Download Movement Disorders Associated With Withdrawal From High

Case 2 may represent rheumatoid arthritis-associated
BOOP.8-9 The chest radiograph and CT scan appearance
are compatible with the "solitary7 focal pneumonia" pre¬
BOOP, with the typical upper lobe location
bronchograms.6 Though diagnosis by transbron¬
chial biopsy specimen instead of surgical lung biopsy
specimen always raises the possibility of missing an alter¬
native etiology7 due to sampling error, we believe that the
clinical and radiographic presentation, good response to
corticosteroids, and extensive workup excluding other
causes of hemoptysis all provide strong evidence for
BOOP as the primary lesion. We suspect that the prior
episode of bloody nasal discharge was most likely caused
by sinusitis secondary to incidental concha bullosa that had
resolved with antibiotic therapy.
The hallmark pathologic change in BOOP is the pres¬
ence of granulation tissue plugs within the lumen of distal
bronchioles extending into alveolar ducts and alveoli.10
That hemoptysis might be expected as a manifestation of
BOOP is suggested by the ultrastructural changes found in
surgically resected lung biopsy specimens. Myers and
Katzenstein11 described extensive areas of epithelial ne¬
crosis and denudation of the epithelial basal laminae in
nine cases of idiopathic BOOP. There was evidence of
endothelial damage to alveolar capillaries in seven of these
cases, with some demonstrating endothelial necrosis and
extravasation of erthyrocytes into the interstitium. Inflam¬
mation, either as an integral part of BOOP or as a result of
some unidentified infectious/noxious agent, is the likely
cause of this parenchymal damage and resultant bleeding.
In summary7, we describe two cases of histologically
confirmed BOOP whose primary presenting symptom was
submassive hemoptysis. BOOP should be considered in
any patient presenting with hemoptysis and unexplained
radiographic infiltrates.
bronchiolitis obliterans,
11
sentation of
and air
1
Epler
GR,
et
al. Bronchiolitis
J Med 1985; 312:
Engl
Lange W. Ueber eine eigenthumliehe erkrankung der kleinen
obliterans
152-58
2
Colby
References
TV, McCloud TC,
organizing pneumonia.
N
bronchien und bronchiolen. Dtsch Arch Klin Med 1901;
70:342-64
3
4
5
6
7
8
Epler GR. Bronchiolitis obliterans organizing pneumonia:
definition and clinical features. Chest 1992; 102:2S-6S
King TE. BOOP: an important cause of migratory7 pulmonary
infiltrates? Eur Respir J 1995; 8:193-95
Nizami IY, Kissner DG, Visscher DW, et al. Idiopathic
bronchiolitis obliterans with organizing pneumonia: an acute
and life threatening syndrome. Chest 1995; 108:271-77
Cordier JF, Loire R, Brune J. Idiopathic bronchiolitis obliterans
organizing pneumonia: definition of characteristic clinical pro¬
files in a series of 16 patients. Chest 1989; 96:999-1004
Alegre-Martin J, de Sevilla TF, Falco V, et al. Three cases of
idiopathic BOOP. Eur Respir J 1991; 4:901-02
van Thiel RJ, van der Burg S, Groote AD, et al. Bronchiolitis
obliterans organizing pneumonia and rheumatoid arthritis.
Eur Respir J 1991; 4:905-11
9 Rees JH, Woodhead MA, Sheppard MN, et al. Rheumatoid
arthritis and cryptogenic organizing pneumonitis. Respir Med
10
1991; 85:243-46
TV, Myers JL. Clinical and
Colby
histologic spectrum
of
1778
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including bronchiditis obliterous or¬
ganizing pneumonia. Semin Respir Med 1992; 13:119-33
Myers JL, Katzenstein AA. Ultrastructural evidence of alve¬
olar epithelial injury in bronchiolitis obliterans-organizing
pneumonia. Am J Pathol 1988; 132:102-09
Movement Disorders
Associated With Withdrawal
From High-Dose Intravenous
Haloperidol Therapy in
Delirious ICU Patients*
Richard R. Riker, MD; Gilles L. Fraser, PharmD; and
Peter Richen, MD
is recommended as the
haloperidol
of
choice
to
in ICU patients.
treat
delirium
drug
Movement disorders and other adverse events com¬
monly occur with oral haloperidol use but are rarely
seen with IV haloperidol use, and withdrawal symp¬
toms have not been reported with short-term ICU
use. We describe self-limited dyskinesia during with¬
drawal of high-dose continuous IV haloperidol ther¬
apy in five ICU patients.
