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`GENERAL §§EM€28f:\§E
`
`35$?! EDITEGN
`
`I PS EX. 2166
`
`CFAD V. NPS
`
`I PR2015-00990
`
`Page 1
`
`NPS Ex. 2166
`CFAD v. NPS
`IPR2015-00990
`
`

`
`THE
`
`MERCK
`
`MANUAL
`
`FIFTEENTH EDITION
`
`1st Edition —‘ 1899
`2nd Edition -1901
`3rd Edition — 1905
`4th Edition — 1911
`5th Edition — 1923
`6th Edition— 1934
`7th Edition —- 1940
`8th Edition — 1950
`
`9th Edition— 1956
`10th Edition -1961
`11th Edition— 1966
`12th Edition- 1972
`13th Edition~— 1977
`14th Edition- 1982
`15th Edition- 1987
`
`VOLUMEI
`
`GENERAL MED1C|NE
`
`Page 2
`
`
`Page 2
`
`

`
`FIFTEENTH EDITION
`
`THE
`
`IVIERCK
`
`MANUAL
`
`OF
`
`DIAGNOSIS AND THERAPY
`
`VOLUMEI
`
`GENERAL MEDICINE
`
`Robert Berkow, M.D.. Ea‘/tor-/n-Ch/ef
`
`Andrew J. FIetcher, M.B., B.Chir., Ass/sz‘éntEa’/tor
`
`Ed/tor/a/I Board
`
`PhiIip K. Bondy, M.D.
`L. Jack Faling, M.D.
`Alvan R. Feinstein, MD.
`Eugene P. Frenkel, MD.
`Robert A. Hoekeiman, MD.
`Robert G. Petersdorf, MD.
`
`Fred Plum, MD.
`John Romano, MD.
`G. Victor Rossi, Ph.D.
`John H. TaIbott, MD.
`Pauf H. Tanser, MD.
`
`Published by
`
`MERCK SHARP & DOHME RESEARCH LABORATORIES
`D/‘v/‘s/on of
`MERCK & Co., INC.
`Rahway, N.J.
`»
`1987
`
`Page 3
`
`
`Page 3
`
`

`
`MERCK & CO, INC.
`
`Hahway, N.J.
`U.S.A.
`
`MERCK SHARP & DOHME
`West Point, Pa.
`
`MERCK SHARP 84 DOHME INTERNATIONAL
`Hahway, N.J.
`
`MERCK SHARP & DOHME RESEARCH LABORATORIES
`Rahwa y, N../. West Point, Pa.
`MSD AGVET DIVISION
`Woodbridge, N.J.
`
`HUBBARD FARMS, INC.
`Walpole, N. H.
`
`MERCK CHEMICAL MANUFACTURING DIVISION
`Hahway, N.J.
`
`CALGON CORPORATION
`Water Management Division
`Pittsburgh, Pa.
`Commercial Division
`St. Louis, Mo.
`
`KELCO DIVISION
`San Diego, Calif.
`_._.._____.___.___._.__._
`
`Library Of Congress Catalog Card Number 1—3176O
`ISBN Number 0-91 1910-07-7
`ISSN Number 0076-6526
`
`First Printing——August I987
`
`COpyrigl'Iz© $987 by MERCK 8: Co., NC.
`AH rights reserved. Copyright under the Universat Copyright
`Convention and the internationai Copyright Convention.
`Copyright reserved under the Pan»American Copyright Convention,
`Prmwd ir xhe U, S A.
`
`Page 4
`
`
`Page 4
`
`

`
`M
`48 infectious and Parasitic Diseases
`tenderriesss over the ilexor tr;-moo":
`signs
`generalizeri swelling and inflammation of" me finger,
`
`sheaths. Careful maintenance of a flexed finger A
`mom. and exouiszire pain on active or D€3SSlV(;'
`
`izriger extension Fever, lyrtipharigitis, lymphaden is, and leumcytosis are usual. Treatment is surgi-
`cal oramage plus antibiotics. Gram stain of the pus should o‘=c:ate axiiil:iotic choice: streptococci and
`staphylococci are the usual pathogens.
`
`K,
`
`6. BACTEREMIA AND SEPTIC SHOCK
`
`i‘ to term septicemia is reserved for
`Bacteremia connotes invasion of me C.n'Cu.-"ar‘.fon by bacteria.
