Treatment of dialysis access puncture wound bleeding with chitosan by nsr11162

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									          TREATMENT OF HD ACCESS PUNCTURE SITE BLEEDING

Treatment of Dialysis Access
Puncture Wound Bleeding with
Chitosan Dressings
Nathan Bachtell, MD; Teresa Goodell, RN, CNS, PhD; Gary Grunkemeier, PhD; Ruyun Jin, MD; Kenton Gregory, MD

Drs. Bachtell, Grunkemeier, and Jin are with Providence Health System; T. Goodell is with Oregon Health & Science Center School
of Nursing; and Dr. Gregory is with Oregon Medical Laser Center, Portland, Oregon.


Background. Bleeding from coagulopathic hemodialysis puncture sites can contribute to anemia in dialysis patients, and current
compressive dressings may contribute to graft thrombosis. We studied the safety and efficacy of a new chitosan-based bandage
with an active clotting surface and compared its time to hemostasis and compression strap usage in dialysis access puncture
wounds with that of conventional gauze dressings.
Methods. Fifty patients received both the chitosan-based and conventional gauze dressings in random order on 2 successive
visits. Time to hemostasis and compression strap usage were compared between the visits. Time to hemostasis was analyzed
using the binary response variable at 2 and 4 minutes. A compression strap was used if dressing application was unsuccessful at
4 minutes. Covariates included coagulation state as measured by laboratory analysis and anticoagulation therapy.
Results. Hemostasis was achieved by 2 minutes in 30% of the chitosan-based and 38% of the conventional dressings (p ¼ 0.608)
and by 4 minutes in 86% of the chitosan-based and 72% of the conventional dressings (p ¼ 0.040). Compression strap usage was
reduced by 50% in the chitosan-based group compared to the conventional group (7 vs. 14 patients; p ¼ 0.052). No adverse events
were reported with either dressing.
Conclusions. The chitosan-based bandage from HemCon is a safe and effective hemostatic agent to reduce prolonged post-
hemodialysis puncture site bleeding and may reduce the use of occlusive compression straps.




B
        leeding at dialysis puncture       post-dialysis bleeding, compression            Improved hemostasis dressings
        sites is a source of chronic       devices are frequently used that            with active clotting surfaces and
        blood loss that can contribute     are effective but may create trauma         components have been recently
to the chronic anemia seen in hemo-        or stasis and subsequent graft              reported in trauma and other litera-
dialysis-dependent patients with           thrombosis.                                 ture to accelerate hemostasis in
renal failure. Hemodialysis patients          Stenosis and thrombosis of the           moderate to severe bleeding.4,5 We
have coagulopathies associated             arteriovenous fistulas are the most          investigated the safety and efficacy of
with chronic renal failure and iatro-      frequent complications of vascular          a chitosan-based dressing (HemCon
genic coagulopathy as a result of          access1 accounting for 20% of hospi-        Bandage, HemCon, Portland, Ore.) to
systemic heparinization and the            tal admissions of dialysis patients.2       improve hemostasis at dialysis site
common use of oral anticoagulant           The cost of access procedures and           punctures and to reduce the need for
drugs to treat comorbid conditions.        complications has been estimated at         compressive devices.
These factors can contribute to occa-      $1 billion annually, the single greatest       Chitosan is a naturally occurring
sional difficulties achieving prompt        categorical expense for dialysis pa-        substance whose molecular makeup
hemodialysis-site hemostasis, which        tient care.2 Although repeated access       and preparation have been discussed
contributes to further blood loss          to these sites with catheters is consid-    previously.6 Chitosan hemorrhage
and consumes valuable staff time           ered the most common traumatic in-          control dressings have been shown
treating and monitoring these              sult, occlusive pressure dressings and      to be effective in animal models
patients. In patients with prolonged       compression devices also contribute.3       of severe hemorrhage.4 Preclinical
                                                                                       studies in swine surgical spleen
                                                                                       trauma, carotid lacerations, liver
 Financial disclosure: Dr. Gregory is an equity holder in HemCon. Dr. Goodell,
                                                                                       lacerations, and aortic perforation
 Grunkemeier, and Jin were paid an hourly stipend by HemCon.
                                                                                       have been successfully treated with

