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. Properties of mucus The mucus layer and a periciliary watery layer surround the respiratory airway cilia. Mucus consists of a mixture of transudate and secretions from surface epithe lial lining cells and submucosal glands of the conducting airways. It is mainly water (95%) with glycoproteins (2 \200\2233%), proteogly- cans (0.1 \200\2230.5%), lipids (0.3 \200 \2230.5%), proteins and DNA. The composition changes in disease states, with a reduction in the water component . Mucolytic therapy in speci \201 c clinical practice In COPD The volume of mucus secretion is 15ml/day. However, mucus secretion can increase 3-fold in COPD. A number of oral mucoly tics have been studied in the short term. The first reports of aerosolized mucolytics (NAC) in chronic bronchitis in 1968/9 suggested potential bene \201 ts. Carbocysteine can impro ve exacerbation rates and inter- val in COPD exacerbators. This has been corroborated in an elderly cohort . A Cochrane review (n = 6,415, 23 randomized controlled trials, duration 2 \200\22324 months) of 10 different oral mucolyt- ics in mild COPD showed a modest reductio n in exacerba- tions, with an number needed-to-treat of 6 to prevent 1 exacerbation . NAC u sed over at least 24 weeks can produce clinically relevant improvements in symptoms and exa cerbation rates, which extend to a year, without notable side effects. NICE recomends a tri al of oral mucolytics in chronic pro- ductive cough associated with COPD. Types of mucolytics Naturally occurring mucolytics include Mugwort, Bromelain, Papain and C lerodendrum. Pharmacological mucolytics include N-acetylcysteine (NAC), Carbocysteine (Muco dyne ), Mecysteine (Visiclair ), and Erdosteine (Erdotin ). These agents hydro- lyse gly cosaminoglycans \200\224they break down/lower the vis- cosity of mucin-containing body secr etions. They are also antioxidants through the thiol groups being able to reduce free radic als. NAC is the most widely studied mucolytic. It is a N-acetyl derivative of the amino aci d l-cysteine, and is a precursor in the formation of the antioxidant glutathione within the body. NAC acts to split the sul \201 de bonds in the macromol- ecules, thereby decreasing viscosity, allowing for removal by normal physiological clearance mechanisms. The action o f NAC is pH dependent. Mucolytic action is signi \201 cant at ranges of pH 7 \200\2239. Re combinant DNase (Pulmyzme ) breaks down DNA as the mechanism for its mucolyic action, and has been stud- ied extensively in cystic \201 brosis . In bronchiectasis As part of bronchial hygiene, hydration, physiotherapy and mucolytic agen ts are important considerations in the man- agement of bronchiectasis. Nebulized NAC is ben e \201 cial in some patients, but has not demonstrated clinical improvement in the randomi zed controlled trial setting. There are con \202 icting results on the ef \201 cacy of ae rosolized recombinant DNase, which breaks down DNA, a major gelatinous product of neutrophi ls. DNase improves pulmo- nary function (FEV1) and reduces hospitalizations in cystic \201 brosis, but is not effective in non-cystic \201 brosis bron- chiectasis. Clinical application Strategies Mucolytics can be given via the inhaled route or orally. \200 Hydration. Traditionally steam inhalation and nebulized saline has been used to facilitate expectoration. There is no evidence of it changing the properties of mucus. 159 CHAPTER 10.3 Mucolytics In mechanically ventilated patients The delivery of inhaled drugs to the lower respiratory tract of mechanically ventilated patients is complicated by deposition of the aerosol parti cles in the ventilator circuit and ETT, and the factors governing pulmonary deposition in m echanically ventilated patients are different from those in ambulatory patients. Systematic reviews of pharmacological therapies for ARDS have shown no bene \201 t on outcomes with the use of NAC (n = 235, 5 studies, relative risk 0.89; 95% con \201 dence inter- val 0.65 \200\2231.21) . There are reports of resolution of mucus plugging exacer- bating status as thmaticus through endotracheal instillation of recombinant DNase . The use of inhaled agent s such as NAC and in mechanically ventilated patients has not demonstrated outcome bene- fi ts in larger studies. Furthermore, the possibility of increased airways resistance due to b ronchospasm has been reported and, if considered as a rescue therapy, it should only be use d with a bronchodilator. Allegra