Hutter JC, Kuehnert MJ, Wallis RR, Lucas AD, Sen S, Jarvis WR. Acute Onset of Decreased Vision and Hearing Traced to Hemodialysis Treatment With Aged Dialyzers. JAMA. 2000;283(16):2128-2134. doi:10.1001/jama.283.16.2128
Author Affiliations: Center for Devices and Radiological Health, Food and Drug Administration, Rockville, Md (Drs Hutter, Wallis, Lucas, and Sen), and Hospital Infections Program, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Ga (Drs Kuehnert and Jarvis).
Context A recent event in which 7 patients at 1 hospital developed decreased
vision and hearing, conjunctivitis, headache, and other severe neurologic
symptoms 7 to 24 hours after hemodialysis drew attention to the issue of the
long-term integrity of dialysis machines and materials.
Objective To determine the cause of the adverse reactions that occurred during
Design, Patients, and Setting Retrospective cohort study of all 9 patients who received hemodialysis
at hospital A on September 18, 1996, the day of the outbreak. A case-patient
was defined as any hospital A patient with acute onset of decreased vision
and hearing and conjunctivitis after dialysis on that day. Non–case-patients
were all others who underwent dialysis at hospital A on that day but did not
develop adverse reactions. In an attempt to reproduce the conditions of the
event, cellulose acetate dialysis membranes of various ages were retrieved
from other sources and tested for physical and chemical degradation, and degradation
products were identified, characterized, and injected intravenously into rabbits.
Main Outcome Measures Clinical signs and symptoms, time to resolution of symptoms, mortality,
and dialyzer type and age, for case- vs non–case-patients.
Results Seven of the 9 patients met the case definition. In addition to diminished
vision and hearing, conjunctivitis, and headache, some case-patients had blood
leak alarm activation (n=6), confusion/lethargy (n=5), corneal opacification
(n=4), cardiac arrest (n=2), or other neurologic signs and symptoms. One case-patient
died during hospitalization after the event; 5 of 7 case-patients died within
13 months. Resolution of signs and symptoms varied but persisted more than
3 years or until death in 3 of the 6 patients who survived hospitalization.
All case-patients but no non–case-patients were exposed to 11.5-year-old
cellulose acetate dialyzers (all of these dialyzers were discarded by the
hospital before our investigation). Laboratory investigation of field-retrieved
0- to 13.6-year-old dialyzers of similar type indicated significant chemical
degradation in the older membranes. In vivo injection of extracts of membrane
degradation products produced iritis and hemorrhages in rabbits' eyes.
Conclusions Severe patient injury was associated with exposure to aged cellulose
acetate membranes of dialyzers, allowing cellulose acetate degradation products
to enter the blood. Clinicians should be aware that aged cellulose acetate
membranes may cause severe adverse reactions.
Severe reactions associated with hemodialysis are rare but can be life-threatening.1 The majority of such reactions are caused by bacterial
and/or endotoxin contamination of the dialysate or product water and are manifested
by fever and hypotension.2- 8
Oba et al9 reported sporadic eye and hearing
injuries attributed to degradation products of hemicellulose found in new
cellulose acetate hemodialyzers. This early event was traced to improper manufacturing
of these devices, and the injuries were manifest as soon as this new product
line was introduced to the market. Since that time, similar incidents related
to manufacturing or packaging have been reported in many parts of the world.10 Currently, there are approximately 250,000 patients
undergoing dialysis treatment in the United States alone. According to the
Centers for Disease Control and Prevention's surveillance system, 43% of centers
use cellulose acetate and an additional 14% of centers use cellulose triacetate
for high-flux dialysis. Due to this widespread use in dialysis and other blood
contacting devices (eg, blood filters), the long-term integrity of cellulose
acetate and other medical device polymers has become an important issue.