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     TREATMENT OF HD ACCESS PUNCTURE SITE BLEEDING


the HemCon Bandage.4 The HemCon               All aspects of the research, includ-   trauma throughout the graft. The
Bandage is a lyophilized chitosan-         ing patient consent forms, were           distance between the 2 catheter sites
acetate–based hemostatic dressing.         approved by the Providence Health         during any visit typically varied from
U.S. military personnel in the con-        System IRB committee. All patients        1 to 3 inches. Simply by convention,
flicts in Iraq and Afghanistan have         were given a copy of the consent form     the first catheter removed was
successfully used the HemCon Ban-          to review both before and after           labeled catheter A and the second
dage to stop severe hemorrhage not         consent was obtained. Once written        removed was labeled catheter B.
controlled by conventional bandages        consent was obtained, each patient           The pressure differential across
in more than 64 patients without           was assigned a unique identifying         the access site was considered negli-
adverse effects.7 The HemCon               number used in all paperwork related      gible despite each site having both
Bandage is also an FDA-cleared             to the study in order to maximize         arterial and venous anatomic origins.
hemostatic dressing suitable for use       confidentiality.                           Given the proximity of the sites to
in hemodialysis-associated bleeding.                                                 each other, bleeding from one site
Clinical characteristics and efficacy,      Dressings                                 could influence interpretation of
though, have not yet been studied          Sterilized pieces of HemCon Bandage       bleeding from the next. That is,
in randomized fashion in this              20 mm in diameter and 5.5 mm thick        any attempt to look at the sites
population.                                were used. The control dressing was       individually was considered difficult
   The treatment of post-hemodialy-        standard surgical 20 Â20 gauze (Ken-      in practice, compromising the inde-
sis bleeding at our center uses regular    dall Versalon by Tyco; Mansfield,          pendence of the observations.
gauze with manual pressure or com-         Mass.) folded twice to make a 10 Â10      Because of this, the final analysis
pression straps, with most vascular        gauze dressing (the standard of care      combined data from sites A and B,
access sites being occluded for 8–         at this dialysis center).                 with the longer of the 2 times (2, 4,
12 minutes. For refractory bleeding,          All patients had either an arterio-    or > 4 minutes) recorded as the bleed-
Gelfoam (RxMed, Louisville, KY.) is        venous fistula or nylon graft as access    ing time for a visit. Accordingly, if a
often used, with repeated vascular         on an upper extremity. Hemodialysis       compression strap was needed for
access occlusion using a strap. If         was initiated after the nurse placed      either puncture site during a visit,
bleeding is still not achieved, transfer   both needle-based catheters into          then bleeding control during that
to the emergency department for            the access site. Blood flowed out one      visit was designated as requiring a
more definitive treatment may be            catheter to the hemodialysis device       compression strap.
required. A more effective hemo-           and back to the patient through
static agent in this setting may           the other (Figure 1). The placement       Procedure
decrease time to hemostasis, as well       of these catheters within the access      Patient data were collected on 3
as reduce the need for occlusive           site was random and varied from visit     consecutive hemodialysis visits.
compression devices. We studied the        to visit in order to distribute the       Patients were randomized to receive
time to hemostasis and usage of
compression devices in 50 patients
using both routine treatment and the
HemCon Bandage.

Patients and Methods
Patients
Patients who underwent routine
outpatient hemodialysis at the
Providence     Outpatient      Kidney
Dialysis Center between July 18
and October 15, 2005, were consid-
ered for inclusion in the study.
Exclusion criteria were: cognitive
inability to provide informed con-
sent; participation in another IRB-
confirmed clinical trial; allergy to
shellfish, shrimp, chitin, or chitosan;
and central line–based hemodialy-                           Figure 1. Vascular access site of hemodialysis.
sis access.

