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 a
Trang 1of 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
asymp-tomatic at follow-up
The role of therapeutic bronchoscopy remains
contro-versial In the series by Cole and colleagues, of 42 patients
with broncholithiasis, bronchoscopy was performed in
40, with successful stone removal achieved in 8 (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
complica-tions, observation alone may be the best management
strategy
References
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ausculation 4th ed Translated by J Forbes New York: S.
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2 Kutlay H, Cangir AK, Enön S, et al Surgical treatment in
bronchiectasis: analysis of 166 cases Eur J Cardiothorac
Surg 2002;21:634–7.
3 Sealy WC, Bradham RR, Young WG The surgical treatment
of multisegmental and localized bronchiectasis Surg Gynec
6 Heller G Beitrage zur lehre van den fremdkorpern in den
luftwegen Göttingen: WF Kaestner; 1890.
7 Kartagener M Zur pathogenese der bronchiectasien.
Bronchiectasien bei situs inversus viscerum Beitr Klin
Tuberk 1933;8:489–501.
8 Heidenhain L Ausgedehnte lungenresektion wegen
zahlmeicher eiternder bronchiectasien in einem
unter-lapen, verlandl.deutsch gesselsch Chir 1901;30:636.
9 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
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, ologic, and microbiologic characterization of bronchiecta- sis in an aging cohort Chest 1995;108:955–61.
pathophysi-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 cardio- surgical 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 (Williams- Campbell 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: ment by thin-section CT Radiology 1986;161:95–9.
assess-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.
Trang 232 Chipps BE, Talamo RC, Winkelstein JA IgA deficiency,
recurrent pneumonias, and bronchiectasis Chest
1978;73:519–26.
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.
34 Jaffe HJ, Katz S Current ideas about bronchiectasis Am
Fam Physician 1973;7:69–76.
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.
39 Ripe E Bronchiectasis Scand J Respir Dis 1971;52:96–112.
40 Fujimoto T, Hillejan L, Stamatis G Current strategy for
surgical management of bronchiectasis Ann Thorac Surg
2001;72:1711–5.
41 Deslauriers J, Dion L Le traitment des bronchiectasies primitives Indications chirurgicales et resultats Semin Hôp Paris 1985;18:1199–201.
42 Faber LP, Jensik RJ, Chawla SK, Kittle CF The surgical implication of broncholithiasis J Thorac Cardiovasc Surg 1975;70:779–89.
43 Cole FH, Cole FH Jr, Kandedar A, Watson DC Management of broncholithiasis: is thoracotomy necessary? Ann Thorac Surg 1986;42:255–7.
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 treat- ment 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.
47 Trastek VF, Pairolero PC, Ceithame EL, et al Surgical management of broncholithiasis J Thorac Cardiovasc Surg 1985;90:842–8.
48 Potaris K, Miller DL, Trastek VF, et al Role of surgical resection in broncholithiasis Ann Thorac Surg 2000;70:248–52.
Trang 3ROBERT 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.1Prior to
the discovery of blood types, around 1900, and the
intro-duction 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
hemoglo-bin, 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 O2to effectively oxygenate tissue Clinical trials
have not been convincing,2and no product is currently
approved for use in patients
Other more exotic solutions to the blood substituteproblem have been devised, including artificial red cells(liposomes)3and a variety of approaches based onrecombinant hemoglobins.4However, the products thathave been most successful in clinical development to datehave been chemical modifications of either human oranimal (cow) hemoglobin.5
Historical Background
In 1949 Amberson published a landmark paper thatdescribed a case report of a 22-year-old female withsevere postpartum hemorrhage as a result of retainedplacenta (Figure 22-1).6Her hemoglobin was 5 g/dL, andall compatible blood in the hospital had been exhausted.She remained in shock, and her blood pressure was notresponsive to conventional plasma expanders or crystal-loids She was finally given an experimental hemoglobin-saline solution that Amberson had been developing inthe laboratory Upon administration of this solution, theblood pressure rose dramatically and the heart rate fell.Over two liters of hemoglobin solution were adminis-tered to this patient, and for a time she seemed toimprove Eventually however her urine output dimin-ished as renal failure progressed and she finally died
In his discussion of this case, Amberson expressed hisbelief that the hemoglobin solution had been effectivetreatment for shock However, he cautioned that theblood pressure responses and the abrupt fall in heart ratewere peculiar properties of hemoglobin solutions, and hefelt that these effects were most likely owing to impuri-ties Amberson concluded, “It must be emphasized thatevery investigator in this field has used a differentmethod for the preparation of his hemoglobin-saline
Trang 4However 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
hear t rate relative to baseline, consistent w ith
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 O2-carrying capacity
afforded by infusion of hemoglobin solution
In summary, the US Army had succeeded in ing a suitable model hemoglobin that had the aimed-forcharacteristics:
produc-• is sterile
• is free of red cell membranes
• is endotoxin-free
• does not dissociate into subunits
• does not cause significant renal toxicityNevertheless,-Hb still caused significant hyperten-sion in pigs Of even more concern, however, was the factthat cardiac output was depressed, presumably because ofintense vasoconstriction, as evidenced by severelyincreased vascular resistance The overall conclusion wasthat there was no advantage of resuscitation with -Hbcompared with Ringer’s lactate The mechanism of thisvasoactivity was not clear, and the Army concluded thatmore basic research was needed in the field in order to
Albumin Ao RL aaHb
Heart Rate
120 130 140 150 160 170 180 190 200
FIGURE 22-2 Simulation of a battlefield injury by the US Army Dehydrated pigs were subjected to hemorrhage (arrow at 0 hours) and then
resuscitated with test solution (arrow at 1 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
Trang 5produce 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.16Baxter continued to develop -Hb until phase III
clinical trials in stroke17and trauma18showed 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
hemoglobin-induced 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,
arteri-olar 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
demon-strating the marked vasoactivity of this product A
poly-merized 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 ofmodified hemoglobins was directly correlated with thefall in functional capillary density observed in hamsters(Figure 22-4) That is, PEG-modified hemoglobin had nosignificant effect on rat blood pressure, polymerizedhemoglobin had a small effect, and cross-linked hemo-globin was markedly hypertensive
Thus, in the early 1990s products from all classes ofmodified hemoglobins were entering advanced clinicaltrials in humans, but there was still no good explanationfor the hemodynamic pattern observed more than 40years previously One potential explanation seemed obvi-ous when NO was identified as an endothelial-derivedrelaxing factor.20 Hemoglobin was well known to bind
NO with high affinity,21and experiments with isolatedvascular rings seemed to support this explanation.22Oneproblem with this as a complete explanation, however,was that hemoglobin within red blood cells also binds
NO, but without a hypertensive effect A second problemwas that different modified hemoglobins demonstratedhypertension 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 thereactivity with NO does not correlate with the degree ofvasoactivity Rohlfs and colleagues prepared solutions ofmodified hemoglobins with differences in molecular sizeand other significant properties (Table 22-1).24The cross-linked hemoglobin was the Army’s -Hb, with a molec-
Crosslinked PEG
30 40 50
60
FIGURE 22-3 Functional capillary density (FCD) as a function of
hema-tocrit 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,).
160
Polymerized Crosslinked PEG
60
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 tions Infusion is via a femoral vein, starting at 30 minutes as shown
solu-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).
Trang 6The 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 1 hour.32The
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
vari-ous groups of animals The controls had a hemoglobin of
13.8 g/dL, while the PEG-Hb animals began the
hemor-rhage 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
hemor-rhage These findings point to one of the most important
aspects of blood substitutes research and eventual clinical
use: “blood substitutes” are not simply blood
replace-ments 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 striction Recombinant hemoglobins with mutations thatreduce NO binding have been shown to cause less hyper-tension than native hemoglobin.33Others believe thatextravasation of hemoglobin is responsible, on the theorythat hemoglobin in the interstitial space more effectivelyscavenges NO than hemoglobin in the vascular space.34,35Some workers in the field have shown that vasoactivity isrelated to plasma viscosity36and that shear stress is trans-duced by endothelial cells to alter the release of vasoac-tive molecules such as NO and prostacyclins.37Still othersbelieve that vasoactivity or, more generally, toxicity,results from O2 free radical generation as hemoglobincycles through redox reactions.38It is possible, of course,that the final explanation may lie with a combination ofthese causative factors
vasocon-The Future of Blood Substitutes
Whatever the ultimate explanation for vasoactivityproduced by cell-free hemoglobin, it is very unlikely thatany product that is approved for clinical use will bearmuch resemblance to blood beyond its color It is veryunlikely that a hemoglobin-based red cell substitute can
be produced that has the same hemoglobin tion as normal red blood cells and the same oxygen affin-ity as red blood cells, with the same viscosity and oncoticpressure as human blood Nevertheless, as shown inFigure 22-5, solutions with properties very different fromthose of human blood can effectively reduce the need fortransfusion of allogeneic blood The problem for clinicalimplementation of such solutions, also demonstrated inFigure 22-5, is that the hemoglobin concentration per sewill no longer be a useful guide, or trigger, for giving atransfusion Rather, clinicians in the future must broadlyevaluate each patient’s need for supplemented tissue-oxygenating capacity and be prepared to administer thetherapy that best meets that need In this evaluationprocess, physiological and clinical data will need to beobtained and rapidly integrated into a reliable transfu-sion trigger As safer, more effective solutions are devel-oped for clinical testing, revision of the transfusiontrigger and definition of optimal clinical applicationsrepresent a major challenge for the developing field of
concentra-“blood substitutes.” As research and development withthese products continues, it is likely that the unique phys-iology of oxygen transport will be better understood, and
it should be possible to more effectively oxygenate tissuewhile reducing or avoiding allogeneic blood transfusion
0
7.6
13.8
6.8 11.0 10.2 Controls
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 0 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
Trang 71 Winslow R Hemoglobin-based red cell substitutes.