`srtuar/orig /n which bacteremla /5 £’5SOClar‘Ed win‘; clinical ma.rr:1’esra:rans 0/ //vfecricrr. Bacteremla
`COWWOWY. 8575 U3l«‘3llV Vanslently. accompanies various surgical rrianipuiations (eg, incision of an
`abscess); or it may result from colonization of indwelling intravenous devices and urethral catheter“.
`
`(For infants, see also NEONATAL SEPSlS AND NEONATAL MENlNGlTlS under NEONAYAL INFECTIONS iii v1 .
`ll. Ch. 23.) Bacteremia may be intermittent or sustained, and may cause severe conseouences. in
`patients who abuse IV narcotics. grarmpositive bacteremia is comrnori and may lead to rightsided
`bacterial endocarditis even in the absence of cardiac murrnurs. The oaclerernia of left-sided bacterial
`endocarditis is usually sustained and may be prolonged. Grarrwegative bacteremia lS usually inter-
`mittent and generally fol-ows primary infection in the GU tract, biliary tree, Gl tract. lungs, or
`less
`
`C0-‘=”>mG"lV. skin. bones. or joints.
`in many patients with chronic diseases no primary focus oi i
`tion is apparent.
`Symptoms and Signs
`Few clinical manifestations are unique to bacteremia. Although variable, fever lS almost always
`present and may be intermittent, with wide diurnal variations (septic. or "sp%l<ir~g“}, Chills are coin
`man at the onset Skin eruptions are also common, and may be petechial. purpuric. papular, pusluiat,
`or vesicular. Usually gram—negative bacteremia begins abruptly with chills, =‘over, nausea, vomiisrig,
`diarrhea, and prostration,
`Diagnosis
`The presence of bacteremia is established by blood cultures, which should be perlorrneo for both
`aerobic and anaerobic organisms. A single negative culture does not exclude bactererma; moreover,
`in some patients, especially those with préor antibiotic therapy, blood cultures never do become
`positive. li the patient is not very ill, no more than 6 blood cultures should be performed, In severely
`ill patients. 2 blood cultures taken 30 min apart before treatment is irstitured slioulo suffice. in most
`cases, treatment is required before results of blood Cultures become available.
`Complications
`Metastatic infection of the meninges or of serous cavities, sucln as the pericardium or larger
`joints. may occur. Endocarditis (see also ENoocARDms in Ch. 27) may be the sequel 0‘ bacterernia ii
`the pathogen is a streptococcus or staphylococcus, but rarely occurs
`a result of gramwiegative
`baoteremias. Metastatic abscesses may occur almost anywliere and, when extensive, produce
`symptoms and s=gr2s criaracterrstie of infection in the organ affected, Multiple abscess formation is
`particuarly common with staphylococcal baclererriia. Bacleremia may result iI'1 septic shock, wiiir;
`$3 discussed separately. below.
`Prognosis
`iary
`iiidwellrg l\/ catheters; or
`Transient baoteremias associated with surgical procedures,
`ca‘rhete"s are often undetected and probably do not require therapy. However, persgstent bacteremia
`is dangerous; the prognosis depends on the ability to el rriinaie the source of infection with s gery
`or antibiotics, and on the status of the underlying disease. When multiple organisms are recovered
`consistently (polymicrobial bacteremia). a poor outcome can he expected. Bactarernse unresponsive
`to treatrnerit because 0‘ inadequate entibiobc therapy. poor host resistance, or delay in i§lagTiOSl$ is
`often fetal.
`Treatment of baoteremia is discussed below with septic shock,
`
`
`
`SEPTIC SHOCK
`Wnen bacterernia is associated with inadequate tissue perfusion, especialiy with gram—rregative
`re
`organisms or meningococci. septic shock with hypotension. vascular collapse, renal failure. and
`death may ensue. Septic shock usually occi when bacteremia is due to grarn—rtegative organisms
`and generally in hospitalized patients with underlying diseases. Pre-disposing factors include diabetes
`meilitus; cirrhosis: leukemia; lymphoma; disseminated carcinoma: surgical procedures: antecedent
`
`_
`
`, ,_ ..--A.._._._....—-1
`
`Page 5
`
`
`Page 5
`
`

`
`Bacteremia and Septic Shock 49
`-
`ch, 5
`iniection in the sririary, bzliary, or Gl tracts; indwelling l‘v’ catheters. treatment with antibiotics, step
`aids, gyrotoxic: agents, or inhalation ecurprnent. Septic shock occurs more often In the elderly and in
`zrze newbor :.
`b
`I
`The pathogenesis of septic shock depends upon vasoconstrictson oi the smail arteries and veins.