Intravenous
(CHEST 1997; 111:1778-81)
words: benzodiazepines; critical care; delirium; drug-in¬
Key
duced dyskinesia; haloperidol; intensive care unit; intravenous;
movement disorders; psychomotor agitation; tremor
Abbreviation: EPS
=
extrapyramidal symptoms
gitation and delirium, affecting 5 to 57% of critically ill
patients, frequently complicate the care of these pa¬
tients.1 Though many therapeutic agents, including ben¬
zodiazepines, opiates, propofol, butyrophenones, sympatholytic agents, and neuromuscular blocking drugs, are
available to help relieve or control agitation, haloperidol is
the drug of choice for treating delirium.2-3 Sixty percent of
ICUs use haloperidol, usually via intermittent intravenous
or intramuscular administration.4 Reports of high-dose IV
A
.**¦
use in ICUs have rarely identified movement
haloperidol
disorders during haloperidol use and have not described
movement abnormalities associated with haloperidol with¬
drawal.5-8 We report self-limited movement disorders
associated with haloperidol discontinuation in five ICU
patients.
Department of Critical Care Medicine, Department
of Pharmacy, and Department of Medicine (Division of Neu¬
Medical Center, Portland, Me.
rology), Maine the
Supported by Maine Medical Center Medical Research
*From the
Committee.
Manuscript received September 17, 1996; revision accepted
November 25.
Reprint
requests: Dr. Riker, Department of Critical Care Medi¬
22
cine,
Bramhall Street, Portland, ME 04102
Selected
Reports
Case Reports
Case i
A 33-year-old
man developed bacteremic group A streptococ¬
cal septic shock, acute renal failure, and ARDS requiring inverse
ratio pressure control ventilation, heavy sedation, and intermit¬
tent neuromuscular blockade for 18 days. Delirium complicated
early efforts to wean him from mechanical ventilation, and
intermittent (and later continuous) IV haloperidol (maximum
dose of 240 mg/d) was added to therapy with benzodiazepines
(maximum dose of 146 mg/d of midazolam, later changed to
lorazepam in doses up to 165 mg/d) and morphine sulfate
(maximum dose of 120 mg/d). After dosages of haloperidol and
morphine sulfate were tapered and discontinued over a period of
4 days, and lorazepam was decreased by 90%, vomiting and
intermittent lip smacking and tongue-protruding motions devel¬
oped. No anxiety, sweating, extremity tremor, rigidity, or "cogwheeling" was identified.
Therapy with intravenous lorazepam
was continued at 6 to 10 mg daily and metoclopramide hydro¬
chloride was added in an effort to eliminate vomiting. The
orobuccal dyskinesia persisted for 4 days but resolved without
additional medication. There was no recurrence over the next 12
months.
Case i
A 51-year-old man was transferred to our hospital 2 weeks after
fundoplication (Nissen's operation) complicated by intraopera¬
tive bleeding (requiring splenectomy and distal pancreatectomy),
postoperative pancreatitis, hypoxemic respiratory failure, and a
left subphrenic abscess. Severe agitation and delirium were
treated with intermittent intravenous meperidine hydrochloride
(maximum dose of 650 mg/d) and lorazepam (maximum dose of
75 mg/d) and continuous intravenous haloperidol (maximum
dose of 240 mg/d). Neuromuscular blocking agents were not used
in the ICU. Ten days after lorazepam was decreased to 2 to 8
mg/d and while the patient was still receiving haloperidol at 72
mg/d, he developed tongue tremors which persisted for 2 days
and bilateral hand and leg tremors which were coarse, were
present at rest, and increased with activity. He was calm,
responsive, and denied anxiety. Intravenous haloperidol was
continued at 72 mg daily for 3 days; then therapy was changed to
oral haloperidol at 40 mg, 30 mg, and 7.5 mg for the next 3 days
and then was discontinued. The symptoms gradually decreased
over a
total of 13 days.
