Advanced therapy in thoracic surgery - part 6 pdf

Surgical Treatment of Bronchiectasis and Broncholithiasis / 275 of the pulmonary artery in four patients, esophagus in one, and main stem bronchus in one other patient There were no operative deaths, and most patients were asymptomatic at follow-up The role of therapeutic bronchoscopy remains controversial In the series by Cole and colleagues, of 42 patients with broncholithiasis, bronchoscopy was performed in 40, with successful stone removal achieved in (20%).43 Cole and colleagues recommended that, while removing bronchial stones, excess force or traction should be avoided and that the use of bronchial irrigation may help to separate the stone from the bronchial wall They also concluded that an attempt at endoscopic stone removal should be undertaken before complications develop In the absence of significant symptoms or complications, observation alone may be the best management strategy References Laennec RT A treatise on diseases of the chest and mediate ausculation 4th ed Translated by J Forbes New York: S Woodsons; 1835 p 100 Kutlay H, Cangir AK, Enön S, et al Surgical treatment in bronchiectasis: analysis of 166 cases Eur J Cardiothorac Surg 2002;21:634–7 Sealy WC, Bradham RR, Young WG The surgical treatment of multisegmental and localized bronchiectasis Surg Gynec Obst 1966;123:80–90 Oschner A Bronchiectasis Disappearing pulmonary lesion N Y State J Med 1975;75:1683–9 Perry KMS, Sellers TH (eds) Chest diseases London: Butterworth; 1963 Heller G Beitrage zur lehre van den fremdkorpern in den luftwegen Göttingen: WF Kaestner; 1890 Kartagener M Zur pathogenese der bronchiectasien Bronchiectasien bei situs inversus viscerum Beitr Klin Tuberk 1933;8:489–501 Heidenhain L Ausgedehnte lungenresektion wegen zahlmeicher eiternder bronchiectasien in einem unterlapen, verlandl.deutsch gesselsch Chir 1901;30:636 Jackson C The bronchial tree: its study by the insufflation of opaque substances in the lung Am J Roentgenol 1918;5:454 10 Sicard JA, Forestier J Iodized oil as contrast medium radioscopy Bull Mem Med Hôp de Paris 1922;46:463 11 Brock RC Post-tuberculous bronchostenosis and bronchiectasis of the right middle lobe Thorax 1950;5:5 12 Wager KB, Johnston MR Middle lobe syndrome Ann Thorac Surg 1983;35:679–86 13 Saha SP, Mayo P, Lang GA, McElvein RB Middle lobe syndrome: diagnosis and management Ann Thorac Surg 1982;33:28–31 14 Reid LM Reduction in bronchial subdivision in bronchiectasis Thorax 1950;5:233–47 15 Whitwell F A study of the pathology and pathogenesis of bronchiectasis Thorax 1952;7:213–9 16 Ashour M Hemodynamic alterations in bronchiectasis: a base for new subclassification of the disease J Thorac Cardiovasc Surg 1996;112:328–34 17 Ashour M, Al-Kattan K, Rafay MA, et al Current surgical therapy for bronchiectasis World J Surg 1999;23:1096–104 18 Nicotra MB, Rivera M, Dale AM, et al Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort Chest 1995;108:955–61 19 Davis AL, Pierce AK, Naidich D, et al Bronchiectasis Am Rev Respir Dis 1986;134:824–5 20 Eliasson R, Mossberg B, Canner P, Afzelius BA The immobile-celia syndrome A congenital ciliary abnormality as an etiologic factor in chronic airway infection and male sterility N Engl J Med 1977;297:1–6 21 Smit HLM, Schreurs JM, Van den Bosch JMM, Westermann CJJ Is resection of bronchiectasis beneficial in patients with primary ciliary dyskinesia Chest 1996;109:1541–4 22 Tkebuchrava T, Neiderhauser U, Weder W, et al Kartagener’s syndrome Clinical presentation and cardiosurgical aspects Ann Thorac Surg 1996;62:1474–9 23 Vevaina JR, Teichberg S, Buschman D, Kirkpatrick CH Correlation of absent inner dyneic arms and mucociliary clearance in a patient with Kartagener’s syndrome Chest 1987;91:91–5 24 Wayne KS, Taussig LM Probable familial congenital bronchiectasis due to cartilage deficiency (WilliamsCampbell syndrome) Am Rev Respir Dis 1976;114:15–22 25 Mounier-Kuhn P Dilatation de la trachée: constatations radiographiques et bronchoscopiques Lyons Med 1932;150:106–9 26 James DK, Godden D, Cavanagh P Alpha-1-antitrypsin deficiency presenting as bronchiectasis Br J Dis Chest 1985;79:301–4 27 Grenier P, Maurice F, Mussel D, et al Bronchiectasis: assessment by thin-section CT Radiology 1986;161:95–9 28 Muller NL, Begin CJ, Ostrow DN, Nichols DM Role of computed tomography in the recognition of bronchiectasis Am J Radiol 1984;143:971–6 29 Kang EY, Miller RR, Müller N Bronchiectasis: comparison of preoperative thin-section CT and pathologic findings in resected specimens Radiology 1995;195:649–54 30 Cooke JC, Currie DC, Morgan AD, et al Role of computed tomography in the diagnosis of bronchiectasis Thorax 1987;42:272–7 31 Munro NC, Cooke JC, Currie DC, et al Comparison of thin-section computed tomography with bronchography for identifying bronchiectatic segments in patients with chronic sputum production Thorax 1990;45:135–9 276 / Advanced Therapy in Thoracic Surgery 32 Chipps BE, Talamo RC, Winkelstein JA IgA deficiency, recurrent pneumonias, and bronchiectasis Chest 1978;73:519–26 41 Deslauriers J, Dion L Le traitment des bronchiectasies primitives Indications chirurgicales et resultats Semin Hôp Paris 1985;18:1199–201 33 Ellis DA, Thornley PE, Wrightman AJ, et al Present outlook in bronchiectasis: clinical and social study and review of factors influencing prognosis Thorax 1981;36:659–64 42 Faber LP, Jensik RJ, Chawla SK, Kittle CF The surgical implication of broncholithiasis J Thorac Cardiovasc Surg 1975;70:779–89 34 Jaffe HJ, Katz S Current ideas about bronchiectasis Am Fam Physician 1973;7:69–76 43 Cole FH, Cole FH Jr, Kandedar A, Watson DC Management of broncholithiasis: is thoracotomy necessary? Ann Thorac Surg 1986;42:255–7 35 Hodder RV, Cameron R, Todd TRJ Bacterial infections In: Pearson FG, et al, eds Thoracic surgery New York: Churchill Livingstone: 1995 p 433–70 36 Mazières J, Murris M, Didier A, et al Limited operation for severe multisegmental bilateral bronchiectasis Ann Thorac Surg 2003;75:382–7 37 Barlow CW, Robbins RC, Moon MR, et al Heart-lung versus double-lung transplantation for suppurative lung disease J Thorac Cardiovasc Surg 2000;119:466–76 38 Agasthian T, Deschamps C, Trastek VF, et al Surgical management of bronchiectasis Ann Thorac Surg 1996;62:976–80 44 Schwartz J, Schaen MD, Picardi JL Complications of the arrested primar y histoplasmic complex JAMA 1976;236:1157–61 45 Dixon GF, Donnenberg RL, Schonfeld SA, Whitcomb ME Clinical commentary Advances in the diagnosis and treatment of broncholithiasis Am Rev Respir Dis 1984;129:1028–30 46 Kowal LE, Goodman LR, Zarro VJ, et al CT diagnosis of broncholithiasis J Comput Assist Tomogr 1983;7:21–3 39 Ripe E Bronchiectasis Scand J Respir Dis 1971;52:96–112 47 Trastek VF, Pairolero PC, Ceithame EL, et al Surgical management of broncholithiasis J Thorac Cardiovasc Surg 1985;90:842–8 40 Fujimoto T, Hillejan L, Stamatis G Current strategy for surgical management of bronchiectasis Ann Thorac Surg 2001;72:1711–5 48 Potaris K, Miller DL, Trastek VF, et al Role of surgical resection in broncholithiasis Ann Thorac Surg 2000;70:248–52 CHAPTER 22 BLOOD SUBSTITUTES ROBERT M WINSLOW, MD Blood substitutes are solutions that are intended to be used instead of blood In fact, there are many “blood substitutes” in clinical use now, including colloids and crystalloids, which are given to perform one function of transfused blood: plasma volume expansion However, the term “blood substitutes” is usually reserved for solutions that also carry and deliver oxygen Various workers in the field of blood substitutes research have used other terms to more accurately describe these new solutions, including “oxygen carriers,” “oxygen-carrying plasma expanders,” or, in reference to those solutions based on hemoglobin, “hemoglobin-based oxygen carriers.” Although perfluorocarbon-based oxygen carriers also have been tested extensively, as a class they have limitations that have slowed development In this chapter, main emphasis is placed on hemoglobin-based products, since they hold the most promise for successful clinical application The search for alternatives to blood transfusion is almost as old as the practice of medicine itself.1 Prior to the discovery of blood types, around 1900, and the introduction of blood banks, just prior to the outbreak of World War II, there was no effective replacement for blood lost in hemorrhage Great efforts have been invested in alternatives to products based on hemoglobin, such as the perfluorocarbons Perfluorocarbons are synthetic materials that have greatly increased solubility for O2 and that can be produced cheaply and in large volume They suffer from two significant problems, however: they are completely immiscible with aqueous solutions and so must be emulsified prior to infusion, and under normal circumstances they cannot transport sufficient O2 to effectively oxygenate tissue Clinical trials have not been convincing,2 and no product is currently approved for use in patients Other more exotic solutions to the blood substitute problem have been devised, including artificial red cells (liposomes) and a variety of approaches based on recombinant hemoglobins.4 However, the products that have been most successful in clinical development to date have been chemical modifications of either human or animal (cow) hemoglobin.5 Historical Background In 1949 Amberson published a landmark paper that described a case report of a 22-year-old female with severe postpartum hemorrhage as a result of retained placenta (Figure 22-1).6 Her hemoglobin was g/dL, and all compatible blood in the hospital had been exhausted She remained in shock, and her blood pressure was not responsive to conventional plasma expanders or crystalloids She was finally given an experimental hemoglobinsaline solution that Amberson had been developing in the laboratory Upon administration of this solution, the blood pressure rose dramatically and the heart rate fell Over two liters of hemoglobin solution were administered to this patient, and for a time she seemed to improve Eventually however her urine output diminished as renal failure progressed and she finally died In his discussion of this case, Amberson expressed his belief that the hemoglobin solution had been effective treatment for shock However, he cautioned that the blood pressure responses and the abrupt fall in heart rate were peculiar properties of hemoglobin solutions, and he felt that these effects were most likely owing to impurities Amberson concluded, “It must be emphasized that every investigator in this field has used a different method for the preparation of his hemoglobin-saline 277 Blood Substitutes / 279 However the blood pressure responses after resuscitation with either purified hemoglobin (Ao) or ␣␣-Hb was a marked overshoot compared with baseline, and both hemoglobin solutions caused a modest reduction of heart rate relative to baseline, consistent with Amberson’s earlier observations (see Figure 22-1) Although volume restitution was the same with all the solutions, the cardiac output failed to return even to baseline with either hemoglobin solution In contrast, cardiac output rose to levels even higher than baseline after resuscitation with either albumin or Ringer’s lactate The result of these physiological changes was a marked increase in systemic vascular resistance (Resistance = Pressure/Flow) after resuscitation with any hemoglobin solution Finally, this increased resistance completely offset any added O -carrying capacity afforded by infusion of hemoglobin solution In summary, the US Army had succeeded in producing a suitable model hemoglobin that had the aimed-for characteristics: • is sterile • is free of red cell membranes • is endotoxin-free • does not dissociate into ␣␤ subunits • does not cause significant renal toxicity Nevertheless, ␣␣-Hb still caused significant hypertension in pigs Of even more concern, however, was the fact that cardiac output was depressed, presumably because of intense vasoconstriction, as evidenced by severely increased vascular resistance The overall conclusion was that there was no advantage of resuscitation with ␣␣-Hb compared with Ringer’s lactate The mechanism of this vasoactivity was not clear, and the Army concluded that more basic research was needed in the field in order to Heart Rate MAP 200 160 190 140 Albumin Ao RL aaHb 120 Albumin Ao RL aaHb 180 H 170 /min 100 160 150 80 140 60 130 40 120 -1 -1 Hours Cardiac Output 5 Systemic Vascular Resistance 3500 Albumin Ao RL aaHb Albumin Ao RL aaHb 3000 2500 dyne sec cm-5 c L/min Hours 2000 1500 1000 500 -1 Hours -1 Hours FIGURE 22-2 Simulation of a battlefield injury by the US Army Dehydrated pigs were subjected to hemorrhage (arrow at hours) and then resuscitated with test solution (arrow at hour) The pattern of increased pressure, decreased cardiac output, and markedly elevated vascular resistance is the hallmark reaction to first-generation hemoglobin-based blood substitutes.15 280 / Advanced Therapy in Thoracic Surgery produce a safe and efficacious blood substitute The Army not only abandoned ␣␣-Hb as an experimental product but discontinued further research in the field as well.16 Baxter continued to develop ␣␣-Hb until phase III clinical trials in stroke17 and trauma18 showed increased mortality in treated patients Vasoconstriction and Its Physiological Basis The focus of research efforts in the post-Army era became understanding of the mechanism of hemoglobininduced vasoconstriction Experiments carried on the hamster skinfold model of the microcirculation led to new insight into the cause of hypertension Figure 22-3 shows a study of functional capillary density, defined as the number of capillaries in a given microscopic field in which cells can be observed to be moving Functional capillary density decreases when precapillary