`w'hi(,n leads to increased peripheral vascular resistance, pooling cl blood an the microcirculation, and
`decreased cardiac Output. With poor perfusion there is tissue anoxia anc the decreased blood vol.
`time results in nypotension and oliguria. These vasoactive phenomena are related largely to release
`of endotoxin, the lipopolysaccharide moiety of gram-negative ‘ceciliary Cali. walls, into the circulation,
`Symptoms and Signs
`Manifestations of bacteiamia (see above) usualiy appear first. V\/nevi septic shock develops, there
`are,
`in addition, tachycardia: tachypnea; nypotension: moi. Dale extremities (often with peripheral
`cyariosis); mental obturidation; anc oligtiria. Occasionally the findings are subtle, especially in elderly,
`debilitated patients or infants. Unexplained ‘nypotension,
`increasing confusion and disorientation.
`‘nyperpnea, or oliguria due to decreased renal blood flow may
`the only early clues to gram~r‘=ega-
`
`trve‘shocl<. As shock progresse
`nadecuate renal perfusion may lead to acute renal failure. Cori’
`gestive heart failure, respiratory insufficiency, and coma may progress to dean .
`I
`Different hemodynamic patterns are characteristic of endoroxin-related shock. Some patients have
`normal blood volume, venous pressure. c:irr:uiation time, and cardiac output, but have decreased
`peripheral resistance. These patients have warm, dry skin; often they also have cirrhosis. The progno-
`sis in this type of "warm shock!’ is good unless local acidosis, a consequence of irieifective tissue
`perfusion and impaired oxygen utilization, eventuates in decreased biood volume. central venous
`pressure, and cardiac Output. with by-poterision and oliguria. This 5-iernodynamic pattern may be
`present initially Or may follow a period of warm shock.
`Most patients with septic shock have deficiencies in several clotting factors, probably due to their
`Consumption in the process of disseminated imravascuiar coagulation {see Ch. 99). Respiratory fail-
`ure characterized by decreased pulmonary compliance and irreversiole hypoxia. called "shock lung”
`(see Ch. 35), may ensue even after hemodynamic abnormalities have been corrected.
`Laboratory Findings
`laboratory data in bacteremia and septic shock vary greatly and depend in rrrany instances on the
`cause and stage of hemodynamic decompensation. Usually, leukocytosis of between l5,000 and
`30,000 WBC/i1L with a left shift is present However. relative or absolute leukopenia may be pres-
`ent in severe cases, particularly early in the course. The platelet count is usually decreased. Urinalysis
`reveals no specific abnormality.
`initially the urine sp gr is increased. However,
`if oiiguria persists,
`isosthenuria may develop. The BUN and creatinine are increased, and creatinino clearance declines
`Electrolytes vazy considerably, with a trend toward hyponatrernie and ‘rzypocnloremia. Potassium may
`be low or high depending upon the ability of the kidney to excrete this ion.
`Respiratory alkalosis, with a low P502 and increased arteria1pH. is present early and comps ‘rrres
`for lactic acidemia. Serum bicarbonate is usually low, while blood lactate is increased. A.-5 s
`‘
`
`progresses, metabolic acidosis supervenes. Hypoxemia with P02 < 70 mm Hg is common. ‘rie;Trocy—
`namic measurements vary as described above. The ECG shows depressed ST segments with T‘ wave
`inversions and various arrhythrnias.
`Treatment
`Overall mortal ty in septic snock ranges from 50 to 90%, if mild
`
`ctrr; acidosis is severe.
`present, the prognosis is good, t-
`;
`3“
`
`
`
`snt‘2:ig" C=n..~‘
`d, shock
`often
`peirsated metabolic a dosis pace
`cause most patients liiaE“_/ to eveéop
`y:=ripto;ns an
`, sivorik are in *" hospital b
`
`of slrocir appear, this grave
`i‘
`or infection is of ..
`» avo¥‘«a‘r.>le by vigilant care
`’
`Patients with septic: snr
`sled}
`.
`iv
`c is _t="li!S Pulrnoriary artery and systemic
`pressures, arterial and y'€=i>E>.
`5 pH. artenal blood gases:
`plate, renal furiclioi‘, am elect"cw‘y'es
`
`should be ¥nO!"lf0i'E‘.'g ‘i
`,
`n _[){O\:’idS.‘; a clue to iiuiph
`1
`resistance. but does not accurate
`gy. brain, or gm Trierszrore,-*1‘
`output sht:-iisd be used to mom
`ffriaflclirlic blood flow a d visceral r
`.osi0z‘.
`lndweli
`oath»,
`s
`usually recurred.
