 |
|
A Randomized Multicenter Trial of Crotalinae Polyvalent Immune Fab (Ovine) Antivenom for the Treatment for Crotaline Snakebite in the United States
Richard C. Dart, MD, PhD;
Steven A. Seifert, MD;
Leslie V. Boyer, MD;
Richard F. Clark, MD;
Edward Hall, MD;
Patrick McKinney, MD;
Jude McNally, RPh;
Craig S. Kitchens, MD;
Steven C. Curry, MD;
Gregory M. Bogdan, PhD;
Suzanne B. Ward, PharmD;
R. Stephen Porter, PharmD
Arch Intern Med. 2001;161:2030-2036.
ABSTRACT
| |
Background Current therapy for crotaline snakebite includes antivenin (Crotalidae)
polyvalent, an antivenom with numerous adverse effects. We compared the efficacy
and safety of 2 dosing regimens with a new antivenom, Crotalinae polyvalent
immune Fab (Fab AV).
Methods A single dose of Fab AV alone (as-needed [PRN] group) was compared with
an initial dose plus repeated treatments during 18 hours (scheduled group)
in a multicenter randomized trial. The study included patients with minimal
or moderate envenomation by a crotaline snake within the preceding 6 hours,
aged 10 years or older, in whom worsening of the envenomation syndrome was
observed before Fab AV treatment. After treatment with Fab AV to achieve initial
control, patients were randomized to the scheduled or PRN treatment group.
Scheduled group patients received additional doses of Fab AV every 6 hours
for 3 doses. The PRN group received no planned additional doses of antivenom.
Results The mean severity score of the 31 patients decreased from 4.35 to 2.39
points (P<.001); there was no difference between
scheduled and PRN groups. No patient in the scheduled group received unplanned
Fab AV doses, but 8 of 16 patients in the PRN group received unplanned doses
(P = .002). Acute reactions occurred in 6 patients
(19%), and serum sickness occurred in 6 (23%) of 26 patients who returned
for follow-up.
Conclusions In the first randomized trial of antivenom in the United States, Fab
AV effectively terminated venom effects. Since the unplanned use of Fab AV
in the PRN group was common, the treatment regimen may require more than 1
initial dose.
INTRODUCTION
VENOMOUS snakebite is an important health problem. Several thousand
victims suffer snakebite each year in the United States.1
There are approximately 6 deaths per year from snakebite.2
In addition, 15% to 40% of patients develop long-term sequelae of envenomation
ranging from minor limb disfigurement to death.3
In the United States, rattlesnakes, water moccasins, and copperhead
snakes cause nearly all medically important snakebites. Currently, the therapy
for snakebite is limited to general supportive care of local tissue injury,
coagulopathy, and hypotension as well as the administration of antivenom to
selected patients. The only antivenom available in the United States is antivenin
(Crotalidae) polyvalent (Wyeth-Ayerst Laboratories, Philadelphia, Pa), a hyperimmune
horse serum product that neutralizes many components of crotaline snake venom.
Although effective, its use has been limited by the frequency of adverse effects.
Acute reactions occur in 20% to 25% of patients; the severity of reaction
ranges from minor rashes to life-threatening anaphylaxis.4-6
Death caused by overwhelming acute bronchospasm and hypotension has occurred.
Equally troublesome is the frequent occurrence of serum sickness, a delayed
type III hypersensitivity reaction that occurs in 50% to 75% of patients treated
with the Wyeth-Ayerst Laboratories product.4, 7
Serum sickness may cause fever, diffuse rash, intense urticaria, arthralgia,
hematuria, and constitutional symptoms that persist for several days and often
prevent normal activities unless treated with antihistamines and systemic
administration of corticosteroids.
A new medication has been developed for the treatment of crotaline snakebite.