2 DIALYSIS & TRANSPLANTATION NOVEMBER 2006
                                                TREATMENT OF HD ACCESS PUNCTURE SITE BLEEDING


either the HemCon Bandage or a            tape was placed over the dressing           patient was asked about any side
routine gauze dressing during visit 1     simply to keep it in place. If bleeding     effects observed outside the dialysis
and to get the treatment not received     was again observed, the dressing was        center since the last visit, including
the first time at visit 2. They were       replaced once more, and a compres-          evidence of a rash or delayed bleed-
interviewed about side effects at         sion strap was positioned over the          ing (this was the only intervention
visits 2 and 3. Patient demographic       site. Every 4 minutes for the next          during visit 3).
data, including age, sex, access type,    12 minutes the site was evaluated for
and anticoagulation status, were          evidence of rebleeding.                     Statistical Analysis
recorded at visit 1 (anticoagulation          Once bleeding had stopped at            The 2 primary efficacy variables
status was rechecked at visit 2           catheter puncture site A, the catheter      considered were compression time
in order to document any new              at site B was removed, and the type of      required for hemostasis and use of a
medications).                             dressing used at site A was applied         strap compression device. The sec-
    The study protocols employed in       immediately at site B. If site A had not    ondary efficacy variables were cross-
visits 1 and 2 were identical for all     required a compression strap, site B        over rate and evidence of short-term
patients, except for the dressing used.   was treated identically and also did        (within 48 hours) thrombosis of the
On arrival at the dialysis unit, the      not get a strap. However, if catheter       vascular access site (observed at the
patients had blood drawn for both a       site A had required a compression           following hemodialysis run).
complete blood count and an inter-        strap, then site B automatically               Compression times (<2 minutes,
national normalized ratio (INR).          received one as well. There were 3          2–4 minutes, >4 minutes) were
During the last 15 minutes of each        reasons for this:                           compared using the Stuart-Maxwell
hemodialysis run, blood was drawn                                                     test,8,9 which tested the marginal
                                          1. A significant change in pressure to
to determine the activated clotting                                                   homogeneity of all 3 categories
                                             the access site occurred at that
time (ACT).                                                                           simultaneously, taking the pairing
                                             time;
    Following dialysis, blood pressure                                                between observations into account.
                                          2. A visit was categorized as having
was measured and recorded. One                                                        The use of strap compression (yes/
                                             more than 4 minutes of bleeding if
catheter (catheter A) was removed                                                     no) in the 2 groups (HemCon vs.
                                             a strap had been used at either
from each patient, immediately fol-                                                   control) was compared using the
                                             site, regardless of there being 2
lowed by placement of the appro-                                                      McNemar test10 in order to ensure
                                             sites; and
priate dressing. A hemodialysis staff                                                 proper pairing.
                                          3. This would reduce the impact on
member manually applied pressure                                                         Covariates included systolic and
                                             staff and patient time.
at the site for 2 minutes. (Because in-                                               diastolic blood pressure, coagulation
consistently applying pressure could          If either site started to bleed after   state of the patient as measured by
have confounded the results, the          placement of the tape (4–12 minutes         ACT, INR, and platelet count, as
performance of this procedure was         after removal of the catheter), the         well as anticoagulation state with
standardized by having all participat-    dressing was replaced, and a com-           heparin, Coumadin, or platelet inhi-
ing staff undergo training in which       pression strap was used to hold             bitors (aspirin, Plavix, Aggrenox).
they repeatedly practiced generating      pressure on the site. If rebleeding         The paired t test was used to com-
approximately 500 mmHg of force as        was noted after placement of a strap,       pare the means of the continuous
measured on a standard pressure           the dressing was removed and the            variables, and the Wilcoxon signed-
gauge.)                                   patient was crossed over to the other       rank test was used to compare
    After 2 minutes, pressure was         dressing, with a strap used immedi-         the medians of the continuous
removed to look for evidence of           ately to maintain adequate pressure.        variables.
bleeding around the dressing. If no           During either visit, once complete
bleeding was noted, a 4-inch piece        hemostasis had been achieved for at         Results
of paper tape was placed over             least 12 minutes, each dressing was         Fifty patients were enrolled in the
the dressing. If any bleeding was         gently removed and replaced with            study, 26 men and 24 women, aged
observed, a new dressing was placed       20 Â20 piece of gauze that was taped in     24–85. Among them, 34 patients
over the catheter site, which on          place (a routine practice at our            had an arteriovenous fistula and
average took less than 3 seconds,         center). This was done so patients          16 patients had a nylon graft. All
and pressure was applied at the site      would leave with the standard-of-           patients were heparinized; most
for another 2 minutes. Then pressure      care treatment of their access sites.       were on heparin only, and the others
was again released and bleeding               At the beginning of visits 2 and 3,     were also on Coumadin, Aggrenox,
assessed. If no evidence of bleeding      each access site was assessed for           Plavix, or ASA (Figure 2). There were
was observed, a 4-inch piece of paper     evidence of thrombosis, and each            no significant differences between