`Fluid therapy: The central venous pressure {CVP) or pulmonary artery pressure shouic‘ be mea~
`sired in every patient, and fluid replacement given until the CV? reaches ll} to ‘:2 cm of water o’
`until the pulmonary wedge pressure reaches 12 to 15 mm Hg. Blood volume should be replaced
`with blood if anemia is present; otherwise. plasma, dextran, human serum abumin. or appropriate
`eiectlfilyte solutions {usually dextrosesaiine with bicarbonate. which is preferable to lactate) are
`used. Ollguria in the presence of bypotension is not a contraindication to continuing vegorous fluid
`l*l9l'5r'3Y- The Quantity of ilurd required often
`exceeds the riormal blood volume and may amount
`{O 8 $0 1:2 L in a few hgurg,
`
`
`
`_
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 6
`
`
`Page 6
`
`

`
`
`
`
`
`50 infectious and Parasitic Diseases
`
`5’:
`
`tracheal intubation, or tracheostomy as
`Respiration should be supported with nasal oxygen.
`necessary. The pulrronary artery pressure may be the best guide for anticipating incipient pulmonary
`edema. Treatment of shock lung is described in Ctr. 35.
`Parenteral, bactericidal antibiotics sliouzd be administered after cultures of biood and approprr
`ate sites have been taken. Usually at the onset of bacteremia or septic shock, while awaiting cultures
`and sensitivities, an etiologic diagnosis entails an educated guess based on previous cultures from a
`primary focus or on the setting in which
`action occurs. Pus must be drained and foreign bodies
`and necrotic tissue must be removed Failure to do so often results in a poor outcome despite
`antbrotir; therapy. Specific therapy »s the serve as for me primary infection, but more intense. Since
`early acirninistratron of antibiotics may be critical to save the patient‘s life, an effective regzmen for
`
`
`bacreremia of unknown etiology before arm :rCfObl8i sensltr ties are known is gentamicin or tobra~
`mycin 3 to 5 mg/kg/day llvi or lV plus either rtafcillin 4 to 8 gm/day iv or a parenteral cephalosporin.
`Carbenicillin or trcarctllin 30 grrr/day lV may be added if Pseudomcnas .5 susoected. As soon as
`cultures have revealed the putative pathogen. unnecessary agents are stopped. Antibiotics should be
`continued for several days after shock has resolved and the primary focus of infection has healed
`adequately.
`Vasoactive drugs, pa:'7%cu:‘ar.y alph5~.receptcr blocking agents leg, phenoxyberxzamine) or beta—re~
`ceptor stimulators leg. rsoproterenol) have been of value in septic shock. Dopamine is now the
`preferred agent because it erihartces renal pertusion. The response to therapy is determined clinical.
`ly. and return of peréusron to norrrial :s the best guide to stopping vasopressors.
`
`
`
`itrgate ‘me cellular
`Adrenal corticosteroids ii‘
`lar
`doses suppn" peririh ral resists ce and .
`
`
`
`
`
`
`
`
`'
`’
`...etr us: .
`$~.3«re:s.tt£, nwst cirrrruram v‘~zl3I
`~’i§4..';"/ Se
`’
`C} Eng
`'lV7:‘$ 39
`
`mg,/kg meihylprednrsolorro as a bolus and rep at it at 6- to l2—h intervals for 24 to 48 ii.
`Control of hemorrhage, with fresh frozen p?asrna when it
`‘IS a cor-sequence of clotting factor
`rieficiency or wtth platelets when due to znrombocytoperna, is importart.
`
`Surgical intervention to drain absce
`s or excise irttecr-ed tissuesweg, lniarcteo bowel. inflamed
`galstiiacmer,
`infected uterus. or pyc
`{.>hrOSiS——~ShUi,'id be performed. The patient's condition. al«
`though grave, rnav rzontanue to date ’
`rate unless the septic food is re oved or drained.
`Other therapeutic modalities are indicated, ceoending on the patients clinical status, and include
`
`marmtel or furoeernirie to induce diuresés :n patients with oligurie, a rapidly acting digit
`3 preoara—
`tion in patients with hea
`failure.
`or:<:as.onal'y. heparin in patients with disseminated zntravascu—
`lar coagulation.
`
`
`
`7.