Crotalinae polyvalent immune Fab (ovine) (Therapeutic Antibodies Inc, Nashville,
Tenn) is produced in a manner similar to digoxin immune Fab (Digibind; Glaxo
Wellcome Inc, Research Triangle Park, NC). Individual flocks of sheep are
immunized with 1 of 4 crotaline venoms (Western diamondback, Eastern diamondback,
and Mojave rattlesnakes and the cottonmouth). The immune serum from each flock
is digested with papain to produce antibody fragments (Fab), which are then
purified by chromatographic methods to remove the immunogenic Fc portion of
the antibody and the nonneutralizing components of ovine serum. The 4 monospecific
antivenoms thereby produced are combined to form the final antivenom product.
The new antivenom averaged 5.2 times (range, 3.0-11.7 times) more potent than
antivenin (Crotalidae) polyvalent on the basis of weight in a mouse lethality
model.8 A prospective open-label trial of the
new antivenom in 11 patients found that all patients improved after treatment
and no acute or delayed allergic reactions occurred.9
However, progression of limb swelling was found in 3 patients, with time of
onset ranging from 6 to 19 hours. To suppress local recurrence, an improved
dosing schedule was devised. The purpose of this study was to compare the
efficacy and safety of Crotalinae polyvalent immune Fab (Fab AV) with the
use of 2 dosing regimens. We believe this to be the first randomized trial
of antivenom in North America.
PATIENTS AND METHODS
PATIENTS
Inclusion criteria were (1) minimal or moderate envenomation (defined
herein) by a North American crotaline snake within the 6 hours preceding administration
of the study drug, (2) age 10 years or older, and (3) progression of the envenomation
syndrome. Progression was defined as worsening under direct observation of
an evaluation measure used in grading the envenomation: local injury, coagulation
abnormality, or systemic symptoms or signs.
Minimal envenomation was defined as swelling, pain, and ecchymosis limited
to the immediate bite site; no systemic symptoms and signs; and normal coagulation
measures with no clinical evidence of bleeding. Moderate envenomation was
defined as swelling, pain, and ecchymosis involving less than 1 extremity
(if on the trunk, head, or neck, extending less than 50 cm); systemic symptoms
and signs may be present but not life-threatening (may include but are not
limited to nausea, vomiting, oral paresthesia or unusual tastes, mild hypotension
[systolic blood pressure >90 mm Hg], mild tachycardia [heart rate <150
beats per minute], and tachypnea); and coagulation measures may be abnormal,
but without clinical evidence of bleeding (minor hematuria, gum bleeding,
and nosebleeds are allowed if not deemed severe by the investigator).
Exclusion criteria were (1) lack of progression of the envenomation,
(2) severe venom poisoning (swelling, pain, and ecchymosis involving more
than an entire extremity or threatening the airway; markedly abnormal systemic
symptoms and signs, including severe alteration of mental status, severe hypotension,
severe tachycardia, tachypnea, or respiratory insufficiency; and abnormal
coagulation measures with serious bleeding or severe threat of bleeding),
(3) bite by the copperhead snake (Agkistrodon contortrix), (4) infusion of more than 1 vial of antivenin (Crotalidae) polyvalent
before enrollment, (5) history of hypersensitivity to a sheep-derived product,
(6) use of corticosteroids or any experimental medication in the 4 weeks preceding
study enrollment, (7) pregnancy or lactation, (8) previous enrollment in the
study, (9) inability to give informed consent, or (10) the presence of any
disease that would interfere with patient examination.
STUDY DESIGN
This study was a prospective, randomized, controlled, open-label comparative
trial (Figure 1) performed at 7
sites (Table 1). The study was
performed between June 11, 1994, and November 1, 1996. Written informed consent
was obtained and the study was approved by the institutional review board
at each site. After enrollment and standardized initial assessment (history,
physical examination, and laboratory tests), each patient received an intravenous
dose of 6 or 12 vials of Fab AV to achieve initial control. Initial control
of the envenomation syndrome was prospectively defined as cessation of progression
of all components of envenomation: local effects, systemic effects, and coagulopathy.
This included complete termination of swelling progression and complete reversal
of systemic effects. Coagulopathy had to return to normal or near-normal values.
Because the study was not blinded, patients were randomized to a treatment
group only after initial control was achieved to distribute evenly any bias
in the investigator's assessment of when initial control had been achieved.