arterioles constrict Thus, if blood volume does not change, arteriolar vasoconstriction produces hypertension and decreased functional capillary density.19 In the experiment in Figure 22-3, animals were progressively hemodiluted with dextran or hemoglobin solutions When the hematocrit fell below 20% and plasma hemoglobin concentration increased, functional capillary density fell rapidly In contrast to this normal response, when animals were progressively hemodiluted with ␣␣-Hb, the drop in functional capillary density occurred at a much higher hematocrit, directly demonstrating the marked vasoactivity of this product A polymerized human hemoglobin demonstrated this effect to a lesser degree, and a hemoglobin modified by surface decoration with polyethylene glycol (PEG) was even less vasoactive These experiments suggested that not all hemoglobin solutions are equally vasoactive In rats, hypertension produced by these three types of modified hemoglobins was directly correlated with the fall in functional capillary density observed in hamsters (Figure 22-4) That is, PEG-modified hemoglobin had no significant effect on rat blood pressure, polymerized hemoglobin had a small effect, and cross-linked hemoglobin was markedly hypertensive Thus, in the early 1990s products from all classes of modified hemoglobins were entering advanced clinical trials in humans, but there was still no good explanation for the hemodynamic pattern observed more than 40 years previously One potential explanation seemed obvious when NO was identified as an endothelial-derived relaxing factor.20 Hemoglobin was well known to bind NO with high affinity,21 and experiments with isolated vascular rings seemed to support this explanation.22 One problem with this as a complete explanation, however, was that hemoglobin within red blood cells also binds NO, but without a hypertensive effect A second problem was that different modified hemoglobins demonstrated hypertension to differing degrees, depending on the type of chemical modification (see, for example, Figure 22-4) A New Model for Blood Substitute Design A problem with this interpretation, however, is that the reactivity with NO does not correlate with the degree of vasoactivity Rohlfs and colleagues prepared solutions of modified hemoglobins with differences in molecular size and other significant properties (Table 22-1).24 The crosslinked hemoglobin was the Army’s ␣␣-Hb, with a molec160 100 mm HG 90 FCD (%) Polymerized Crosslinked PEG 140 PEG 80 Controls (dextran) 70 120 100 Polymerized 60 Crosslinked 80 50 60 50 40 30 20 10 10 20 30 Minutes 40 50 60 Hematocrit (%) FIGURE 22-3 Functional capillary density (FCD) as a function of hematocrit in the hamster skinfold model with progressive hemodilution with the indicated solutions Data for dextran and ␣␣-Hb are from Tsai A et al (1995).19 Data for PEG-Hb and polymerized hemoglobin are unpublished (personal communication, A Tsai and M Intaglietta,) FIGURE 22-4 Blood pressure in the rat in response to infusion of test “blood substitutes.” Table 22-1 gives the properties of the test solutions Infusion is via a femoral vein, starting at 30 minutes as shown by the arrow Note that the degree of blood pressure elevation is inversely proportional to functional capillary density, as shown in Figure 22-3 (unpublished data) 282 / Advanced Therapy in Thoracic Surgery Hemorrhage 1.0 Fraction alive 0.8 0.6 Hb, g/dl , 0.4 0.2 Controls 13.8 Crosslinked 10.2 Polymerized 11.0 Pentastarch 6.8 PEG-Hb 7.6 0.0 20 40 60 80 100 120 140 Minutes after start of hemorrhage FIGURE 22-5 Survival of rats after 50% exchange transfusion with “blood substitutes” followed by hemorrhage of 60% of blood volume For properties of the hemoglobin solutions, see Table 22-1 Pentastarch was used as an additional control because its viscosity and oncotic pressure are similar to those of PEG-Hb The hemorrhage starts at minutes and takes place over 60 minutes The controls represent a group of animals that were not exchange-transfused The hemoglobin concentrations are the values measured at the start of the hemorrhage.32 The test of any design has to be in animals and then humans In anticipation of clinical trials, rats were exchange-transfused 50% of their blood volume and then subjected to a 60% hemorrhage over hour.32 The result of this study was that animals exchanged with a new experimental PEG-modified human hemoglobin survived the hemorrhage, while 50% of the control subjects (no exchange) and animals exchanged with either cross-linked or polymerized hemoglobins did not (Figure 22-5) A striking feature of this experiment was the difference in hemoglobin concentrations in the various groups of animals The controls had a hemoglobin of 13.8 g/dL, while the PEG-Hb animals began the hemorrhage with a hemoglobin of only 7.6 g/dL According to conventional clinical practice, these animals were at or near the transfusion trigger at the beginning of hemorrhage These findings point to one of the most important aspects of blood substitutes research and eventual clinical use: “blood substitutes” are not simply blood replacements but rather represent an entirely new category of oxygen delivery therapy based on a new understanding of oxygen transport physiology Alternative Explanations for Vasoconstriction The theoretical basis for the success of PEG-modified hemoglobin is not yet completely proven and remains controversial Many workers in the field believe that NO binding does account for hemoglobin-induced vasoconstriction Recombinant hemoglobins with mutations that reduce NO binding have been shown to cause less hypertension than native hemoglobin.33 Others believe that extravasation of hemoglobin is responsible, on the theory that hemoglobin in the interstitial space more effectively scavenges NO than hemoglobin in the vascular space.34,35 Some workers in the field have shown that vasoactivity is related to plasma viscosity36 and that shear stress is transduced by endothelial cells to alter the release of vasoactive molecules such as NO and prostacyclins.37 Still others believe that vasoactivity or, more generally, toxicity, results from O2 free radical generation as hemoglobin cycles through redox reactions.38 It is possible, of course, that the final explanation may lie with a combination of these causative factors The Future of Blood Substitutes Whatever the ultimate explanation for vasoactivity produced by cell-free hemoglobin, it is very unlikely that any product that is approved for clinical use will bear much resemblance to blood beyond its color It is very unlikely that a hemoglobin-based red cell substitute can be produced that has the same hemoglobin concentration as normal red blood cells and the same oxygen affinity as red blood cells, with the same viscosity and oncotic pressure as human blood Nevertheless, as shown in Figure 22-5, solutions with properties very different from those of human blood can effectively reduce the need for transfusion of allogeneic blood The problem for clinical implementation of such solutions, also demonstrated in Figure 22-5, is that the hemoglobin concentration per se will no longer be a useful guide, or trigger, for giving a transfusion Rather, clinicians in the future must broadly evaluate each patient’s need for supplemented tissueoxygenating capacity and be prepared to administer the therapy that best meets that need In this evaluation process, physiological and clinical data will need to be obtained and rapidly integrated into a reliable transfusion trigger As safer, more effective solutions are developed for clinical testing, revision of the transfusion trigger and definition of optimal clinical applications represent a major challenge for the developing field of “blood substitutes.” As research and development with these products continues, it is likely that the unique physiology of oxygen transport will be better understood, and it should be possible to more effectively oxygenate tissue while reducing or avoiding allogeneic blood transfusion Blood Substitutes / 283 References Winslow R Hemoglobin-based red cell substitutes Baltimore (MD): Johns Hopkins University Press; 1992 Gould S, Rosen A, Sehgal L, et al Fluosol-DA as a red-cell substitute in acute anemia N Engl J Med 1986;314:1653–6 Rudolph A Encapsulation of hemoglobin in liposomes In: Winslow R, Vandegriff K, Intaglietta M, editors Blood substitutes Physiological basis of efficacy New York: Birkhaüser; 1995 Looker D, Abbott-Brown D, Cozart P, et al A human recombinant haemoglobin designed for use as a blood substitute Nature 1992;356:258–60 Stowell CP, Levin J, Spiess BD, Winslow RM Progress in the development of RBC substitutes Transfusion 2001;41:287–99 Amberson W, Jennings J, Rhodes C Clinical experience with hemoglobin-saline solutions J Appl Physiol 1949;1:469–89 Christensen S, Medina F, Winslow R, et al Preparation of human hemoglobin Ao for possible use as a blood substitute J Biochem Biophys Methods 1988;17:143–54 Rabiner S, Helbert J, Lopas H, Friedman L Evaluation of stroma-free haemoglobin for use as a plasma expander J Exp Med 11967;26:1127–42 Bunn H, Jandl J Renal handling of hemoglobin II Catabolism J Exp Med 1967;129:925–34 10 Payne J Polymerization of proteins with glutaraldehyde Soluble molecular-weight markers Biochem J 1973;135:867–73 11 Hsia J, Song D, Er S, et al Pharmacokinetic studies in the rat on a o-raffinose polymerized human hemoglobin Artif Cells Blood Substit Immobil Biotechnol 1992;20:587–95 12 Chatterjee R, Welty E, Walder R, et al Isolation and characterization of a new hemoglobin derivative crosslinked between ␣ chains (Lysine 99␣1-Lysine 99␣2) J Biol Chem 1986;261:9929–37 13 Keipert PE, Gomez CL, Gonzales A, et al Diaspirin crosslinked hemoglobin: tissue distribution and long-term excretion after exchange transfusion J Lab Clin Med 1994;123:701–11 14 Hess J, Macdonald V, Winslow R Dehydration and shock: an animal model of hemorrhage and resuscitation of battlefield injury Artif Cells Blood Substit Immobil Biotechnol 1991;19:518 18 Sloan EP, Koenigsberg M, Gens D, et al Diaspirin crosslinked hemoglobin (DCLHb) in the treatment of severe traumatic hemorrhagic shock A randomized controlled efficacy trial JAMA 1999;282:1857–64 19 Tsai A, Kerger H, Intaglietta M Microcirculatory consequences of blood substitution In: Winslow R, Vandegriff K, Intaglietta M, editors Blood substitutes Physiological basis of efficacy New York: Birkhäuser; 1995 p 143–54 20 Ignarro L, Buga G, Wood K, et al Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide Proc Natl Acad Sci U S A 1987;84:9265–9 21 Gibson QH, Roughton FJW The kinetics and equilibria of the reactions of nitric oxide with sheep hemoglobin J Appl Physiol 1956;136:123–34 22 Palmer R, Ferrige A, Moncada S Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor Nature 1987;327:524–6 23 Vandegriff K, McCarthy M, Rohlfs R, Winslow R Colloid osmotic properties of modified hemoglobins: chemically cross-linked versus polyethylene glycol surface-conjugated Biophys Chem 1997;69:232–30 24 Rohlfs RJ, Bruner E, Chiu A, et al Arterial blood pressure responses to cell-free hemoglobin solutions and the reaction with nitric oxide J Biol Chem 1998;273:12128–34 25 Wittenberg J Myoglobin-facilitated oxygen diffusion: role of myoglobin in oxygen entry into muscle Physiological Reviews 1970;50:559–636 26 Lindbom L, Tuma R, Arfors K Influence of oxygen on perfusion capillary density and capillary red cell velocity in rabbit skeletal muscle Microvasc Res 1980;19:197–208 27 Intaglietta M, Johnson P, Winslow R Microvascular and tissue oxygen distribution Cardiovasc Res 1996;32:632–43 28 Vandegriff K, Winslow R A theoretical analysis of oxygen transport: a new strategy for the design of hemoglobinbased red cell substitutes In: Winslow R, Vandegriff K, Intaglietta M, editors Blood substitutes Physiological basis of efficacy New York: Birkhäuser; 1995 29 Winslow RM, Vandegriff KD Hemoglobin oxygen affinity and the design of red cell substitutes In: Winslow RM, Vandegriff KD, Intaglietta M, editors Advances in blood substitutes Industrial opportunities and medical challenges Boston (MA): Birkhäuser; 1997 p 167–88 15 Hess J, Macdonald V, Brinkley W Systemic and pulmonary hypertension after resuscitation with cell-free hemoglobin J Appl Physiol 1993;74:1769–78 30 McCarthy MR, Vandegriff KD, Winslow RM The role of facilitated diffusion in oxygen transport by cell-free hemoglobin: implications for the design of hemoglobin-based oxygen carriers Biophys Chem 2001;92:103–17 16 Hess J, Riess R Resuscitation and the limited utility of the present generation of blood substitutes Transf Med Rev 1996;10:276–85 31 Winslow RM, Gonzales A, Gonzales M, et al Vascular resistance and the efficacy of red cell substitutes J Appl Physiol 1998;85:993–1003 17 Saxena R, Wijnhoud AD, Carton H, et al Controlled safety study of a hemoglobin-based oxygen carrier, DCLHb, in acute ischemic stroke Stroke 1999;30:993–6 32 Richmond KN, Shonat RD, Lynch RM, Johnson PC Critical PO(2) of skeletal muscle in vivo Am J Physiol 1999;277(5 Pt 2):H1831–40 284 / Advanced Therapy in Thoracic Surgery 33 Doherty DH, Doyle MP, Curry SR, et al Rate of reaction with nitric oxide determines the hypertensive effect of cellfree hemoglobin Nature Biotechnology 1998;16:672–6 34 Baldwin AL Modified hemoglobins produce venular interendothelial gaps and albumin leakage in the rat mesentery Am J Physiol 1999;277(2 Pt 2):H650–9 35 Bucci E Hemoglobin based oxygen carriers at a cross road: the old paradigms must be abandoned and much more basic science investigation is necessary [editorial] Artif Cells Blood Substit Immobil Biotechnol 2001;29:vii–x 36 Tsai AG, Friesenecker B, McCarthy M, et al Plasma viscosity regulates capillary perfusion during extreme hemodilution in hamster skinfold model Am J Physiol (Heart Circ Physiol 