`
`INFECTIONS lN THE COMPROMlSED HOST
`
`/nfacrrons ranging from ff”/z'»"lO.’ to fatal. caused by norma//y nonpat/vogemc organrsms in patients
`whose frost‘ defense mechanisms nave been compromrsed. Malnly,
`the problems presented take
`place in the rospital setting and are the prtce at medical advances that have erzablad us to deal more
`ettectiveiy with prEv'OLl$iy unmanageable disorders. Noscrcornial
`infection in the newborn is dis-
`cussed under NEONATAL mrecrrons in vol, ft, Ch. 23.
`Etiology
`9-lost defense mechanssmsmphysiologic. anatomic. or immur‘roiogi:——may be altered or breached
`by disease or trauma, or by procedures or agents used for atagnosis or there y. infections occurring
`in this setting, also uafled opportunistic infections, are seen if antirnicrobial therapy alters the nor-
`mal relationship between host and microbe, or if host defense mechanisms have been altered by
`burns. anemia, other inferztéons. neoplasms, metabolic disorders. lrraoiiatéon, foreign bod:es.immu1o~
`suppressive
`cytotoxic drugs. corticosterosds, or diagnostic or therapeutic instrumentation.
`The underfyirig alteration oreoisposes the patient to irziections lrarri his usually rzollfiaf-‘IUQBMC
`endogenous microfiora or irorn ordinarly lnarrnless. saprophytlc Organisms acquired by’ Collie“ Wl‘3li
`other patients. hospital personnel. or equiprnerit. Managernent is complicated by the ‘ad Illa‘ 159
`
`orgarisrrrs that oopor’ttmisti<:ally take advantage of the r:ornprontis‘%d host ii uallv are resstant to
`antibiotics. lhese organisms may be bacteria. fungi. viruses. or other n .as‘
`and ‘me '»
`
`
`
`
`
`aracter of the host 3 alte-re-5: defenses detarrnirres which Wganisrns are T081 ll
`:lv Y0 U VM/Olvéd.
`1. Antibiotic resistance and impaired anatomic host defense mechanisms: Antimicrobial treat
`
`
`ment alters the nor: al miciotlora of N“
`skin. mucous membranes. and G’ tract and may result .r*
`
`
`i
`:
`r of these organs. Coloniz ‘Jon oer se is narrniess uniests §Ol‘3V*"~’:d 53’ 3Ul3el’l"f9‘3t5°“
`
`
`-Cir-:;a.<;}on by erxdcrgenous or ertvsrorzrrten as organisms ~’eS'Siar\i to the ant
`lotto hemg given), which is
`
`demonstrable mécroruolog ally or cirn.
`llv. Factors predisposing to superinlecliori iriglude smremes
`of age, chrome irifectig-=1 or other d€l}lliIaIlllg di;-:
`e><cess.ive doses 0: one or serve-:al arrtimicroimu
`
`Page 7
`
`
`Page 7
`
`

`
`502 Puimonary Disorders
`can best be relieved by surgery, radiation, or chemotherapy.
`efi‘ective¥y reduced obstruction from an endobronchial lesion.
`
`M
`in selected cases, laser therapy has
`
`I
`
`39. PULMONARY EMBOUSM (PE)
`(Thromboembolisrn)
`
`éodgnieni ofa brood clot in a pulmonary artery wir.'r,« subsequent obstruction of b/ood supp/-,' to the
`lung parenchymar Pulmonary infarction (Pl); Hemorrhagic consolidation {often fa//owed by necro-
`sis) of /ung pa/anchyma resu/I/ng from mromboembo/rc pu/monary arterial’ occlusion.
`Etiology and Pathogenesis
`The most common type of pulmonary embolus is a thrombus that usually has formed in a leg or
`
`pelvic vein. Most of those causing serious hemodynamic disturbances form in an ilioiernorai vein,
`either de novo or by propagation from cali vein thrombi. Thromboemboli that originate in the ve
`of
`the upper extremities or in the right cardiac chambers are infrequent. Amniotic fluid emboli and rat
`emboli following fractures are rarer types of’ PE whose primary site of vascuiar obstruction is the
`pulmonary rnicrocircuiation (arterioles and capillaries rather than pulmonary arteries); izivoivemerit of
`
`the microcirculation may initiate the so-caiied adult re
`ratory distress syndrome (see in Ch. 35}
`
`‘Pi is an infiequerit {< 16% oi cases} conseouerace or Fe. it is sour» imes due it; ihr
`of the pulmonary arteries as might occur in congenital heart disease associated with severe puimnv
`nary hypertension or in hematologic disorders (eg. sickle celi anemia).
