1. health and fitness
2. addiction

NIDA Conference
Report on
of
Complications
Cardiopulmonary
"Crack" Cocaine Use*
Clinical Manifestations and
Pushpa V. Thadani, PhD*
Pathophysiology
(CHEST 1996; 110:1072-76)
Key words: cocaine; crack; cardiovascular; pulmonary; complica¬
tions; pathophysiology; abused drugs; biological mechanisms
Abbreviations: AM=alveolar macrophage; Dco=diffusion of car¬
bon monoxide; DM=pulmonary membrane component of diffusion;
IL=interleukin; PChE=plasma cholinesterase; VC=alveolar capil¬
lary volume component
nasal insufflation or IV injection of
T^xperimental
cocaine
-*--1
hydrochloride (HCl) (water-soluble, pow¬
der cocaine) is known to cause both lethal and nonlethal carciovascular complications in young, otherwise
For related material see page 904
asymptomatic, individuals.1 Currently, smoking of al¬
kaloidal cocaine (freebase or "crack" cocaine) alone or
in combination with other smokable substance(s) is on
the rise. In 1993, lifetime prevalence of crack cocaine
use reached 7 to 8% among young adults.2 Unlike co¬
caine HCl, crack cocaine is both hpid soluble and re¬
sistant to thermal degradation and, therefore, can be
smoked. This new mode of drug use has replaced na¬
sal insufflation in some demographic regions as it pro¬
duces an instantaneous euphoric effect (similar to that
achieved by IV injection) due to its rapid absorption
through the extensive network of pulmonary capil¬
laries. Along with this increased use, there appears
to be a parallel rise in the reported incidence ofcardio¬
users, par¬
complicationschestin crack cocaine
pulmonarycrack-related
the
most
frequent
pain,
ticularly
cocaine-associated hospital
presenting symptom invisits.
With the restructuring
emergency department
*From the Division of Basic Research (Dr. Thadani), National In¬
stitute on
Abuse, Rockville, Md.
^ConferenceDrug
Session Chairs: Eugene R. Passamani MD; Donald P.
Wilkerson, PhD. Partici¬
Tashkin, MD, FCCP; and R.
Douglas
pants included: Tames V. Dingell, PhD; Armando E. Fraire, MD,
FCCP; Richard A. Gillis, PhD; Robert S. Hoffman, MD; Judd E.
Hollander, MD; Jag Khalsa, PhD; Mark M. Knuepfer, PhD;
Michael L. Lippmann, MD, FCCP; Benedict R. Lucchesi, MD;
P. Morgan, MD; Michael D. Roth, MD, FCCP; David
James
Sachs, MD, FCCP; Renu Virmani, MD; and Stephen Zukin, MD.
This article was prepared by a federal government employee as part
of official duties; therefore, the material is in public domain and
permission.
may be reproduced or copied without revision
26, 1996;
accepted April 9.
January
Manuscript received
Reprint requests: Dr. Thadani, NIDA, 10A-19, 5600 Fishers Lane,
Rockville, MD 20857
1072
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of the health-care provision system, the treatment of
this manifestation alone could be a major concern
contributing to the rising cost of medical care in this
country. This concern and the paucity of information
on the true frequency, clinical significance, and un¬
derlying pathophysiology of crack cocaine-induced
pulmonary
complications prompted the National In¬
stitute on Drug Abuse to hold a workshop at which
basic and clinical researchers discussed their current
the gaps and future research
findings and identified
in
opportunities this area. The workshop was held in
Bethesda, Md, on August 3 and 4, 1995. This confer¬
ence report summarizes the major findings and the
issues discussed by the participants and attendees at
the meeting.
