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EMBARGOED UNTIL
12:01 AM EDT/Friday, May 1, 2009
Contact: Donna Krupa
Office: (301) 634-7209
communicationsoffice@the-aps.org
Cell: (703) 967-2751
Chemical Used in the
Production of Intravenous (IV) Bags and Other Medical Equipment Can
Reproduce Complications Seen in Patients Following Extracorporeal
Circulatory (EC) Support
Study
by Hopkins researchers finds solvent cyclohexanone (CHX) leaches into IV
fluids and can replicate clinical abnormalities
BETHESDA, Md. (May 1, 2009)
− Medical science took a giant leap forward with the development
of techniques that, at least temporarily, perform the function of vital
organs. These processes, including the use of the heart-lung machine and
renal dialysis, require the blood to be circulated through tubing outside
the body and are hence known as extracorporeal circulation (EC) and have
provided critical life support for millions of patients. Yet EC is not
without its own risks. Among them are unique morbidities such as depressed
cardiac output, abnormal heart rhythm, and swelling of the major organs.
Studies have been conducted for decades to determine how these effects can
be reduced and eliminated. In a new study conducted by a Johns Hopkins team,
the researchers examined whether a solvent used in the production of
intravenous (IV) bags and EC circuits could play a role. Their results
indicate that 1) the solvent cyclohexanone (CHX) can leach into IV and EC
fluids, and 2) CHX administered in controlled doses in an animal model
replicates the cardiovascular and lung morbidities that are seen in patients
during and after EC treatment. The study sheds new light on the potential
causes of EC-related disorders.
The study was conducted by Caitlin S. Thompson-Torgerson
and Lakshmi Santhanam, Department of Biomedical Engineering; Hunter C.
Champion, Department of Medicine (Division of Cardiology); Z. Leah Harris,
Department of Anesthesiology and Critical Care Medicine; and Artin A.
Shoukas, Departments of Biomedical Engineering, Anesthesiology and Critical
Care Medicine, and Physiology, The Johns Hopkins University School of
Medicine, Baltimore, MD. The study, entitled Cyclohexanone Contamination
From Extracorporeal Circuits Impairs Cardiovascular Function, is
published in the online edition of the American Journal of
Physiology—Heart and Circulatory Physiology.
The Study
Cyclohexanone (CHX) is an organic solvent widely used
in the production of polyvinyl chloride (PVC) medical devices, including IV
fluid bags and EC circuits. CHX can migrate from PVC tubing and connections
into fluids that come in contact with PVC. CHX can leach from PVC bags and
IV tubing into intravenous fluids in sufficient concentrations to be
detected in neonatal urine samples. Therefore, it is possible that patients
on EC support are at risk for CHX exposure, given that their full blood
volumes circulate continuously through CHX-treated tubing and are frequently
augmented with IV fluids.
While the toxicity of PVC and CHX has been previously
documented in animal models, no studies have made comparisons to clinical
intravenous CHX exposure. Accordingly, the researchers developed a series of
experiments to establish current values for CHX contamination in crystalloid
fluid from IV bags and EC circuits, and to test the hypothesis that a
clinically observed dose of CHX could reproduce the vital organ dysfunction
that can accompany EC support/treatment.
Methodology
To quantify the degree of
CHX contamination of fluids, researchers from Johns Hopkins Medical
Institutions collected saline samples from IV bags and other commercially
available bags, bypass circuits, ECMO circuits and dialysis circuits. CHX
levels were measured using gas chromotography-mass spectrometry (GCMS).
These results were used to determine a clinically relevant intravenous dose
of CHX. A dose of CHX was then calculated and given intravenously to adult
male rats. Saline stored in and administered from glass bottles was given to
a control group. Dosing calculations were designed so that they approximated
a conservative adult EC patient exposure to CHX, including the abrupt nature
of the exposure that EC patients undergo when they are connect to circuit
tubing.