`The pathogenesis of venous thrombosis involves stasis. increased blood coagulability, and vascuiar
`wall damage (Virchows triad). Factors predisposing to tnromboembolic disease inciude prolonged
`bed rest with irnmobiiity, chronic heart failure, the postooerativerstate, pregnancy, hip fracture. use
`of oral contraceptives, cnronsc obstru<;tive pulmonary disease (COED), obesity. malignancy’, friernato~
`logic disorders (eg, polycythemia Vera), vascular inguries resulting from minor trauma, and immobiliza-
`tion with stasis as may occur in chronic disease states, in ,. any patients, no predisposing factor can
`be found.
`Once released into the venous crculation, embcli are distributed to both lungs in about 65% of
`cases. to the righ: lurig in 20%, and to the left lung in 10%. Lower lobes are ‘mvoived 4 times more
`often than upper lobes. Most thromboemboli lodge in larger or intermediate (elastic or muscular)
`pulmonary arteries: 35% or fewer reach the smaller arteries.
`Pathophyslology
`The pathophysiologéc changes that follow PE invciive adjustments in oulmonary hemodynamios,
`gas exchange, and mechanics. The extent of change in cardiopulmonary function is determined by
`the extent of pulmonary arterial obstruction, which varies with the size and number of thrombi
`embolizing and obstructing the pulmonary arteries. and by the patients preennbolic cardiopulmonary
`status. A consideration of the pathophysiology of PE must include the mechariisrris responsible for
`the following: (l) pulmonary hypertension, right ventricular failure, and shock; (2) dyspiiea with ta-
`chypnea and hyperventilation; (3) arterial hypoxemia; and (4) Pl.
`1. Pulmonary hypertension, a most important physiologic aiteration, resuits from increased pul-
`monary vascular resistance. As a consequence, the right ventricle must generate higher pulmonary
`artery pressure to maintain normal CO. Significant pulmonary hypertension (> 25 mm Hg mean
`pressure) usually occurs only when > 30 to 50% of the pulmonary arterial tree is occluded in a
`previously healthy lung. Pulmonary hypertension may be increased by preexisting cardiopulmonary
`disease (eg, mitral stenosis or obstructive lung disease).
`
`The primary mechanism of increased resistance is obstruction of pulmonary arteries by thrombi
`a decrease in the total cross-sectional area of the pulmonary vascular bed. l-lowevery because some
`degree or’ pulmonary hypertension often develops with obstruction of < 50% of the vascular bed,
`pulmonary vasoconstriction appears to play a definite, but secondary. rote. Vasoconstriction is partly
`mediated by hypoxemia, by serotonin release from platelet aggregates on me thrombi, and possibly
`by other humeral substances, zncfudmg prostagiandins.
`if pulmonary vascuiar resistance nncreasas acutely to the extent that the right ventricle cannot
`generate sufficient pressure (ie. > 70 to 80 mm Hg systolic‘ to maintain CO, hypotension develops
`(in which the central venous and right atrial mean pressures are increased). This occurs only after
`massive embotizatmn involving at least 50% and usually Z’5‘i/c or more of the pulmonary vascular bed
`without preexisting cardiopulmonary disease With severe hypoteneion and shock, mean central
`venous pressure tends to fall
`2. Techypnea, often with dyspnea, aimost always occurs after an emboic episode. it appears to
`be of reflex origin, most iikely due to stimulation of iuxtacaoillary receptors in the alveolar capillary
`
`I
`
`.
`
`,
`
`.
`
`Page 8
`
`
`Page 8
`
`

`
`Ch. 39
`Pulmonary Embolism 503
`mernbrane by swelling of the alveolar rnte'ststial space. Tris stirnulation increases vagal afferent
`gct'v:‘.y that in turn stimulates rnaduliarv f€SDll’8lO5"y neurons. Consequent alveolar hyperver-tilation is
`manifested by a lowered Pacijg.
`Following occlusion of the pulmonary artery, areas of the lung are ventilated but not perfused.
`;esi,-lting in "wasted ventilation" {the plrysiolo-git: hallmark ol P‘E). The existence of wasted ventilation
`
`the settrg of acute PE is signaled by increased arterial-alveolar CO2 tension differenr
`reflecting
`
`augmented -
`“
`siologrc oeadspace, but this is not specific tor 9E;
`t occurs also V‘.‘i‘.'= coexisting
`pulmonary disease. as well as systemic hypotension.