Case 3
A 29-year-old man was involved in a motor vehicle accident
and sustained facial, chest, and extremity trauma. Despite intra¬
venous therapy with morphine sulfate (maximum dose of 480
mg/d), agitation interfered with mechanical ventilation, and
lorazepam (maximum dose of 112 mg/d) and haloperidol (maxi¬
mum dose of 250 mg/d) w7ere added to control his symptoms.
Intermittent neuromuscular blockade was used on ICU days 4,
16, and 18, and he received oral haloperidol 1, 2, and 7 days after
intravenous haloperidol was discontinued. After receiving his last
dose of oral haloperidol, he developed a tongue tremor which
lasted 3 days and a coarse tremor of his hands which was present
at rest, increased with activity, and persisted for 7 days. No
anxiety, confusion, or sweating was identified.
Case 4
A 29-year-old male
hemophiliac sustained blunt head and
chest trauma and multiple bilateral upper and lower extremity
fractures in a motor vehicle accident. Hypoxemic respiratory
failure and agitation complicated his clinical diagnosis of fat
emboli syndrome. Because of worsening agitation and delir¬
lorazepam (maximum dose of 58 mg/d) and
dose of 500 mg/d) were added to
(maximum
haloperidol
morphine sulfate (maximum dose of 175 mg/d) therapy. Single
ium, intravenous
doses of vecuronium bromide were administered for proce¬
dures on ICU days 3, 4, and 8. On the 3rd day after haloperidol
treatment was stopped (7 days after tapering dosages of
benzodiazepines), he developed bilateral coarse hand tremors
which progressed to cogwheeling, tongue tremor, and lower
extremity tremors. His symptoms persisted for 9 days, and
though confused, he did not appear anxious or agitated while
experiencing the movement disorders.
Case 5
A 35-year-old woman
developed severe Mycoplasma pneumo¬
agita¬
mg/d)
and morphine sulfate (maximum dose of 240 mg/d), and halo¬
peridol was added (maximum dose of 280 mg/d) to the therapy.
Neuromuscular blockade was avoided except for single doses of
vecuronium on ICU day 5 and pancuronium bromide on ICU day
12. On ICU day 39 (4 days after tapering benzodiazepines and 2
days after tapering haloperidol dosages), she developed fluctuat¬
ing bilateral coarse hand tremors without anxiety, tongue or
perioral symptoms, or cogwheeling. Her symptoms declined over
the next 7 days and resolved with no recurrence over the next 12
nia and hypoxemic respirator)7 failure. Severe anxiety7 and
tion were refractory7 to lorazepam (maximum dose of 168
months.
Discussion
Haloperidol frequently is selected to treat delirium in
patients despite potential uncommon complica¬
use including QT interval pro¬
torsades
de
longation,
pointes, neuroleptic malignant
syndrome, and movement disorders.5911 Extrapyramidal symptoms (EPS) including Parkinsonism, acute or
ICU
tions with intravenous
tardive dystonia, dyskinesia, and akathisia have been
described in ambulatory patients during oral haloperi¬
dol therapy and in critically7 ill patients while they are
receiving intravenous haloperidol therapy.5712 Abnor¬
mal movements such as tremor, rigidity, and akathisia
can develop or worsen with abrupt withdrawal of
long-term oral haloperidol therapy13 but have not been
after short-term intravenous halo¬
reported previouslyOther
treatment.
withdrawal symptoms associ¬
peridol
ated with discontinuation of long-term oral neuroleptic
therapy, such as nausea, vomiting, restlessness, insom¬
nia, diaphoresis, diarrhea, headaches, and dizziness,
usually are mild and resolve in 1 to 3 weeks.1415
Rebound cholinergic hypersensitivity may7 explain these
events which seem to occur less commonlv with neurothat have weaker anticho¬
leptics, such as haloperidol,
linergic effects.1416 Prior ICU reports of haloperidol
use have claimed that sudden discontinuation of intra¬
venous haloperidol would not cause withdrawal dyski¬
nesia.3-5 The movement disorders we report most likely
represent drug-induced Parkinsonism associated with
haloperidol withdrawal. This previously has been de¬
scribed following oral haloperidol use with onset of the
Parkinsonian symptoms 2 to 10 days after drug cessa¬
tion; these effects are similar to those observed in our
patients17 (Table 1). Only one component of the
classic triad of rigidity, bradykinesia, and tremor needs
to be present to diagnose drug-induced Parkinsonism.18
CHEST / 111 / 6 / JUNE, 1997
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1779
Table 1.Characteristics of Five Patients With Movement Disorders During Haloperidol Withdrawal
Case
Age (yr),
Gender
33,
51,
29,
29,
35,
male
male
male
male
female
Mean 35
Haloperidol Duration of
Maximum
Haloperidol Duration of
Daily Dose, mg Therapy, d Dyskinesia, d
240
240
250
500
280
302
14
23
17
16
23
19
After
Tapering, d
4
13
may
uted to the movement abnormalities in our patients.