Randomization was assigned individually by means of a predetermined randomization
procedure administered by a central call center.
|
|
|
|
Schematic diagram of study. PRN indicates as needed.
|
|
|
|
|
|
|
Table 1. Demographic Data of Enrolled Patients*
|
|
|
Treatment with Fab AV was administered in 2 phases. First, a dose of
6 vials was administered to obtain initial control. If necessary, a second
dose of 6 vials was allowed to achieve initial control. If initial control
could not be achieved with 12 vials of Fab AV and within 6 hours of initial
treatment, treatment was deemed to have failed.
After initial control was achieved, patients were randomized to the
as-needed (PRN) or scheduled group for the second phase. The second phase
involved clinical monitoring for progression or resolution of venom effect.
Patients in the PRN group received no further Fab AV unless the investigator
detected progression of one of the signs of envenomation: local effects, systemic
effects, or coagulopathy. Additional Fab AV could then be administered without
limit in 2-vial increments. Patients in the scheduled group received 2 vials
of Fab AV every 6 hours for a total of 3 doses (18 hours) and could receive
additional doses if the investigator detected worsening of the envenomation.
The severity score was determined at 1, 6, and 12 hours after the establishment
of initial control. Swelling measurements were performed every 2 hours from
6 to 12 hours and then every 12 hours until 36 hours after initial control.
Safety evaluations, including laboratory tests, were performed at 1, 2, 6,
12, 24, and 96 hours and at 14 days. All patients were discharged within 36
hours.
STUDY DRUG
Each vial of lyophilized Crotalinae polyvalent immune Fab (ovine) contained
750 mg of Fab and sodium phosphate buffer. The Fab preparation has been described
previously.8 Each vial was prepared for infusion
by reconstitution in 10 mL of sterile water. The initial dose of 6 vials was
diluted in normal saline to a final volume of 250 mL and infused during 60
minutes. Two-vial doses were administered during 30 to 60 minutes.
EVALUATIONS AND DEFINITIONS
To assess efficacy, each patient was examined at baseline, on achievement
of initial control, and at 1, 6, and 12 hours after initial control was achieved.
Initial control was defined as the cessation of worsening of all evaluation
measures as assessed by the investigator. The primary assessment tool was
the snakebite severity score, a previously tested measure that quantifies
the clinical effects of venom.10 A secondary
measure, the investigator's clinical assessment, was used to confirm the severity
score and ascertain its clinical relevance. To perform each assessment, the
investigator assigned the patient's response to 1 of 4 categories: (1) clinical
response: pretreatment signs and symptoms associated with the bite improved
or progression was arrested after treatment with antivenom; (2) partial response:
pretreatment signs and symptoms associated with the bite site worsened, but
at a slower rate than anticipated; (3) clinical nonresponse: the patient's
condition was not favorably affected by the administration of study drug;
or (4) not evaluable.
Evaluations for acute hypersensitivity reactions were performed by the
investigator at baseline, during study drug administration, and 1, 2, 6, and
12 hours after initial control. An acute reaction was defined broadly as any
apparent adverse response that occurred during or within 2 hours of Fab AV
infusion. Evaluations for delayed hypersensitivity reactions (serum sickness)
were performed at 2, 4, 7, and 14 days after discharge from the hospital.
Delayed reactions were defined as any adverse event involving 1 of the following:
cutaneous eruption, arthralgia, gastrointestinal tract complaints, or lymphadenopathy
occurring more than 24 hours after antivenom administration. In addition,
each patient completed a diary for recording of symptoms that occurred between
visits.
STATISTICAL ANALYSIS
Sample size calculations were calculated using data from a pilot study.9 A sample size of 28 patients was calculated to achieve
80% power to detect a severity score difference of 1.0 point between groups,
assuming an  level of .05 and using 2-sided independent-group t test. A 5% dropout rate was postulated, producing a planned
study size of 30 patients.