L, Cardaro Cl, Grassi A. Prevention of acute exacerbations of chronic obstructive b ronchitis with carbocysteine lysine salt monohydrate: a multicenter double blind placebo-co ntrolled trial. Respiration 1996; 63: 174 \200\22380. Clarke, SW, Pavia, D. Mucociliary clearance. In: Scientific Foundations, Crystal, RG, West, JB, eds. The lung. New York: Raven Press, 1991. Durward A, Forte V, Shemie SD. Resolution of mucus plugging and atelectasis after intratrac heal rhDNase therapy in a mechanically ventilated child with refractory status asthmaticus. Crit Care Med. 2000;28: 560 \200\2232. Elkins, MR, Robinson, M, Rose, RR, et al. A controlled trial of long- term inhaled hyperton ic saline in patients with cystic \201 brosis. N Engl J Med 2006; 354: 229. Fuchs, HJ, Borowitz, DS, Christiansen, DH, et al. Effect of aero- solized recombinant human DNase on exacerbations of respira- tory symptoms and on pulmonary function in patients wit h cystic \201 brosis. The Pulmozyme Study Group. N Engl J Med 1994; 331: 637. Grandjean EM, Berthet P, Ruffmann R, et al. Ef \201 cacy of oral long- term N-acetylcystei ne in chronic bronchopulmonary disease: a meta analysis of published double blind, placebo- controlled clini- cal trials. Clin Ther 2000; 22: 209 \200\22321. Kory RC, Hirsch SR, Giraldo J. Nebulization of N-acetylcysteine combined with a bronchodila tor in patients with chronic bron- chitis. A controlled study. Dis Chest 1968; 54: 504 \200 \2239. Summary \200 There are a number of pharmacological and non-phar- macological methods for altering the co mposition of mucus in respiratory disease. There has not been any evidence for the bene \201 t of inhaled mucolytics in mechanically ventilated patients except reports of rescue t herapy in status asthmaticus. Furthermore, they may cause short-lived bronchospasm, and inc reased airway resistance. Thus, they are not rec- ommended for general use. There is eviden ce for clinically practical improvements in mild and moderate COPD through oral mucolytics such as Carbocysteine and NAC. Poole, PJ, Black, PN. Oral mucolytic drugs for exacerbations of chronic obstructive pulmona ry disease: systematic review. BMJ 2001; 322: 1271. Poole, PJ, Black, PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmon ary disease (Cochrane review). The Cochrane library, issue 3, 2004, Chicester, UK: John Wil ey & Sons Ltd. Richardson PS, Phipps RJ. The anatomy, physiology, pharmacology and pathology of tracheobro nchial mucus secretion and the use of expectorant drugs in human disease. Pharmacol Ther [B ] 1978; 3: 441 \200\22379. Task Group on Mucoactive Drugs. Recommendations for guidelines on clinical trials of mucoac tive drugs in chronic bronchitis and chronic obstructive pulmonary disease. Task Group on M ucoactive Drugs. Chest 1994; 106: 1532. Further reading Adhikari N, Burns KE, Meade MO. Pharmacologic treatments for acute respirat ory distress syndrome and acute lung injury: sys- tematic review and meta-analysis. Treat R espir Med 2004; 3: 307 \200\2232. Yasuda H, Yamaya M, Sasaki T, et al. Carbocisteine reduces fre- quency of common colds and exacerbations in patients with chronic obstructive pulmonary disease. J Am Geriatr Soc 2006 ; 54: 378 \200\22380. 160 G BELLINGHAN & K SATKANAM Surfactant the lung to decrease in size. The surface tension plays a much more signi \201 cant role i n this balance, and without sur- factant would completely collapse the lung alveoli. Pulmon ary surfactant adsorbs to the alveolar air \200\223water interface and causes dynamic reduc tion in the surface ten- sion with changes in alveolar size, i.e. surface tension reduces w ith decrease in alveolar size during expiration until near zero, hence stopping collapse an d atelectasis, then rises again with inspiration. This means that alveolar pressure is kept near constant throughout a ventilatory cycle and the respiratory workload is reduced. This surface tension reduction is achieved by the hydro- phobic ends of the phospholipids align ing in parallel and lifting out of the liquid alveolar lining into the air space. The surfa ctant proteins, particularly SP-B and SP-C, enhance this activity. This structure remains d ynamically stable throughout the ventilatory cycle. A substance in lung oedema \202 uid and lung extracts was found in the mid-1950s by Pattl e and Clements which low- ered surface tension dramatically. It was termed surfactant, i.e. surface active agent. In 1959, Avery and Mead clari \201 ed the role played by a lack of surfactant in