In September 1996, 7 patients at hospital A (inpatient dialysis unit)
developed acute onset of diminished vision and hearing less than 24 hours
after hemodialysis using cellulose acetate dialyzers with a previous excellent
safety record. Because of the severity of the adverse reactions, the Centers
for Disease Control and Prevention and the Food and Drug Administration (FDA)
initiated an investigation to identify the source of the adverse events.
A case-patient was defined as any patient with onset of decreased vision
and hearing within 48 hours of the initiation of hemodialysis at hospital
A on September 18, 1996 (ie, the epidemic day). To identify case-patients,
we reviewed patient medical records, laboratory results, and interviewed facility
staff caring for all patients receiving hemodialysis at hospital A on the
epidemic day. Non–case-patients were all those who underwent dialysis
on the same day who did not develop adverse reactions.
To identify risk factors, a retrospective cohort study of all patients
who underwent hemodialysis at hospital A on the epidemic day was conducted.
Variables examined included demographics, clinical signs and symptoms, laboratory
results, dialyzer type, time undergoing dialysis, indication as to whether
a hemodialysis machine alarm sounded indicating blood leakage in the dialyzer,
visible blood in the dialysis fluid, and medications received.
Although not routine in the unit, but because of the severity of the
visual and hearing abnormality, unit personnel arranged for ophthalmologic
and auditory testing of all case-patients. Visual and auditory acuity were
measured at multiple times 1 to 8 days after dialysis. Visual acuity was assessed
with the standard ophthalmologic descriptions of no light perception, light
perception only, hand motion detected, ability to count fingers, and vision
better than 20/200. Audiometry results were categorized as profound, severe
to profound, severe, moderate to severe, moderate, mild to moderate, mild,
and no discernable hearing loss. When multiple tests were done, the worst
reading was recorded. Data were collected on standardized forms, entered into
a computer, and analyzed using EPI Info statistical
software (version 6.02).11 The Fisher exact
test was used for comparison of categorical variables and the t test or Kruskal-Wallis test was used to compare continuous variables.
Cellulose acetate is one of the most commonly used dialysis membrane
materials. Its properties (eg, melt viscosity, solution solubility, phase
equilibrium, tensile strength, and crystallinity) are determined from both
average molecular weight and acetyl content. Degradation of the material over
time will change these properties. To determine the potential mechanism of
the patients' reactions, we assessed material degradation by measuring changes
in polymer molecular weight, degree of acetylation, and isolated extractable
compounds of cellulose acetate dialyzer membranes of various ages. Staff at
hospital A discarded all of the 11.5-year-old dialyzers used for the 7 case-patients
as well as 5 unused 11.5-year-old dialyzers before our investigation. Dialyzers
were not reused at hospital A. To identify the possible degradation products
and to reconstruct the event, the FDA retrieved dialyzers of various ages
from commercial sources and dialysis centers nationwide. Some variation in
the storage conditions of these devices was anticipated, since the dialyzers
were retrieved from warehouses and clinical storage areas; however, these
ambient storage conditions were typical of the real-world storage conditions
for these devices. We characterized dialyzer membranes and their degradation
products by chromatographic, chemical, and spectroscopic methods.
First, to determine changes in molecular weight of the polymers of dialyzer
membranes of different ages, we performed gel permeation chromatographic analyses.
Cellulose acetate fibers were removed from the dialyzers and dissolved in
Chromatographic analyses were completed using a Waters 150C-gel permeation
chromatograph (Waters, Milford, Mass) equipped with Styragel columns (Waters)
(molecular weight ranges, 2000-4,000,000; 5000-500,000; and 500-30,000 g/mol)
and a refractive index detector. Number-average molecular weight, weight-average
molecular weight, peak-average molecular weight, and polydispersity index
were calculated using statistical software (Millennium, Waters). The polydispersity
index is equal to the weight-average molecular weight divided by the number-average
molecular weight. The Mark-Houwink-Sakurada viscosity parameters used for
universal calibration were obtained from the literature,12
and were in good agreement with our own measurements.