The primary assessment of efficacy was the snakebite severity score.10 Efficacy was defined as a stable or decreasing severity
score during the 12-hour evaluation period after establishment of initial
control. Because of the discrete nature of the data, severity scores were
compared nonparametrically over time by means of the Friedman test. Severity
scores between the 2 dosing regimens were compared at each time point by means
of the 2-sided Mann-Whitney test. The 6 components of the severity score were
also compared over time by the Friedman test. Statistical significance was
defined as a probability less than 5% (P<.05).
All tests were performed with commercially available statistical software
(Arcus Quickstat Biomedical Version 6.2; Longman Software, Cambridge, England).
The proportion of patients in each regimen who developed local swelling or
coagulopathy recurrence was compared by Fisher exact test. The total number
of vials used in each dosing regimen was compared by a 2-tailed unpaired t test. Safety was assessed by means of descriptive statistics
and individual case analysis and review.
RESULTS
There were 31 patients enrolled (Figure
1). No patients were excluded or dropped from the study. The study
groups were similar in age, weight, sex and racial composition, initial severity
score, range of severity scores, and the amount of Fab AV required to achieve
initial control of the envenomation (Table
1). Progression of local swelling was present in all patients before
treatment.
EFFICACY EVALUATION
All patients were included in the efficacy evaluation. Initial control
of the envenomation syndrome was achieved in all patients. The mean total
severity score began to decrease on the infusion of Fab AV in all patients
and continued to decrease in both groups through the evaluation period (Table 2). The mean severity score of the
31 patients decreased from 4.35 to 2.39 points (P<.001);
there was no statistical difference between the scheduled and PRN groups.
The decrease in the severity of illness after Fab AV infusion, as represented
by the severity score, was composed entirely of reductions in the coagulation,
central nervous system, gastrointestinal tract, cardiac, and pulmonary components
(data not shown). The local wound component did not decrease or increase after
treatment. There were also no differences in the individual component scores
between the PRN and scheduled groups. At the follow-up visits, local venom
effects were described as improved throughout the study period.
|
|
|
|
Table 2. Comparison of Total Severity Scores for PRN and Scheduled
Groups*
|
|
|
Investigators also categorized the time needed to reconstitute Fab AV
into 4 categories (0-10, >10-20, >20-30, or >30 minutes). Overall, for 27
of the patients, 6 (22%) took 0 to 10 minutes for reconstitution, 13 (48%)
took greater than 10 to 20 minutes, and 8 (30%) took greater than 20 to 30
minutes; the time was not recorded for 4 patients.
RECURRENCE PHENOMENON
Recurrence was defined as the return of any venom effect after that
abnormality had resolved. Thus, return of progression of swelling after its
initial arrest had been documented was described as a local recurrence, while
return of thrombocytopenia, hypofibrinogenemia, prolongation of prothrombin
time, or elevation of levels of fibrin split products was described as a coagulopathy
recurrence. The issue of coagulopathy has been addressed in detail previously.11
The planned dose of Fab AV in the scheduled group was a total of 12
to 18 vials (6 or 12 vials for initial control and then 2 vials every 6 hours
for 3 doses). The dose in the PRN group was 6 to 12 vials with no planned
doses after initial control. As a safety precaution, the protocol allowed
the investigator to administer additional "rescue" doses of Fab AV to patients
in either group if clinically needed. No patient in the scheduled group received
additional Fab AV, while 8 patients (50%) in the PRN group received additional
doses for recurrence of local wound progression during the first 12 hours
(P = .002; Table
3). Despite the use of different dosing regimens, the total amount
of study drug administered was not statistically different between groups:
a mean (± SD) total of 13.0 ± 3.9 vials was used in the scheduled
group, while 11.1 ± 4.5 vials were used in the PRN group. Each episode
of local recurrence was successfully terminated with 2 additional vials of
Fab AV. There were no recurrences of local effects after discharge from the
hospital.
|
|
|
|
Table 3. Recurrence of Local Venom Effects
|
|
|
SAFETY EVALUATION
Six patients (19%) developed an acute reaction during Fab AV infusion;
3 occurred in each study group (Table 4). As categorized by the investigator, there were 4 mild cases of
transient urticaria. There were 2 moderate cases: 1 in a patient who developed
wheezing and dyspnea and 1 in a patient who developed cough and urticaria.