Pulmonary Complications
the true frequency and extent of lung in¬
Although
caused
crack cocaine and/or its pyrolysis
by
jury
is
uncertain
at present, its use has resulted
byproducts
in a broad spectrum of pulmonary complications.3
These
from acute
to clin¬
respiratory symptoms
range
ical reports of acute exacerbations of asthma,
barotrauma (pneumomediastinum and pneumotho¬
rax), noncardiogenic pulmonary edema, diffuse alveo¬
lar hemorrhage, recurrent pulmonary infiltrates with
obliterans with organiz¬
eosinophilia, andasbronchiolitis
well
as autopsy evidence of pulmo¬
ing pneumonia,
nary vascular abnormalities. Acute respiratory symp¬
toms, such as cough productive of carbonaceous
sputum, chest pain, and hemoptysis, generally develop
within 1 or more hours of smoking crack cocaine4 and
are suggestive of a local irritant effect of cocaine on the
airways since similar complaints are not reported after
nasal insufflation or IV injection of cocaine HCl.
While the number of dramatic examples of acute
lung
injury that have been reported is relatively small,3
it is possible that regular cocaine smoking might cause
more frequent, clinically silent chronic lung damage
that could progress with continued use and ultimately
be manifested clinically. To assess this possibility, re¬
searchers have measured pulmonary function in ha¬
bitual crack smokers both with and without chronic
to date show no
Findings
pulmonary symptoms.adverse
effects
of habitual crack
significant long-term
Special Reports
smoking on lung mechanics, as reflected by
normal results of spirometry, even in heavier habitual
users.4"6 However, its effects on the single-breath dif¬
fusing capacity ofthe lung for carbon monoxide (Deo),
a physiologic marker of the integrity of the alveolarcapillary membrane, are still unclear. While some in¬
cocaine
vestigators, in small-scale studies, have failed to find an
effect on Deo,6 Tashkin and his coworkers4 more re¬
cently reported a small but significant decrease in Deo
in a large cohort of habitual crack smokers after con¬
trolling for use of other substances confirming earlier
Factors such as sample size, inappropriate
findings.5concomitant
use of other smoked substances,
controls,
of
and/or intensity cocaine use are thought to contrib¬
ute to the observed differences.
Although the precise mechanism(s) underlying the
cocaine-associated impairment in gas transfer in the
lung are not yet known, the presence of abnormalities
in the diffusing capacity suggest structural lung dam¬
age. The lung damage could be reflected by changes
in either the pulmonary membrane component of dif¬
fusion (Dm) or the alveolar capillary volume compo¬
nent (Vc). Findings presented indicated that cocaineinduced reduction in Dm, rather than Vc, is probably
responsible for the impaired diffusion seen in habitual
crack smokers (DP Tashkin, MD, FCCP; 1995; un¬
data). Since alterations in pulmonary clear¬
published
ance of 99mTc-DTPA, a sensitive marker of alveolar
epithelial integrity, were observed in only 4 of 7 young,
otherwise healthy, habitual crack smokers, it was sug¬
gested that subtle alveolar epithelial damage may oc¬
cur only inconsistently in these individuals/ These
preliminary
findings were somewhat different from an
earlier study in which more consistent increases in
pulmonary clearance of 99mTc-DTPA were observed.8
Thus, these findings need to be interpreted cautiously
until confirmed in a larger cocaine-smoking popula¬
tion. It was also emphasized that the health, duration,
intensity of cocaine smoking, and concomitant expo¬
sures to other noxious inhaled substances, as well as the
size of population, may influence the study outcome.