Second, we further assessed the age-related degradation of cellulose
acetate by measuring the pendant acetyl groups (total acetyl content) on the
polymer chain. Cellulose acetate used for these dialyzer membranes has an
acetyl content of 39.9% by weight. As membranes degrade with age, the acetyl
content decreases. We measured the acetyl content by a standard saponification
and titration procedure.13
Third, we measured the dialyzers' extractable compounds as an indication
of membrane degradation. The fibers from 40 dialyzers of various ages were
removed and rinsed with 1 L of cold deionized water to remove the glycerol,
and extracted in 600 mL of deionized water for 2 hours at 50°C. Then,
the solutions were filtered through a 0.45-mm filter, the filtrate was evaporated
at 70°C, mixed with 10 mL of ethanol, dried at 50°C under vacuum pressure,
and then weighed.
Fourth, to confirm the chemical structure of the suspected membrane
causative agent, we synthesized model degradation compounds. Cellulose acetate
resin (Aldrich, Milwaukee, Wis) was degraded in phosphate-buffered saline
(PBS; pH of 7.0) under oxidative conditions using sodium hypochlorite and
cobalt as an accelerant.14 The water-soluble
fraction was dialyzed and lyophylized to dryness. Next, we used infrared spectroscopy
to compare the chemical structure of the dialyzer extracts and the synthesized
degradation compounds with the spectrum of high-purity, cellulose-acetate
resin. Samples were deposited on sodium chloride windows and scanned using
a Fourier-transformed infrared spectrometer (Nicolet Instrument Corp, Madison,
Finally, we attempted to duplicate the human adverse reactions by injecting
rabbits with either the water-soluble material recovered from extraction of
a 13.6-year-old dialyzer, the synthetic degradation compounds, or a PBS control
solution. The 13.6-year-old dialyzer was chosen since it was the oldest dialyzer
available with a diminished acetyl content (33.1% by weight) and was the most
similar in type to that used at hospital A at the time of the outbreak. The
isolated materials were dissolved in a solution consisting of 70% ethanol
and 30% PBS, then diluted in sufficient PBS solution to attempt to obtain
a final target concentration of approximately 50 mg/mL filtered. To determine
the actual dissolved concentration, 1 mL of each filtered test solution was
dried and the recovered material weighed so that the dose to each animal could
be accurately determined. The 13.6-year-old dialyzer extract achieved a maximum
dose due to solubility of 270 mg per rabbit, whereas the synthetic degradation
products achieved a maximum dose of 470 mg per rabbit.
Healthy female New Zealand rabbits (2.5-2.7 kg) were used for the in
vivo experiments. The eyes of all the animals were examined with slit-lamp
biomicroscopy and indirect ophthalmoscopy following 1% of tropicamide mydriasis
1 week before and 2, 4 to 6, and 24 hours after doses were administered. Four
animals each were randomly assigned to 1 of 3 groups. Group 1 received 13.6-year-old
dialyzer extract; group 2, synthetic model degradation compounds; and group
3, PBS control solution. Each animal received a 10-mL dose through the right
auricular vein at the rate of 2 mL/min or less.
Seven of 9 patients who received dialysis on the epidemic day met the
case definition. All case-patients underwent dialysis with conventional capillary
flow cellulose acetate dialyzers with the same lot number. A serial number
trace revealed that the dialyzers used on the case-patients were manufactured
in April 1985. The 2 non–case-patients underwent dialysis with a newer
(<1 year old) conventional, capillary-flow, cellulose acetate dialyzer
from the same manufacturer. Case-patients ranged in age from 25 to 65 years
(median, 51 years) and 5 were women. Duration of hemodialysis using the 11.5-year-old
implicated dialyzers ranged from 5 to 167 minutes (median, 100 minutes). Six
case-patients were removed from the implicated dialyzer after the blood leak
alarm activated. The seventh case-patient was removed from the implicated
dialyzer after only 5 minutes of treatment to preempt the blood leak alarm.