hyaline membrane disease of premature infants, now called respiratory dis- tr ess syndrome (RDS) of the newborn. Surfactant therapy has since been used as routine life- saving therapy in infant RDS, and extension of its use to ALI/ARDS is being currently studi ed. Furthermore, eluci- dation of functions outside of surface tension reduction, important ly lung defense and immunomodulation, are being uncovered, leading to studies of its role a nd possible therapeutic uses in other lung diseases. Composition Pulmonary surfactant forms a thin layer at the surface of the lining \202 uid layer on the alveolar epithelial surface. It is a complex biological mixture of lipids and proteins, with lipids making up to 90% of the total by weight. Of the lipids, 90% are a m ixture of phospholipids, with the remaining 10% being mainly cholesterol. Dipalmitoylphosph atidylcholine (DPPC) is the phospholipid predominantly responsible for the surface tension reduction properties of surfactant. The protein composition includes four unique surfactant pro- teins (SP)-A, -B -C and -D, in addition to the remaining 80% which are contaminating serum and lung tissue proteins. SP-A is the most abundant surfactant protein and, along wit h SP-D, is the more hydrophilic protein, playing a role both in pulmonary host defense and in the recycling of surfactant. SP-B and SP-C are hydrophobic surfactant pro- teins which a re critical in the formation of the surfactant monolayer with its surface tension-lowering properties. Pulmonary defense Surfactant forms part of the alveolar and bronchial epithe- lial lining \202 uid which acts as a non-speci \201 c barrier against foreign particles and microorga nisms. There are antibacterial properties of surfactant itself. SP-A and SP-D are collectin s, a family of collagenous lectins believed to play an important in \201 rst-line innate defense by binding to viruses and by opsonizing yeasts and bacteria. Additionally, both hav e been shown to have immunomodu- latory roles and have been shown to be involved in modu- l ating the functions of cells of the adaptive immune system, including dendritic cells and T cells. Lung \202 uid balance The presence of the high surface pressure of surfactant within the alveolar space counteracts \202 uid movement into the alveoli and contributes to preventi ng alveolar oedema. Metabolism Surfactant metabolism involves a continuous process of synthesis and degradation . The protein and lipid compo- nents are both synthesized by type II alveolar epithelial ce lls. The surfactant phospholipids, which are synthesized from blood-derived phospholipid pr ecursors and from recycled products from the alveoli, are stored in lamellar bodies which a re secretory granules found in the cyto- plasm of alveolar type II cells. These are release d into the alveolar lumen by exocytosis. After secretion and combination with the surfactan t pro- teins, surfactant is initially transformed into tubular myelin, a transitory large a ggregate structure that is then trans- formed into the \201 nal functional layer. The lip id and protein components are separated as the lipid is inserted into a monolayer at the ai r \200\223liquid interface. As part of a recycling process, most of the surfactant is taken back up by the type II cells. Additional degradation involves alveolar macrophage phagocyt osis, local intra- alveolar catabolism and mucociliary clearance. Certain components are re cycled directly back into the new sur- factant. Surfactant half-lives of between 15 and 30h have been demonstrated in phospholipid turnover studies. Surfactant products Currently there are several types of surfactant prepara- tions availabl e. The majority of them in clinical use are animal-derived products, of either bovine or po rcine origin, which contain some of the surfactant proteins. These prod- ucts are obtained either by animal lung lavage or lung minc- ing in saline, with extraction of the active pho spholipids and proteins with organic solvents. The synthetic surfactants available contain DPPC with a synthetic emulsi \201 er to facilitate surface adsorption. The synthetic prepa rations available for clinical use do not con- tain surfactant proteins. ALI/ARDS ALI and the more severe ARDS are de \201 ned as syndromes of in \202 ammation an d increased permeability associated with a constellation of radiological and physiological abnor- malities that cannot be explained by left atrial or pulmo- nary capillary hypertensi on. They are characterized by diffuse