Orobuccal dyskinesia and extremity tremor have been
described during withdrawal from long-term oral ben¬
treatment.26
1780
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cogwheeling, tongue tremor
this less likely.2627 Similarly, opiate withdrawal may
induce motor abnormalities, possibly due to dopaminergic supersensitivity.28 The balance between the dopaminergic and cholinergic nervous systems is critical in
movement control, and Tune et al29 have documented
effects from medications
significant anticholinergic
commonly used in the ICU.
We believe this is the first report of movement disorders in
critically ill patients during wididrawal from intravenous
haloperidol use. These symptoms should be anticipated, and
we must learn more to know how to treat and prevent them.
Many factors may have contributed to these movement
disorders including wididrawal or toxicity from other medi¬
cations or the underlying illness itself. Whether a slower
taper or lower doses of haloperidol may prevent these
symptoms is unknown. Although none of these abnormalities
persisted, additional study is warranted to assess the risk to
patients and to identify any similarities between these selflimited events and more persistent movement disorders.
References
1 Fish DN. Treatment of delirium in the critically ill patient.
Clin Pharm 1991; 10:456-66
2 Shapiro BA, Warren J, Egol AB, et al. Practice parameters for
intravenous analgesia and sedation for adult patients in the
intensive care unit: an executive summary. Crit Care Med
1995; 23:1596-1600
3 Tesar GE, Stem TA. Evaluation and treatment of agitation in
the ICU. J Intensive Care Med 1986; 1:137-48
4 Hansen-Flaschen JH, Brazinsky S, Basile C, et al. Use of
sedating drugs and neuromuscular blocking agents in patients
requiring mechanical ventilation for respiratory failure. JAMA
1991; 266:2870-75
5 Ziehm SR. Intravenous
6
7
8
Although benzodiazepine
withdrawal may have contributed to the symptoms our
patients experienced, the lack of agitation, anxiety,
tinnitus, and perceptual changes in our patients makes
Symptoms
Lip smacking, tongue protrusion
Tongue tremor, coarse hand and leg tremor
Tongue tremor, coarse hand tremor
Coarse hand and leg tremor,
Coarse hand tremor
9
7
8
dyskinesia frequently complicates
Although tardive
long-term oral haloperidol use, it has not been
reported with short-term intravenous haloperidol use.
The features seen in our cases are not consistent with
tardive dyskinesia, though patient 1 had symptoms
consistent with acute dyskinesia, which were short¬
lived.19
Casey18 has proposed that neuroleptics have an inverted
dose-response curve for the development of EPS.
U-shaped,
If true, the decreasing haloperidol levels associated with
stopping high-dose infusions may increase the likelihood of
EPS and may explain the late movement abnomialities in our
patients. The haloperidol doses we report are uncommon in
our ICU; these five patients with identified movement
abnormalities during drug withdrawal represent only 0.2% of
ICU patients and only 2% of ICU patients treated with
haloperidol. This dose range is well below the
highest
dose of 1,200 mg/d.8 Adams has
reported ICU haloperidol
safely used doses of 240 mg/d (similar to our median dose of
250 mg) for weeks,20 and Tesar et al6 and Seneff and
Mathews21 have used doses higher than we report for
severely agitated patients. The large benzodiazepine doses
also are uncommon but are similar to the doses of lorazepam
and midazolam required to sedate mechanically ventilated
patients in a randomized study.22
Intravenous haloperidol use may be associated with less
intense EPS than oral administration, perhaps related to
less first-pass metabolism and lower concentrations of
reduced haloperidol or other metabolites.23 Haloperidol is
structurally similar to l-methyl-4-phenyl-l,2,3,6-tetrahy(MPTP), a substance known to induce Par¬
dropyridine
kinson-like neurologic abnormalities.24 A metabolite of
this substance induces nigrostriatal toxicity in animals,25
and a structurally similar haloperidol metabolite has been
isolated from patients receiving long-term oral haloperidol
or Parkinsonian side
therapy who have tardive dyskinesia
effects.25 This pyridinium metabolite of haloperidol has
not been reported with patients receiving haloperidol
intravenously.