Two patients received no treatment, and all other patients responded promptly
to treatment.
|
|
|
|
Table 4. Adverse Events During Infusion of Crotalinae Polyvalent Immune
Fab (Ovine)
|
|
|
Five patients did not return for the 14-day visit. Of the remaining
26 patients, 6 (23%) developed serum sickness (Table 5). Two cases were rated as mild, 2 were moderate, and 2 were
severe. The worst case of serum sickness involved diffuse hives and urticaria,
which was treated successfully on an outpatient basis with antihistamines
and a short course of prednisone. There were no reported sequelae of serum
sickness at the 28-day follow-up visit. Notably, the first 5 patients who
developed serum sickness were treated with a batch of Fab AV that was later
found to contain excess Fc fragments retained from a flawed step in the manufacturing
process. A new purification step was introduced, and only 1 (6%) of the subsequent
16 patients developed serum sickness. In contrast, the rate of acute reactions
was similar among batches of Fab AV.
|
|
|
|
Table 5. Delayed Adverse Events (Serum Sickness)
|
|
|
The Fab AV was administered concomitantly with opioid, minor analgesic,
antiemetic, and anxiolytic medications in nearly all patients (90%). No drug-drug
or drug-disease interactions were reported. Preexisting patient conditions
included hypertension in 3 patients, hypothyroidism in 2 patients, and renal
insufficiency, diabetes, congestive heart failure and hypertension in 1 patient.
A total of 3 patients with a history of asthma were enrolled; 2 developed
an early reaction during Fab AV infusion.
COMMENT
Crotaline snakebite is a dynamic disease process. By definition, a crotaline
envenomation begins with minimal clinical effects (fang marks and perhaps
localized pain and swelling). In many cases, however, the initial minimal
injury worsens to threaten limb or life. Every envenomation that is destined
to become severe must therefore progress through the grades of minimal and
moderate. In untreated cases, death has occurred within hours from shock and
multiple-organ injury. Conversely, the venom effects may worsen in an indolent
manner during many hours or may fail to worsen at all, if no venom was actually
injected (the "dry bite"). The variable nature of venomous snakebite renders
clinical evaluation difficult. If therapy is applied to a bite that is not
destined to worsen, it may erroneously appear to be an effective treatment,
while a massive envenomation could overwhelm all forms of therapy, causing
an otherwise effective therapy to appear ineffective.
To address these difficulties, we used a comparative trial design with
inclusion criteria designed to maximize the probability that the patient had
suffered a clinically important envenomation. Patients were enrolled within
6 hours of envenomation, while they still had minimal or moderate grade envenomations
and evidence of clinical worsening at the time of antivenom administration.
Patients with severe envenomation were excluded because extensive injury may
obscure antivenom effect. For example, if the maximal amount of swelling has
already occurred, then the antivenom would be expected to have minimal clinical
effect.
The primary limitation of this study is the open label design. We attempted
to minimize this effect by using a randomized design and a validated severity
score with specific definitions to limit and distribute investigator bias.
However, the potential bias of open-label studies may manifest in forms for
which we could not compensate. Another limitation is the exclusion of patients
with severe envenomation, which was desired by the regulatory agency. While
an antivenom effective in less severe cases would also be expected to be useful
in severe envenomations, further evaluation in this patient group is needed.
Crotalinae polyvalent immune Fab (ovine) successfully achieved initial
control of the envenomation syndrome in all study patients, and both groups
continued to improve during the 12-hour evaluation period. As judged by the
snakebite severity score, the 2 treatment strategies (PRN vs scheduled) showed
similar effectiveness. However, additional unscheduled doses to recover control
of recurrent local swelling were administered to one half of patients in the
PRN group, while no patient in the scheduled group required unplanned doses.
This increased the actual total dose administered to the PRN group and caused
the 2 groups to receive similar total amounts of antivenom, despite the fact
that the dosing regimen for the scheduled group required a minimum dose of
12 to 18 vials while the PRN group required only 6 to 12 vials. This result
indicates that repeated doses of Fab AV will likely be needed to provide adequate
clinical treatment of envenomation.