44) 1998;275:H2170–H2180 37 Frangos JA, Eskin SG, McIntire LV, Ives CL Flow effects on prostacyclin production in cultured human endothelial cells Science 1985;227:1477–9 38 D’Agnillo F, Alayash AI Redox cycling of diaspirin crosslinked hemoglobin induces G2/M arrest and apoptosis in cultured endothelial cells Blood 2001;98:3315–23 CHAPTER 23 UPDATE IN THE MANAGEMENT OF PULMONARY HYPERTENSION AUSTIN B THOMPSON, MD, FACCP Classification of Pulmonary Hypertension The WHO symposium of 1998 also provided a functional classification that is a modification of the New York Heart Association functional classification (Table 23-2) The first classification of pulmonary hypertension was proposed at a World Health Organization (WHO) symposium in 1973 Pulmonary hypertension was classified based upon etiologies with primary pulmonary hypertension (PPH) classified as a separate class, that of pulmonary hypertension of unknown etiology and lacking associated clinical conditions PPH was further subdivided into three groups based on pathology: plexogenic, recurrent thromboembolism, and veno-occlusive disease Later it became apparent from epidemiological data and the pathology of pulmonary hypertension that no distinct pathological findings were pathopneumonic for PPH, including lesions consistent with plexogenic arteriopathy Epidemiological studies have demonstrated a growing list of diagnoses that are associated with a clinical condition and are indistinguishable from PPH In 1998, the WHO convened a second symposium to update the classification system of pulmonary hypertension and collate state-of-the-art understanding of pulmonary hypertension In the new classification system (Table 23-1), PPH is one of a group of entities that share common clinical and pathological presentations included under the broader heading of pulmonary arterial hypertension (PAH) Four other classifications of pulmonary hypertension include pulmonary venous hypertension, pulmonary hypertension associated with disorders of the respiratory system or hypoxemia, pulmonary hypertension due to chronic thrombotic or embolic disease, and pulmonary hypertension due to disorders directly affecting the pulmonary vasculature Physiology and Pathobiology Normally the pulmonary circulation is a low-pressure, high-flow vascular bed that has a remarkable capacity to permit increased cardiac output, such as exercise, without increasing pulmonary arterial pressure The ability of the pulmonary vasculature to respond to increases in cardiac output is felt to be the result of the recruitment of underperfused vessels and engorgement of highly capacitant vessels in response to increases in blood flow The physiology and histology of the pulmonary vasculature reflect the normal state of affairs as the native smooth muscle tone of pulmonary arterioles is lower and the smooth muscle layer is thinner than that of the systemic circulation Pulmonary arterial pressure is a function of the pulmonary venous pressure, cardiac output, and pulmonary vascular resistance (Table 23-3) The National Institutes of Health (NIH) Registry defined a normal mean pulmonary artery pressure at rest of 25 mm Hg, rising to 30 mm Hg with exercise.2 A recent report of a series of estimates of pulmonary arterial systolic pressure measured by Doppler transthoracic echocardiography found that normal pulmonary artery pressures may be higher than previously appreciated In this study of 3,790 echocardiographically normal subjects, pulmonary arterial systolic pressure increased with age, body mass index, and sex Twenty-eight percent had pulmonary artery systolic pressure > 30 mm Hg; it was suggested that the upper limit of normal may reach 40 mm Hg in older patients or obese patients 285 Update in the Management of Pulmonary Hypertension / 287 pulmonary vascular tone.7 Platelets, endothelial cells, smooth muscle cells, and the extracellular matrix all are important for the maintenance of normal vascular tone Perturbations of the normal function of all these elements have been postulated to contribute to the pathological changes of PAH Table 23-4 lists examples of cell products and functions that contribute to normal vascular tone and alterations associated with PPH Hypoxic vasoconstriction is the most important physiological mechanism of pulmonary vasoconstriction The mechanisms that lead to hypoxic vasoconstriction are incompletely described Hypoxia at the level of the alveoli causes local vasoconstriction, which is acutely reversible by administration of oxygen If this phenomenon occurs globally, then pulmonary hypertension results Chronic states of hypoxia lead to vascular remodeling and result in fixed increases in pulmonary vascular resistance Hypoxia may further stimulate pulmonary hypertension through the release of cytokines from the endothelial cell Inflammatory cells may contribute as well through a production of cytokines and growth factors Several of the vasoactive compounds are also mitogens and may to contribute to vascular remodeling Endothelial cells are capable of producing a number of vasoactive substances including vasodilators and vasoconstrictors Abnormality in the metabolism of these substances, favoring vasoconstriction, has been noted in patients with PPH and in experimental animal models of pulmonary hypertension Growth factors released from the endothelial cell may stimulate to vascular remodeling and alteration of the extracellular matrix In the smooth muscle cells, much attention has been placed upon the role of calcium and potassium channel regulation K+ channels regulate calcium influx into the cell through a number of mechanisms Influx of calcium into the smooth muscle cell leads to activation of the contractile apparatus and vasoconstriction and possibly initiates mitogenic effects as well Acute hypoxia triggers pulmonary vasoconstriction at least in part by inhibiting one of the K + channels found in pulmonary artery smooth muscle cells Vascular remodeling is a central feature of pulmonary hypertension from all causes and has been used to both classify and grade the severity of pulmonary hypertension Vascular remodeling includes changes in the intima (fibrosis, media, hypertrophy, and muscularization) and adventitia (increased deposition of extracellular matrix) Endothelial injury early in the course of PAH has been hypothesized to permit exudation of factors that stimulate smooth muscle cells to release mitogens such as basic fibroblast growth factor directly and adenosine indirectly Membrane-bound metalloproteins and serine elastases have been postulated to be central in this process The recent identification of mutations in the gene for bone morphogenetic protein receptor II in patients with familial PPH promises to provide insight into the pathogenesis of PPH.8,9 Bone morphogenetic protein receptor II is a member of the transforming growth factor ␤ (TGF-␤) receptor family TGF-␤ family of growth factors have pleiotropic effects on endothelial cells, smooth muscle cells, and fibroblasts The activities of the TGF-␤ family are dependent upon the cellular milieu; they are modified by complex cytokine networks in ways that may be as divergent as promoting or inhibiting endothelial cell proliferation Thus, describing the common pathway that leads to PPH continues to present significant investigational challenges Primary Pulmonary Hypertension Primary pulmonary hypertension is a rare condition with an estimated annual incidence of one to two per million people per year in Europe and the United States 6,10 However, this may be an underestimate, as autopsy studies have shown a prevalence of 1,300 per million population The incidence of PPH rises drastically among users of appetite suppressants to 25–50 per TABLE 23-4 Examples of Pathogenetic Factors in Pulmonary Arterial Hypertension Source Factor Normal Function Association with PAH Platelets Thrombomodulin Thromboxane A2 Endothelial cells Serotonin Inhibits platelet aggregation Vasoconstrictor; stimulates platelet aggregation Prostacyclin NO Thromboxane A2 Endothelin K+ channels Serine elastases Matrix-bound: SMC mitogens MMP Vasoconstrictor; EC mitogen Elevated Elevated Vasodilator Vasodilator Vasoconstrictor; stimulates platelet aggregation Vasoconstrictor Ca+-mediated SMC relaxation Liberate SMC mitogens from ECM Elevated Diminished Diminished Elevated Elevated Down-regulated Elevated Stimulate SMC proliferation Degrades ECM Elevated Elevated Smooth muscle cells Extracellular matrix EC = endothelial cell; ECM = extracellular matrix; MMP = matrix metalloproteinase; NO = nitric oxide; SMC = smooth muscle cell Extracorporeal Membrane Oxygenation and Extracorporeal and Arteriovenous Carbon Dioxide Removal / 315 Aminocaproic acid use has been recommended for ECMO patients at high risk for bleeding complications The use of Amicar has been shown to reduce bleeding complications when patients undergo other surgical procedures while on ECMO, but has failed to reduce the incidence of intracranial hemorrhage in the pediatric population.61 Thrombocytopenia is expected during the use of ECMO as platelets are altered and as platelet aggregates in the extracorporeal circuit are preferentially sequestered in the lung, liver, and spleen.62–64 Thrombocytopenia must be avoided by using platelet transfusion as often as necessary to maintain adequate platelet counts during, as well as after, ECMO when thrombocytopenia may occur The development of heparin-bonded, nonthrombogenic surfaces is attractive, but the initial experiences with heparin-bonded circuits have not shown significant advantages Catastrophic hemodynamic deterioration is unusual while a patient is on VA ECMO The factors that deserve immediate evaluation when this occurs include venous catheter displacement, inadequate systemic volume status, and the possibility of ECMO circuit failure Pericardial tamponade and tension hemothorax or pneumothorax show a similar pathophysiology of increasing intrapericardial pressure and decreasing venous return Perfusion is initially maintained by the nonpulsatile flow of the ECMO flow and progressive hemodynamic deterioration With decreased venous return to the heart, pulmonary blood flow as well as the native cardiac output is decreased Therefore, the relative contribution of the extracorporeal circuit to peripheral perfusion is increased, and peripheral perfusion is initially maintained by the nonpulsatile flow of the ECMO circuit (post-oxygenator pO2 > 300 torr) The triad of increased PaO2, decreased peripheral perfusion (as evidence by decreased pulse pressure and decreased SvO2) followed by decreased ECMO flow with progressive hemodynamic deterioration is consistently associated with tension pneumothorax.65–67 Tension hemothorax and pneumothorax is initially identified by chest radiograph An echocardiogram will demonstrate a pericardial effusion or hemothorax with or without cardiac compression For emergency drainage of tension hemothorax, pneumothorax, and pericardial tamponade, a percutaneous drainage catheter should be placed to remove the blood or fluid and reverse the pathophysiology Sepsis is both an indication for and a complication of ECMO However, according to the ELSO Registry, only 5% of all patients requiring ECMO demonstrate positive blood cultures This is a remarkably low incidence given the duration of cannulation, the large surface area involved, and frequency of access to the circuit Infection rates vary by institution and are as high as 27%.68 Over one-half of all nosocomially acquired infections in patients on ECMO are bacterial with gram-positive organisms predominating, while 30% of infections are fungal To decrease the incidence of infection, broadspectrum coverage with antibiotics based on institutionspecific bacterial patterns, aseptic technique, and attempts to minimize the time on ECMO are encouraged When ECMO is initiated, a patent ductus arteriosus (PDA) is often present in the newborn The pathophysiology of persistent fetal circulation is a right-to-left shunt through a PDA during severe respiratory failure in the newborn When pulmonary hypertension resolves, flow through the ductus reverses (becomes left-to-right shunting) A persistent left-to-right shunt across the ductus arteriosus may lead to pulmonary edema Decreased systemic oxygenation may result both from pulmonary edema and decreased systemic blood flow Both of these conditions will require increasing ECMO flow to maintain adequate gas exchange and perfusion A PDA on ECMO may present with various signs: (1) a decreased PaCO2; (2) decreased peripheral perfusion; (3) decreased urine output; (4) acidosis; and (5) rising ECMO flow and volume requirements The clinical diagnosis may be confirmed as with other neonatal patients using Doppler echocardiography or angiography Some centers have tried using intravenous indomethacin to treat PDA while on ECMO; however, this may increase the risks of bleeding in patients on ECMO because of its effects on platelet function Once the diagnosis is established, most programs will “run the patient relatively dry” while maintaining supportive ECMO flow until the PDA closes While this often means a few additional days on ECMO, surgical ligation is rarely necessary Occasionally, a patient’s respiratory status does not improve despite to weeks of ECMO support An echocardiogram is repeated to ensure an absence of PDA with predominant left-to-right shunt as well as congenital heart defect such as total anomalous venous return Weaning and Decannulation As native lung function improves, flow rates are decreased until the native lung is supporting the majority of gas exchange The patient is then subjected to ventilator trials, with the circuit excluded If gas exchange and hemodynamic parameters remain adequate, decannulation occurs Patients requiring cardiac