Baltimore (MD): Johns Hopkins University Press; 1992.
2 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.
3 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.
4 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.
5 Stowell CP, Levin J, Spiess BD, Winslow RM Progress in the
development of RBC substitutes Transfusion
2001;41:287–99.
6 Amberson W, Jennings J, Rhodes C Clinical experience with
hemoglobin-saline solutions J Appl Physiol 1949;1:469–89.
7 Christensen S, Medina F, Winslow R, et al Preparation of
human hemoglobin Ao for possible use as a blood
substi-tute J Biochem Biophys Methods 1988;17:143–54.
8 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.
9 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
charac-terization of a new hemoglobin derivative crosslinked
between chains (Lysine 991-Lysine 99 2) J Biol Chem
1986;261:9929–37.
13 Keipert PE, Gomez CL, Gonzales A, et al Diaspirin
cross-linked 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.
15 Hess J, Macdonald V, Brinkley W Systemic and pulmonary
hypertension after resuscitation with cell-free hemoglobin.
J Appl Physiol 1993;74:1769–78.
16 Hess J, Riess R Resuscitation and the limited utility of the
present generation of blood substitutes Transf Med Rev
1996;10:276–85.
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.
18 Sloan EP, Koenigsberg M, Gens D, et al Diaspirin linked hemoglobin (DCLHb) in the treatment of severe traumatic hemorrhagic shock A randomized controlled efficacy trial JAMA 1999;282:1857–64.
cross-19 Tsai A, Kerger H, Intaglietta M Microcirculatory quences of blood substitution In: Winslow R, Vandegriff K, Intaglietta M, editors Blood substitutes Physiological basis
conse-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 reac- tion 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 hemoglobin- based 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 chal- lenges Boston (MA): Birkhäuser; 1997 p 167–88.
30 McCarthy MR, Vandegriff KD, Winslow RM The role of facilitated diffusion in oxygen transport by cell-free hemo- globin: implications for the design of hemoglobin-based oxygen carriers Biophys Chem 2001;92:103–17.
31 Winslow RM, Gonzales A, Gonzales M, et al Vascular tance and the efficacy of red cell substitutes J Appl Physiol 1998;85:993–1003.
resis-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.
Trang 833 Doherty DH, Doyle MP, Curry SR, et al Rate of reaction
with nitric oxide determines the hypertensive effect of
cell-free 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 ity regulates capillary perfusion during extreme hemodilu- tion in hamster skinfold model Am J Physiol (Heart Circ Physiol 44) 1998;275:H2170–H2180.
viscos-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 linked hemoglobin induces G2/M arrest and apoptosis in cultured endothelial cells Blood 2001;98:3315–23.
Trang 9The first classification of pulmonary hypertension was
proposed at a World Health Organization (WHO)
symposium in 1973 Pulmonary hypertension was
classi-fied based upon etiologies with primary pulmonary
hypertension (PPH) classified as a separate class, that of
pulmonary hypertension of unknown etiology and
lack-ing associated clinical conditions PPH was further
subdivided into three groups based on pathology:
plexo-genic, 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
clin-ical condition and are indistinguishable from PPH
In 1998, the WHO convened a second symposium to
update the classification system of pulmonary
hyperten-sion and collate state-of-the-art understanding of
pul-monary 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).1
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
The WHO symposium of 1998 also provided a tional classification that is a modification of the New YorkHeart Association functional classification (Table 23-2)
func-Physiology and Pathobiology
Normally the pulmonary circulation is a low-pressure,high-flow vascular bed that has a remarkable capacity topermit increased cardiac output, such as exercise, withoutincreasing pulmonary arterial pressure The ability of thepulmonary vasculature to respond to increases in cardiacoutput is felt to be the result of the recruitment of under-perfused vessels and engorgement of highly capacitantvessels in response to increases in blood flow The physiol-ogy and histology of the pulmonary vasculature reflect thenormal state of affairs as the native smooth muscle tone ofpulmonary arterioles is lower and the smooth muscle layer
is thinner than that of the systemic circulation
Pulmonary arterial pressure is a function of the monary venous pressure, cardiac output, and pulmonaryvascular resistance (Table 23-3) The National Institutes
pul-of Health (NIH) Registry defined a normal meanpulmonary artery pressure at rest of 25 mm Hg, rising to
30 mm Hg with exercise.2A recent report of a series ofestimates of pulmonary arterial systolic pressure meas-ured by Doppler transthoracic echocardiography foundthat normal pulmonary artery pressures may be higherthan previously appreciated.3In this study of 3,790echocardiographically normal subjects, pulmonary arter-ial systolic pressure increased with age, body mass index,and sex Twenty-eight percent had pulmonary arterysystolic pressure > 30 mm Hg; it was suggested that theupper limit of normal may reach 40 mm Hg in olderpatients or obese patients
Trang 10pulmonary vascular tone.7Platelets, 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
ele-ments have been postulated to contribute to the
patho-logical changes of PAH Table 23-4 lists examples of cell
products and functions that contribute to normal
vascu-lar tone and alterations associated with PPH
Hypoxic vasoconstriction is the most important
phys-iological 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
vaso-constrictors 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 inhibitingone of the K+ channels found in pulmonary arterysmooth muscle cells
Vascular remodeling is a central feature of pulmonaryhypertension from all causes and has been used to bothclassify and grade the severity of pulmonary hyperten-sion Vascular remodeling includes changes in the intima(fibrosis, media, hypertrophy, and muscularization) andadventitia (increased deposition of extracellular matrix).Endothelial injury early in the course of PAH has beenhypothesized to permit exudation of factors that stimu-late smooth muscle cells to release mitogens such as basicfibroblast growth factor directly and adenosine indirectly.Membrane-bound metalloproteins and serine elastaseshave been postulated to be central in this process
The recent identification of mutations in the gene forbone morphogenetic protein receptor II in patients withfamilial PPH promises to provide insight into the patho-genesis of PPH.8,9 Bone morphogenetic protein receptor
II is a member of the transforming growth factor (TGF-) receptor family TGF- family of growth factorshave pleiotropic effects on endothelial cells, smoothmuscle cells, and fibroblasts The activities of the TGF-family are dependent upon the cellular milieu; they aremodified by complex cytokine networks in ways that may
be as divergent as promoting or inhibiting endothelialcell proliferation Thus, describing the common pathwaythat leads to PPH continues to present significant investi-gational challenges
Primary Pulmonary Hypertension
Primary pulmonary hypertension is a rare conditionwith an estimated annual incidence of one to two permillion people per year in Europe and the UnitedStates.6,10 However, this may be an underestimate, asautopsy studies have shown a prevalence of 1,300 permillion population The incidence of PPH rises drasti-cally among users of appetite suppressants to 25–50 per
TABLE 23-4 Examples of Pathogenetic Factors in Pulmonary Arterial Hypertension
EC = endothelial cell; ECM = extracellular matrix; MMP = matrix metalloproteinase; NO = nitric oxide; SMC = smooth muscle cell.