have contrib¬
Other medications or conditions
zodiazepine
Symptoms
Haloperidol
Time to
9
haloperidol for tranquilization in
critical care patients: a review and critique. AACN Clin Issues
1991; 2:765-77
Tesar GE, Murray GB, Cassem NH. Use of high-dose
intravenous haloperidol in the treatment of agitated cardiac
patients. J Clin Psychopharmacol 1985; 5:344-47
Riker RR, Fraser GL, Cox PM. Continuous infusion of
haloperidol controls agitation in critically ill patients. Crit
Care Med 1994; 22:433-40
Sanders KM, Murray GB, Cassem NH. High dose intrave¬
nous haloperidol for agitated delirium in a cardiac patient on
intra-aortic balloon pump. J Clin Psychopharmacol 1991;
11:146-47
Metzger E, Friedman R. Prolongation of the corrected QT and
torsades des pointes cardiac arrhythmia associated with intrave¬
nous haloperidol. J Clin Psychopharmacol 1993; 13:128-32
Selected
Reports
TG, O'Gara PT. Torsades de pointes caused by
high-dose intravenous haloperidol in cardiac patients. Clin
Cardiol 1995; 18:285-90
11 Shalev A, Hermesh H, Munitz H. Mortality7 from neuroleptic
malignant syndrome. J Clin Psychiatry 1989; 50:18-25
12 Settle EC, Ayd FJ. Haloperidol: a quarter century of experi¬
ence. J Clin Psychiatry7 1983; 44:440-48
13 Dixon L, Thaker G, Conley R, et al. Changes in psychopathology and dyskinesia after neuroleptic withdrawal in a
double-blind design. Schizophrenia Res 1993; 10:267-71
14 Lieberman J. Cholinergic rebound in neuroleptic withdrawal
syndromes [letter]. J Clin Psychiatry 1981; 42:179
15 Eppel AB, Mishra R. The mechanism of neuroleptic with¬
drawal. Can J Psychiatry 1984; 29:508-09
16 Luchins DL, Freed WJ, Wyatt RJ. The role of cholinergic
supersensitivity in the medical symptoms associated with
withdrawal of antipsychotic drugs. Am J Psychiatiy 1980;
10 DiSalvo
137:1395-98
17 Nelli AC, Yarden PE, Guazzelli M, et al. Parkinsonism
following neuroleptic withdrawal. Arch Gen Psychiatry 1989;
46:383-84
18 Casey DE. Neuroleptic-induced acute extrapyramidal syn¬
dromes and tardive dyskinesia. Psychiat Clin North Am 1993;
16:589-610
19 Casey DE. Tardive dyskinesia. West J Med 1990; 153:535-41
20 Adams F. Emergency intravenous sedation of the delirious,
medically ill patient. J Clin Psychiatry 1988; 49(suppl):22-6
MG, Mathews RA. Use of haloperidol infusions to
control delirium in critically ill adults. Ann Pharmacother
21 Seneff
1995; 29:690-93
22 Pohlman
AS, Simpson KP, Hall JB. Continuous intravenous
infusions of lorazepam versus midazolam for sedation during
mechanical ventilatory7 support: a prospective, randomized
study. Crit Care Med 1994; 22:1241-47
23 Menza MA, Murray GB, Holmes VF, et al. Decreased
extrapyramidal symptoms with intravenous haloperidol. J Clin
24
Psychiatiy 1987;'48:278-80
Tsang MW, Shader Rl, Greenblatt DJ. Metabolism of halo¬
peridol: clinical implications and unanswered questions.