injury to the alveolar \200\223capillary barrier, res ulting in severe impairment in gas exchange. The etiology is diverse but can be broadly div ided into direct and indirect lung injury. There is an associated mortality of up to 40% fo r ARDS. Surfactant dysfunction within ALI/ARDS is thought to con- tribute signi \201 cantl y to the disease \200\231s morbidity and mortality. Normal function Surface tension reduction and alveolar size regulation The combination of e lasticity of lung parenchyma and sur- face tension of the \202 uid at the air \200\223alv eolar interface causes 161 CHAPTER 10.4 Surfactant The prophylactic and early strategies have been demon- strated to be superior to rescue the rapy in 2 separate Cochrane meta-analyzes. No speci \201 c trials have as yet been done co mparing early vs prophylactic therapy though there is suggestive indirect evidence that pro phylactic is better. The initial exudative phase is characterized histologically by diffuse alveolar damage. The re is a combination of defective surfactant and a reduction in the synthesis and recycling of surfactant due to damage and loss of type II alveolar cells. The presence of a protein-r ich oedema contaminates the surfactant present, leading to a reduced functional capacity th rough both a dilutional effect and inactivation by proteolytic effects of the oedema. Furth ermore, lung injury leads to an increase in the ratio of minor phospholipids to phosphatidy lcholine, thought to be due to the damage and release of cell membrane lipids, thus leading to reduced surface tension-lowering properties. The administration of exogenous surfactant would seem a logical approach in addressing some of the deleterious effects within ALI/ARD S. There have been several preclini- cal and small clinical trials using a variety of surfa ctant preparations, dosing regimes and modes of drug delivery. These have suggested that th e use of exogenous surfactant may be bene \201 cial in ALI/ARDS in terms of improving phys - iological outcomes and potential survival bene \201 ts. However, a large multi-centered, double-blind, placebo-con- trolled trial in adults showed no bene \201 ts; but the surfac tant was administered using by nebulizer (with only 5% deposi- tion) and employed a prepara tion of surfactant without surfactant-speci \201 c proteins. Following on from this, there have been 3 recent large multi-center phase III trials employing direct intratracheal inst illation. One of these was with HL 10, a preparation of natural surfactant isolated from pi g lungs and containing a mixture of SP-B and SP-C. This trial was concluded for futility. T wo further trials using surfactant containing a recombinant protein C with treat- ment up t o 24h including up to four doses have recently been reported. These have shown an improveme nt of oxy- genation but no survival bene \201 t or reduction in the need for mechanical ve ntilation. A post hoc analysis of these two trials, however, suggested that those patients with a direct pulmonary insult causing ARDS tended towards a reduced mortality. To address this issue, a further trial looking into surfactant use in patients with severe respiratory insuf \201 ciency due to direct pulmo- nary insult is ongoing. Other uses of exogenous surfactant One recent study suggested a protective effect of exoge- nous surfactant instilled to donor lungs before retrieval on post-lung transplantation sur factant function and on early clinical outcome. This was done as post-transplant graft reje ction was often found to be related to post-reperfusion surfactant dysfunction. This may pr ovide a further avenue of use for surfactant. Surfactant dysfunction or de \201 ciency may also play a role in the pathophysiology of other respiratory disorders affect- ing newborn infants. Hence there may be a role for its use in babies with meconium aspiration syndrome , pneumonia and possibly bronchopulmonary dysplasia. Conclusion Current evidence does not support the use of exogenous surfactant in adult patie nts with ALI/ARDS, although there may be a role for it in certain subgroups, i.e. those wit h direct lung injury. Further studies looking into different doses, delivery modes (nebuliz ed, intratracheal or bron- choscopic instillation) and duration of treatments are required, and the range of side effects from the drug and delivery need to be clearly understood. Ho wever, for RDS in infants, both synthetic and natural products have been shown to be effect ive, though natural