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     TREATMENT OF HD ACCESS PUNCTURE SITE BLEEDING


                                                                                                    Discussion
                                                                                                    Many factors contribute to the high
                                                                                                    morbidity and mortality associated
                                                                                                    with end-stage renal disease, includ-
                                                                                                    ing complications from hemodial-
                                                                                                    ysis. These complications include
                                                                                                    chronic anemia, vascular access-
                                                                                                    site thrombosis and failure, and life-
                                                                                                    threatening bacteremia. Although
                                                                                                    the exact causes of these complica-
                                                                                                    tions are not always well understood,
                                                                                                    anything that would minimize their
                                                                                                    frequency should be considered.
                                                                                                    How long it takes and the technique
                                                                                                    used to stop post-hemodialysis
                                                                                                    bleeding are areas worthy of such
                                                                                                    consideration.
                                                                                                       The current standard of care at our
                                                                                                    center is to use regular gauze, manual
                                                                                                    pressure, and a plastic compression
                                                                                                    device to control hemorrhage. For
                           Figure 2. Anticoagulation therapy.                                       prolonged bleeding, Gelfoam is used
                                                                                                    with direct pressure, and if neces-
                                                                                                    sary, the patient is transferred to
treatment groups in platelet count,                 who had a HemCon dressing and                   the emergency department for more
INR, ACT, and systolic and diastolic                38% of the patients who had a                   definitive treatment. Although it is
blood pressures (Table I). No throm-                control dressing (p ¼ 0.608), and by            unusual for vascular access puncture
bosis or other vascular access site                 4 minutes in 86% of those with                  sites to bleed severely enough for
complications were reported in either               HemCon and 72% of those with a                  transfusion to be required and no one
treatment arm. Rebleeding 6 hours                   the control (p ¼ 0.040). Compression            has died at our center, we investi-
post-hemodialysis while at home                     straps were used in 14 of 50 patients           gated an alternative mechanism for
was reported by 1 patient after use                 (28%) in the control group and 7 of             achieving hemostasis.
of the HemCon Bandage. This                         50 patients (14%) in the HemCon                    In animal studies, chitosan dres-
stopped spontaneously.                              group (p ¼ 0.052; Figure 3). An insig-          sings were found to be effective in
   The comparison of time to hemo-                  nificant number of patients required             controlling major arterial bleeding.11
stasis is depicted in a 3Â3 table                   crossover to stop bleeding beyond               Recent data have also demonstrated
(Table II). Hemostasis was achieved                 4 minutes (2 gauze, 4 HemCon:                   that chitosan is bactericidal.13
by 2 minutes in 30% of the patients                 p > 0.05).                                      Prospective, randomized clinical
                                                                                                    research in hemorrhage control is
                                                                                                    challenging because of the variability
                                                                                                    in patient characteristics and presen-
                                                                                                    tation. In fact, no prospective, rando-
                   Table I. Coagulation status by group.                                            mized human studies in which a
                                                                                                    chitosan dressing was used have
 Variable                                         HemCon            Control          p Value*       been done. The HemCon Bandage
 platelet count (mean Æ SD)                        244 Æ 77         243 Æ 79            0.773       is a chitosan-based hemorrhage-
                                                                                                    control dressing already approved
 activated clotting time (mean Æ SD)               175 Æ 36         168 Æ 33            0.138
                                                                                                    for use in the hemodialysis setting.
 systolic blood pressure (mean Æ SD)               138 Æ 26         134 Æ 24            0.248       Therefore, we developed a prospec-
 diastolic blood pressure (mean Æ SD)               68 Æ 16           68 Æ 14           0.946       tive, randomized study to evaluate
 international normalized ratio (INR)           1.1 (median) 1.1 (median)               0.129       whether or not the HemCon Bandage
                                                                                                    improved post-hemodialysis hemor-
 *p Value for paired t test for all variables except INR, for which Wilcoxon signed-rank test was   rhage control and reduced excessive
 performed.
                                                                                                    compression.