The effect of Fab antivenom was most noticeable in the components of
the severity score involving the coagulation system, central nervous system,
gastrointestinal tract, and cardiovascular system. Each of these measures
decreased during the initial infusion of Fab AV and continued to decrease
throughout the evaluation period. Thus, venom-induced dysfunction in these
areas appears to be a dynamic process that can be terminated and reversed
by antivenom. In contrast, the local injury component of the score did not
improve. This observation may be explained by the fact that ecchymosis and
edema formation involve hemorrhage, cell swelling, and cell death, processes
that are less reversible or only slowly reversible.12
It is important that the snakebite severity score did not worsen. Because
we did not include an untreated control group, it is impossible to assert
that the severity scores of these patients would have worsened. However, an
increase in the score would be the expected course for patients who met the
inclusion criteria for this study.
This study alters understanding of crotaline snakebite in other ways
as well. As noted above, local manifestations recurred in 8 of 16 patients.
While this was easily managed by the administration of additional Fab AV,
this phenomenon has not been described previously. A related finding is much
more striking. In addition to recurrence of local effects, return of coagulation
abnormalities was noted in many patients who exhibited a coagulopathy at presentation.
Although the information has not entered the mainstream medical literature,
anecdotal evidence of this phenomenon has been reported sporadically for nearly
20 years.13 A retrospective analysis of a large
database of crotaline snake envenomations indicates that the phenomenon also
occurs after the use of the currently available antivenom, antivenin (Crotalidae)
polyvalent.14
The pathophysiology underlying either local or coagulopathy recurrence
is unknown. However, there are at least 4 potential explanations. First, the
snake may have injected sufficient venom to overwhelm the neutralization capacity
of the antivenom. A related concept involves the half-life of the antivenom;
the elimination half-life of ovine Fab is relatively short for an antibody,
12 to 30 hours.15-17
Perhaps all venom in the blood was neutralized initially, but continued to
be absorbed from the bite site. Unbound Fab AV would be eliminated renally.
As the antivenom was eliminated, the point would be reached where further
venom absorbed from the bite site could not be neutralized by the unbound
Fab AV remaining in the blood. Renewed venom effect could then occur.
Second, it is possible that the venom–Fab AV complex dissociated,
allowing the venom injury to redevelop. The antigen-antibody complex in snake
venom poisoning may be predisposed to this phenomenon. Many of the venom components
have molecular weights of 20 000 to 150 000 daltons. When bound
to a Fab with a molecular weight of 50 000 daltons, the complex would
be too large for renal excretion, and persistence in the circulation would
be expected. A similar phenomenon of recurrence has been documented with digoxin
immune Fab, where recurrence of free (unbound) digoxin levels has been documented
as early as 12 to 24 hours after administration.18
Because of the high affinity of digoxin immune Fab for digoxin, however, it
has been concluded that the cause is much more likely to be redistribution
of digoxin.18
Third, the composition of venom components absorbed from the bite site
may change over time. Since crotaline snake venom has dozens of components,
perhaps those that are absorbed later differ from components absorbed earlier
and are not bound as well by antivenom. The components with delayed absorption
might then produce effects that could not be terminated by antivenom administration.
This explanation seems unlikely because the recurrent coagulopathy caused
the same abnormalities as the original coagulopathy and was successfully treated
with additional doses of antivenom in most of the patients with recurrence.
Fourth, human antisheep antibodies may have developed. If the patient
rapidly produced antibodies against the ovine Fab, these antibodies might
have interfered with the binding of Fab to venom components. This is not likely
because recurrence occurred within hours to days, and this type of response
requires 7 to 19 days to develop.19
We believe the most likely explanation is that venom continues to be
absorbed from the bite site for days after injection. Animal and clinical
data support this conclusion.17, 20-21
The recurrence of venom effect, therefore, should be responsive to further
antivenom administration. This was the case in all patients with local recurrence
and nearly all patients with coagulopathy recurrence.