These case-patients continued undergoing dialysis using the newer, but the
same model, dialyzer as the non–case-patients without further incidents.
No non–case-patients had any visual or hearing complaints.
Signs and symptoms of case-patients are reported in Table 1. When we compared case-patients with non–case-patients,
case-patients were significantly more likely to have diminished vision and
hearing, headache, and conjunctivitis (Table 2). Corneal opacification was noted in 4 case-patients (57%).
Other neurologic and ophthalmologic findings in case-patients included 1 case
each of optic neuritis, optic atrophy, uveitis, seventh cranial nerve palsy,
and vertical nystagmus.
Initial signs and symptoms in case-patients appeared 7 to 48 hours (median,
9 hours) after hemodialysis on the epidemic day. In all case-patients, headache
and conjunctivitis presented within 24 hours, while decreased vision, decreased
hearing, tinnitus, and vertigo presented 24 to 48 hours after hemodialysis
There was 1 case-patient for each of the following visual acuity scores:
no light perception, light perception only, hand motion detected, and more
than 20/200 vision. Three case-patients had visual acuity scores classified
as count fingers. Audiometry revealed hearing loss was profound in 2 case-patients,
moderate to severe in 4, and mild to moderate in 1.
After onset of symptoms, 2 case-patients suffered cardiopulmonary arrests
during hospitalization after the event, 1 was 24 hours after the epidemic
day and the other 5 days later. Both case-patients required transfer to the
intensive care unit for further treatment; 1 patient died. These case-patients
had a history of heart disease, and the cardiac arrest could not be clearly
linked to the events on the epidemic day. However, the incidence of cardiac
arrest during or after dialysis was significantly higher for case-patients
who received dialysis on the epidemic day than for patients who received dialysis
during the prior 23 months at hospital A (2/7 vs 13/2099; P=.001). Postarrest mortality during hospitalization was not significantly
different for patients who underwent dialysis during these 2 periods (1/2
vs 7/52; P=.28).
Case-patients' median white blood cell count predialysis and postdialysis
increased from 9.5×109/L to 28.4×109/L.
There were no other significant changes in blood chemistry or hematologic
values from hemodialysis on the epidemic day until 6 days after the epidemic
day. Five case-patients had blood cultures within 5 days of dialysis on the
epidemic day; all were negative. Head magnetic resonance imaging was performed
on 1 case-patient and showed no acute changes.
There were 43 different drugs administered to the 7 case-patients, no
drug was common to all of the case-patients, and there were no significant
differences in medications given to case- and non–case-patients.
Long-term follow-up for the case-patients is shown in Table 4. Case-patients 1, 2, and 3 nearly fully recovered within
1 month of the event. For the others, some signs and symptoms lingered and
some resolved. Five of the case-patients died of cardiac or renal disease,
which could not be fully attributed to the event.
The FDA retrieved dialyzers ranging in age from 0 to 13.6 years (storage
conditions varied and were undocumented). We examined dialyzer membranes from
all the suppliers of cellulose acetate dialyzers marketed in the United States.
Degradation rates were similar between membranes of different suppliers.
Gel-permeation chromatography was used to evaluate changes in molecular
weight of the dialyzer membrane polymer. After 13.6 years in storage, the
number-average molecular weight of the dialyzer membrane polymer decreased
from 40,000 to 30,000 g/mol (25% by weight; Figure 1), and the polydispersity index (weight-average molecular
weight divided by number-average molecular weight) increased from about 1.7
To evaluate dialysis membrane degradation by deacetylation, we measured
the total acetyl content. Of the 40 membranes evaluated that were 0 to 13.6
years old, only 2 (aged 5.8 and 13.6 years) were significantly deacetylated
(31% and 33% by weight, respectively). All of the other dialyzer membranes
showed only a gradual decrease in acetyl content with age in the range of
40% to 37% by weight.