support undergo a similar trial but also have ECMO flow reduced to 10 to 20% of supportive flow If filling pressures remain low and contractility remains adequate, with or without inotropes, the patient may be decannulated If percuta- 316 / Advanced Therapy in Thoracic Surgery neous catheters were used, they are removed and local pressure is applied for at least an hour If operative placement of the cannulas was required, operative removal and hemostatic control is necessary Femoral vessels usually require repair Repair of neck vessels is controversial, since immediate embolism or late stenosis can result Many centers prefer ligation of the vessels, since the vessel was already obstructed by the cannula If not already present, a tracheostomy may be placed for ventilator weaning and patient comfort in adults Specific Therapies Congenital Diaphragmatic Hernia In 1981, the first cases of infants with congenital diaphragmatic hernia (CDH) treated with ECMO were reported.69 CDH has the lowest survival rate of all categories of neonatal respiratory failure for which ECMO is used 10 The impact on mortality, however, has been institution-specific, with survival rates ranging from 43 to 87% Aggregate survival data in the ELSO registry is 62%.10 At first, infants were placed on ECMO only after they developed severe respiratory failure following immediate repair of the diaphragmatic defect ECMO then was used preoperatively in attempts to stabilize the patient prior to definitive repair Current strategies involve delay of surgical repair as long as possible while employing ventilator management techniques to optimize preductal arterial saturation, avoid high airway pressures in the hypoplastic lungs, and correct underlying pulmonary vascular resistance Wung and colleagues have reported 85% overall survival with a strategy based on surgery delayed until pulmonary hypertension is minimized by respiratory care based on spontaneous respiration, permissive hypercapnea, and no chest tube.35 ECMO is required in only 14% of these patients pre- or postoperatively Although the role of ECMO as a treatment option for patients with CDH has been widely accepted, the timing of the surgical repair and timing of ECMO initiation has drastically changed over the last 10 years Previously, the overall mortality rate of CDH had remained approximately 50% with the increased utilization of ECMO support.70–74 Delayed repair until the patient’s hemodynamic and pulmonary parameters are stabilized is now generally accepted as the standard of care Patients with low PIP and minimal shunting are repaired within the first 24 to 48 hours of life with good survival outcomes High PIPs are managed with a variety of ventilator schemes including low tidal volume, permissive hypercapnea, and early employment of high frequency oscillator ventilation until they are controlled and maintained < 25 cm H2O.35,75 Pulmonary hypertension can be diagnosed by the pre- or postductal saturation gradient or by echocardiogram Although inhaled nitric oxide (iNO) has not been shown to improve overall survival in CDH,76 there is a subset of patients who will respond to iNO therapy Maintaining a patent ductus arteriosis with prostaglandin if necessary in special circumstances can also allow for right ventricular decompression and prevent ventricular failure ECMO is reserved for those patients who show rapid deterioration with preductal hypoxemia and severe right to left shunting secondary to high PVR and who have failed medical therapies mentioned above Institutions that have implemented these strategies of delayed repair and judicious use of ECMO have shown improved survival from < 50 to > 75% while reducing the use of ECMO to < 15% of cases involving CDH.35,75,77–80 Operative repair of the defect while on ECMO has shown variable survival rates.81–85 Delaying repair until the infant is off ECMO is an option in which favorable results have been reported 86,87 The cannulation technique is determined by operator experience and patient’s need No difference has been shown in the rate of complications, time to recovery, or overall survival between VV ECMO and VA ECMO.88,89 A recent report from the Congenital Diaphragmatic Hernia Study Group showed neonates who not require ECMO for support at any point during their hospitalization have the best survival rates (94%) followed by those repaired after stabilization by and weaning from ECMO (83%) Those patients repaired while on ECMO had a survival rate of only 49% Selection bias is clearly a factor with these results since the only repairs currently done on ECMO are patients who not initially improve or wean from the ventilator Cardiac Support ECMO applied to patients with severe cardiac failure was first reported in the 1950s but it was not commonly used until the 1980s.91 Since then, the use of ECMO has been extended to both infants and children after cardiac surgery – There have been nearly 4,000 patients supported with ECMO for myocardial dysfunction, with overall survival of about 37%,10 ECMO provides greater flexibility in dealing with some forms of complex congenital heart disease in which pulmonary hypertension and hypoxia contribute significantly to the pathophysiology.95 The effect of ECMO on the heart includes a decrease in preload, a slight increase in afterload, and a concomitant elevation in left ventricular wall stress Advantages include support of both right and left ventricles, improvement of systemic oxygenation, and ease of placement VA cannulation provides the optimal cardiac support when ventricular dysfunction predominates the Extracorporeal Membrane Oxygenation and Extracorporeal and Arteriovenous Carbon Dioxide Removal / 317 clinical picture However, studies have also been shown that VV bypass, primarily by improving venous oxygenation, may improve myocardial oxygenation and decrease pulmonary vascular resistance in selected patients, thus providing adequate cardiac recovery and support.96 The majority of patients have received ECMO postoperatively after repair of congenital heart defects.93,95,97 In these patients, factors associated with poor survival despite ECMO support include residual cardiac defect, single ventricle physiology, initiation of ECMO in the operating room, and failure of return of adequate cardiac function to wean from ECMO within to days Two changes in the philosophy of cardiac ECMO have occurred with time and experience The first change involves utilization of ECMO as a bridge to transplant More than 100 children have received ECMO either as a bridge to heart transplant or following cardiac transplant Key points in management of bridge to transplant patients include deciding as early as possible to list patients for transplant and avoiding complications that remove patients from transplant consideration The second change regarding cardiac ECMO involves patients with sudden cardiac arrest There are several reports of survival in patients requiring active cardiopulmonary resuscitation at the time of ECMO cannulation with overall survival ranging from 41 to 53% Rapiddeployment ECMO can be a useful tool in support of patients who suffer cardiopulmonary arrest.99 In most circumstances it is not feasible to employ ECMO as a bridge to transplant while patients wait months for an available organ ECMO can be used for short periods of support in acute cardiac failure to allow time for endorgans to recover and the patient to be diuresed to dry weight If the patient shows stabilization of end-organ function without improvement in cardiac function, the patient can be transitioned to a long-term ventricular assist device to await cardiac transplant A resurgence of interest in non–heart-beating organ donation has lead to a novel new application for ECMO Once patients have been extubated and declared dead for minutes an ECMO circuit is initiated to provide total body circulation and lessen the effects of warm ischemia time while abdominal organs are procured.100 Both technical and ethical considerations have yet to be fully resolved on this matter Perioperative Supportive ECMO Occasionally, surgical procedures are necessary while patients are on ECLS (Table 25-3) Evacuation of hemothorax, open lung biopsy, and congenital diaphragmatic hernia repair have been performed during ECMO Michaels and colleagues reported on 30 adult trauma patients, of which 19 (63.3%) underwent operative procedures while on ECMO.15 Procedures on ECMO for ongoing critical care include open reduction and internal fixation, repair of iatrogenic laceration, diagnostic peritoneal lavage, tracheostomy, abscess drainage, and gastrointestinal reconstruction.15,101 ECMO has been reported to allow unrushed, precise reconstruction during complex tracheal surgery and provide brief postoperative support – Laryngotracheoesophageal cleft repair is a complicated procedure, first reported by Geiduschek and colleagues in 1993 whose major challenge was maintaining oxygenation, both during the surgical repair and the postoperative healing period.105 An additional postoperative complication is trauma to the fresh tracheal repair from ventilator y pressures and endotracheal tube motion Geiduschek and colleagues used ECMO to facilitate surgical exposure of the defect and for postoperative respiratory support to avoid trauma to the fragile tracheal suture lines.105 Amakawa and colleagues reported using ECMO to provide gas exchange during placement of metallic stents in a patient with tracheobronchial stenosis secondary to a large metastatic tumor.106 ECMO obviated the need for an endotracheal tube and maximized exposure of the operative field Trauma to the tracheal side of the repair is minimized by maintaining ECMO postoperatively, thereby eliminating the barotrauma of positive pressure ventilation and the mechanical trauma to the posterior tracheal wall that would be produced by a larger endotracheal tube Additionally, liver transplantation, lung transplantation, heart transTABLE 25-3 Operations Performed on Neonates, Children, or Adults while on Extracorporeal Life Support (ECLS) Performed while on ECLS Tracheostomy Video-assisted thoracoscopic bullectomy Open lung biopsy Hemothorax evacuation Intracranial hematoma evacuation Cardiac catheterization Gastrointestinal reconstruction Abscess drainage Diagnostic peritoneal lavage Laceration repair Open reduction and internal fixation of fractures Skin homografting (without débridement) Facilitated by ECLS for intraoperative cardiorespiratory support Complex tracheal reconstructions for congenital tracheal stenosis Tracheobronchial stent placement for tracheobronchial stenosis from a metastatic tumor mass Laryngotracheoesophageal cleft repair Pneumonectomy Lung transplant Heart transplant 318 / Advanced Therapy in Thoracic Surgery plantation, and evacuation of intracranial hematoma in patients on ECMO have also been performed ECMO in Lung Transplantation The potential uses of extracorporeal membrane oxygenation in lung transplant patients include the support of severe pulmonary insufficiency immediately prior to transplant, the support of the lung transplant patient in the immediate postoperative period and support of late graft dysfunction during an acute rejection episode.107 Lung transplantation in a patient placed on ECMO for severe ARDS may represent the only option for those patients who fail to recover adequate pulmonary function The most common indication for ECMO in the lung transplant patient is in the immediate postoperative period as a means of support following primary graft failure or severe ischemia reperfusion injury.107–110 Primary graft failure is a potentially lethal complication of lung transplant that occurs in to 20% of recipients.111 ECMO in this scenario relinquishes the lungs from high pressure and high oxygen concentration requirements during ventilation, thereby allowing the lung to heal without additional barotrauma or oxygen toxicity A final role for ECMO in the lung transplant patient is as a supportive measure during a period of late graft dysfunction (lung failure > days after transplant).109,112 Trauma Respiratory failure adds significant morbidity, mortality, and cost to the care of patients with multiple trauma ARDS has been reported to occur in between 14 and 35% of trauma patients113–116 and to have a 50% overall mortality ECMO has been used primarily for acute cardiac support, rewarming, and oxygenation during resuscitation117–119 and for the management of acute and severe respiratory failure33,34,114,120–122 in trauma patients ECMO can provide total cardiorespiratory support for the trauma patient, allowing reduction of ventilatory support to less-damaging levels.120,123,124 The primary risk with ECMO in trauma patients is severe bleeding because of the need for systemic heparinization Hill and colleagues successfully applied ECMO to a trauma patient suffering from acute posttraumatic pulmonary insufficiency days following repair of a transected aorta 20 Anderson and associates published Bartlett’s experience with 24 moribund pediatric and adult patients who received ECMO support for respiratory failure from trauma.120 Fifteen patients (63%) survived and were discharged from the hospital Early intervention was thought to be a key factor in their successful outcome ECMO with heparin-bonded circuits can aid the resuscitation and cardiopulmonary support of massively injured patients while their primary injuries are being evalu- ated.119 ECMO has been used successfully on both pediatric and adult patients with posttraumatic ARDS requiring laparotomies for intra-abdominal injuries including splenectomy and liver lacerations.125 The Future The future of extracorporeal support depends on the development of techniques and devices to make the circuits less invasive, safer, and simpler in management