There were three protocols
used in the study:
Protocol 1 was designed to
measure several aspects cardiovascular function. Animals were anesthetized,
tracheotomized, ventilated using a rodent ventilator, and then instrumented
so that the researchers could measure cardiac output, heart rate, stroke
volume, blood pressure, and heart contractile function. Measurements were
made at baseline and again 60 minutes after infusion of CHX or saline.
Protocol 2 was designed to
measure cardiovascular autonomic function, including how well the nervous
system was able to maintain blood pressure in the face of a challenge.
After the animals were anesthetized and instrumented to measure blood
pressure, both carotid arteries were occluded (obstructed), which stimulates
a reflex called the baroreflex that controls blood pressure. After this
baseline assessment of reflex function, CHX or saline was infused and
allowed to circulate for 30-40 minutes, followed by another round of
occlusions. A subsequent identical infusion was given and allowed to
circulate for an additional 30-40 minutes, followed by a final round of
occlusions.
Protocol 3 was designed to
measure edema formation, or the volume of water that has been retained in
major organs of the body. After the animals were anesthetized, each rat
received an infusion of either CHX or saline, which was allowed to circulate
through the body for 2 hours. After 2 hours, the animal was euthanized, and
the liver, kidneys, lungs, and skin were harvested, weighed, dried at 100°C,
and weighed again to quantify the fluid content in each organ at the time of
death.
Results
In protocol 1, all baseline
values were similar between saline and CHX groups. In the 60 minutes
following saline infusion, none of the variables changed significantly from
baseline. The CHX infusion, however, induced significant adverse changes in
all cardiovascular variables. Both stroke volume and heart rates values were
significantly depressed after one hour of CHX, resulting in a significant
decline in cardiac output in the CHX rats. Stroke volume, in turn, was
depressed because the inherent contractile ability of the heart was
significantly reduced. CHX exposure also resulted in high blood pressure in
the lung vessels, a dangerous condition known as pulmonary hypertension.
In protocol 2, prior to
infusions, both saline and CHX groups exhibited similar significant
baroreflex pressor responses to carotid occlusion. After both 1st and 2nd
saline infusions, the pressor response in the control group did not differ
significantly from baseline. However, in the CHX group, the pressor response
was blunted after the first infusion and was undetectable after the 2nd
CHX infusion. There are a myriad of neurological complications that develop
in patients who undergo EC support. The relative contributions of the
underlying disease vs. the treatment are often difficult to discern.
Moreover, the potential contribution of CHX to the evolution of these
complications has not been investigated.
In protocol 3, the wet/dry
ratio of organ weights served as an index of tissue fluid retention and,
thus, edema formation. The ratios for all individual organs within each
treatment group were pooled to create an overall index of edema formation.
The pooled ratio for the CHX group was significantly higher than the saline
group.
Conclusions
According to Dr. Thompson-Torgerson,
lead author on the paper, and Dr. Shoukas, the senior researcher on the
study, “The data from this study provide a current estimate of CHX
contamination in most commercially available IV bags and EC circuits. The
data allowed us to determine a clinically relevant CHX exposure. A similar
level of exposure in animals resulted in cardiovascular morbidities
analogous to those observed following clinical EC treatment. This supports
our hypothesis that CHX may contribute to EC-related cardiovascular
insufficiency. However, we would never tell patients to decline EC
treatment if they need it. On the contrary, EC technologies are life-saving
medical advances, and the benefits of EC therapy still far outweigh the
risks of the associated morbidities. If a patient and doctor have decided
that EC treatment is the best course, then stick to that plan. As
scientists, we are simply trying to understand how the side effects are
triggered and what the best method will be to mitigate, and ultimately
remedy, these morbidities. ”
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Physiology is the study of how molecules,
cells, tissues and organs function to create health or disease. The American
Physiological Society (APS;
www.The-APS.org/press) has been an
integral part of this discovery process since it was established in 1887.
***
NOTE TO EDITORS: To receive a copy of the full
study or arrange an interview with a member of the research team, please
contact Donna Krupa at 301.634.7209 (office), or
DKrupa@the-APS.org.
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