Trang 11million people per year.11The U.S NIH Registry
demon-strated that PPH can occur at any age and has a peak
incidence at 36 years The disease is more common in
females than males with a ratio of about 2:1 Familial
cases of PPH were noted in the registry This observation
led to further understanding of the genetic basis of PPH
(see below) Familial PPH occurs in approximately 10%
of cases There is no association between race and PPH
There is a spectrum of clinical signs and symptoms
that occur at presentation in PPH (Table 23-5) The most
common presentation, however, is the insidious onset
and progression of dyspnea on exertion The nonspecific
nature of the presentation led to a delay in diagnosis on
an average of 2 years in the NIH Registry
Physical findings may suggest the diagnosis Most
commonly noted are an accentuated second heart sound
and a right ventricular S4 As the condition worsens, the
right ventricle becomes hypertrophied, which leads to a
right ventricular heave and tricuspid regurgitation
Dilatation of the annulus of the pulmonary valve or right
ventricle outflow track leads to a murmur of pulmonic
regurgitation A right ventricular S3 gallop occurs with
right ventricular failure and is an ominous sign,
associ-ated with decreased cardiac output and increased right
atrial pressures
The diagnosis of PPH is a diagnosis of exclusion
Following the recommendations and experience gained
from the NIH Registry open lung biopsy is no longer
recommended for the diagnosis of PPH
Quite often, patients will have had a series of tests to
evaluate their dyspnea prior to the diagnosis of pulmonary
hypertension Typically, these tests include pulmonary
function tests, which may be normal or demonstrate early
restrictive disease (which may become prominent in severe
PPH) and mild to moderate impairment of the diffusing
capacity The chest radiograph commonly shows large
pulmonary arteries (Figure 23-1).12The right pulmonary
interlobar artery is considered enlarged when it is 16 mm
or greater in men and 15 mm or greater in women With
enlargement, the left main pulmonary artery causes a
convexity under the aortic arch Pulmonary function tests
and chest radiograph are of assistance also in ruling outsignificant pulmonary airway or parenchymal diseases asthe cause of the dyspnea
The initial evaluation of the pulmonary ics is best made by echocardiography Transthoracicechocardiography can characterize the shape and size ofthe chambers and identify hypertrophy of the right
hemodynam-TABLE 23-5 Prevalence of Symptoms of Primary
FIGURE 23-1 Young woman with primary pulmonary hypertension
associated with anorexigen use A, Chest radiograph demonstrates mild cardiomegaly, enlargement of the interlobar artery (small arrow),
and convexity resulting from enlargement of the left main pulmonary
artery (large arrow) B, Chest computed tomography scan
demon-strates normal pulmonary parenchyma and confirms that cardiomegaly is due to right ventricular enlargement.
A
B
Trang 12ventricle Decreased filling of the left ventricle may be
noted, as may paradoxical movement of the
intraventric-ular septum towards the left ventricle Doppler
echocar-diography can be used to estimate the pulmonary arterial
systolic pressure This is done by measuring systolic flow
velocity across pulmonic valve or, more accurately, by
regurgitant flow across the tricuspid valve.3The
echocar-diogram is also useful in ruling out intracardiac shunts,
which cause high flow states and secondary pulmonary
hypertension Small shunts are best demonstrated by
transesophageal echocardiography
Once the diagnosis of pulmonary hypertension is
confirmed, associated medical conditions need to be
excluded Blood tests are obtained to screen for liver
disease, connective tissue diseases, and serology for
human immunodeficiency virus (HIV)-1 infection
Sufficient screening tests for connective tissue disorders
in patients who are otherwise asymptomatic include
antinuclear antibody, antineutrophil cytoplasmic
anti-body, rheumatoid factor, and an erythrocyte
sedimenta-tion rate A major category of disease that needs to be
excluded is thromboembolic disease Ventilation
perfu-sion scan or computed tomography (CT) angiography
can be used to exclude chronic thromboembolic disease
If chronic thromboembolic disease is suggested, then
pulmonary angiography should be performed to further
characterize the degree and distribution of the
throm-boembolic deficits.13Polysomnography is indicated if
there are clinical findings suggestive of sleep apnea.14
If testing rules out secondary causes of pulmonary
hypertension, the diagnosis of PPH can be made
However, further physiological evaluation is appropriate
In particular, cardiac catheterization is needed to fully
assess right ventricular and left ventricular
hemodynam-ics to confirm echocardiogram estimates of right
ventric-ular and pulmonary artery pressures and to further rule
out left-to-right shunts If risk factors for coronary artery
disease are present, the inclusion of coronary artery
angiography is useful as patients with PPH often present
with, or develop, atypical chest pain Cardiac
catheteriza-tion should include acute vasodilator testing Results
from the NIH Registry show that a positive response to
acute vasodilator test is predictive of clinical response to
oral vasodilatory agents A positive acute vasodilator test
is one in which there is a fall in the pulmonary artery
pressures of 20% or 10 mm Hg with either no change or
an increase in cardiac output.15
A 6-minute walk test provides important information
about the potential need for supplemental oxygen
ther-apy It is less time-consuming and expensive than a
formal cardiopulmonary stress test and is more easily
repeated for monitoring of response to therapy
Following the diagnosis of PPH and initiation of
ther-apy, transthoracic echocardiography can be used forsequential estimates of pulmonary artery systolic pres-sure to monitor response to therapy Follow-up with 6-minute walk tests is useful for ongoing titration ofsupplemental oxygen
The medical therapy of PPH has three aims The first
is vasodilation, the second is modulation of pulmonaryvascular remodeling, and the third is the prevention of insitu thrombosis
Vasodilator therapy is directed by the results of theacute vasodilatory test performed in the cardiac catheter-ization lab and the severity of pulmonary hypertensionupon presentation Historically, observations on the use
of multiple vasodilators identified that only a minority ofpatients would respond to these agents The responsivepatients are identified by the acute vasodilator test in thecardiac catheterization lab, and oral therapy with acalcium channel blocker is indicated The dosage should
be titrated to the maximal recommended dose if ated, avoiding systemic hypotension.16
toler-Intravenous infusion of epoprostenol (prostacyclin, orPGI2) has been shown to be efficacious even in patientswho do not have a positive acute vasodilator test.17In themajority of these patients, epoprostenol has been shown
to improve hemodynamics, increase exercise tolerance,and prolong survival Epoprostenol has the disadvantage
of a very short half-life of 3 to 5 minutes, requiringcontinuous intravenous infusions Administrationrequires an indwelling vascular catheter Meticulous care
of the catheter is essential, as line sepsis can quicklybecome life threatening in patients with fixed flowthrough their pulmonary vasculature Epoprostenol hasless worrisome side effects as well, including jaw pain (aclaudication-like pain relieved by chewing), headache,rash, diarrhea, and musculoskeletal pains, particularly inthe ankles and feet The dose of the drug is titrated toprovide for maximum exercise tolerance and is limited bydiscomfort from the minor side effects There is apparenttachyphylaxis to epoprostenol and dosing needs to becontinuously advanced to maintain efficacy
A newer alternative to epoprostenol is bosentan, aninhibitor of both the endothelin 1 and endothelin 2 recep-tors.18This drug has been demonstrated to improve hemo-dynamics and exercise tolerance in patients treatedfollowing the initial diagnosis of their PPH Long-termstudies documenting survival advantage are not yet avail-able Bosentan clearly has the advantage of not requiring acontinuous infusion, but liver toxicity and dose-dependent fall in hemoglobin require frequent monitoring.The possibility of switching patients from epoprostenol tobosentan has not yet been formally investigated Data toguide the selection of either epoprostenol or bosentanupon initial presentation do not yet exist Thus, one sug-
Trang 13gestion is that patients with class IV dyspnea on exertion
receive epoprostenol, reserving a trial of bosentan for
patients with class III dyspnea on exertion Other oral and
subcutaneous preparations are undergoing evaluation in
the United States or are available in Europe As these
become available, and until improvement in mortality is
documented, beginning patients with class IV dyspnea
on exertion on epoprostenol would remain a valid
recommendation
Care must be taken with the administration of any of
the vasodilators for PPH The sudden cessation of
vasodilator therapy may lead to rapid rebound in
pul-monary artery pressures, which can be life threatening
There is investigational evidence that both
epoprost-enol and bosentan have antimitogenic activities There
has also been some suggestion in the investigational
liter-ature that calcium channel blockers may have similar, if