The extractable component of the dialyzers depends on age and acetyl
content. For newer dialyzers, typically less than 1 mg of total material was
recovered from the fibers. For older dialyzers, the amount and type of material
recovered depended on both the age and the acetyl content of the fibers. For
example, a 13.3-year-old dialyzer with a 38.0% weight acetyl content yielded
40 mg of extractable material, whereas a 13.6-year-old dialyzer with 33.0%
weight acetyl content yielded more than 6000 mg of extractable material.
Infrared spectra of purchased high-purity, cellulose-acetate resin,
the extract from a 13.6-year-old dialyzer, and the synthesized, degraded model
compounds are shown in Figure 2.
Both the old dialyzer extract and the synthesized degraded model compounds
spectra were consistent with virgin cellulose acetate, but each spectra had
some differences due to different mechanisms of degradation. The old dialyzer
extract showed a diminished peak at 1375 cm−1 (acetate stretch),
consistent with deacetylation. Since deacetylation events produce more O-H
(oxygen-hydrogen) bonds, the broader absorption at 3347 cm−1
is attributed to increased O-H stretching in this material. By contrast, the
synthesized degraded model compounds, as well as the degradation products
identified by Oba et al9 in 1984, did not show
nearly as much diminished acetate stretch at 1375 cm−1. Thus,
the acetyl content of this material is considerably higher than the old dialyzer
extract. This is also evident in the less broad O-H stretching absorption
in this spectrum. The model compound and the material identified by Oba et
al9 also had an additional peak at 1625 cm−1, which is characteristic of the carboxylate ion group absorption.
Since the older deacetylated dialyzers gave the most water-extractable
material, we used the extract from a 13.6-year-old dialyzer with 33% weight
acetyl content in the group 1 animal tests. We used the synthesized degraded
model compounds in the group 2 animal tests.
Both the extract from the 13.6-year-old dialyzer and the model compounds
caused eye injuries similar to the case-patients at hospital A in our in vivo
experiments (Table 5).
This outbreak was severe and unusual because of the serious neurologic
signs and symptoms and the association with old (ie, >10 years) dialyzer membranes.
All patients exposed to the old dialyzers developed acute onset of diminished
vision and hearing. The adverse exposure was associated with severe morbidity
and mortality as 4 case-patients never fully recovered and 5 of 7 case-patients
died within 13 months. Once this unusual outbreak was traced epidemiologically
to old dialyzers, we sought to identify and isolate the inciting agent and
to reproduce the adverse effects in our animal experiments.
When blood comes in contact with dialysate through a hollow-fiber membrane,
material-degradation products can be directly transferred to the blood. Since
the membranes are thin (30 µm), and porous (30% porosity),15
there can be a rapid mass transfer. One of our case-patients was connected
to the dialyzer for only 5 minutes yet developed severe sequelae. The wide
bore of the fiber lumen (200 µm) will allow any potential contaminant
from the membrane itself to be rapidly returned directly back to the patient
in the venous catheter.
Cellulose acetate-hemodialysis fibers degrade over time as indicated
by a decrease in fiber integrity; number-average molecular weight decreases,
and the polydispersity index increases with dialyzer age. The events at hospital
A indicate that fiber integrity was compromised because the blood leak alarms
were activated on most case-patients. The rate of blood leakage was much higher
than expected in a dialysis unit of similar size (6/7 vs 1/1265; P<.001).16 Further evidence of membrane
degradation included the decrease in number-average molecular weight over
time from 40,000 to 30,000 g/mol in the dialyzers tested (Figure 1). This decrease in molecular weight can be attributed to
either chain scission or deacetylation. For deacetylation alone, a change
of that magnitude would require removal of more than 50% of the acetyl groups.
Since even the oldest dialyzers did not have this much deacetylation, most
of the molecular weight decrease occurred because of chain scission of the
cellulose polymer. Chain scission, which can occur by a number of mechanisms
(eg, oxidation, hydrolysis, or exposure to radiation), results in cleavage
of the 1,4-β-D glycosidic linkage in the polymer.17
Thus, when chain scission occurs, the polymer chain is transformed into 2
lower-molecular weight pieces, which reduces the average molecular weight
of the entire membrane.