Finally, the reconstitution profile for the new antivenom may be clinically
important. The antivenom currently available, antivenin (Crotalidae) polyvalent,
requires at least 30 to 60 minutes to enter solution. This can become a serious
clinical problem when swelling occurs in critical areas such as the airway
or the patient manifests systemic effects such as hypotension. An antivenom
that could be administered within 15 to 30 minutes would be desirable under
these conditions.
The administration of Crotalinae polyvalent immune Fab (ovine) was consistently
associated with prompt improvement in the patient's condition. Antivenom dosage
was contingent on an individual patient's response. On the basis of our data,
the recommended initial dose is 6 vials, with further 6-vial doses until initial
control of the envenomation syndrome has been achieved. After initial control
has been established, additional 2-vial doses every 6 hours for 3 doses may
be needed. Additional 2-vial doses may be needed on the basis of close follow-up
for late recurrences of coagulopathy, especially if these effects were present
during hospitalization.
AUTHOR INFORMATION
Accepted for publication March 13, 2001.
This research was supported by a grant from Protherics Inc, formerly
Therapeutic Antibodies Inc.
Corresponding author and reprints: Richard C. Dart, MD, PhD, Rocky
Mountain Poison and Drug Center, 1010 Yosemite Cir, Denver, CO 80230 (e-mail: rdart{at}rmpdc.org).
From the Rocky Mountain Poison and Drug Center, Denver Health Authority,
Denver, Colo (Drs Dart and Bogdan); University of Colorado Health Sciences
Center, Denver (Dr Dart); Department of Emergency Medicine, Kino Community
Hospital, Tucson, Ariz (Dr Seifert); Department of Pediatrics, University
of Arizona, Tucson (Dr Boyer); Division of Medical Toxicology, University
of California–San Diego Medical Center and the San Diego Division of
the California Poison Control System (Dr Clark); Department of Surgery, John
D. Archbold Memorial Hospital, Thomasville, Ga (Dr Hall); Department of EmergencyMedicine
and the New Mexico Poison Center, University of New Mexico Health Sciences
Center, Albuquerque (Dr McKinney); Arizona Poison and Drug Information Center,
School of Pharmacy, University of Arizona, Tucson (Mr McNally); Department
of Medicine, Veterans Affairs Hospital, Gainesville, Fla (Dr Kitchens); Department
of Medical Toxicology, Good Samaritan Regional Medical Center, Phoenix, Ariz,
and Division of Clinical Medicine, University of Arizona College of Medicine,
Tucson (Dr Curry); and Therapeutic Antibodies Inc, Nashville, Tenn (Drs Ward
and Porter).
REFERENCES
| |
1. Russell FE. Identification and distribution of North American venomous snakes. In: Snake Venom Poisoning. Great Neck, NY:
Scholium International Inc; 1984:45-85.
2. Langley RL, Morrow WE. Deaths resulting from animal attacks in the United States. Wild Environ Med. 1997;8:8-16.
PUBMED
3. Dart RC. Sequelae of pit viper envenomation. In: Campbell JA, Brodie ED Jr, eds. Biology of
the Pit Vipers. Tyler, Tex: Selva Publishing; 1992:395-404.
4. Jurkovich GJ, Luterman A, McCullar K, Ramenofsky ML, Curreri WP. Complications of Crotalidae antivenin treatment. J Trauma. 1988;28:1032-1037.
WEB OF SCIENCE
| PUBMED
5. Dart RC, Horowitz RS. Use of antibodies as antivenoms: a primitive solution for a complex
problem? In: Bon C, Goyffon M, eds. Envenomings and Their
Treatments. Paris, France: Institut Pasteur; 1996:83-94.
6. Parrish HM. Incidence of treated snakebites in the United States. Public Health Rep. 1966;81:269-276.
WEB OF SCIENCE
| PUBMED
7. Corrigan P, Russell FE, Wainschel J. Clinical reactions to antivenin. Toxicon. 1978;16 (suppl 1):457-465.
8. Consroe P, Egen NB, Russell FE, et al. Comparison of a new ovine antigen binding fragment (Fab) for United
States Crotalidae with the commercial antivenin for protection against venom-induced
lethality in mice. Am J Trop Med Hyg. 1995;53:507-510.