not as potent, activities Thus, therapies with these
vasodilatory drugs also address the issue of vascular
remodeling Occasionally, patients do not show
improve-ment in their pulmonary artery pressures following
treat-ment with epoprostenol for up to 12 months This delay
in response supports the contention that the drug is
effecting vascular remodeling and is not acting merely as
a vasodilator
In situ thrombosis is an important complicating
feature of primary pulmonary hypertension
Non-randomized trials in which anticoagulation was initiated
with patients with abnormal ventilation–perfusion scans
but not in those with normal scans demonstrated a
survival advantage for patients receiving warfarin.16 On
the basis of these trials, the standard of care includes
anticoagulation with warfarin to maintain the
interna-tional normalized ratio (INR) between 2 and 3
The use of digoxin in patients with cor pulmonale is
controversial Some authorities recommend its use
because of its inotropic activity and reversal of the
neurohumoral activation that occurs with right heart
failure Diuretics should be used judiciously in patients
with cor pulmonale They are indicated for peripheral
edema associated with cor pulmonale or secondary to
high-dose calcium channel blockers Ascites can be a very
difficult complication of cor pulmonale to manage and
may respond to the addition of spironolactone to loop
diuretics Patients on diuretics must be closely monitored
for electrolyte abnormalities and to ensure that
intravas-cular volume is not depleted
Surgical approaches to PPH include atrial septostomy
This has been suggested for patients with severe
right-sided heart failure that is refractory to diuretics and in
patients with syncope resulting from poor filling of the
left ventricle The resulting right-to-left shunt leads to
decompression of the right ventricle and improved filling
of the left ventricle, but it is also associated with cant desaturation, which may not respond to oxygensupplementation
signifi-If medical therapy fails, then lung transplantation may
be a lifesaving intervention Single or double lung plants may be offered to patients with PPH Heart–lungtransplantation is generally reserved for patients withabnormal left ventricular function or congenital anom-alies Outcomes for lung transplantation for pulmonaryhypertension are slightly worse than for other diagnoses.Primarily this is because of higher morbidity and mortal-ity in the immediate postoperative period, which resultsfrom the stress placed upon the transplanted vascularbed by the hypertrophied right ventricle One and five-year survival rates are respectively 64 and 42%
trans-PPH tends to be a disease of young women Thus,pregnancy is a frequent issue in the care of these patients.Since patients with PPH have a cardiac output fixed bytheir abnormal pulmonary vasculature, the hemody-namic changes associated with pregnancy and the imme-diate postpartum period may be life threatening.Successful pregnancies with safe deliveries have beenreported, but contraception should be recommended as arule Oral contraceptives are contraindicated as they mayincrease the risk of deep venous thrombosis and pul-monary embolism
Prognosis for untreated PPH is poor with a meansurvival time of 212years in the NIH Registry.19Patientswho respond to oral vasodilation have a 95% 5-yearsur vival rate.1 6 The nonresponders treated withepoprostenol have significant improvement in theirsurvival rate as reflected by the fact that, in one study,91% of the patients with pulmonary hypertensionavoided listing for lung transplantation after initiation oftherapy.20
As listed in Table 23-1, ingestions and a number ofclinical conditions have been identified as probableetiologies for PAH Some such as HIV, portal hyperten-sion, and collagen vascular diseases are long-term condi-tions that have the potential to modify the pulmonaryvasculature on an ongoing basis Others, particularly thetoxic ingestions and use of weight-reduction aids, suggestthat PAH can be triggered by limited injury or exposure
It has been suggested that these short-term exposures,either by increasing shear forces or by direct stimulation,alter endothelial cell biology, which sets off a vicious,self-sustaining cycle of changes that eventuate in pul-monary arterial hypertension
Trang 14Chronic Thromboembolic Pulmonary
Hypertension
Chronic thromboembolic pulmonary hypertension
(CTPH) results as a rare sequela of pulmonary
embo-lism It accounts for a small fraction of patients who
survive acute pulmonary emboli, estimated at 0.1 to
0.5% Since pulmonary emboli can be an asymptomatic
event, the true incidence of patients with CTPH is not
known However, estimates place the total number in the
United States between 500 and 2,500 patients Patients
with CTPH can present with the insidious onset of
dysp-nea on exertion in a manner identical to the presentation
of PAH Since there is an effective surgical intervention
available, it is important to distinguish CTPH from other
causes of pulmonary hypertension.10
Acute pulmonary embolism rarely causes pulmonary
hypertension The exception occurs with massive acute
pulmonary embolism in which the embolus occludes
50% or more of the pulmonary vasculature in patients
with normal cardiopulmonary physiology or 30% for
patients with pulmonary or cardiac disease In patients
with massive pulmonary embolism, the risk of death is
greatest in the first few hours following the acute event
The vast majority of the patients who survive the first
few hours go on to have their embolus resolved within 3
weeks, with normalization of the pulmonary artery
pres-sures However, as noted above, in a minority of patients
resolution is incomplete Residual obstruction of 40% of
the pulmonary vasculature is associated with pulmonary
hypertension on the basis of the obstruction of large (ie,
main, lobar, or proximal segmental) arteries.21
Progres-sion of pulmonary hypertenProgres-sion occurs with recurrent
embolization or in situ thrombosis in the pulmonary
arteries Alternatively, progression of pulmonary
hyper-tension can occur as a result of vascular remodeling, with
pathological changes indistinguishable from those found
in pulmonary arterial hypertension In these cases,
pulmonary hypertension is out of proportion to the
degree of embolic obstruction of the pulmonary arteries,
hemodynamic worsening occurs without evidence of
recurrent thromboembolic events even in patients who
are fully anticoagulated, and, in cases where open
biop-sies were performed, the pathological changes of PAH in
the small distal arterioles were noted Only those patients
whose hemodynamic abnormalities are proportionate to
the degree of proximal arterial obstruction are candidates
for thromboembolectomy.10,22
As mentioned above, the presentation of patients with
CTPH is the same as with other forms of pulmonary
hypertension Dyspnea on exertion with insidious onset
and relentless worsening is the hallmark The other
symptoms, noted in Table 23-5, occur as the pulmonary
hypertension progresses On the whole, CTPH presentswith physical findings identical to PAH One distinguish-ing characteristic on physical exam is the finding ofbruits that are presumed to originate from turbulent flowthrough partially occluded pulmonary arteries in 30% ofpatients.23
The evaluation of patients with suspected CTPH issimilar to the evaluation of patients with PPH However,effort should be undertaken to assure that ongoing silentpulmonary embolism is not a continuing problem.Duplex scanning of the legs is noninvasive and indicated
in the clinic evaluation A large fraction of duplex scans
in patients with CTPH reveal evidence of prior venousthrombosis (35–45%) and are useful to rule out acuteactive thrombosis Patients should also be evaluated forcoagulopathies that put them at risk for recurrent emboliand failure of standard anticoagulation Up to 10% ofpatients have been found to have anticardiolipin anti-body.24,25Ventilation–perfusion scanning is often thestudy that provides the initial suspicion for CTPH Inpatients with CTPH, mismatched perfusion defects areseen usually at the segmental or larger levels However,ventilation–perfusion scans cannot be used to judge theextent of obstruction in thromboembolic disease.2 6Angiography, angioscopy, or surgery often shows moreextensive disease than that revealed by ventilation–perfusion scanning The role of CT angiography in theevaluations of patients with CTPH is undefined.Obstruction or partial obstruction of main, lobar, orsegmental arteries is common but is not yet felt to be asubstitute for angiography for defining the extent ofdisease
Right heart catheterization is indicated, as for PPH,for accurate hemodynamic characterization Pulmonaryangiography can be safely performed in patients withpulmonary hypertension but requires modifications ofstandard practices and careful monitoring and thusshould be performed in centers with experience.13,27Angiography provides the best characterization of theextent of chronic thromboembolic disease and the deter-mination if the disease is present in surgically approach-able vessels The angiographic appearance of chronicthromboemboli differs from acute pulmonary embolus.Rather than the well-delineated intraluminal fillingdefects seen in acute pulmonary emboli, patients withCTPH have defects that are irregular and partiallyrecanalized and which may appear as bands or webs.Angioscopy employing a fiberoptic device has also beenused to characterize CTPH patients However, this is notwidely available