Our results indicate that the combination of chain scission and deacetylation
is a relatively rare event (only 2 of 40 dialyzers had acetyl content reduced
by >10%). Most of the retrieved dialyzers only had a minor amount of deacetylation
over the period studied, which is a result of the manufacturers' practice
of conditioning the membranes to about pH 5 to minimize deacetylation.18 The additional recommendation that dialyzers be stored
under cool and dry conditions will also minimize degradation.19- 23
Under such conditions, chain scission is the major degradation route, but
deacetylation can occur over time if the dialyzer membrane was inadvertently
exposed to a solution of pH less than 4 during manufacturing. At ambient temperatures,
these reaction rates are slow, so long periods are required to allow the deacetylated
degradation products to accumulate. Our animal studies show that material
released by membranes degraded through both chain scission and deacetylation
most likely produced some or all of the symptoms observed in patients at hospital
There has been a previous report of similar eye injuries associated
with use of cellulose acetate dialyzers.9 However,
the mechanism of the previously reported outbreak is different from the mechanism
identified at hospital A. The degradation products identified by Oba et al,9 as well as by our own synthetic model compounds, were
produced by a combination of chain scission and oxidation, not deacetylation.
The oxidative stress could have resulted in either oxidation of a pendant
group or a ring-opening reaction as indicated by the appearance of the carboxylate
ion group in the degradation products' spectrum. If the rings in some of the
monomer units of cellulose acetate open, the chain flexibility of the molecule
is considerably increased. Either this change or deacetylation (as was the
case at hospital A) can increase the aqueous solubility of the degradation
products, making these products more likely to be leached into the blood during
dialysis. Oba et al9 identified the suspect
impurity in the material as hemicellulose. The hemicellulose was more susceptible
to chain scission and oxidative stress during membrane fabrication24,25 and sporadic and transient patient
injuries occurred immediately on first use of these products. Since that incident,
dialysis manufacturers have taken great pains to avoid contamination of dialysis
membranes with hemicellulose. These type of injuries are now a rare occurrence.
In contrast, the material that most likely caused the event at hospital A
resulted from long-term degradation due to both chain scission and deacetylation,
and produced much more severe and persistent injuries in every exposed patient.
The events at hospital A were unusual since a combination of deacetylation,
chain scission, and long storage time are unlikely combinations. There were
no previous incidents like this reported for this particular model of dialyzer
or lot number.
Regardless of the factors that caused degradation, our data suggest
that cellulose acetate degrades with age, and the combination of chain scission
and deacetylation will produce large quantities of leachable degradation products,
which can cross into the dialyzer blood compartment and cause severe neurologic
symptoms in humans. Before this event, no outdating or expiration dating on
dialyzers was required by the FDA. As a result of the event at hospital A,
the FDA and Centers for Disease Control and Prevention sent a letter to all
US dialysis centers advising that all dialyzer stock be properly rotated (first
in, first out) and that any suspected old dialyzers be cleared by the manufacturer
before use.26 In addition, the FDA now requests
a date of manufacture to be indicated on the labels of all new dialyzers.27 Also, the FDA is in the process of developing shelf-life
criteria for these devices in cooperation with industry, standards organizations,
and health care providers.
The events at hospital A vividly demonstrate that material degradation
is not only a performance issue, but also a safety issue. Clinicians should
be aware of the age of the medical devices that they use and should not attempt
to use products (especially those containing cellulose acetate) beyond the
expiration date. The device manufacturer should be consulted if there is any
doubt whether to use an old medical device. Finally, this outbreak illustrates
the value of combined epidemiologic and laboratory investigations of unusual
adverse events, which can lead to identification of the source and prevention
of the events at other facilities.