9. Dart RC, Seifert SA, Carroll L, et al. Affinity-purified, mixed monospecific crotalid antivenom ovine Fab
for the treatment of crotalid venom poisoning. Ann Emerg Med. 1997;30:33-39.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
10. Dart RC, Garcia RA, Hurlbut KM, Boren JL. Development of a severity score for the assessment of crotalid snakebite. Ann Emerg Med. 1996;27:321-326.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
11. Boyer LV, Seifert SA, Clark RF, et al. Recurrent and persistent coagulopathy following pit viper envenomation. Arch Intern Med. 1999;159:706-710.
FREE FULL TEXT
12. Ohsaka A. Hemorrhagic, necrotizing and edema-forming effects of snake venoms. In: Lee C-Y, ed. Snake Venoms. New York,
NY: Springer-Verlag; 1979:480-546.
13. Hardy DL, Jeter M, Corrigan JJ. Envenomation by the Northern blacktail rattlesnake (Crotalus molossus molossus): report of two cases and the in vitro effects
of the venom on fibrinolysis and platelet aggregation. Toxicon. 1982;20:487-493.
PUBMED
14. Bogdan GM, Dart RC, Falbo SC, McNally J, Spaite D. Recurrent coagulopathy after antivenom treatment of crotalid snakebite. South Med J. 2000;93:562-566.
WEB OF SCIENCE
| PUBMED
15. Scherrmann JM, Pepin S. Biodynamics of antigen-antibody neutralization in vivo. In: Bon C, Goyffon M, editors. Envenomings and
Their Treatments. Paris, France: Institut Pasteur; 1996:109-115.
16. Sjöström L. Fab and Venom Concentrations in Blood and Urine Samples
Following Administration of ViperaTAbTM. Nashville, Tenn: Therapeutic Antibodies Inc; 1995.
17. Seifert SA, Boyer LV, Dart RC, Porter RS, Sjöström L. Relationship of venom effects to venom antigen and antivenom serum
concentrations in a patient with Crotalus atrox envenomation
treated with a Fab antivenom. Ann Emerg Med. 1997;30:49-53.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
18. Ujhelyi MR, Rober S. Pharmacokinetic aspects of digoxin-specific Fab therapy in the management
of digitalis toxicity. Clin Pharmacokinet. 1995;28:488-493.
19. Chatenoud L. Humoral immune response against OKT3. Transplant Proc. 1993;25(2, suppl 1):68-73.
20. Meyer WP, Habib AG, Onayade AA, et al. First clinical experiences with a new ovine Fab Echis ocellatus snakebite antivenom in Nigeria: randomized comparative
trial with Institut Pasteur serum (IPSER) Africa antivenom. Am J Trop Med Hyg. 1997;56:291-300.
21. Burgess JL, Dart RC, Egen NB, Mayersohn M. Effects of constriction bands on rattlesnake venom absorption: a pharmacokinetic
study. Ann Emerg Med. 1992;21:1086-1093.
PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLE
Archives of Internal Medicine Reader's Choice: Continuing Medical Education
Arch Intern Med. 2001;161(16):2054-2055.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Utilisation of Crotalidae polyvalent immune fab (ovine) for Viperidae envenomations in children
Johnson et al.
Emerg. Med. J. 2008;25:793-798.
ABSTRACT
| FULL TEXT
Venomous Snakebites Worldwide with a Focus on the Australia-Pacific Region: Current Management and Controversies
Cheng and Currie
J Intensive Care Med 2004;19:259-269.
ABSTRACT
Crotaline Fab Antivenom for Treatment of Children With Rattlesnake Envenomation
Behm et al.
Pediatrics 2003;112:1458-1459.
FULL TEXT
Crotaline Fab Antivenom for the Treatment of Children With Rattlesnake Envenomation
Offerman et al.
Pediatrics 2002;110:968-971.
ABSTRACT
| FULL TEXT
Bites of Venomous Snakes
Gold et al.
NEJM 2002;347:347-356.
FULL TEXT
|