To delineate the long-term vs short-term functional
effects of cocaine smoking on the lung, Tashkin and his
associates
(DP Tashkin, MD, FCCP; 1995; unpub¬
lished data) measured airway dynamics, pulmonary gas
exchange, and pulmonary vascular pressures (estimat¬
ed from Doppler echocardiography) in habitual co¬
caine users both before and after acute administration
of smoked alkaloidal cocaine or IV cocaine HCl. Data
presented from this pilot study showed that cocaine
smoking caused significant decreases in specific airway
conductance within minutes following cocaine inhala¬
tion. No significant changes in specific airway conduc¬
tance were noted after IV cocaine HCl, suggesting that
the bronchoconstriction was due to a local irritant ef¬
fect ofthe inhaled smoke, rather than a pharmacologic
effect of cocaine itself. The observed acute broncho¬
constriction could also be caused by anhydroecgonine
methylester, a major pyrolysis product of cocaine, as
has been reported in experimental animals.9 However,
the method of generating cocaine vapor in the studies
presented would be expected to maximize the delivery
of alkaloidal cocaine while minimizing the generation
ofthe pyrolysate, anhydroecgonine methylester. These
physiologic findings are consistent with earlier reports
of crack cocaine-induced exacerbations of clinical
asthma.10"12 However, no acute changes were observed
in either Deo or its components (Dm or Vc) after ei¬
ther smoked or IV cocaine. This suggested that the
impairment in Deo and Dm observed in habitual crack
cocaine users may result from the accumulated effects
of long-term cocaine-induced damage to the alveolarcapillary membrane that is not apparent following
acute exposure to cocaine. Furthermore, the lack of
any demonstrable changes in estimates of mean pul¬
monary artery pressure as measured by continuous
Doppler echocardiography by either route of acute
cocaine administration fails to support the concept that
crack cocaine-induced lung injury may result from in¬
tense pulmonary vasoconstriction, leading to anoxic
damage.
Smoking of cocaine is thought to increase suscepti¬
bility to infections and
inflammatoryinpulmonary com¬
an
plications implying impairment pulmonary host
defense.13 Pulmonary alveolar macrophages (AMs) are
known to provide the first line of host defense and are
also exposed to the highest concentrations of inhaled
cocaine. Data presented showed that AMs recovered
from the BAL fluid of cocaine smokers produced less
inflammatory
cytokines (interleukin [IL]6, IL-8, tumor
necrosis factor-a) and more immunosuppressive fac¬
tor, transforming growth factor-(3, than AMs from
individuals.14 Enhanced elaboration of
nonsmoking
activated transforming growth factor-(3 is one of the
mechanisms by which cocaine enhances HIV replica¬
tion in vitro.15 On a functional
AMs from
level,
cocaine abusers were less active than AMs from
non-
smokers in their capacity to destroy Staphylococcus
aureus and to prevent growth of cancer cells.16 Pre¬
liminary
findings also showed that AMs from cocaine
smokers were more susceptible to HIV infection and
promoted a several-fold increase in HIV replication
when infected in vitro. These observations suggest that
long-term useinof crack cocaine can result in a profound
impairment pulmonary host defense. Cocaine also
suppressed the production of interferon-gamma and
IL-8 by lymphocytes in vitro and acted at the transcriptional level
by preventing upregulation of cytokine
RNA
that normally occurs when lympho¬
messenger
are
stimulated.1'
In contrast, acute administracytes
CHEST / 110 / 4 / OCTOBER, 1996
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crack
1073
tion of cocaine to
long-term cocaine users was associ¬
ated with neutrophil activation. This acute activation of
neutrophils may therefore play a role in the syndrome
of "crack lung," while chronic immunosuppression
may impact on the risk for HIV and other infections.
The mechanisms by which cocaine mediated these
effects are undefined at present.
immunologic
Mechanisms for pathologic changes seen in lungs of
cocaine users at autopsy are also unclear at present.
Pathologic evaluations have revealed that pulmonary
hemorrhage occurs more often than is described clin¬
ically and thatinchronic interstitial
pulmonary fibrosis
may develop long-term cocaine users.18 The ob¬
served pulmonary vascular alterations could be due to
direct toxic effects of cocaine, to cardiac compromise,
or to cocaine-induced pulmonary vasoconstriction.18
Hypersensitivity response to the drug was speculated
to be another possible mechanism for pulmonary
interstitial changes. It was suggested that animal
models be developed to elucidate the underlying
mechanisms for these cocaine-associated pulmonary
manifestations.
Cardiovascular Complications
Use of cocaine "freebase" or cocaine HCl in humans
may cause a number of cardiovascular events, such as
dilated cardiomy¬
myocardial infarction, myocarditis,and
and
heart
failure,
coronary
peripheral vas¬
opathy
cular spasm, dysrhythmia, and sudden cardiac death.