4 DIALYSIS & TRANSPLANTATION NOVEMBER 2006
                                                   TREATMENT OF HD ACCESS PUNCTURE SITE BLEEDING



                        Table II. Time to hemostasis and usage of strap by group.

                                                             Control Group
                             <2 minutes/strapÀ             2–4 minutes/strapÀ          >4 minutes/strapþ           Total
 HemCon Group
   <2 minutes/strapÀ                    12                             2                           1                 15
   2–4 minutes/strapÀ                   6                              13                          9                 28
   >4 minutes/strapþ                    1                              2                           4                   7
 Total                                  19                             17                         14                 50

   The dressings used to control             face is in contact with blood. Our      time to hemostasis if the results of
vascular access bleeding vary from           protocol called for pressure to be      this informal survey were, in fact,
center to center, as do the techn-           applied immediately after removal of    accurate. The effectiveness of gauze
iques used to augment this control.          the catheter, which may have limited    alone at 2 and 4 minutes was surpris-
The HemCon Bandage used in this              the amount of blood available for       ing, knowledge of which may pro-
study was small enough to facilitate         contact below the dressing site.        mote improvements in the standard
easy manipulation within the vasc-           This may have contributed to the        of care. Regardless, the HemCon
ular access site yet large enough to         observed lower efficacy of the Hem-      Bandage was shown to be as effective
ensure adequate coverage of the              Con Bandage after 2 minutes of          at 2 minutes and more effective at
puncture site. The size and thick-           applied pressure.                       4 minutes (p ¼ 0.04). There were
ness of the HemCon Bandage made                 According to the results of an       no significant adverse reactions
its use by the staff simple and              informal survey prior to the study,     reported in either group. Further-
straightforward after only minimal           time to hemostasis in our patient       more, these results were obtained
training.                                    population averaged 8–15 minutes.       from patients anticoagulated with
   Previous clinical results showed          The results reported for patients who   heparin, some of them with ad-
that the HemCon Bandage works                received the regular gauze would        ditional anticoagulants, a finding
most effectively if the chitosan sur-        demonstrate a profound reduction in     not previously reported in human
                                                                                     subjects.
                                                                                        Despite these findings, the study
                                                                                     had several methodological limita-
                                                                                     tions. Sample size was restricted by
                                                                                     limited patient availability because of
                                                                                     the small size of our center and by
                                                                                     patient inclusion in other studies.
                                                                                     Many staff members were trained
                                                                                     and subsequently participated in the
                                                                                     study, certainly contributing to varia-
                                                                                     bility in technique and possibly in
                                                                                     outcomes. The time taken to remove
                                                                                     failed dressings was considered
                                                                                     negligible yet may have influenced
                                                                                     placement and adhesion of the next
                                                                                     bandage. Substituting unsuccessful
                                                                                     dressings with fresh replacements
                                                                                     at the 2-minute interval may have
                                                                                     disrupted clot formation, whereas
                                                                                     continuing pressure with the same
                                                                                     dressing may have more effectively
                                                                                     reduced hemorrhage in both groups.
                                                                                        Future studies, which may answer
           Figure 3. Time to hemostasis and usage of strap by group.
                                                                                     these and other questions, are

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     TREATMENT OF HD ACCESS PUNCTURE SITE BLEEDING


needed. Any impact on the develop-      Acknowledgements                                    6. Evans EE, Kent SP. The use of basic
ment of access malfunction, includ-     We would like to acknowledge                           polysaccharides in histochemistry and
                                        HemCon, the U.S. Department of                         cytochemistry: IV—precipitation and ag-
ing thrombosis, would require a
                                                                                               glutination of biological materials by
larger study population and longer-     Defense, Providence Kidney Dialysis                    aspergillus polysaccharide and deacetyl-
term follow-up. Other clinical appli-   Center, Margo Clark, RN, and Staci A.                  ated chitin. J Histochem Cytochem. 1962;
cations related to needle puncture      McAdams in the preparation of this                     10;24–28.
bleeding should also be considered      manuscript.                                         7. Wedmore I, McManus JG, Pusateri AE,
for study given the risks associated                                                           Holcomb JB. A special report on the
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