CLINICAL EVALUATION

Negative pressure wound

therapy with instillation:
a pilot study describing
a new method for treating
infected wounds
Allen Gabriel, Jaimie Shores, Cherrie Heinrich, Waheed Baqai, Sharon
Kalina, Norman Sogioka, Subhas Gupta

Gabriel A, Shores J, Heinrich C, Baqai W, Kalina S, Sogioka N, Gupta S. Negative pressure wound therapy with
instillation: a pilot study describing a new method for treating infected wounds. Int Wound J 2008;5:399–413.

ABSTRACT
This data review reports the results of 15 patients who were treated with Vacuum-Assisted Closure
(VAC)
negative pressure therapy system in addition to the timed, intermittent delivery of an instilled topical solution for
management of their complex, infected wounds. Prospective data for 15 patients treated with negative pressure
wound therapy (NPWT)-instillation was recorded and analysed. Primary endpoints were compared to
a retrospective control group of 15 patients treated with our institution‘s standard moist wound-care therapy.
Culture-specific systemic antibiotics were prescribed as per specific patient need in both groups. All data were
checked for normality of distribution and equality of variance and appropriate parametric and non parametric
analyses were conducted. Compared with the standard moist wound-care therapy control group, patients in the
NPWT-instillation group required fewer days of treatment (36
5  13
1 versus 9
9  4
3 days, P , 0
001),
cleared of clinical infection earlier (25
9  6
6 versus 6
0  1
5 days, P , 0
001), had wounds close earlier
(29
6  6
5 versus 13
2  6
8 days, P , 0
001) and had fewer in-hospital stay days (39
2  12
1 versus 14
7
 9
2 days, P , 0
001). In this pilot study, NPWT instillation showed a significant decrease in the mean time to
bioburden reduction, wound closure and hospital discharge compared with traditional wet-to-moist wound care.
Outcomes from this study analysis suggest that the use of NPWT instillation may reduce cost and decrease
inpatient care requirements for these complex, infected wounds.
Key words: Instillation • Negative pressure wound therapy • Silver nitrate • Vacuum-assisted closure therapy • Wound-care
infection

INTRODUCTION Infections complicate the treatment of wounds

Key Points
The detrimental effect of infection on wound and impede the healing process by damaging
healing has long been universally known. tissue, reducing wound tensile strength and • the detrimental effect of infec-
tion on wound healing has long
been universally known
Authors: Allen Gabriel, MD, Department of Plastic Surgery, Loma Linda University Medical Center, Loma Linda, CA, USA; Jaimie
Shores, MD, Department of Plastic Surgery, Loma Linda University Medical Center, Loma Linda, CA, USA; Cherrie Heinrich, MD,
Department of Plastic Surgery, Loma Linda University Medical Center, Loma Linda, CA, USA; Waheed Baqai, MPH, Health Research
Consulting Group, Loma Linda University, Loma Linda, CA, USA; Sharon Kalina, MD, Department of Plastic Surgery, Kaiser Foundation
Hospitals, Kaiser Permanente, Fontana, CA, USA; Norman Sogioka, MD, Department of Plastic Surgery, Kaiser Foundation Hospitals,
Kaiser Permanente, Fontana, CA, USA; Subhas Gupta, MD, Department of Plastic Surgery, Loma Linda University Medical Center, Loma
Linda, CA, USA
Address for correspondence: Subhas Gupta, MD, PhD, FRCSC, FACS, Department of Plastic Surgery, Loma Linda University, 11175
Campus Drive, Coleman Pavilion 21126, Loma Linda, CA 92354, USA
E-mail: sgupta@ahs.llumc.edu

ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc 399
• International Wound Journal • Vol 5 No 3