preparations containing surfactant proteins (speci \201 cally SP-B and SP-C) have been found to be superior. With the development of new synthetic products conta ining sur- factant proteins, it remains to be seen whether these will prove to be more effe ctive in this group of patients. Ongoing research into surfactant pathophysiology may revea l other potential lung diseases that may bene \201 t from therapeutic intervention. Further reading Anzueto A, Baughman RP, Guntapalli KK, et al. Aerosolized sur- factants in adults with sepsis-induced acute respiratory distress syndrome. N Engl J Med 1996; 334: 141 7 \200\22321. RDS of newborn RDS is the main cause of respiratory distress in newborn infants, particular ly preterm infants. There is a signi \201 cant reduction in the amount of surfactant prese nt secondary to the immaturity in the development of the type II alveo- lar cells. This lea ds to increased surface tension within the terminal respiratory units, resulting in atelect asis and sub- sequent respiratory failure. Clinical trials have shown that surfactant thera py (synthetic and animal derived) led to improvements in oxygenation, decreased ventilatory support, decreased risk of pneumot- horax and decreased mortality. When possible, antenata l corticosteroid administration is given to those women at risk of having preterm deliverie s. This is believed to speed maturation of fetal lungs and to increase surfactant synthesis and release. There are several strategies of surfactant treatment: immediate preventative treatment in those at high risk of developing RDS, early treatment given within the \201 rst 2h of being born and res- cue treatment to those with established RDS. All have been sh own to lead to improved clinical outcomes. Hohlfeld JM. Pulmonary surfactant and lung \202 uid balance. In: Gibson GJ, Geddes DM, Co stable U, et al. Respiratory medicine, 3rd edn, Philadelphia: Saunders, 2003: 93 \200\22310 4. Horbar JD, Wright EC, Onstad L. Decreasing mortality associated with the introduction of su rfactant therapy: an observational study of neonates weighing 601 to 1300 grams at birth. T he Members of the National Institute of Child Health and Human Development Neonatal Researc h Network. Pediatrics 1993; 92: 191 \200\2236. Schwarts RM, Luby AM, Scanlon JW, et al. Effect of surfactant on morbidity, mortality, and resource use in newborn infants weigh- ing 500 to 1500 g. N Engl J Med 1994; 330: 1476 \200 \22380. Spragg RG, Lewis JR, Walmrath H et al. (2004). Effect of Recombinant Surfactant Protein C-B ased Surfactant on the Acute Respiratory Distress Syndrome. N Engl J Med 351: 884-892. Struber M, Fischer S, Niedermeyer J, et al. Effects of exogenous sur- factant instillation in clinical lung transplantation: a prospective, randomized trial. J Thorac Cardiovasc Surg 2007; 133: 1620 \200\2235. 162 J BALL Helium \200\223oxygen gas mixtures Nomenclature Helium \200\223oxygen mixtures are sometimes referred to as heliox, whilst nit rogen \200\223oxygen mixtures are referred to as nitrox. However, heliox is sometimes used to refer speci \201 - cally to helium 79% \200\223oxygen 21%. In this chapter, heliox will refer to any mixture of helium and oxygen, whilst heliox21 refers to helium 79% \200\223ox ygen 21%. \202 ow rates of \211 15l/min as compared with air or oxygen which run at 6 \200\2238l/m in. Thus the ef \201 ciency and reliability of respirable particle generation using heliox 21 are subopti- mal. As a carrier gas for respirable particles, however, heliox21 demonstra tes signi \201 cantly higher delivery than more dense gas mixtures. Ideally, therefore, an alternative particle generation technique should be employed, such as ultrasound or vibrat ing mesh. Unfortunately, these tech- niques are not widely available. The choice in an indi vidual circumstance will usually be decided by practicalities such as the need for suppleme ntal oxygen or heliox21 availabil- ity. It may be dif \201 cult to run a reservoir bag and a nebulizer simultaneously off the same cylinder. Rationale The ef \201 ciency of gas \202 ow is dependent upon, amongst other things, the physical properties of the gas, speci \201 cally its density and viscosity. Reducing the density increases the ef \201 ciency of gas \202 ow. Helium is a colorless, odorless gas , is chemically and biologically inert, and its density is 7 times less than nitrogen and 8 times less than oxygen, with a comparable viscosity. Thus, substituting helium for nitroge n in inspired gas mixtures