Angioscopy has been used at its originating center tohelp characterize the extent of thromboembolism inpatients with milder pulmonary hypertension and ques-
Trang 15tionable angiographic findings and to determine
operabil-ity in patients with severe pulmonary hypertension with
inadequate findings on angiography to justify surgery.28
Pulmonar y thromboendarterectomy remains a
complicated procedure that is best carried out at centers
with expertise In the most experienced hands, the
mortality is 7%, with reports of mortality ranging as high
as 24%.10Reperfusion injury following the procedure
remains the major cause of morbidity and mortality The
surgery is contraindicated in patients with severe
under-lying lung disease Advanced age, severe right heart
fail-ure, and significant collateral disease are relative
contraindications Coronary artery angiography is
performed for all patients with risk factors for coronary
artery disease with the possibility of coronary artery
bypass grafting concurrent with
thromboendarterec-tomy, if warranted Placement of an inferior venacaval
filter is recommended prior to surgery to assure that
pulmonary embolism does not recur Following the
thromboendarterectomy, a reduction in the pulmonary
vascular resistance of approximately 65% is expected
This is associated with improvements in gas exchange
and exercise tolerance with patients improving from New
York Heart Association class III or IV to class I or II after
surgery Lifelong anticoagulation is recommended
A subgroup of patients who have had acute
pul-monary embolism with apparent resolution or who have
chronic thromboembolic disease in the pulmonary artery
but of an extent too small to explain the progression and
severity of pulmonary hypertension present with a
syndrome very similar to PPH Once these patients are
ruled out as candidates for surgical therapy, the medical
therapies recommended for PPH are appropriate An
inferior venacaval filter should be considered if there is
any question of failure of anticoagulation therapy
Pulmonary Veno-Occlusive Disease
Pulmonary veno-occlusive disease (PVOD) was initially
recognized as a subcategory of PPH The presentation of
PVOD is clinically similar to PAH.29However, a
patholog-ical hallmark is the diffuse occlusion of pulmonary veins
by fibrous tissues Pathological findings suggest evolution
of the fibrotic lesions from loose, edematous fibrosis to
dense, sclerotic fibrosis Typically, intimal involvement is
seen in venules and smaller veins, but involvement of
larger veins can be seen as well Medial thickening tends
to be eccentric and heterogenous as seen in the small
arterioles in PAH In time the thickened intima may
become arterialized and completely occluded vessels may
become revascularized.30
It is felt that the cause of elevated pulmonary vascular
resistance lies in the venous changes As might be
ex-pected in response to the raised pulmonary artery sures, the pulmonary arterioles may demonstrate medialhypertrophy, but other findings of pulmonary arterialhypertension such as plexiform lesions are absent.PVOD, historically, accounted for 5 to 25% of PAH Asfor PAH, the age of onset spans life expectancy.2 9However, unlike for PAH, the ratio of men to women isapproximately 1:1 Infections with various agents havebeen suggested as leading to PVOD Some of these agents
pres-are Toxoplasma gondii, measles, Epstein-Barr virus,
cytomegalovirus, and HIV A genetic risk has beensuggested by case reports in siblings, but unlike PPH, nogene has, as yet, been linked to the condition A casereport suggested an association with sniffing cleaningpowder.31A better-characterized association has beenfound with chemotherapy including bleomycin, mito-mycin, and carmustine and with both allogeneic andautologous bone marrow transplantation.32,33An autoim-mune association has been suggested by the presentation
of patients with associated myopathy, alopecia, toid arthritis, systemic lupus erythematosus, CRESTsyndrome, and positive antinuclear antibodies However,these associations are missing in most individuals
rheuma-A distinguishing radiographic feature of PVOD is thepresence of radiographic changes in the pulmonaryparenchyma.34Since the vascular obstruction is postcapil-lary, the pulmonary capillaries are exposed to higherpressures and, thus, radiographic changes associated withinterstitial edema may be observed, such as Kerley’s Blines and pleural effusions Patchy pulmonary infiltratesmay be observed as well and, when present, may be asso-ciated with crackles on physical exam On high-resolution CT scan, ground glass opacities, thickenedseptal lines, and multiple small nodules have beenobserved
Physiologically, there is little to distinguish PVODfrom PAH Cardiac catheterization will show elevatedpulmonary artery pressures and, if the pulmonary arterycatheter is successfully wedged, normal pulmonary arterywedge pressures Failure to obtain a pulmonary arterywedge pressure tracing is common in PVOD.34In thepulmonary function lab, the diffusion capacity of thelung for carbon monoxide is usually reduced Spirometryand lung volumes may be normal or demonstrate arestrictive impairment
The finding of PAH, evidence of pulmonary edema onthe chest radiograph, and normal ventricular functionhas been suggested to be diagnostic of PVOD However,patients with PVOD may not demonstrate radiologicalfindings Open lung biopsy is a possible approach for thedefinitive diagnosis of PVOD Confirming the diagnosishas been felt to be appropriate as treatment withvasodilators may be hazardous An alternative approach
Trang 16is to cautiously test the hemodynamic response of
patients with suspected PVOD with short-acting
vasodilators during cardiac catheterization prior to
initi-ation of therapy
Patients with PVOD are at increased risk for the
administration of pulmonary vasodilators.35,36The
dila-tion of pulmonary arterioles, in the presence of fixed
venous occlusion, can lead to sudden increase in
pulmonar y capillar y pressure with formation of
pulmonary edema and even death However, as PVOD is
a relentlessly progressive and fatal disease, cautious
administration of vasodilators may be warranted The
response of PVOD to vasodilators is not well established
However, some studies have suggested alleviation of
elevated pulmonary vascular resistance in response to
vasodilators.37Similarly, anticoagulation is suggested
based on the experience with PPH Oxygen should be
administered to hypoxic patients If therapeutic
modali-ties fail, then PVOD becomes an indication for
consider-ation for lung transplantconsider-ation
Pulmonary hypertension may also result from the
occlusion of large pulmonary veins Inflammatory
diseases or neoplastic diseases of the mediastinum can
impinge upon and obstruct the pulmonary veins
Fibro-sing mediastinitis is a rare cause of pulmonary vein
occlusion It is characterized by exuberant fibrotic
re-sponse to inflammation in mediastinal lymph nodes,
which often spills over into other mediastinal structures
Some cases have been associated with histoplasmosis
infections by the finding of organisms on culture of
surgical specimens, while other cases have no clear
docu-mented etiology Successful surgical bypass of the
affected veins has been reported Case reports suggest
efficacy for treatment with tamoxifen
Lung Disease Associated with
Pulmonary Hypertension
Secondary causes of pulmonary hypertension are by far
more common than PAH, and the most common cause
of secondary pulmonary hypertension is lung diseases
The initial presentation of pulmonary hypertension
asso-ciated with lung diseases is that of the underlying lung
disease Lung diseases commonly associated with
pulmonary hypertension include COPD, restrictive lung
disease including the interstitial lung diseases, and
syndromes associated with hypoventilation
A central characteristic of these diseases is alveolar
hypoxia Alveolar hypoxia causes vasoconstriction
Teleologically, this mechanism helps to recruit
pulmonary vascular circulation distant from an area of
injury (eg, an underventilated portion of the lung
involved with pneumonia) When the alveolar hypoxia
becomes global, the vasoconstriction results inpulmonary hypertension Persistent alveolar hypoxialeads to vascular smooth muscle hypertrophy and vascu-lar remodeling eventually leading to fixed pulmonaryhypertension.38
Other mechanisms unique to the underlyingpulmonary pathology are associated with pulmonaryhypertension caused by pulmonary diseases In COPD,emphysematous changes lead to loss of alveolar septa andthe associated pulmonary capillary bed Progressive airtrapping leads to raised intra-alveolar pressure, which hasthe effect of collapsing alveolar vessels, further contribut-ing to the raised pulmonary artery pressure In COPD,factors that exacerbate hypoxia such as desaturation withexercise or desaturation associated with sleep-disorderbreathing can worsen the pulmonary hypertension.39The therapeutic approach to pulmonary hypertension
in COPD is to maximize bronchodilation, relieving areas
of poor ventilation and air trapping, and supplementaloxygen, especially during periods of increased physiolog-ical stress such as with exercise and sleep.40
Pulmonary hypertension associated with COPD tends