Using percutaneous catheters without surgical exploration can reduce potential bleeding from wounds Most ECMO for respiratory support will be carried out in the VV mode using a single catheter with two lumens or a single-lumen tidal flow system The use of the Seldinger wire-guided technique with sequential dilators and placement of large catheters directly or with peel-away sheaths has had an impact on decreasing the incidence of bleeding complications from cannulation sites Cannulation can be accomplished quickly and easily under a variety of circumstances, including on ECMO transport and emergency access Heparin-bonded oxygenators, pump chambers, and extracorporeal circuits may allow ECMO for days without bleeding, complications, or formation of clots Various groups have tested heparin coated circuits and reported reduced thrombogenicity and reductions in required systemic heparinization for prolonged support.126–129 Applications of ECMO will include emergency room and cath lab resuscitation in cardiac failure, resuscitation in trauma and hemorrhagic shock, and use as an adjunct to perfusion and temperature control The ECMO experience has stimulated the development of artificial lung prototypes, which are being evaluated in large animal trials.130–132 The future of ECLS also includes laminar flow oxygenators; safe, simple automatic pumps; nonthrombogenic surfaces to eliminate bleeding complications; advances in respiratory and cardiac care; and new approaches to clinical trials References Rashkind WJK, Freeman A, Klein D Evaluation of a disposable plastic, low-volume, pumpless oxygenator as a lung substitute J Pediatr 1965;66:94–102 Bartlett RH, Gazzaniga AB, Jefferies MR, et al Extracorporeal membrane oxygenation (ECMO) cardiopulmonary support in infancy Trans Am Soc Artif Intern Organs 1976;22:80–93 Bartlett RH, Andrews AF, Toomasian JM, et al Extracorporeal membrane oxygenation for newborn respiratory failure: forty-five cases Surgery 1982;92:425–33 Bartlett RH, Gazzaniga AB, Wetmore NE, et al Extracorporeal membrane oxygenation (ECMO) in the treatment of cardiac and respiratory failure in children Trans Am Soc Artif Intern Organs 1980;26:578–81 Extracorporeal Membrane Oxygenation and Extracorporeal and Arteriovenous Carbon Dioxide Removal / 319 Kirkpatrick BV, Krummel TM, Mueller DG, et al Use of extracorporeal membrane oxygenation for respiratory failure in term infants Pediatrics 1983;72:872–6 Bartlett RH, Gazzaniga AB, Toomasian J, et al Extracorporeal membrane oxygenation (ECMO) in neonatal respiratory failure 100 cases Ann Surg 1986;204:236–45 The collaborative UK ECMO (Extracorporeal Membrane Oxygenation) trial: follow-up to year of age Pediatrics 1998;101:E1 Bartlett RH, Roloff DW, Cornell RG, et al Extracorporeal circulation in neonatal respiratory failure: a prospective randomized study Pediatrics 1985;76:479–87 O’Rourke PP, Crone RK, Vacanti JP, et al Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: a prospective randomized study Pediatrics 1989;84:957–63 10 Extracorporeal life support organization ECMO registry report Extracorporeal Life Support Organization; Ann Arbor (MI), July, 2003 11 Green TP, Moler FW, Goodman DM Probability of survival after prolonged extracorporeal membrane oxygenation in pediatric patients with acute respiratory failure Extracorporeal Life Support Organization Crit Care Med 1995;23:1132–9 12 Green TP, Timmons OD, Fackler JC, et al The impact of extracorporeal membrane oxygenation on survival in pediatric patients with acute respiratory failure Pediatric Critical Care Study Group Crit Care Med 1996;24:323–9 13 Goldman AP, Kerr SJ, Butt W, et al Extracorporeal support for intractable cardiorespiratory failure due to meningococcal disease Lancet 1997;349:466–9 14 Linden V, Karlen J, Olsson M, et al Successful extracorporeal membrane oxygenation in four children with malignant disease and severe Pneumocystis carinii pneumonia Med Pediatr Oncol 1999;32:25–31 15 Michaels AJ, Schriener RJ, Kolla S, et al Extracorporeal life support in pulmonary failure after trauma J Trauma 1999;46:638–45 16 O’Toole G, Peek G, Jaffe W, et al Extracorporeal membrane oxygenation in the treatment of inhalation injuries Burns 1998;24:562–5 17 Dos Santos CC, Slutsky AS Invited review: mechanisms of ventilator-induced lung injury: a perspective J Appl Physiol 2000;89:1645–55 18 Laffey JG, Kavanagh BP Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury N Engl J Med 2000;343:812–4 19 Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respirator y distress syndrome The Acute Respiratory Distress Syndrome Network N Engl J Med 2000;342:1301–8 20 Hill JD, O’Brien TG, Murray JJ, et al Prolonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock-lung syndrome) Use of the Bramson membrane lung N Engl J Med 1972;286:629–34 21 Zapol WM, Snider MT, Hill JD, et al Extracorporeal membrane oxygenation in severe acute respiratory failure A randomized prospective study JAMA 1979;242:2193–6 22 Gattinoni L, Pesenti A, Mascheroni D, et al Lowfrequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure JAMA 1986;256:881–6 23 Bartlett RH, Anderson HL III Extracorporeal membrane oxygenation revisited Ann Thorac Surg 1992;53:738–9 24 Pranikoff T, Hirschl RB, Remenapp R, et al Venovenous extracorporeal life support via percutaneous cannulation in 94 patients Chest 1999;115:818–22 25 Zwischenberger JB, Toomasian JM, Drake K, et al Total respiratory support with single cannula venovenous ECMO: double lumen continuous flow vs single lumen tidal flow Trans Am Soc Artif Intern Organs 1985;31:610–5 26 Anderson HL III, Otsu T, Chapman RA, et al Venovenous extracorporeal life support in neonates using a double lumen catheter ASAIO Trans 1989;35:650–3 27 Anderson HL III, Snedecor SM, Otsu T, et al Multicenter comparison of conventional venoarterial access versus venovenous double-lumen catheter access in newborn infants undergoing extracorporeal membrane oxygenation J Pediatr Surg 1993;28:530–4 28 Chevalier JY, Couprie C, Larroquet M, et al Venovenous single lumen cannula extracorporeal lung support in neonates A five year experience ASAIO J 1993;39:M654–8 29 Kolla S, Crotti S, Lee WA, et al Total respiratory support with tidal flow extracorporeal circulation in adult sheep ASAIO J 1997;43:M811–6 30 Kolobow T An update on adult extracorporeal membrane oxygenation-extracorporeal CO2 removal ASAIO Trans 1988;34:1004–5 31 Kolobow T, Gattinoni L, Tomlinson T, et al An alternative to breathing J Thorac Cardiovasc Surg 1978;75:261–6 32 Anderson H III, Steimle C, Shapiro M, et al Extracorporeal life support for adult cardiorespiratory failure Surgery 1993;114:161–72 33 Kolla S, Awad SS, Rich PB, et al Extracorporeal life support for 100 adult patients with severe respiratory failure Ann Surg 1997;226:544–64 34 Rich PB, Awad SS, Kolla S, et al An approach to the treatment of severe adult respiratory failure J Crit Care 1998;13:26–36 35 Wung JT, Sahni R, Moffitt ST, et al Congenital diaphragmatic hernia: survival treated with very delayed surgery, spontaneous respiration, and no chest tube J Pediatr Surg 1995;30:406–9 320 / Advanced Therapy in Thoracic Surgery 36 Alpard SK, Zwischenberger JB, Tao W, et al Reduced ventilator pressure and improved P/F ratio during percutaneous arteriovenous carbon dioxide removal for severe respiratory failure Ann Surg 1999;230:215–24 37 Alpard SK, Zwischenberger JB, Tao W, et al New clinically relevant sheep model of severe respiratory failure secondary to combined smoke inhalation/cutaneous flame burn injury Crit Care Med 2000;28:1469–76 38 Brunston RL Jr, Tao W, Bidani A, et al Prolonged hemodynamic stability during arteriovenous carbon dioxide removal for severe respirator y failure J Thorac Cardiovasc Surg 1997;114:1107–14 39 Brunston RL Jr, Tao W, Bidani A, et al Determination of low blood flow limits for arteriovenous carbon dioxide removal ASAIO J 1996;42:M845–9 40 Brunston RL Jr, Zwischenberger JB, Tao W, et al Total arteriovenous CO2 removal: simplifying extracorporeal support for respirator y failure Ann Thorac Surg 1997;64:1599–604 41 Conrad SA, Zwischenberger JB, Grier LR, et al Total extracorporeal arteriovenous carbon dioxide removal in acute respiratory failure: a phase I clinical study Intensive Care Med 2001;27:1340–51 50 Alpard SK, Tao W, Bidani A, et al Intravascular membrane oxygenation and carbon dioxide removal — devices and management techniques In: Zwischenberger JB, Barlett RH, editors Extracorporeal cardiopulmonary support in critical care Ann Arbor (MI): ELSO; 2000 p 735–61 51 Alpard SK, Zwischenberger JB Extracorporeal membrane oxygenation and respiratory and cardiac support In: Gravlee GP, Davis, Utley, et al, editors Cardiopulmonary bypass: principles and practice Williams and Wilkins; 2000 p 662–95 52 Rich PB, Awad SS, Crotti S, et al A prospective comparison of atrio-femoral and femoro-atrial flow in adult venovenous extracorporeal life support J Thorac Cardiovasc Surg 1998;116:628–32 53 Karl TR, Sano S, Brawn WJ, et al Critical aortic stenosis in the first month of life: surgical results in 26 infants Ann Thorac Surg 1990;50:105–9 54 Kolobow T, Moretti MP, Mascheroni D, et al Experimental meconium aspiration syndrome in the preterm fetal lamb: successful treatment using the extracorporeal artificial lung Trans Am Soc Artif Intern Organs 1983;29:221–6 42 Frank BR, Tao W, Brunston RL Jr, et al High flow/low resistance cannulas for percutaneous arteriovenous carbon dioxide removal ASAIO J 1997;43:M817–20 55 Keszler M, Ryckman FC, McDonald JV Jr, et al A prospective, multicenter, randomized study of high versus low positive end-expiratory pressure during extracorporeal membrane oxygenation J Pediatr 1992;120:107–13 43 Jayroe JB, Alpard SK, Wang D, et al Hemodynamic stability during arteriovenous carbon dioxide removal for adult respiratory distress syndrome: a prospective randomized outcomes study in adult sheep ASAIO J 2001;47:211–4 56 Shapiro MB, Kleaveland AC, Bartlett RH Extracorporeal life support for status asthmaticus Chest 1993;103:1651–4 44 Tao W, Brunston RL Jr, Bidani A, et al Significant reduction in minute ventilation and peak inspiratory pressures with arteriovenous CO2 removal during severe respiratory failure Crit Care Med 1997;25:689–95 45 Zwischenberger JB, Alpard SK, Tao W, et al Percutaneous extracorporeal arteriovenous carbon dioxide removal improves survival in respiratory distress syndrome: a prospective randomized outcomes study in adult sheep J Thorac Cardiovasc Surg 2001;121:542–51 46 Zwischenberger JB, Conrad SA, Alpard SK, et al Percutaneous extracorporeal arteriovenous CO2 removal for severe respirator y failure Ann Thorac Surg 1999;68:181–7 47 Conrad SA, Brown EG, Grier LR, et al Arteriovenous extracorporeal carbon dioxide removal: a mathematical model and experimental evaluation ASAIO J 1998;44:267–77 57 Upp JR Jr, Bush PE, Zwischenberger JB Complications of neonatal extracorporeal membrane oxygenation Perfusion 1994;9:241–56 58 Zwischenberger JB, Nguyen TT, Upp JR Jr, et al Complications of neonatal extracorporeal membrane oxygenation Collective experience from the Extracorporeal Life Support Organization J Thorac Cardiovasc Surg 1994;107:838–48 59 Sell LL, Cullen ML, Whittlesey GC, et al Hemorrhagic complications during extracorporeal membrane oxygenation: prevention and treatment J Pediatr Surg 1986;21:1087–91 60 Karl TR Extracorporeal circulatory support in infants and children Semin Thorac Cardiovasc Surg 1994;6:154–60 61 Downard CD, Betit P, Chang RW, et al Impact of AMICAR on hemorrhagic complications of ECMO: a ten-year review J Pediatr Surg 2003;38:1212–6 48 Zwischenberger JB, Conrad SA, Alpard SK, et al Percutaneous extracorporeal arteriovenous CO2 removal for severe respirator y failure Ann Thorac Surg 1999;68:181–7 62 Anderson HL III, Cilley RE, Zwischenberger JB, et al Thrombocytopenia in neonates after extracorporeal membrane oxygenation ASAIO Trans 1986;32:534–7 49 Wang D, Lick S, Alpard SK, et al Toward ambulatory arterio-venous CO2 removal: initial studies and prototype development ASAIO J 2003;49:564–7 63 DePuydt LE, Schuit KE, Smith SD Effect of extracorporeal membrane oxygenation on neutrophil function in neonates Crit Care Med 1993;21:1324–7 Extracorporeal Membrane Oxygenation and Extracorporeal and Arteriovenous Carbon Dioxide Removal / 321 64 Robinson TM, Kickler TS, Walker LK, et al Effect of extracorporeal membrane oxygenation on platelets in newborns Crit Care Med 1993;21:1029–34 65 Zwischenberger JB, Bartlett RH Extracorporeal circulation for respiratory or cardiac failure Semin Thorac Cardiovasc Surg 1990;2:320–31 66 Zwischenberger JB, Lilley RE, Hirschl RB, et al Lifethreatening intrathoracic complications during treatment with extracorporeal membrane oxygenation J Pediatr Surg 1988;23:599–604 79 Al-Shanafey S, Giacomantonio M, Henteleff H Congenital diaphragmatic hernia: experience without extracorporeal membrane oxygenation Pediatr Surg Int 2002;18:28–31 80 Downard CD, Jaksic T, Garza JJ, et al Analysis of an improved survival rate for congenital diaphragmatic hernia J Pediatr Surg 2003;38:729–32 81 Connors RH, Tracy T Jr, Bailey PV, et al Congenital diaphragmatic hernia repair on ECMO J Pediatr Surg 1990;25:1043–6 67 Zwischenberger JB, Bovers RM, Pickens GJ Tension pneumothorax during extracorporeal membrane oxygenation Ann Thoracic Surg 1989;48:365–70 82 Lally KP, Paranka MS, Roden J, et al Congenital diaphragmatic hernia Stabilization and repair on ECMO Ann Surg 1992;216:569–73 68 O’Neill J, Schutze G, Heulitt MJ, Taylor BJ Nosocomial infection during extracorporeal life support Presented at the 10th Annual ELSO Conference; 1999 Sept 23–26; Ann Arbor, Michigan 83 Stolar CJ, Crisafi MA, Driscoll YT Neurocognitive outcome for neonates treated with extracorporeal membrane oxygenation: are infants with congenital diaphragmatic