increases the ef \201 ciency of convec- tional and diffusional gas transportation. Caution: managing hypoxia (SpO2 <88%) In hypoxic patients, a balance needs to be struck bet ween improving ventilation (by minimizing gas density and hence minimizing the FiO2) and ac hieving adequate oxygenation (by diluting heliox21 with supplemental oxygen). As a start- i ng guide, aim to achieve an SpO2 of 88 \200\22392%. Indications Helium \200\223oxygen mixtures should be considered as a rescue therapy in the immediate management of upper and/or lower airway obstruction due to such conditions as: cr oup, epiglottitis, laryngitis, tracheitis, foreign body aspiration, post-extubation or peri bronchoscopy stridor, tumor (upper airway or proximal tracheobronchial tree), trache- omala cia, tracheal stenosis, acute severe asthma and acute severe (hypercapnic) exacerbation of COPD. Treatment with a helium \200\223oxygen mixture should be initi- ated in a patient wit h any of these conditions who despite \201 rst-line therapy develops severe respiratory d istress, spe- ci \201 cally: reports severe dyspnoea, has a very high respira- tory rate, is making excessive respiratory effort, is tiring, becomes drowsy or agitated, or is becomi ng hypoxic and/ or hypercapnic. It may prevent the need to intubate or at least create a ti me window to allow this to be done urgently rather than as an emergency. Patient monitoring during therapy Routine respiratory monitoring is all that is required (a ir- way patency, respiratory rate, clinical evaluation of the adequacy of ventilation, SpO2 and blood gas analysis). Continuous oxygen saturation monitoring should be used in all hyp oxic patients. Always assess and optimize face mask position as any air entrainment will re duce the effec- tiveness of this intervention. Safety Standard safety precautions for compressed gasses are all that is required. Helium i s inert and insoluble in human tis- sues at atmospheric pressure. Helium does have a high t hermal conductivity but does not cause signi \201 cant airway or whole patient cooling, ev en in neonates. Stopping helium \200\223oxygen therapy Helium \200\223oxygen therapy can be withdrawn as soon as de \201 nitive therapy has taken suf \201 cient effect to reduce res- piratory distress. It may be useful as an intermitte nt ther- apy in such conditions as acute severe asthma where periodic reductions in the wor k of breathing can prevent decompensation and thereby prevent the need for intuba- tion and mechanical ventilation. Expected effects Administering helium \200\223oxygen should improve the ef \201 - ciency o f ventilation and thereby reduce respiratory dis- tress. However, it is only a temporizing intervention, i.e. it extends the period of time available for de \201 nite treatment for the underlying condition to be delivered; it is not in itself therapeutic. Indications for helium \200\223oxygen mask ventilation (CPAP, BiPAP, PSV) Heliox may reduce the work of breathing to a similar extent to positive pressure mask ventilation. The effec t of these two interventions is additive such that a patient fail- ing one, may benefit fro m the addition of the other. Delivering heliox mixtures through positive pressure mask vent ilation devices is problematic, as none is currently designed for this. Some clinicians hav e tried entraining heliox21 at 15l/min into the mask, or as near to it in the circuit as pr actical. However, the ef \201 cacy of this technique, in particular the actual gas mixture delivered to the patient, is uncertain. Presentation Helium should only be available as heliox21 (79% helium \200\223 21% oxygen). This is because you will never want to deliver a gas mixture with <21% oxygen. Face mask administration Helium \200\223oxygen gas mixtures can be delivered through any ti ght- \201 tting mask. The mask should preferably have a reser- voir bag into which the hel iox is delivered, and one or more one-way expiratory valves. Every effort should be made to minimize air entrainment. Specialist masks and mixing/neb- ulizing circuits are available commercially. Supplemental oxy- gen can be provided either through a Y-piece mixing circuit or via nasal specs worn underneath the tight- \201 tting mask. Indications for helium \200\223oxygen IPPV via endotracheal or tracheostomy tube Severe ins piratory and/or expiratory \202 ow limitation neces- sitates the use of dangerously high airway pressures Nebulization Generating a respirable aerosol using heliox21 through a standard, gas-driven, updraft