to occur in more severe lung disease and is predictive ofmortality.41However, the correlation between pulmonaryfunction tests and pulmonary hypertension in COPD issomewhat variable Patients who have a predominantlychronic bronchitic picture, with severe ventilation–perfusion mismatch and sleep-disorder breathing, canhave pulmonary hypertension fairly early in the course oftheir disease On the other hand, patients with a primar-ily emphysematous picture do not tend to developpulmonary hypertension until the forced expiratoryvolume in 1 second drops well below 1 L The best deter-minants for suspicion of pulmonary hypertension inpatients with COPD are the clinical findings of corpulmonale.42, 43
Restrictive lung diseases can be associated withpulmonary hypertension as well Restrictive lung diseasesare defined by impairment of the total lung capacity.These can be divided into a group of diseases that causeparenchymal lung disease and those that cause abnor-malities of the muscles of respiration and the thoraciccage The former group includes idiopathic interstitiallung diseases (eg idiopathic pulmonar y fibrosis,eosinophil granuloma, and sarcoidosis) and the pneumo-conioses (eg, asbestosis and hypersensitivity pneumoni-tis) The latter group includes diseases causing grossdistortions of the thoracic cage such as severe kyphoscol-iosis and neuromuscular disorders, which affect thediaphragm
The fibrosing interstitial lung diseases cause monary hypertension in part through the mechanismsassociated with alveolar hypoxia Additionally, progres-
Trang 17pul-sive fibrosis causes destruction of normal parenchymal
structures leading to distortion and destruction of the
pulmonary vasculature.44Pulmonary hypertension can
occur with exercise in patients with fairly well-preserved
lung volumes (total lung capacity in the range of 50 to
80% of predicted) Pulmonary hypertension at rest tends
to occur when total lung capacity falls below 50%
The treatment of interstitial lung diseases, once
fibro-sis has occurred, is universally disappointing Specific
therapies for some conditions such as prednisone for
sarcoidosis and prednisone and removal from exposure
to the inciting agent in hypersensitivity pneumonitis can
be quite effective early in the course of the disease at a
stage in the disease preceding the usual appearance of
pulmonary hypertension
Recently, an association has been described between
pulmonary hypertension and sarcoidosis In a subset of
patients with sarcoidosis, pulmonary artery pressures have
been known to be elevated and progressive in a manner
similar to that in PAH These patients are now classified as
a subgroup of patients with conditions that directly affect
the pulmonary vessels Patients with sarcoidosis and
pulmonary hypertension should be evaluated and treated
medically as described above for patients with PAH.45
Disorders of the muscles of respiration and the
thora-cic cage cause pulmonary hypertension through a variety
of mechanisms.46 The most obvious is hypoxia due to
hypoventilation However, the distribution of ventilation
is not homogenous, leading to areas of atelectasis and of
exaggerated ventilation–perfusion mismatch, which
contribute to alveolar hypoxia, vasoconstriction, and
even-tual fixed vascular changes of pulmonary hypertension
The treatment of pulmonary hypertension for
pa-tients with disorders of ventilation is primarily
mechani-cal in nature Supplemental oxygen can minimize the
severity and progression of pulmonary hypertension
However, the atelectasis and uneven distribution of
ventilation can only be addressed by mechanical support
Nocturnally administered continuous positive airway
pressure or bilevel positive airway pressure (BiPAP) can
be efficacious However, if the condition results from a
progressive disease, such as multiple sclerosis, then full
mechanical support via tracheostomy may be indicated
Treatment of pulmonary hypertension associated with
pulmonary diseases by the use of vasodilators has not
been shown to be effective Anecdotal reports have
suggested efficacious response in individuals, but control
trials have not supported vasodilator therapy
Theoretically, vasodilation of diseased lungs would be
expected to cause a variable response across the vascular
bed possibly leading to worsening of ventilation–
perfusion mismatch and, in turn, more severe alveolar
do the pulmonary venous pressures; vascular remodelingoccurs on the arterial side in response to chronic increase
in a passively increased pulmonary artery pressure.PAH can also be a manifestation of high flow states.48Congenital abnormalities of the heart, such as ventricularseptal defect, atrial septal defect, and patent ductus arterio-sus, are associated with left-to-right shunts Chronic expo-sure of the pulmonary arterial bed to high flow leads toinitially reversible changes of medical hypertrophy and inti-mal hyperplasia but eventually will be characterized byocclusion of vascular lumens by intimal hyperplasia andthe formation of plexiform lesions Repair of the congenitalanomaly while the lesions are still reversible can potentiallylead to normalization of the pulmonary artery pressure.Echocardiography with infusion of saline bubbles is effec-tive for demonstrating shunts Transesophageal echocardio-graphy is especially useful for the investigation of theintra-atrial septa Sampling of the oxygen content of theblood at the time of right heart catheterization can alsodocument a left-to-right shunt Finally, measurement of thepulmonary artery wedge pressure will confirm the diagno-sis of left ventricular dysfunction
Surgical Implications of Pulmonary
Trang 18occur, if possible, prior to surgery Vasodilator therapy
should be optimized and clinical conditions contributing
to secondary pulmonary hypertension, such as hypoxia,
should be corrected when possible.50In cases of acute PAH
due to pulmonary embolism, acute interventions with
more selective pulmonary vasodilators, such as inhaled
nitric oxide or epoprostenol infused into the central
venous system, may assist in control of hemodynamic
status Pulmonary hypertension is an indication for
intra-operative monitoring with a pulmonary artery catheter to
provide for more precise control of volume status Patients
with PAH anticoagulated with warfarin should not have
their anticoagulation discontinued, if possible, until the
time of surgery Either the anticoagulation can be reversed
and the patient placed on heparin, or the warfarin may be
discontinued and bridged to operation using daily
injec-tions of low molecular weight heparin
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hypertension A national prospective study Ann Intern
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3 McQuillan BM, Picard MH, Leavitt M, Weyman AE.
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4 Rubin LJC Primary Pulmonary Hypertension; ACCP
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5 Rubin LJ Primary pulmonary hypertension N Engl J Med
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8 Newman JH, Wheeler L, Lane KB, et al Mutation in the
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12 Rich S, Pietra GG, Kieras K, et al Primary pulmonary hypertension: radiographic and scintigraphic patterns of histologic subtypes Ann Intern Med 1986;105:499–502.
13 Nicod P, Peterson K, Levine M, et al Pulmonary phy in severe chronic pulmonary hypertension Ann Intern Med 1987;107:565–8.
angiogra-14 Kessler R, Chaouat A, Weitzenblum E, et al Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences Eur Respir J 1996;9:787–94.
15 Rich S, Kaufmann E High dose titration of calcium nel blocking agents for primary pulmonary hypertension: guidelines for short-term drug testing J Am Coll Cardiol 1991;18:1323–7.
chan-16 Rich S, Kaufmann E, Levy PS The effect of high doses of calcium-channel blockers on sur vival in primar y pulmonary hypertension N Engl J Med 1992;327:76–81.
17 McLaughlin VV, Genthner DE, Panella MM, Rich S Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension N Engl J Med 1998;338:273–7.
18 Rubin LJ, Badesch DB, Barst R, et al Bosentan therapy for pulmonar y arterial hy pertension N Engl J Med 2002;346:896–903.
19 D’Alonzo GE, Barst RJ, Ayres SM, et al Survival in patients with primary pulmonary hypertension Results from a national prospective registr y Ann Intern Med 1991;115:343–9.
20 Conte JV, Gaine SP, Orens JB, et al The influence of uous intravenous prostacyclin therapy for primar y pulmonary hypertension on the timing and outcome of transplantation J Heart Lung Transplant 1998;17:679–85.
contin-21 Moser KM, Bloor CM Pulmonary vascular lesions ring in patients with chronic major vessel thromboembolic pulmonary hypertension Chest 1993;103:685–92.
occur-22 Jamieson SW, Kapelanski DP Pulmonary endarterectomy Curr Probl Surg 2000;37:165–252.
23 Auger WR, Moser KM Pulmonary flow murmurs: a distinctive physical sign found in chronic pulmonary thromboembolic disease Clin Res 1989;37:145A.
24 Wolf M, Boyer-Neumann C, Parent F, et al Thrombotic risk factors in pulmonary hypertension Eur Respir J 2000;15:395–9.
25 Auger WR, Permpikul P, Moser KM Lupus anticoagulant, heparin use, and thrombocytopenia in patients with chronic thromboembolic pulmonary hypertension: a preliminary report Am J Med 1995;99:392–6.
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27 Pitton MB, Duber C, Mayer E, Thelen M Hemodynamic effects of nonionic contrast bolus injection and oxygen inhalation during pulmonary angiography in patients with chronic major-vessel thromboembolic pulmonary hyper- tension Circulation 1996;94:2485–91.
Trang 1928 Sompradeekul S, Fedullo PF, Kerr KM, et al The role of
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patients with thromboembolic pulmonary hypertension
(CTEPH) Am J Respir Crit Care Med 1999;159:A456.