hernia different? J Pediatr Surg 1995;30:366–71 69 Hardesty RL, Griffith BP, Debski RF, et al Extracorporeal membrane oxygenation Successful treatment of persistent fetal circulation following repair of congenital diaphragmatic hernia J Thorac Cardiovasc Surg 1981;81:556–63 70 Adzick NS, Harrison MR, Glick PL, et al Diaphragmatic hernia in the fetus: prenatal diagnosis and outcome in 94 cases J Pediatr Surg 1985;20:357–61 71 Harrison MR, Adzick NS, Estes JM, et al A prospective study of the outcome for fetuses with diaphragmatic hernia JAMA 1994;271:382–4 72 Lessin MS, Thompson IM, Deprez MF, et al Congenital diaphragmatic hernia with or without extracorporeal membrane oxygenation: are we making progress? J Am Coll Surg 1995;181:65–71 73 Sharland GK, Lockhart SM, Heward AJ, et al Prognosis in fetal diaphragmatic hernia Am J Obstet Gynecol 1992;166:9–13 74 Wilson JM, Lund DP, Lillehei CW, et al Congenital diaphragmatic hernia: predictors of severity in the ECMO era J Pediatr Surg 1991;26:1028–33 75 Kays DW Detrimental effects of standard medical therapy in congenital diaphragmatic hernia Ann Surg 1999;230:340–8 76 Inhaled nitric oxide and hypoxic respiratory failure in infants with congential diaphragmatic hernia The Neonatal Inhaled Nitric Oxide Study Group (NINOS) Pediatrics 1997;99:838–45 77 Boloker J Congential diaphragmatic hernia in 120 infants treated consecutively with permissive hypercapnia/spontaneous respiration/elective repair J Pediatr Surg 2002;37:357–66 78 Frenckner B, Ehren H, Granholm T, et al Improved results in patients who have congential diaphragmatic hernia using preoperative stabilization, extracorporeal membrane oxygenation, and delayed surgery J Pediatr Surg 1997;32:1185–9 84 Wilson JM, Bower LK, Lund DP Evolution of the technique of congenital diaphragmatic hernia repair on ECMO J Pediatr Surg 1994;29:1109–12 85 Wilson JM, Lund DP, Lillehei CW, et al Delayed repair and preoperative ECMO does not improve survival in high-risk congenital diaphragmatic hernia J Pediatr Surg 1992;27:368–72 86 Adolph V, Flageole H, Perreault T, et al Repair of congenital diaphragmatic hernia after weaning from extracorporeal membrane oxygenation J Pediatr Surg 1995;30:349–52 87 Sigalet DL, Tierney A, Adolph V, et al Timing of repair of congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation support J Pediatr Surg 1995;30:1183–7 88 Kugelman A, Gangitano E, Pincros J, et al Venovenous versus venoarterial extracorporeal membrane oxygenation in congenital diaphragmatic hernia J Pediatr Surg 2003;38:1131–6 89 Pettignano R, Fortenberry JD, Heard ML, et al Primary use of the venovenous approach for extracorporeal membrane oxygenation in pediatric acute respiratory failure Pediatr Crit Care Med 2003;4:291–8 90 Lally KP The use of ECMO for stabilization of infants with congenital diaphragmatic hernia — a report of The Congenital Diaphragmatic Study Group Presented at the 13th Annual ELSO Conference; 2002 Sept 27–29; Scottsdale, Arizona 91 Bartlett RH, Gazzaniga AB, Fong SW, et al Extracorporeal membrane oxygenator support for cardiopulmonary failure Experience in 28 cases J Thorac Cardiovasc Surg 1977;73:375–86 92 Bavaria JE, Ratcliffe MB, Gupta KB, et al Changes in left ventricular systolic wall stress during biventricular circulatory assistance Ann Thorac Surg 1988;45:526–32 93 Kanter KR, Pennington G, Weber TR, et al Extracorporeal membrane oxygenation for postoperative cardiac support in children J Thorac Cardiovasc Surg 1987;93:27–35 322 / Advanced Therapy in Thoracic Surgery 94 Mehta U, Laks H, Sadeghi A, et al Extracorporeal membrane oxygenation for cardiac support in pediatric patients Am Surg 2000;66:879–86 95 Duncan BW, Hraska V, Jonas RA, et al Mechanical circulatory support in children with cardiac disease J Thorac Cardiovasc Surg 1999;117:529–42 96 Miyamura H, Sugawara MA, Watanabe H, et al BlalockTaussig operation with an assist of venovenous extracorporeal membrane oxygenation Ann Thorac Surg 1996;62:565–6 108 Glassman LR, Keenan RJ, Fabrizio MC, et al Extracorporeal membrane oxygenation as an adjunct treatment for primary graft failure in adult lung transplant recipients J Thorac Cardiovasc Surg 1995;110:723–6 109 Macha M, Griffith BP, Keenan R, et al ECMO support for adult patients with acute respiratory failure ASAIO J 1996;42:M841–4 110 Slaughter MS, Nielsen K, Bolman RM III Extracorporeal membrane oxygenation after lung or heart-lung transplantation ASAIO J 1993;39:M453–6 97 del Nido PJ Extracorporeal membrane oxygenation for cardiac support in children Ann Thorac Surg 1996;61:336–9 111 Zenati M, Yousem SA, Dowling RD, et al Primary graft failure following pulmonary transplantation Transplantation 1990;50:165–7 98 Dalton HJ, Siewers RD, Fuhrman BP, et al Extracorporeal membrane oxygenation for cardiac rescue in children with severe myocardial dysfunction Crit Care Med 1993;21:1020–8 112 Whyte RI, Deeb GM, McCurry KR, et al Extracorporeal life support after heart or lung transplantation Ann Thorac Surg 1994;58:754–8 99 Duncan BW, Ibrahim AE, Hraska V, et al Use of rapiddeployment extracorporeal membrane oxygenation for the resuscitation of pediatric patients with heart disease after cardiac arrest J Thorac Cardiovasc Surg 1998;116:305–11 100 Bartlett R, Arenas J, Ruddich S, et al ECLS for support of “Cardiac Death” organ donors Presented at the 14th Annual ELSO Conference; 2003 Sept 12–14; Chicago, Illinois 101 Voelckel W, Wenzel V, Rieger M, et al Temporary extracorporeal membrane oxygenation in the treatment of acute traumatic lung injur y Can J Anaesth 1998;45:1097–102 102 Angel C, Murillo C, Zwischenberger J, et al Perioperative extracorporeal membrane oxygenation for tracheal reconstruction in congenital tracheal stenosis Pediatr Surg Int 2000;16:98–101 103 Connolly KM, McGuirt WF Jr Elective extracorporeal membrane oxygenation: an improved perioperative technique in the treatment of tracheal obstruction Ann Otol Rhinol Laryngol 2001;110:205–9 104 Kamata S, Usui N, Ishikawa S, et al Experience in tracheobronchial reconstruction with a costal cartilage graft for congenital tracheal stenosis J Pediatr Surg 1997;32:54–7 105 Geiduschek JM, Inglis AF Jr, O’Rourke PP, et al Repair of a laryngotracheoesophageal cleft in an infant by means of extracorporeal membrane oxygenation Ann Otol Rhinol Laryngol 1993;102:827–33 106 Amakawa K, Tsuno K, Adachi N, et al Placement of selfexpanding metallic stents in the stenotic trachea and bronchus under the support of gas exchange by extracorporeal lung assist (ECLA) Masui 1998;47:180–4 107 Zenati M, Pham SM, Keenan RJ, et al Extracorporeal membrane oxygenation for lung transplant recipients with primary severe donor lung dysfunction Transpl Int 1996;9:227–30 113 Maunder RJ, Hudson LD Management of adult respiratory distress syndrome In: Kelly WN, editor Textbook of internal medicine Philadelphia (PA): Lippincott; 1988 114 Maunders RG, Hudson LD Clinical risks associated with the adult respiratory distress syndrome In: Zapol WM, Lemaire F, editors ARDS New York: Marcel Dekker; 1991 115 Montgomery AB, Stager MA, Carrico CJ, et al Causes of mortality in patients with the adult respiratory distress syndrome Am Rev Respir Dis 1985;132:485–9 116 Pepe PE, Potkin RT, Reus DH, et al Clinical predictors of the adult respiratory distress syndrome Am J Surg 1982;144:124–30 117 Bennett JB, Hill JG, Bruhn PS Heparin-free cardiopulmonary support, utilizing a Carmeda coated circuit for a patient with pulmonary hemorrhage and multiple trauma J Extra Corpor Technol 1992;23:86 118 Hill JG, Bruhn PS, Cohen SE, et al Emergent applications of cardiopulmonary support: a multiinstitutional experience Ann Thorac Surg 1992;54:699–704 119 Perchinsky MJ, Long WB, Hill JG, et al Extracorporeal cardiopulmonary life support with heparin-bonded circuitry in the resuscitation of massively injured trauma patients Am J Surg 1995;169:488–91 120 Anderson HL III, Shapiro MB, Delius RE, et al Extracorporeal life support for respiratory failure after multiple trauma J Trauma 1994;37:266–72 121 Bartlett RH Extracorporeal life support for cardiopulmonary failure Curr Probl Surg 1990;27:621–705 122 Pranikoff T, Hirschl RB, Steimle CN, et al Efficacy of extracorporeal life support in the setting of adult cardiorespiratory failure ASAIO J 1994;40:M339–43 123 Anderson HL III, Coran AG, Schmeling DJ Extracorporeal life support (ECLS) for pediatric trauma: experience with five cases J Pediatr Surg 1990;5:302 124 Sasadeusz KJ, Long WB III, Kemalyan N, et al Successful treatment of a patient with multiple injuries using extracorporeal membrane oxygenation and inhaled nitric oxide J Trauma 2000;49:1126–8 Extracorporeal Membrane Oxygenation and Extracorporeal and Arteriovenous Carbon Dioxide Removal / 323 125 Fortenberr y JD, Meier AH, Pettignano R, et al Extracorporeal life support for posttraumatic acute respiratory distress syndrome at a children’s medical center J Pediatr Surg 2003;38:1221–6 126 Moen O, Fosse E, Braten J, et al Differences in blood activation related to roller/centrifugal pumps and heparincoated/uncoated surfaces in a cardiopulmonary bypass model circuit Perfusion 1996;11:113–23 129 Weerwind PW, van der Veen FH, Lindhout T, et al Ex vivo testing of heparin-coated extracorporeal circuits: bovine experiments Int J Artif Organs 1998;21:291–8 130 Lick SD, Zw ischenberger JB, Alpard SK, et al Development of an ambulatory artificial lung in an ovine survival model ASAIO J 2001;47:486–91 127 Nojiri C, Hagiwara K, Yokoyama K, et al Evaluation of a new heparin bonding process in prolonged extracorporeal membrane oxygenation ASAIO J 1995;41:M561–7 131 Lick SD, Zwischenberger JB, Wang D, et al Improved right heart function with a compliant inflow artificial lung in series with the pulmonary circulation Ann Thorac Surg 2001;72:899–904 128 Palmer K, Ehren H, Benz R, et al Carmeda surface heparinization in neonatal ECMO systems: long-term experiments in a sheep model Perfusion 1995;10:307–13 132 Lynch WR, Montoya JP, Brant DO, et al Hemodynamic effect of a low-resistance artificial lung in series with the native lungs of sheep Ann Thorac Surg 2000;69:351–6 CHAPTER 26 LUNG PRESERVATION FOR TRANSPLANTATION ANDREW F PIERRE, MD, MSC, FRCSC SHAF KESHAVJEE, MD, MSC, FRCSC, FACS sion of the deflated lung was the preservation technique of choice A coordinated effort was established at the University of Toronto under the direction of Dr Joel Cooper, and in 1983 this resulted in the first successful clinical single lung transplant.7 Again, preservation for that case consisted simply of hypothermic immersion of the atelectatic donor lung The patient lived years and died of renal failure Hypothermic atelectatic immersion continued to be used by the Toronto Lung Transplant Group from 1983 to 1987 for both single and then double lung transplantation However, this technique has subsequently given way to a single antegrade pulmonary artery flush with hypothermic solutions of various compositions Current lung preservation techniques in common use allow for distant procurement with reliable graft function after to hours of ischemia Donors no longer need to be transported to the recipient institution, thus allowing better organ distribution from the multiorgan donor The surgical techniques for lung preservation and extraction from the donor also allow for separate procurement of heart and lung grafts that may then be sent to different institutions Prediction of early lung dysfunction in lung transplantation has proved difficult because of the complexity of the interactions between the donor lung and the recipient In order to determine the influence of donor and recipient parameters, Sommers and colleagues have compared early allograft function after single lung transplantation in twin recipients, each of them receiving one lung from the same donor.8 They observed that immediate allograft function was associated with donor-related characteristics, but these lost importance over the ensuing 24 hours after transplantation Factors that have been shown to influence postoperative lung function include Since 1983, lung transplantation has enjoyed increasing success and has become the mainstay of therapy for endstage lung disease Currently, approximately 10,000 lung transplantations have been performed worldwide and more than 1,000 transplants are performed annually.1 The goal of lung preservation is to minimize the effects of ischemia and reperfusion injury on the transplanted lung Refinements in lung preservation techniques have significantly increased organ availability and sharing, and reduced post-transplant organ dysfunction However, despite the improvements in lung preservation, the majority of recipients still develop some degree of reperfusion injury,2,3 and approximately 20% of them experience severe reperfusion injury, requiring extended support with positive pressure ventilation, pharmacological therapy, and occasionally extracorporeal membrane oxygenation.4,5 In addition to a high mortality rate in the early postoperative period, severe reperfusion injury may also be associated with an increased risk of acute rejection that may lead to graft dysfunction in the long term.6 The optimal techniques for lung preservation have not been discovered and this remains an area of active basic and clinical investigation Hardy reported the first clinical attempt at a lung transplant in 1963 Lung preservation consisted simply of topical cooling with the graft stored in an atelectatic state The donor was located at the same institution and thus the ischemic time was kept short The donor for that initial transplant had in fact died of a myocardial infarction and there was a period of warm ischemia before the graft was harvested Nevertheless, the recipient lived 19 days and had adequate gas exchange for some of this time There were approximately 