nebulization chamber requires 163 CHAPTER 10.5 Helium \200\223oxygen gas mixtures Further reading Ball JA, Grounds RM. Calibration of three capnographs for use with helium a nd oxygen gas mixtures. Anesthesia 2003; 58: 156 \200\22360. ( \211 35cm H2O) and/or high levels of intrinsic PEEP. The effectiveness of instituting hel ium \200\223oxygen will be limited by the degree to which oxygen supplementation is require d. A reversible pathology should have been identi- \201 ed and a treatment plan institute d. Patients may respond to relatively small reductions in gas density such that even an FiO 2 of 0.7 should not necessarily preclude a therapeu- tic trial. It is sometimes possible to decrease the FiO2 gradually as ventilation improves, thus decreasing the gas density furth er. Chatmongkolchart S, Kacmarek RM, Hess DR Heliox delivery with noninvasive positive pressure ventilation: a laboratory study. Respir Care 2001; 46: 248 \200\22354. Colebourn CL, Barber V, Young YD. Use of helium \200\223oxygen mixture in adult patients pr esenting with exacerbations of asthma and chronic obstructive pulmonary disease: a systemat ic review. Anesthesia 2007; 62: 34 \200\22342. Fink JB. Opportunities and risks of using heliox in your clinical prac- Patient monitoring during IPPV therapy Routine respiratory/ventilator monitoring is all tha t is required. There are currently only two commercially avail- able ventilators designed f or use with heliox. Of note, both of these can be used to deliver mask ventilation. Some ot her ventilators can be connected to heliox in place of air. Heliox may interfere with both internal performance and patient monitoring. Extreme care needs to employed to avoid the de livery of excessive or inadequate tidal volumes. Always use a pressure control mode and mea sure the FiO2. Switching gas mixtures between heliox and nitrox usually requires recalibrat ion of the pneumotachograph, which in most ventilators cannot be performed whilst deliverin g ventilation to a patient. Capnography is also affected by substituting helium for nitroge n. The ef \201 cacy of heliox over nitrox should be evident almost immediately, with a max i- mal effect seen within 15min. tice. Respir Care 2006; 51: 651 \200\22360. Hess DR. Heliox and noninvasive positive-pressure ventilation: a role for heliox in exacerb ations of chronic obstructive pulmo- nary disease? Respir Care 2006; 51: 640 \200\22350. Hess DR, Fink JB, Venkatamaran ST, et al. The history and physics of heliox. Respir Care 2006; 51: 608 \200\22312. Hurford WE, Cheifetz IM. Should heliox be used for mechanically ventilated patients? Respir Care 2007; 52: 582 \200\22394. Kim IK, Saville AL, Sikes KL. et al. Heliox-driven albuterol nebuliza- tion for asthma exac erbations: an overview. Respir Care 2006; 51: 613 \200\2238. Myers TR. Use of heliox in children. Respir Care 2006; 51: 619 \200\22331. Oppenheim-Eden A , Cohen Y, Weissman C, et al. The effect of helium on ventilator performance: study of \201 ve ventilators and a bedside pitot tube spirometer. Chest 2001; 120: 582 \200\2238. Smith SW, Biros M. Relief of imminent respiratory failure from upper airway obstruction by use of helium \200\223oxygen: a case series and brief review. Acad Emerg Med 1999; 6: 953 \200\223-6. Stopping helium \200\223oxygen therapy Assuming that helium \200\223oxygen has proven to be ef \201 cacious and that a suf \201 cient time interval has elapsed to allow de \201 ni tive therapy to have taken effect, then institute a trial of switching the inspiratory gas mixture back to nitrogen oxygen. If this results in a signi \201 cant deterioration in res pi- ratory mechanics, then re-institute helium \200\223oxygen and set a time interval at wh ich a re-trial of nitrogen \200\223oxygen will be undertaken. Intermittent use of a helium \200\223oxygen mix- ture may be considered as part of a weaning strategy. Tassaux D, Jolliet P, Thouret JM, et al. Calibration of seven ICU ven- tilators for mechani cal ventilation with helium \200\223oxygen mixtures. Am J Respir Crit Care Med 1999; 160: 2 2 \200\22332. Wigmore T, Stachowski E. A review of the use of heliox in the criti- cally ill. Crit Care Resusc 2006; 8: 64 \200\22372. Published trials There are a signi \201 cant number of published trials of heliox in a var iety of settings. These have been extensively reviewed However, there is currently insuf \201 cient evidence to justify its routine use. This page intentionally left blank 165 Chapter 11 Cardiovascular drugs