`Changes tend to occur in lung mechanics as airways resistance increases and lung compsiance
`decreases. A decrease in the rnaxrrnal expiratory flow rate results from cirninished lung volume and
`possibly from ‘oronchoconstriction. Reduced lung volume following PE sornezirnes is manifested on
`the chest x«ray by elevation of the diaphragm due to atelectatrc or intarcted segments. Heparin
`appears to lessen oronchoconstriction, when present, as evidenced by improved maximal expiratory
`ilow rates. Since changes in ‘Ling mechanics are usually transient and manor, they are unlikely to be
`important in the genesis of prolonged dyspnea. However, they probably‘ contribute to development
`of arterial hypoxemia, described below,
`3. Arterial hypoxemia: S302 is characteristically diminished (94 to 85% or lower)-. but may be
`normal. Hypoxernia is due to right-to-left shunting in areas of partial or complete atelectasis in areas
`not involved by the embolic process. Characteristically this atelectasis can be partially corrected by
`deep breathing. either voluntary or induced by a positive pressure ventilator. Ventilatiori/perfusion
`(‘~71/‘{5} rnbalance probably also contributes to the liypoxsmia. The mechanisms responsible for the
`W./C‘) imbalance and atelectasis are not fully defined. One important factor relates to regional chang-
`es in compliance. which together with hyperventilation sets the stage for varying degrees of airways
`hypocapnia. producing nonuniform constriction of distal airways and peripheral lung units. Under-
`ventilation of the units results with respect to perfusion. and atelectasis ensues it these changes are
`severe. Tachypnea may augment the changes. in "nassive embolization, severe hypoxemia may result
`from right atrial hypertension that causes right-to-left shunting of blood through a patent forarnen
`ovale.
`4. Pulmonary infarction (Pl): Most PE do not produce infarction. When bronchial circulation is
`‘intact and normal (is.
`in the absence of neart failure or underlying mronic lung disease). Pl rarely
`develops. This suggests that collateral circulation of the bronchial artery keeps the lung tissue viable
`despite blockage of the puirnonary artery. However, patients with previously abnormal pulmonary
`circulation are prone to develop Pl. Such infarcts may heal by absorption and fibrosis, leaving a linear
`scar, or may resorb completely. leaving a normal lung (incomplete infarction).
`Acute PE is a dynamic process. Thrombi begin to iyse immediately after reaching the lung. Usually,
`complete clot lysis takes place within several weeks in the absence of preexisting cardiopulrnonary
`disease. but, in some instances, even large thrombi may lyse in a few days. The physiologic altera-
`tions lessen over hours or days as the pulmonary circulation improves. Massive emboli may cause
`death within minutes or hours without sufficient time for infarction to develop. Smaller ernboli may
`produce infarction that can heal with recarialization and restored blood flow. lnfrequently, embolic
`events recur for months or years, causing progressive pulmorary arterial obstruction with chronic
`pulmonary hypertension. increasing dyspnea, and cor pulmonale.
`Symptoms and Signs
`The clinical manifestations of PE are nonspecific. Diagnosis may be diflicult without using special
`procedures. the most important of which are radioisotope perfusion lung scans and pulmonary arteri-
`ography (see Diagnosis. below). The symptoms and signs vary in frequency and -ntensity depending
`on the extent of pulmonary vascular occlusion, the development of Pl, and the patients preembolic
`cardiopulmonary mrictiori. There may be no symptoms with small thromboemboli.
`Embolism without infarction is manifested by breathlessness. which may be the only syrnptorn if
`infarction does not develop. Tachypnea is a consistent and often striking leatr_re. Anxiety and rest-
`lessness may be prominent.
`Pulmonary hypertension, if severe. may cause dull substernal chest drscornfort due to pulmonary
`artery distention or possibly myocardial rschemla, it may be manifested by a
`increase in the intensity
`of the pulmonary component of the basal 2nd sound or abnormal splitting rise. w. ened with less
`variation of splitting during inspiration) or’ ‘me aortic and pulmonary components of the basal 2nd
`sound.
`ll‘ pulmonary vascular obstruction ‘s massive. acute RV insufficiency may supen he, with
`distended cervical veins. RV heave, RV presystolic or protodrastolic gallop, sometimes w
`arterial
`hvpotension and evidence of peripheral vasoconstriction. Lightheadedness, syncopal episodes. con-
`vJlSlV€: phenomena. and neurologic deficits may be the presenting events in a significant number of
`patients. usually reflecting a transient fall in CO with secondary cerebral ischemia. Cyanosis is usual
`in patients with massive embolism, out riot with lesser obstruction.
`
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`§4
`504 Pulmonary Disorders
`Examination of the lungs lS usually normal in the absence 0:‘ Pl. Wheezing is sometimes heard,
`particularly it underlying bronchopulmonary or cardiac disease is present.