40 failed clinical attempts following Hardy’s pioneering case Hypothermic immer324 Lung Preservation for Transplantation / 325 donor age, length of donor hospitalization, as well as primary pulmonary hypertension and a body mass index greater than 27 kg/m2 in the recipient.8–10 Organ transplantation is also limited by a significant shortage of available donor organs Approximately 20% of patients die while waiting for suitable organs every year.11,12 Various strategies such as living-related donors and non–heart-beating donors have been introduced in the field of lung transplantation in attempt to reduce the shortage of organs.13,14 However, the primary source to make up the shortage of lung donors may potentially be derived from heart-beating cadaveric donors Indeed, currently only 10 to 20% of lung donors are deemed suitable for transplantation because of trauma, aspiration, or pulmonary edema Hence, over the last few years, there has been a tendency to extend lung donor criteria to decrease the organ shortage.15 In the future, the development of new strategies to improve the quality of donor lungs and their tolerance to the phenomenon of ischemia-reperfusion could have a tremendous impact on the number of transplants performed and on the recipients’ outcome In this report, we review the current state of the art in lung preservation and future strategies to improve post-transplant lung function Donor Assessment The success of lung preservation primarily depends on proper organ selection Indeed, a number of donor events such as mechanism of injury, brain death, aspiration, episodes of hypotension, mechanical ventilation, and others can potentially affect lung function and its tolerance to ischemia However, the impact of these events on the development of ischemia-reperfusion injury has been difficult to assess Currently, the parameters used to assess donor lungs are based on donor history, arterial blood gas tensions, chest radiograph appearance, bronchoscopy findings, and physical examination of the lung at the time of retrieval.16 These parameters attempt to determine the function and viability of the lung, but their accuracy in determining the risk of reperfusion injury is not optimal and correlates poorly with the risk of primary graft dysfunction.17–19 The repercussions of brain stem death on organ function has been extensively studied over the last few years Studies have demonstrated that brain death causes disruption in homeostatic regulation with profound disturbance in endocrine function.20 This is characterized by sudden rises in circulating catecholamines associated with systemic and pulmonary hypertension (“autonomic storm”) In addition, a sudden fall in thyroid hormone levels associated with disturbance in insulin and glucagon regulation may cause defective aerobic metabolism with a decrease in intracellular high-energy phosphates, reduced levels of tissue and circulating glycogen, and mitochondrial dysfunction The clinical importance of these changes has been demonstrated by the functional improvement of borderline heart donors after an aggressive approach that included invasive monitoring, a bolus of steroids (methylprednisolone 15 mg/kg) and a continuous infusion of insulin, vasopressin, and triiodothyronine In lung transplantation, Follette and colleagues have also shown that the injection of a bolus of steroids (methylprednisolone ~15 mg/kg) after brain death declaration can improve arterial oxygen tension and increase lung donor recovery when compared with a historical control group of lung donors.21 The bolus of steroids may compensate for the deficit in hypophyseal hormones as well as limit the inflammatory reaction due to brain death Recent animal studies have shown that sudden brain death induced by inflation of an intracranial Fogarty catheter can produce an intense systemic inflammation The inflammatory reaction is characterized by the release of cytokines, the upregulation of adhesion molecules, and the expression of major histocompatibility complex (MHC) class I and II antigens, as well as by an infiltration of leukocytes into various organs.22 This phenomenon is enhanced by episodes of hypotension and is associated with progressive organ dysfunction that may reduce their tolerance to ischemia and be associated with accelerated graft rejection.23,24 In the human, organs donation from living donors and from cadaveric donors represents a unique situation to study the effect of brain death on early outcome Recent studies have shown that kidney biopsies from cadaveric kidney donors had significantly higher levels of inflammatory cytokines, adhesion molecules, and human leukocyte antigen (HLA)-DR than did biopsies from living donors and that the expression of these markers on tubular cells before transplantation was associated with a higher incidence of primary graft dysfunction and early acute rejection.25,26 In human lung transplantation, the chemokine interleukin-8 (IL-8) has been shown to be up-regulated in bronchoalveolar lavage (BAL) from brain-dead donors and the level was found to significantly correlate with the incidence of primary graft dysfunction after reperfusion.27 In the future, methods to rapidly assess the degree of inflammation in the lung, for instance by measuring the levels of proinflammatory cytokines or adhesion molecules may be extremely useful to determine the type of lung suitable for transplantation and its tolerance to prolonged ischemia These methods would help to reduce the incidence of primary graft failure and to optimize the current shortage of organs avail- 326 / Advanced Therapy in Thoracic Surgery able for transplantation Lung Preservation Solutions Currently, most centers have adopted a single antegrade pulmonar y arter y flush to preserve the lungs Preservation solutions include intracellular-type solutions, such as modified Euro-Collins (EC) and University of Wisconsin (UW), and extracellular-type solutions, such as low-potassium dextran (LPD) and Celsior EC was developed for kidney preservation, UW for liver preservation, and Celsior for heart preservation LPD is the only solution specifically developed for lung preservation LPD glucose solution (Perfadex; Vitrolife, Uppsala, Sweden) has become available for clinical practice in most European and North American countries, and many centers have recently switched to the use of LPD glucose as their clinical lung preservation solution (Table 26-1) The concept of using a modified extracellular fluid solution to preserve the lung was developed in Japan in the mid-1980s Fujimura and colleagues demonstrated that a modified extracellular solution was superior to the intracellularly based EC solution for prolonged lung allograft preservation Following these experiments, Keshavjee and colleagues demonstrated that the association of low-potassium (4 mmol/L) and dextran 40 (2%) provided significantly better lung function than EC after 12 hours of ischemic time in a canine model of left single lung transplantation 30 The same group also demonstrated that the combination of both dextran 40 and lowpotassium concentration during the pulmonary flush and storage period was more beneficial than the use of low-potassium or dextran alone 31,32 Following these experiments, Date and colleagues observed that the addition of 1% glucose to the LPD solution provided a substrate for the aerobic metabolism that takes place in the inflated stored lungs and allowed for the safe extension of the ischemic time to 24 hours in dogs.33 Steen and colleagues as well as other groups repeated these experiments and found safe pulmonary preservation for 12 to 24 hours with LPD glucose in porcine, canine, and TABLE 26-1 Composition and Ionic Concentration of Perfadex Solution Composition Dextran 40 NaCl KCl MgSO4 Na2HPO4 KHPO4 Dextrose pH 50 g/L g/L 0.4 g/L 98 mg/L 46 mg/L 63 mg/L g/L 7.5 Ionic Concentration (mmol/L) Sodium Potassium Magnesium Glucose Chloride Sulfate Total phosphates Osmolarity 138 0.8 142 0.8 0.8 295 mmol/L primate models of left single and double lung transplantation.34,35 In his experiments, Dr Steen increased the concentration of dextran from to 5%, which has been shown to further increase cell viability after prolonged ischemic storage.36 Ultrastructural analyses have shown significantly better conservation of lung integrity with extracellular type preservation solutions than with intracellularly based solutions Although these findings may not translate into better lung function after short ischemic periods, after up to hours of ischemic time or longer, lungs preserved with LPD solution have always had significantly better lung function upon reperfusion than lungs preserved with intracellular-type preservation solutions.37–39 Celsior, which is an extracellular-type preservation solution developed for the heart, has also been shown to achieve good results in experimental lung preservation.40 Only one study has compared Celsior with LPD in lung preservation and found that Celsior was slightly better.41 However, in contrast to LPD, which does not have antioxidant properties,42 Celsior contains high amounts of reduced glutathione, histidine, and lactobionate, which may play an important role in the prevention of free radical injury Future studies should determine if the addition of antioxidants or radical scavengers could enhance the quality of LPD solution As previously mentioned, the beneficial effect of LPD is owing to the combination of both a low potassium concentration and the presence of dextran.32 Low potassium concentration may be less detrimental to the functional and structural integrity of endothelial cells, which may thus produce fewer oxidants and release fewer pulmonary vasoconstrictors.31,43 Dextran 40 is a macromolecule with an average molecular weight of 40 kD, exerting an oncotic pressure of mm Hg and 24 mm Hg when diluted at concentrations of and 5%, respectively The oncotic pressure obtained with a dilution of 5% should therefore prevent the expansion of the interstitial space during the flush period if the perfusion pressure is kept lower than 24 mm Hg However, despite their large size, the molecules of dextran 40 may still be able to partially filter through capillary pores, especially at low temperature Hence, larger molecules of dextran, such as dextran 70 or dextran 160 with a mean molecular weight of 70 kD and 160 kD, respectively, have been advocated by Fukuse and colleagues.44 Dextran also improves erythrocyte deformability, prevents erythrocyte aggregation, and induces disaggregation of already aggregated cells, in addition to an antithrombotic effect induced by coating endothelial surfaces and platelets.32 These effects improve pulmonary microcirculation and preserve the endothelial–epithelial barrier, which may secondarily prevent the no-reflow Lung Preservation for Transplantation / 327 phenomenon and reduce the degree of water and protein extravasation at the time of reperfusion In vitro studies have demonstrated that LPD solution (1) can exert a suppressive effect on polymorphonuclear leukocyte chemotaxis,45 (2) be less cytotoxic for type II pneumocytes,46 and (3) maintain better activity of the alveolar epithelial Na+,K+-adenosinetriphosphatase (ATPase) function during the cold ischemic time when compared with EC or UW solution.47 These effects may result in less lipid peroxidation and better surfactant function at the end of the ischemic time and after reperfusion.48,49 Raffinose is a trisaccharide sugar with a mean molecular weight of 594 daltons that prevents pulmonary water diffusion and cellular swelling in a more efficient way than monosaccharides and dissaccharides Raffinose has been demonstrated to be one of the essential components of the UW solution when compared with EC solution in an ex vivo rat model of lung graft reperfusion.50 Following on these experiments, we have recently shown that the addition of raffinose to LPD glucose may further reduce ischemia-reperfusion injury and improve lung function after 24 hours of ischemic time in a rat single lung transplant model.51 In a subsequent experiment, we have shown that the beneficial effect of raffinose when added to the LPD glucose solution was a result of less tissue damage and better cellular integrity at the end of the ischemic time.52 Three clinical reports have compared the effect of LPD glucose with a historical control group of lungs preserved with EC.53–55 All three reports showed significantly better lung function and a trend towards lower 30day mortality with LPD glucose Currently, the limitation in extending the clinical ischemic time is most likely related to the increasing use of nonideal lung donors rather than to poor lung preservation In our experience, the ischemic time has been safely extended to 17 hours in the case of an excellent donor who was a 16-year-old female intubated for less than 24 hours with excellent gas exchange at the time of retrieval The majority of clinical and experimental evidence suggests that LPD glucose may be the preservation solution of choice for lung transplantation Continuous refinement is nevertheless still required, and in the future, raffinose as well as other components such as reduced glutathione, histidine, and lactobionate may be added to the initial solution to enhance the quality of its preservation Volume, Pressure, and Temperature of Flush Solution Few studies analyzed the effect of pressure, volume, and temperature of the preservation solution during flushing In 1986, after observing that flush perfusion at low flow rates (3–5 cc/kg/min) achieved poor results after moderate to long-term storage, Haverich and colleagues compared a low perfusate volume given at a low flow rate (20 cc/kg given in min) with a low perfusate volume given at a high flow rate (20 cc/kg given in 1.3 min) and a high