicated by m ethaemoglobin reductase de \201 ciency. Potentially damaging reactive nitrogen species are formed in patients with sepsis and ALI, but the contribution of iNO to any pathological ef fects of these radicals is unknown. The effects of NO inhalation on bleeding time and other indexes of platelet function in healthy volunteers and patients are variable. However, the re is an increased risk of intraventricular hemorrhage in preterm infants. Further reading Adhikari NK, Burns KE, Friedrich JO, et al. Effect of nitric oxide on oxyge nation and mortality in acute lung injury: systematic review and meta-analysis. BMJ 2007; 3 34 7597: 779. Atz AM, Le \202 er AK, Fairbrother DL, et al. Sildena \201 l augments the effect of inhal ed nitric oxide for postoperative pulmonary hyper- tensive crises. J Thorac Cardiovasc Surg 2002; 124: 628 \200\2239. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near te rm. Cochrane Database Syst Rev 2006; (4): CD000399. Gerlach H, Keh D, Semmerow A, et al. Dose \200\223response characteris- tics during long-te rm inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, rand- omized, controlled study. Am J Respir Crit Care Med 2003; 167: 1008 \200\22315. Adjunctive therapies Phosphodiesterase (PDE) hydrolyses cGMP the secondary messenger of NO signaling in smooth muscle. Orally administered PDE5 inhibitors are selective pulmonary vas odilators, partially because PDE5 is highly expressed in the lung. For example, sildena \201 l augmented pulmonary vasodilation induced by iNO, although the route of admin- istrat ion of these agents removes their bene \201 cial effects on oxygenation, making them suita ble only for the treatment of pulmonary hypertension and right ventricular failure. Grif \201 ths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med 2005; 353: 2683 \200\22395. Meade MO, Granton JT, Matte-Martyn A, et al. A randomized trial of inhaled nitric oxide to prevent ischemia \200\223reperfusion injury after lung transplantation. Am J Respir Crit Ca re Med 2003; 167: 1483 \200\2239. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, patho- physiology, and pharmacolo gy. Pharmacol Rev 1991; 43: 109 \200\22342. Stamler JS, Loh E, Roddy MA, et al. Nitric oxid e regulates basal sys- temic and pulmonary vascular resistance in healthy humans. Circulati on 1994; 89: 2035 \200\22340. 158 S SINGH Mucolytics Introduction Mucolytic agents increase expectoration by reducing spu- tum viscosity or faci litating hypersecretion. Most of the drugs used as mucolytics have been developed to reduce mucus viscosity. This often helps relieve respiratory dif \201 - culties. The viscosity o f mucus secretions in the lungs is dependent upon the concentrations of mucoprotein, and th e presence of disul \201 de bonds between these macromol- ecules and DNA. Mucoactive drugs are de \201 ned as being able to modify mucus production, secretion, its nature and compo sition, and/or its interactions with the mucociliary epithelium. Mucolytic drugs are a type of mucoactive drug, but both terms are used interchangeably . Expectorants may be confused with mucolytics. Expectorants increase mucus production, without altera- tion of its chemi cal properties. Guaifenesin is a widely used expectorant in over-the-counter antitussive ag ents. It increases volume and thereby decreases viscosity of respi- ratory tract secretions . Bronchodilators given via the nebulized route improve expectoration through increasing ci liary beat frequency of the mucociliary escalator. Hypertonic saline increases expectoration when deliv- ered as an aerosol. It reduces mucus viscoelasticity but can induce bronchospasm. It is effective in cystic \201 brosis long t erm, but this has not been shown in COPD. Other agents such as saturated potassium iodide, in liq- uid form for several weeks, have been studied. However, the metallic taste, rashes and hyperkalaemia prevent its clinical use. Surfactant. A surfactant layer separates layers of mucus and periciliary \202 uid, so facilitating mucus spreading. It also acts to lubr icate the cilia. Several observations sug- gest a potential role for surfactant as a mucoac tive sub- stance, but further studies are required. Indications Inhaled acetylcysteine is indicated for mucolytic therapy as an adjuvant in res piratory conditions with excessive and/or thick mucus production. Such conditions include: COPD, bronchiectasis, cystic \201 brosis and pneumonia. It is also used post-operatively, as a diagnostic aid, and in tracheostomy care. Its use in other situations, such as burns- associated inhala- tional injury, is unclear. Due to its potential for bronchospasm when gi ven neb- ulized, it is often mixed with a bronchodilator. This has pre- vented accurate and robust assessment of its true value, as compared with the oral route.