However, the most frequent presenting symptom in
cocaine-related cardiac emergencies in chest pain.19'20
Clinical evidence appears to suggest a relationship
between cocaine use and myocardial ischemic symp¬
toms even though the latter appear unrelated to
cocaine dose, route, or time of administration. This
suggests wide interindividual variation in susceptibility
to cocaine's adverse effects. To determine clinical cri¬
teria predictive of myocardial infarction associated
with cocaine use, a prospective muiticenter study was
undertaken. Data presented from this study revealed
that at present and to our knowledge, there are no
clinical parameters available to the emergency physi¬
cian that can adequately identify patients at very low
risk for myocardial infarction.21"23 Patients who present
to the emergency department with chest pain follow¬
ing cocaine use have a very low likelihood of serious
cardiac complications if they do not sustain a myocar¬
dial infarction. One retrospective study estimated that
with cocaine-associated
only 1.6 per 1,000 patients cardiovascular
chest pain would experience
complica¬
tions not identified during a 12-h monitored observa¬
tion period utilizing cardiac marker determinations and
It was stressed that 9- to 12-h
electrocardiography. should
not be used routinely until
observation periods
prospective validation confirms the safety of this strategy.
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It is speculated that predisposition to cardiotoxic
effects of cocaine could be due to a genetic determi¬
nant such as its metabolic disposition. Observational
studies show that levels of plasma cholinesterase
(PChE), one ofthe cocaine metabolizing enzymes, are
decreased in patients with life-threatening cardiac
events following cocaine compared to those with nonlethal cardiac complications, confirming previous re¬
sults.24 Experimental findings also showed that pre¬
treatment of mice with human PChE lowered cocaineinduced lethality and seizure with concomitant
increases in PChE activity.20 However, decreases in
PChE activity induced by protein calorie malnourishment in animals was associated with increased sensi¬
tivity to cocaine (RS Hoffman, MD; 1995; unpublished
data). These findings, although preliminary, raise
questions: whether a change in PChE profile occurs
with long-term cocaine use in humans and, if it does,
what impact does this change have on the susceptibil¬
ity of an individual to cocaine's toxic effects. Other ex¬
perimental findings presented also showed that a subpopulation of animals may be more sensitive to the
cardiotoxic effects of cocaine since exposure to the
same cocaine regimen produced different hemody¬
namic responses in different subgroups of animal.26
Central monoaminergic sites appeared to be involved
in these varied responses. For example, norepineph¬
rine overflow was significantly higher in the striatum of
rats whose cardiac
increased
after cocaine,
output
whose cardiac output was decreased,
dopamine overflow was augmented.27 Additional
studies showed ultrastructural changes in the myocar¬
dium of stressed rats similar to those in cocaineexposed rats, suggesting that cocaine-evoked cardio¬
vascular responses may in part be induced by behavioral
stress.28 Other pathologic evaluations have shown that
the presence of focal myocardial necrosis observed in
cocaine abusers may have increased their susceptibil¬
ity to ventricular arrhythmia.29
Although acute myocardial infarction has been
reported in young, otherwise healthy, individuals fol¬
cocaine use, its mechanism(s) remains specu¬
lowing
lative. One ofthe proposed physiologic mechanisms is
that cocaine causes a diffuse increase in coronary vas¬
cular resistance, which may lead to a decrease in cor¬
onary blood flow. Studies performed in miniature
swine showed that cocaine produced decreases in
coronary blood flow and increases in vascular resis¬
tance that were partially reversed by adenosine.30
Similar changes in vasoconstriction have been reported
in isolated vessels and whole heart preparations. These
findings suggest that cocaine can produce profound
microvascular spasm that may contribute to the ische¬
mia/infarction reported in patients who abuse cocaine
and are subsequently found to have normal epicardial
whereas in
rats
Special Reports
coronary arteries. Other recent findings suggest that
there may be a cholinergic component to cocaineinduced coronary vasoconstriction since pretreatment
with atropine blocked cocaine-induced contraction of
bovine coronary artery rings in vitro.31 Cholinergic
modulation of cocaine-induced coronary vasoconstric¬
tion has also been reported in conscious dogs.32
Changes in vascular endothelial function due to co¬
caine may also play a role in cocaine-associated myo¬
cardial infarction since such changes may predispose to
the development of thrombosis resulting in myocardial
ischemia/infarction. In vitro results presented showed
that cocaine enhanced the permeability of vascular
endothelium which could augment the diffusion of
atherogenic lipoproteins into the intima and thereby
increase the predisposition to atherosclerosis develop¬
ment.33 Pathologic findings presented also showed
moderate to severe aorta and coronary artery athero¬
sclerosis in a population of young cocaine abusers who
were otherwise at low risk for coronary atherosclero¬
sis.34'35 Interestingly, atherosclerotic lesions in cocaine
abusers with acute coronary thrombosis did not dem¬
onstrate plaque rupture or hemorrhage suggesting that
the pathophysiology of acute myocardial infarction is
different from that in noncocaine users. Augmented
release of vasoactive mediators through enhanced ac¬
tivation of platelet and recruitment of mast cells may
also be involved in cocaine-related vasospasm and
thrombosis.3436 Thus, cocaine-induced myocardial in¬
farction appears to result by direct and indirect actions
of cocaine at various cellular levels.