perfusate volume given at a high flow rate (60 cc/kg given in min).56 They found that lungs flushed with a high perfusate volume given at a high flow rate had a mean pulmonary artery pressure (PAP) of 18 mm Hg during the flushing period, which resulted in significantly better cooling of the lungs and better lung function after reperfusion This study has never been repeated with more refined groups below or above 60 cc/kg However, Steen and colleagues suggested using 150 to 180 mL/kg of LPD glucose to obtain a more uniform and clean washout of the anterior part of the lungs, which is usually less well flushed because of the pressure gradient in the supine position.34 More recently, Sasaki and colleagues analyzed in a systematic fashion the influence of PAP during the flushing period on lung preservation.57 They observed that flushing pressures of 10 to 15 mm Hg were associated with complete flushing of the pulmonary vascular beds and achieved significantly better lung function after reperfusion than did flushing pressures of 5, 20, and 25 mm Hg in an ex vivo rabbit lung perfusion model They also observed that flushing pressures equal or superior to 20 mm Hg were associated with significantly less endogenous nitric oxide (NO) production, which may have had a detrimental effect on the lungs after reperfusion.58 A flushing pressure of 10 to 15 mm Hg can be precisely achieved by measuring the PAP during the flushing period and by modifying the height of the flushing solution, which should be at approximately 40 to 50 cm above the operating table according to the size of the tubing system The temperature of the flush solution has been the subject of more discussion Andrade and coworkers have observed in an isolated rat model that hypothermic artery flushing with 60 mL/kg of EC solution at a pressure of 15 mm Hg can transiently increase the capillary filtration coefficient and induce persistent lung damage with increased wet-to-dry weight ratio and biochemical surfactant changes.59 This finding could be explained by two mechanisms: one is the absence of an oncotic component in the EC solution to maintain adequate fluid balance between the intravascular and extravascular compartments, and the second is the effect of hypothermia on endothelial cells As mentioned previously, LPD solution has been shown to be superior to EC partially because it contains dextran 40 at a concentration of 5%, which should 328 / Advanced Therapy in Thoracic Surgery prevent the expansion of the interstitial space during the flush period if the perfusion pressure is kept lower than 24 mm Hg However, the use of a cold flushing solution may induce some injuries to the alveolocapillar y membrane, which can enhance the abnormal relaxation of the vascular endothelium after several hours of ischemia.60 Wang and his colleagues showed that a temperature of 23°C for the flush solution was associated with less pulmonary vascular resistance during flushing and more uniform washout of the pulmonary vascular beds than a temperature of 10°C.61 In addition, he and others have observed that lung function was significantly better after reperfusion if the lungs were initially flushed with a temperature of 15°C to 20°C instead of 10°C or lower.61,62 However, it must be emphasized that all these studies were performed in small animals Therefore, surface cooling of the inflated lungs was certainly more rapid than with larger lungs, thus reducing the period of warm ischemic time until core cooling of the lungs was achieved Steen and colleagues have recommended that if the temperature of the flush solution was kept at room temperature, the lungs should be maintained in a collapsed state during storage to avoid the insulating effect of air and to reduce the core temperature quicker.34 This approach has been shown to be efficient in the setting of non–heart-beating donor experiments.14,63,64 Ultrastructural analysis of the lungs at different time points during the preservation period shows that the injuries induced by the flush itself seem to be minimal when compared with the insult induced by ischemia on the endothelial–epithelial barrier.65 Hence, despite some potential injuries induced by cold flush, we think that these lesions are minimal when compared with those induced by ischemia, and we still recommend flushing the lungs with a hypothermic preservation solution in order to cool the lungs as fast as possible Inflation, Oxygenation, and Storage Temperature Although deflated lungs can be safely preserved at cold temperature for to hours for human lungs and up to 24 hours for pig lungs,66,67 there have been a large number of experiments since the early 1970s suggesting that preservation of the lung is improved when it is inflated with oxygen 68–70 Expansion of the lungs with oxygen during the ischemic time protects the lung from injury by three mechanisms: (1) it maintains an adequate aerobic metabolism, (2) it preserves the integrity of the pulmonary surfactant, and (3) it preserves epithelial fluid transport During ischemia, lungs inflated with air are still able to consume oxygen and to produce energy, which prevents the accumulation of cellular metabolites and delays cell death.71,72 Hence, alveolocapillary membranes are better preserved and the amount of total protein and lactate dehydrogenase in the bronchoalveolar lavage fluid are significantly lower than if the lungs were preserved atelectatic or inflated with 100% nitrogen.73 Several authors have shown that static pulmonary compliance and surfactant secretion remain significantly better if the lungs are preserved in an inflated state instead of in a deflated state.73,74 In addition, Sakuma and colleagues have recently demonstrated that lung deflation decreases alveolar fluid clearance, whereas fluid clearance was maintained in inflated lungs, independently of the presence of oxygen.75 The optimal state of lung inflation during preservation remains uncertain Puskas and colleagues have reported successful 30-hour lung preservation in a canine left single transplant model by overventilating the donor before retrieval and hyperinflating the lung during preservation 76 Atelectasis is associated with higher pulmonary vascular resistance and poorer distribution of lung preservation solution.77 Lung reexpansion with positive end-expiratory pressure (PEEP) and a sustained intrapulmonary pressure prior to flushing is certainly an effective measure However, overdistension of the lung by static inflation, high tidal volume (TV), or high PEEP has been shown to be detrimental during mechanical ventilation, and there is evidence suggesting that hyperinflation during storage increases the pulmonary capillary filtration coefficient.78,79 In rat experiments, we, and others, have observed that lung inflation should be limited to 50% of the total lung capacity in order to avoid barotrauma.74,80 In our current clinical practice, we perform a recruitment maneuver before flushing the lungs to fully reexpand the lung; we ventilate the lungs with a (TV) of 10 mL/kg and a PEEP of cm H2O during the flushing period We then inflate the lungs with a pressure of approximately 20 cm H2O before tracheal cross-clamping to obtain complete lung expansion and avoid overdistension Although the majority of the studies have shown that oxygen was required during storage to allow aerobic metabolism, the concentration of oxygen has varied from room air to 100% oxygen , , Some authors have observed that lungs inflated with 100% oxygen during 24 hours of cold preservation had significantly better lung function after reperfusion than lungs preserved with room air In contrast, others have found that lungs expanded with 50 and 100% FiO2 did significantly worse than lungs preserved with room air.81,82 Oxidative stress can occur during lung ischemia, and Lung Preservation for Transplantation / 329 it has been shown that a high inspired oxygen fraction may be associated with more lipid peroxidation, especially if the lungs are preserved at a temperature of 10°C or above.79,80,83,84 In addition, lung metabolism does not change until the alveolar oxygen tension decreases to less than mm Hg, and it has been shown that inflation of rabbit lungs with room air provides enough oxygen for at least 24 hours of hypothermic storage.72 A higher inspired oxygen fraction is also associated with greater loss of lung volume and airway pressure during storage.79 Given the available evidence, inflation with an oxygen fraction of 50% or less should currently be recommended in clinical practice Several studies have shown that lung preservation at 10°C achieved significantly better results than lung preserved at 4°C or 15°C and higher.80,85,86 However, these findings were not confirmed by other groups.87 Lungs preserved at 10°C require a greater amount of metabolic substrate, and the risk of lung injury can increase extremely rapidly if the temperature rises above 10°C during preservation 83 Hence, if a 10°C preservation temperature is used, the temperature inside the cooler should be constantly monitored and the air should be homogeneously distributed to improve security Conversely, if the traditional technique of lung storage in cold saline and iced slush is used, one should be careful to contain the ice at the bottom of the cooler and not to submerge the lungs with ice Retrograde Flush and Late Reflush Retrograde flush, which refers to the administration of the flush solution through the left atrial appendage and drainage through the pulmonary artery, has been described for lung and heart–lung transplantation.88 The technique presents the opportunity to flush the dual bronchial and pulmonary circulation and to limit the effect of pulmonary vasoconstriction on the distribution of the flush Experimentally, the retrograde flush has been found to improve lung preservation by limiting the presence of red blood cells within the capillaries and by achieving better distribution of the flush solution along the trachebronchial trees.89,90 However, despite the retrograde flush, pretreatment with prostaglandin E1 (PGE1) was still helpful in improving pulmonary dynamic compliance after reperfusion.91 Following these results, we and others have adopted a combined procedure with an antegrade flush in situ through the pulmonary artery followed by a retrograde flush on the back table through each of the pulmonary veins Late reflush was initially described in kidney transplantation and refers to the administration of a second flush immediately prior to implantation of the graft This method has been shown to wash out inflammatory agents and to improve post-transplant graft function by limiting cell damage after reperfusion.92,93 The University of North Carolina has developed a specific extracellular solution for late reflush (Carolina rinse solution) to replenish important substrates and provide antioxidant and vasodilators to the graft before reperfusion in order to limit cell injury This solution has been shown to be superior to EC for late reflush in an ex vivo model of lung reperfusion 93 In clinical lung transplantation, Venuta and colleagues have recently completed a randomized study of 14 patients demonstrating that the addition of a late retrograde reflush with LPD glucose to an antegrade flush was associated with improved lung function when compared with an antegrade flush only.94 Future studies should determine whether the improvement in lung function that they observed was owing to the retrograde flush or to the late reflush effect Slow Reperfusion and Protective Ventilation The pulmonary artery flow or pressures during the initial 10 minutes of reperfusion are of prime importance The endothelial permeability is transiently elevated during the early phase of reperfusion Hence, irreversible lung damage, pulmonary edema, and leukocytes sequestration can occur if the lung is rapidly reperfused after a period of ischemia.95–97 Progressive reintroduction of blood flow over a 10-minute period has been shown to reduce lung injury and to improve function of the transplanted lung.96,97 Although similar improvement in lung function has been observed with reperfusion pressures controlled for a longer period of time, shorter times (5 minutes), in contrast, have been shown to be insufficient.98 We have designed a special pulmonary artery clamp with a larger number of notches that allows us to progressively reperfuse the lung over a 10-minute period in our clinical practice Although mechanical ventilation is essential for patients undergoing lung transplantation, a number of animal and clinical studies have shown that mechanical ventilation can worsen preexisting lung injury and produce ventilator-induced lung injury.99 The effect of different modes of ventilation in the early period after lung transplantation has not been explored clinically However, we have recently observed in a rat single lung transplant model that injurious ventilation with high volume and no PEEP significantly decreased lung function after hours of reperfusion when compared with a protective mode of ventilation Future studies should focus more attention on the role of mechanical ventilation in the setting of lung transplantation In our prac- ... maintained in the range of 18 to 25 during profound hypothermia Phenytoin is administered intravenously during cooling at 15 mg/kg, to a maximum dose of g During the cooling period some preliminary... Sehgal L, et al Fluosol-DA as a red-cell substitute in acute anemia N Engl J Med 19 86; 314: 165 3? ?6 Rudolph A Encapsulation of hemoglobin in liposomes In: Winslow R, Vandegriff K, Intaglietta M, editors... crosslinked between ␣ chains (Lysine 99␣1-Lysine 99␣2) J Biol Chem 19 86; 261 :9929–37 13 Keipert PE, Gomez CL, Gonzales A, et al Diaspirin crosslinked hemoglobin: tissue distribution and long-term