J Clin Psychopharmacol 1994; 14:159-62
Subramanyam B, Pond SM, Eyles DE, et al. Identification of
potentially neurotoxic pyridinium metabolite in the urine of
schizophrenic patients treated with haloperidol. Biochem
Biophys Res Commun 1991; 181:573-78
26 Busto U, Sellers EM, Naranjo CA, et al. Withdrawal reaction
after long-term therapeutic use of benzodiazepines. N Engl
J Med 1986; 315:854-59
27 Rosebush PI, Mazurek MF. Catatonia after benzodiazepine
withdrawal. J Clin Psychopharmacol 1996; 16:315-19
28
25
Lane JC, Tennison MB, Lawless ST, et al. Movement disor¬
der after withdrawal of fentanyl infusion. J Pediatr 1991;
119:649-51
29 Tune L, Carr S, Hoag E, et al. Anticholinergic effects of drugs
commonly prescribed for the elderly: potential means for
assessing risk of delirium. Am J Psychiatiy 1992; 149:1393-94
chest x-ray film, and an incomplete response to
corticosteroids with high mortality. In contrast, lu¬
pus patients with a syndrome of acute reversible
hypoxemia (SARH) have hypoxemia with normal
chest x-ray films and a rapid response to corticoste¬
roids. We present a case of biopsy-proven ALP with
normal initial chest x-ray films, and a normal CT
scan. We hypothesize that a continuum of vascular
and parenchymal abnormalities may exist in the
the
lungs of lupus patients. This case also illustrates
in
of
routine
demon¬
chest
insensitivity
radiographs
strating mild or early pneumonitis.
(CHEST 1997; 111:1781-83)
Key words: corticosteroids; hypoxemia; lupus; pneumonitis
Abbreviations: ALP acute lupus pneumonitis; SARH syn¬
drome of acute reversible hypoxemia
=
=
lupus pneumonitis (ALP) traditionally has been
by the presence of fever, dyspnea, tachypnea, hypoxemia, and patchy infiltrates evidenced on a
chest x-ray film. This diagnosis can be made only after
excluding other causes, especially infections. Histologi¬
cally7, ALP presents as acute alveolitis, with alveolar wall
necrosis, hemorrhage, edema, hyaline membrane forma¬
tion, interstitial pneumonitis, capillaritis, or capillary
thrombi.1 In contrast, lupus patients with a syndrome of
acute reversible hypoxemia (SARH) were reported to have
acute hypoxemia without any pulmonary parenchymal
involvement.2 The hypoxemia was rapidly reversed by
corticosteroids. However, histologic specimens were not
available from any7 of these patients. We present a case of
histologically proven ALP with a normal chest x-ray film
A
cute
^*- characterized
and CT scan
on
presentation.
Case Report
A 56-year-old woman presented with dyspnea and bilateral
pleuritic chest pain of 2 weeks' duration. She had no orthopnea,
paroxysmal nocturnal dyspnea, leg swelling, fever, chills, cough,
or hemoptysis. Seven months earlier, she was treated for facial
cellulitis which was painful, erythematous, and swollen over the
malar areas. Her past medical histoiy was significant for uncom¬
plicated hepatitis C-related cirrhosis, chronic sinusitis, and hy¬
pertension. She had no histoiy of smoking. At the time of
admission, she was receiving nadolol, thiamine, and folate.
Physical examination revealed a well-nourished woman in no
acute distress with a BP of 140/80 mm Hg, a pulse of 60 beats per
minute, a respiratory7 rate of 20 breaths per minute, and a
temperature of 36.3°C. Physical examination revealed nontender
sinuses. Her lungs were clear, and her heart rate was regular with
Department of Medicine, Division of Pulmonary
Diseases/Critical Care Medicine, the University of Texas Health
Science Center at San Antonio and, the South Texas Veterans
Health Care System, Audie L. Murphy Memorial Veterans
San Antonio, Tex.
Hospital Division,
received September 16, 1996; revision accepted
Manuscript
December 16.
Reprint
requests: Irawan Susanto, MD, FCCP, the University of
Texas Health Science Center at San Antonio, Department of
Medicine, Div of Pulmonary Diseases/Critical Care Medicine,
7703 Floyd Curl Dr, San Antonio, TX 78284-7885
*From the
Acute Lupus Pneumonitis With
Normal Chest Radiograph*
Irawan Susanto, MD, FCCP; and Jay I. Peters, MD, FCCP
lupus pneumonitis (ALP) usually
hypoxemia, patchy infiltrates evidenced on a
Patients with acute
have
CHEST / 111 / 6 / JUNE, 1997
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1781