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Trang 20Pulmonar y hy pertension as a result of chronic
pulmonary thromboembolic disease is a common yet
underdiagnosed condition Patients with this syndrome
may present with a wide variety of debilitating
pulmonary or cardiac symptoms Once properly
diag-nosed, the only curative treatment is surgical removal of
the disease, by means of pulmonary
thromboendarterec-tomy (PTE) Medical management is only palliative, and
surgery by means of transplantation is an inappropriate
use of resources with less than satisfactory results
PTE is a technically demanding yet highly successful
operation for chronic pulmonary thromboembolic
disease The procedure is widely misunderstood, and
though many have attempted it, it is performed with
success at only a few centers Proper patient selection,
meticulous surgical technique, and careful postoperative
management at selected centers have now clearly shown
that it is an effective therapy The operation seems
diffi-cult to perform well; a true endarterectomy (not an
embolectomy) of all affected parts of the lung remains the
key to success This chapter considers the place of the
operation in the spectrum of patients with pulmonary
hypertension and describes the preoperative work-up, the
technical details of the operation, and the current results
at the University of California, San Diego (UCSD)
Pulmonary hypertension is a manifestation of manycardiac and pulmonary diseases Cardiac causes includethe result of congenital and acquired heart disease Thepulmonary causes can be divided in three general cate-gories: primary, parenchymal, and vascular In primarypulmonar y hypertension, the microvasculature isaffected by an uncertain process, which is generallyconsidered progressive and irreversible Parenchymalpulmonary disease includes a group of patients with anunderlying pulmonary disease, such as emphysema orpulmonary fibrosis, which could progress in pulmonaryhypertension Pulmonary vascular causes refer topatients with acute and chronic pulmonary thromboem-bolic disease, as well as pulmonary veno-occlusivedisease
The prognosis for patients with pulmonary sion is poor, and it is worse for those who do not haveintracardiac shunts Thus, patients with primar ypulmonary hypertension and those with pulmonaryhypertension due to pulmonary emboli fall into a higherrisk category than those with Eisenmenger’s syndromeand encounter a higher mortality rate In fact, once themean pulmonary pressure in patients with thromboem-bolic disease reaches 50 mm Hg or more, the 3-yearmortality approaches 90%.1
Trang 21hyperten-Patients with pulmonary hypertension present one of
the more difficult therapeutic challenges Medical
treat-ment is generally unsatisfactory and palliative at best
Surgical options are dependent on both the primary
disease process and the reversibility of the pulmonary
hypertension With the exception of thromboembolic
pulmonary hypertension, lung transplantation is the only
effective therapy for patients with pulmonary
hyperten-sion, when the disease reaches end-stage Pulmonary
transplantation is also still used in some centers as the
treatment of choice for those with thromboembolic
disease However, a true assessment of the effectiveness of
any therapy should take into account the total mortality
once the patient has been accepted and put on the
wait-ing list Thus, the mortality for transplantation (and
especially double-lung transplantation) as a therapeutic
strategy is much higher than is generally appreciated
because of the significant loss of patients awaiting
donors In addition, the long-term use of anti-rejection
medications with their associated side effects, the higher
operative morbidity and mortality, and the long waiting
time clearly make transplantation an inferior option to
PTE, and we consider it to be inappropriate
PTE should be applied as a treatment for
thromboem-bolic disease whenever possible, provided acceptable
results can be achieved It reduces the mortality rate of
patients on the waiting list and avoids
immunosuppres-sion Further, it appears to be permanently curative
Embolic Pulmonary Hypertension
Laennec originally described pulmonary embolism in
1819, and related the condition to deep venous
thrombo-sis.2Virchow recognized that the three factors
predispos-ing to venous thrombosis were stasis, hypercoagulability,
and vessel wall injury.3Despite our progressive
under-standing of the etiology and pathology of this condition,
deep venous thrombosis with subsequent pulmonary
thromboembolism remains a significant cause of
morbidity and mortality Acute pulmonary embolism,
after cancer and heart disease, remains the third most
common cause of death in the United States
Acute pulmonary thromboembolism is thus a much
more common condition than is generally appreciated,
and in many cases, it is asymptomatic Dalen and Alpert
in 1975, calculated that pulmonary embolism resulted in
630,000 symptomatic episodes in the United States
yearly, making it, at the time, about one-half as common
as acute myocardial infarction and three times as
common as cerebral vascular accidents.1However, this
may be a low estimate, since autopsy studies have shown
that the diagnosis of acute pulmonary embolism was
unsuspected in 70 to 80% of those patients in whom it
was the principal cause of death.4,5Another autopsyanalysis of 13,216 patients showed pulmonary throm-boembolism in 5.5%, and up to 31.3% in the elderly.6
It is almost axiomatic that heightened interest in a given disease leads to an increased incidence of discovery Therefore current opinions regarding the rarity of exten- sive pulmonary thromboembolism may well be revised in the future, and available estimates of its incidence should
be viewed in this light 7
In addition to patients suffering from acutepulmonary embolism from deep vein thrombosis, thereare other special circumstances For example chronicindwelling central venous catheters and pacemaker leadscan be associated with pulmonary emboli Patients withintracardiac shunts who develop pulmonary hyperten-sion may have other factors involved, such as directchemical irritation of the pulmonary vascular bed Otherrare causes include tumor emboli; tumor fragments fromkidneys, breasts, and stomach have been demonstrated tocause chronic pulmonary arterial occlusion Tumoremboli could also originate from right atrial myxomas.However, not every case is the result of embolic material
In situ thrombosis, either as a result of coagulopathy,endothelial damage, or a secondary phenomenon after aninitial embolism has well been described
What happens to the embolic material, once wedged
in the pulmonary artery, depends on a few differentfactors In the majority of patients, spontaneous resolu-tion of acute pulmonary emboli is the rule However, asmall but uncertain percentage develop chronic throm-boembolic pulmonary hypertension Again, the mecha-nisms responsible for the failure of the body to dissolvethe material remain unclear The volume of the embolicmaterial may simply be too overwhelming for the lyticmechanisms The emboli may be made of a substancethat cannot be resolved—materials such as already well-organized fibrous thrombus, fat, or tumor Further,repetitive emboli may not be able to be resolved On theother hand, there may be an abnormal lytic mechanism,
or some patients may have a propensity for thrombus or
Trang 22arteries in nearly 1% of 7,753 autopsies.8This remains a
low estimate for the incidence of operable pulmonary
hypertension, since many patients who have had relief of
their pulmonary hypertension following PTE have had
disease confined to their minor pulmonary arteries, and
chronic thrombus in these smaller pulmonary vessels is
probably often overlooked in autopsy series
The vast majority of cases of pulmonary hypertension
due to pulmonary artery occlusion are the result of
“spontaneous” thromboembolism In a small percentage
(5 to 11%), however, coagulation abnormalities can be
detected, such as lupus anticoagulant, protein C
defi-ciency, or antithrombin III deficiency.9A few patients
have a paradoxical response to heparin, with apparent
heparin-induced platelet antibodies In such cases,
special precautions must be taken during
cardiopul-monary bypass and the perioperative period, and great
care must be taken to eliminate heparin from all
intra-venous lines Studies of the pulmonary vascular
endothe-lium in affected patients have failed to demonstrate any
consistent abnormality; however, an elevation in factor
VIII-related antigen has been shown to occur in
associa-tion with extensive intimal damage.10,11
After a pulmonary embolus, the unresolved residual
pulmonary artery clot organizes and obstructs the
pulmonary arteries to a variable extent, at the main
pulmonary artery, lobar, segmental, or subsegmental
level.8The resultant pulmonary vascular hypertension
may be a very complex process, and factors other than
the simple hemodynamic consequences of redirected
blood flow with higher pressures and flow are most likely
involved In general, more than 50% of the pulmonary
vasculature must be occluded for patients to become
pulmonary hypertensive However, very frequently we
encounter patients with significant pulmonary
hyperten-sion with less than 50% of the vascular bed occluded by
thromboembolic material There may be a sympathetic
neural, hormonal, or combined neurohormonal signal
that initiates pulmonary hypertensive changes on the
initially unaffected pulmonary vascular bed—a process
that can occur in either lung, regardless of the original
site of occlusion In these cases, the operation will open
the vessels occluded by the thromboembolic material or
intimal hyperplasia but cannot resolve the small-vessel
disease of reactive pulmonary hypertension (Figures
24-1–24-3)
Irrespective of the exact etiology, the resultant
pulmonary hypertension and the secondary vasculopathy
is a serious debilitating condition, potentially inoperable
With our increasing experience with patients with
thromboembolic pulmonary hypertension, we have
become much more inclined toward early operation to
avoid these deleterious consequences
FIGURE 24-1 A, Pulmonary artery (PA) chest film of a 72-year-old
physician with severe pulmonary hypertension (PA pressure above systemic levels, pulmonary vascular resistance 1,250 dynes/sec/cm 5 ) Note the right heart enlargement, prominent pulmonary artery shadow,
and hypoperfusion of areas of right and left lungs B, Lateral view of
chest Note right heart enlargement and anterior proximity to sternum.