`In addition to the above symptoms and signs. the manifestations of Pi include cough. hemoptys-
`is, pleuritic chest pain, fever, and signs of pulmonary consolidation or pleural fluid. A pleural friction
`rub may be heard. A small. peripheral embolus may cause infarction but not obstruct the pulmonary
`arteries to the extent that pulmonary hypertension develops.
`The manifestations of embolization usuallydevelop abruptly in minutes: those of infarction over a
`period of hours. They often last several days, depending on the rate of clot lysis and other factors,
`but usually decrease daily in intensity. tn patients with chronic, recurrent emboli, the symptoms and
`signs of chronic cor puimonale tend to develop insidiously during weeks, months. or years.
`Diagnosis and Differential Diagnosis
`The diagnosis of PE with or without infarction is often difficult to establish. Differential diagnosis
`in patients with massive PE includes bacteremic shock. acute myocardial infarction (Ml), peritonitis,
`and cardiac tamponade. Without infarction. the patient's symptoms and signs may be attributed to
`anxiety with hyperventilation because of the paucity of objective pulmonary findings. When infarc-
`tion occurs. the differential diagnosis includes pneumonia, atelectasis, heart failure. and pericarditis.
`A systematic approach to diagnosis is outlined below.
`1. The clinical symptoms and signs should suggest the diagnosis.
`2. Appropriate clinical diagnostic studies, Including chest may, ECG, CBC. and serum enzyme
`{ASP LDH) and serum bilirubin determinations may be helpful. With infarction, the chest x-ray
`f'e>f;i..-ently shows a be pheral inllitrative lesion. often involving the costophrenic angle. with elc-va~
`tion of the diaphragm and pleural fluid on the affected side. Dimiriishecl pulmorsary vascular rnarkirsgs
`in the ernbolized area maybe noted in the absence of infarction. Dilation of the pulmonary arteries ir:
`the hilar area. the superior vena cava, and the azygos vein signal pulmonary hypertension and Fly
`strain Since ECG changes are characteristically transient, serial tracings are often helgirui
`in the
`diagnosis and in the exclusion of acute Ml. Changes most treciuernly seen in the ECG irecliide P
`pulmonale, rzght bundle branch block. right axis deviation. and supraventricular arrhythmies. The
`sensitivity and specificity of serum enzyme studies have been disappointing and the studies are
`rarely helpful in diagnosis. The triad of elevated serum LDH and bilirubin and normal AST (S60?)
`occurs in < ‘i 5% of patients vvith acute PE and Pl. Elevated LDH may be demonstrable in as many as
`85% of patients with Pl. but is nonspecific. occurring also in heart iailure,,snocl<, pregnancy. renal
`and live’ disease, anerrva. pneurnocra, carcinoma. and alter surgical procedures, A profile ct’ enzyme
`studies involving elevated LDH, normal CK, and normal hydroxybutyrate dehydrogenase (HBO) is
`more specific in the diagnosis of Pl and may differentiate acute Ml, but is of little value in diagnosing
`PE without Pl. Blood levels of fibrin split products appear to rise rather consistently after PE wheth-
`er Pl occurs or not. but the interval of time between this rise and the onset of symptoms, and its
`durateon, vary considerably. The specificity of this finding is also questionable since the incidence of
`elevation in other diseases is not well defined.
`’
`3. Radioisotope perfusion lung scanning, sometimes combined with ventilation scanning. is
`very valuable in estabfishing the diagnosis. Lung perfusion scans tollow lV injection of 20» to 50»
`pm particles of biodegradable albumin labeled with technetium 99th. These particles traverse the
`right heart and. via the pulmonary arteries, ultimately lodge in the small precapillary arterioles of both
`lungs. Nearly 100% of the particles remain an the lungs, except whc
`right~to—left shunting is present
`either at the cardiac or oulmoriic level. Regional distribution of these particles is direcfly proportional
`to regional pulmonary arteriolar blood flow. This distribution is relatively homogeneous in normal
`persons, but visible actii/ty is greater at the base and gradually diminishes up to the apex, reflecting
`gravitational effects on perfusion when the patient is injected in the sitting position. The distribution
`of particles depends on the posit=ori of the patient and pulmonary blood flow distribution at the time
`oi njecticn. Perfusion delicit, with reduced or absent radioactivity may result from vascular obstruc-
`tion, displacement of lung by fluid. chest masses. any condition causing pulmonary arterial or venous
`hypertensiori, or loss of lung parenchyma as in pulmonary