Cardiovascular sequelae such as increases in heart
rate, mean arterial BP, cardiac index, and transcardiac
oxygen uptake seen in humans following cocaine use
are thought to be due to activation of the sympathetic
nervous system.3738 Similar changes in cardiovascular
responses have also been reported in experimental
animals exposed to an acute or long-term cocaine reg¬
imen. These observations are not unexpected because
one of the known fundamental pharmacologic actions
of cocaine is to increase peripheral sympathetic tone by
inhibition of neuronal reuptake of monoamines. At
present, however, it is unclear whether the sites of
sympathomimetic actions of cocaine are primarily pe¬
ripheral or a combination of both peripheral and cen¬
tral sympathetic sites. Experimental findings pre¬
sented showed that at least acute effects of cocaine on
the cardiovascular system are mediated via its periph¬
eral sympathomimetic actions which appear to involve
inhibition of catecholamine uptake into postganglionic
sympathetic nerve terminals and increased release of
epinephrine from the adrenal medulla.3940 Data also
indicate that cocaine alters parasympathetic nervous
system activity at the level of the heart.41 At present,
it is unclear whether the modulation is due to inhibi¬
tion or enhancement of its activity and this issue needs
further clarification. In vitro experiments reported that
both catecholamine-dependent and -independent
mechanisms may be involved in cocaine-induced ino¬
tropic and lusitropic responses in ferret myocardium.42
The positive inotropic and lusitropic responses seen in
myocardium at low and moderate doses of cocaine
were mediated probably via catecholamine release
from adrenergic nerve terminals, while at higher doses
the decreases seen in myofilament calcium sensitivity
and maximal calcium-activated force were mediated
most likely by mechanisms independent of catechola¬
mines.
Cocaine has been thought to cause cardiac dysrhyth¬
mias, which may precipitate into sudden death in hu¬
The potential mechanisms could be its proarrhytmic action due to inhibition ofthe sodium channel,
its direct action on the heart, or alteration in the activity
ofthe autonomic nervous system. Experiments in iso¬
lated hearts showed that cocaine attenuated lethal ar¬
rhythmias and, in conscious dogs, it blocked the
induction of ventricular arrhythmia induced by pro¬
grammed electrical stimulation (G Friedrichs, PhD
and B Lucchesi, MD; 1995; unpublished findings).
These findings suggest that cocaine has antiarrhythmic
actions which appear to be mediated via its local
anesthetic effect.
mans.
Future Research Directions
Discussion at this workshop centered on future re¬
search requirements. Appropriate animal models, cel¬
lular and subcellular investigations, and muiticenter
studies of large numbers of well-characterized users of
crack with or without other abused substances are
needed for a better understanding of the cardiopul¬
monary complications of crack cocaine, their clinical
significance, and their underlying physiologic, cellular,
and molecular mechanisms. Ultimately, the results of
these studies will yield information that should enable
us to provide better treatment protocols for these
medical complications in the substance-abusing pop¬
ulation.
1
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