Trang 23thrombosis should be sought, as should a history of leg
swelling, chest pain, cough, hemoptysis, or anything to
indicate episodes of pulmonary embolism The initial
symptoms, being vague, are often attributed to other
causes, such as coronary or myocardial disease,
intersti-tial lung disease, asthma, or age Many cases remain
undiagnosed, especially since the patients may be
asymp-tomatic and have normal pulmonary artery pressures at
rest Other symptoms that may occur, usually in the later
stages of the disease, include exertional chest pain, cough,
and hemoptysis
Physical Examination
Clinical examination is usually nonproductive and
unre-warding if right heart failure has not developed, even if the
patient has a history of severe dyspnea Cyanosis is usually
absent, unless it is peripheral and related to severely
depressed cardiac output or central as the result of
right-to-left shunting in the setting of patent foramen ovale or
an atrial septal defect Clubbing of the fingers is not
usually present Flow murmurs may be heard, especially
over the back, owing either to flow through narrowed
pulmonary arteries or to aggressive bronchial flow
Diagnostic Tests
Chest roentgenogram, electrocardiogram, and pulmonary
function tests are of little value in differentiating
throm-boembolic pulmonary hypertension from other forms of
pulmonary hypertension However, these investigations
often give the initial clues that pulmonary hypertension
exists when the physical findings are less conclusive
The radiographic signs of pulmonary hypertension on
chest film may be difficult to determine Enlargement of
the pulmonar y arter y and paucity of flow to the
pulmonary vascular bed may indicate occlusion of major
vessels (see Figure 24-1A) The lateral chest film will often
show right ventricular hypertrophy (see Figure 24-1B)
Echocardiography demonstrates enlarged right-sided
heart chambers and varying degrees of tricuspid
regurgi-tation Standard two-dimensional echocardiography is
also helpful in defining the presence and severity of
pulmonary hypertension and excluding certain other
causes such as Eisenmenger’s syndrome
Continuous-wave Doppler echocardiography of the tricuspid
regurgi-tant jet will estimate the pulmonary artery systolic
pressure Occasionally, proximal, chronic, organized
thrombus in the main pulmonary artery or main right
and left pulmonary arteries can be seen with transthoracic
echocardiography; however, this technique lacks
sensitiv-ity and is inadequate for visualization of the lobar vessels,
where the embolic material is often localized
Transesophageal echocardiography has proved to be more
promising, especially with multiplane probes that allow
angulation of the imaging plane so that the origin of most
of the lobar vessels can be identified Early attempts arebeing carried out at visualizing the pulmonary arterieswith transbronchial echocardiography
A perfusion scan is almost always performed Themajor differential diagnosis is primary pulmonary hyper-tension, in which the scan is usually normal or has apatchy and mottled appearance, in contrast to the multi-ple punched-out lobar or segmented defects of chronicthromboembolic disease The perfusion scan tends tounderestimate the degree of occlusion of the pulmonaryvessels A computed tomography (CT) scan may beuseful,12 and recent work has been performed usingcomputer-enhanced images of CT scanning, both in theacute and chronic forms of this condition These imagesare capable of confirming occlusion in at least the mainand lobar pulmonary arteries Further, a mosaic pattern
of lung attenuation on CT is a sign of variable regionalperfusion and may suggest chronic pulmonary throm-boembolism as a cause for pulmonary hypertension.13Once pulmonary hypertension as a result of chronicthromboembolic disease is suspected, the evaluation ofthe patient prior to planning surgical interventiondepends on right heart catheterization and pulmonaryangiography These are essential to evaluate the severity
of pulmonary hypertension, to define the presence ofthromboembolic disease, to assess the operative risk andsurgical accessibility, and to exclude other diagnoses Insome patients with only moderate pulmonary hyperten-sion at rest, a striking increase in pulmonary artery pres-sure will be seen with only minimal exercise Thoughconcern is regularly expressed that angiography placesthe pulmonary hypertensive patient at great risk, we havenot found this to be the case,14and pulmonary arteriog-raphy is performed on pulmonary hypertensive patients
on almost a daily basis at our center
Selective power injections of the right and leftpulmonary trunks, using nonionic contrast agents toprevent the cough response, are well tolerated The typi-cal findings of chronic thromboembolic disease onpulmonary angiogram include an irregular lumen, indi-cating thrombus attached to the vessel wall, and theappearance of bands or webs across the lumen of vessels,sometimes with poststenotic dilatation Other findingsmay include occlusion of branches with lack of filling out
to the periphery, often with an abrupt termination ofpulmonary vessels with a pouch-like appearance (Figures24-2 and 24-4)
In addition to pulmonary angiography, patients over
35 years of age undergo coronary arteriography andother cardiac investigation as necessary If significantdisease is found, additional cardiac surgery is performed
at the time of PTE
Trang 24Most patients referred for PTE surger y have a
pulmonary vascular resistance of more than 1,000
dynes/sec/cm 5, and many have suprasystemic
pulmonary artery pressures We have operated on
patients ranging in age from 14 to 83 years The
docu-mented history of pulmonary vascular occlusion has
been as brief as a few months to as long as 24 years Prior
to PTE surgery, an inferior vena cava filter is always
placed Patients are thereafter treated with anticoagulants
indefinitely
Operation
There are some guiding principles that are essential to a
successful outcome in this challenging operation First,
the operation must be performed on both lungs, since
patients with significant chronic embolic pulmonary
hypertension invariably have bilateral disease Second,
cardiopulmonary bypass (CPB), with periods of
circula-tory arrest, is essential to achieve adequate exposure in
the face of the copious bronchial blood flow Third, a
true endarterectomy in the plane of the media must be
accomplished
It is essential to appreciate that the removal of visible
thrombus is largely incidental to this operation Indeed,
in the majority of patients, no free thrombus is present,
and on initial direct examination the pulmonary vascular
bed may appear normal
The operation is thus performed through a median
sternotomy and on cardiopulmonary bypass.20 This
allows a bilateral approach and also the use of circulatory
arrest under profound hypothermia The circulatory
arrest periods are limited to 20 minutes, with restoration
of flow between each interruption With our increased
experience, the endarterectomy usually can be performed
with a single period of circulatory arrest on each side
Although retrograde cerebral perfusion has been
advo-cated for total circulatory arrest in other procedures, it is
not helpful in this operation since it does not allow a
completely bloodless field, and with the short arrest
times that can be achieved with experience, it is not
necessary During circulatory arrest, progressive
circum-ferential dissection is carried into all the involved lobar,
segmental, and subsegmental vessels With proper
expo-sure, all the residua of thromboembolic occlusion can be
removed, no matter how distal, and it is possible to
remove occluding material as far distally as the
diaphrag-matic level
The patient is prepared as for any open-heart
proce-dure, with arterial and pulmonary artery catheters and
electroencephalogram monitoring A femoral artery line
is also placed because the profound vasoconstriction that
tends to occur after hypothermic circulatory arrest makes
readings from the radial artery catheter unreliable duringthe immediate postoperative period A median ster-notomy incision is made and the sternum divided Theright heart is invariably enlarged, with variable degrees oftricuspid regurgitation
Bypass is instituted with high ascending aortic lation and two caval cannulae Standard flow forcardiopulmonary perfusion is used and the patientcooled, maintaining a 10°C gradient between arterialblood and bladder or rectal temperature.21
cannu-A temporarypulmonary artery vent is inserted Once ventricularfibrillation occurs, a second vent is placed in the leftatrium through the right upper pulmonary vein Thisprevents distention from the large amount of bronchialarterial blood flow that is common with these patients.The patient’s head is surrounded by ice and the cool-ing blanket turned on During perfusion the venous satu-rations increase; saturations of 80% at 25°C and 90% at20°C are typical Hemodilution is carried out to decreasethe blood viscosity during hypothermia and to optimizecapillary blood flow The hematocrit is maintained in therange of 18 to 25 during profound hypothermia.Phenytoin is administered intravenously during cooling
at 15 mg/kg, to a maximum dose of 1 g
During the cooling period some preliminary tion can be carried out, with full mobilization of theascending aorta from the pulmonary artery The superiorvena cava is mobilized all the way to the innominate veinand dissected free of the right pulmonary artery Theazygos vein is exposed but not divided The reflection ofthe right pulmonary artery to the left atrium is separated.Most of this dissection is performed with electrocautery,because with advanced right heart failure and hepaticcongestion, coagulation is usually abnormal However,care must be taken to preserve the integrity of the rightphrenic nerve lying lateral to the superior vena cava Alldissection of the pulmonary arteries occurs intrapericar-dially, and it is not necessary to enter either pleuralcavity
dissec-The right pulmonary artery is now exposed so that thetake-off of upper and middle lobes can be seen Theupper pulmonary vein is usually not visualized butreflected upward from the plane of the pulmonary arterywall An incision is made in the right pulmonary arteryfrom beneath the ascending aorta out under the superiorvena cava and entering the lower lobe branch of thepulmonary artery just after the take-off of the middlelobe It is important that the incision stay in the center ofthe vessel Only one incision is needed, and it is easier toendarterectomize the right upper lobe from a centralincision than through a separate incision in the upperlobe artery The distal limit of the incision is usuallyapproximately 1 cm distal to the take-off of the upper