Key Points
• to test the benefits of antimicro-
bial instillation in conjunction
with NPWT, a pilot research
study was designed to explore
the use of VAC therapy plus the
intermittent delivery of an instil-
led antimicrobial topical solution
and its effectiveness in treating
complex, infected wounds
• the number of days of wound
treatment, days to wound
closure and days to patient
discharge were established as
endpoints that would best mea-
sure the effectiveness of NPWT
instillation therapy
• it was hypothesised that en-
hanced reduction in bacterial bio-
burden would lead to quicker
wound closure and patient dis-
charge, resulting in hospital cost
savings and reduced patient
expense
• a prospective study of 15 adult
patients with the diagnosis of
complex, open, infected wounds
that were treated with NPWT in-
stillation between January 2005
and April 2006 was conducted
• in addition, this group was com-
pared to a retrospective control
group of patients treated with
our institution‘s standard moist
wound-care therapy between
January 2004 and December
2005 to determine the effec-
tiveness of NPWT-instillation
therapy
400
Negative pressure wound therapy with instillation
inducing an undesirable inflammatory response
(1,2). It is generally believed that the wound
advances from contamination to colonisation
when the bacteria on the wound’s surface begin
to replicate and increase their metabolic activity.
Bacteria and bacterial products, such as endo-
toxins and metalloproteinases, can disturb all
wound-healing phases.
A heavy bacterial bioburden in a wound
increases the metabolic requirements, stimu-
lates a pro-inflammatory environment and
encourages the in-migration of monocytes,
macrophages and leucocytes, all of which can
negatively impact wound healing (1–4). Bacte-
ria can also secrete harmful cytokines that can
lead to direct vasoconstriction and decreased
blood flow to the wound. Thus, controlling or
preventing infections is essential for the normal
wound-healing process to occur. In addition,
reduction of infection can also yield significant
overall cost savings in health care, as infections
lead to thousands of dollars in excess medical
charges and lengthened hospital stays every
year (5).
Vacuum-assisted closure (VAC) therapy is
a recognised and powerful tool in the wound-
care setting. Chronic and acute wounds of
traumatic, surgical or other origin, have had
great success with the application of this
therapy (6–13). Despite this, VAC therapy was
avoided in infected or heavily colonised
wounds and the mainstay of therapy was
intravenous, oral and/or topical antimicrobials
and frequent standard dressing changes. VAC
therapy was introduced by Argenta and Mor-
ykwas in 1995, based on the principle of
applying topical subatmospheric pressure to
acute, subacute and chronic wounds (14,15).
The negative pressure delivers mechanical
stress to the underlying cells while removing
third space interstitial fluid into a collection
canister. Prolonged stretching of the cytoskele-
ton causes release of intracellular messengers
resulting in matrix molecule synthesis and cell
proliferation (16,17).
Scientific studies have reported that VAC
therapy enhances blood flow (15,18,19) and
increases proliferation of reparative granulation
tissue (20–27). Various studies have also shown
that this therapy reduces wound size faster than
standard moist wound care (28–30) and that it
can be an effective adjunct in bolstering skin
grafts (31,32). As a closed system, negative
pressure wound therapy (NPWT) delivered by
ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc
vacuum-assisted closure (VAC) provides a moist
wound-healing environment and helps protect
wounds from outside bacteria (33,34).
The goal of wound management is to create
an environment that is conducive to wound
healing by decreasing the bacterial bioburden
and improving perfusion to the wound. NPWT
instillation combines NPWT and the timed
delivery of topical irrigation solutions (normal
saline, distilled water or silver nitrate) to the
wound bed. The solutions can be antimicrobials
or other fluids used for irrigation in conjunction
with the added benefits of NPWT.
To test the benefits of antimicrobial instilla-
tion in conjunction with NPWT, a pilot research
study was designed to explore the use of VAC
therapy plus the intermittent delivery of an
instilled antimicrobial topical solution and its
effectiveness in treating complex, infected
wounds. The number of days of wound
treatment, days to wound closure and days to
patient discharge were established as endpoints
that would best measure the effectiveness of
NPWT instillation therapy. It was hypothesised
that enhanced reduction in bacterial bioburden
would lead to quicker wound closure and
patient discharge, resulting in hospital cost
savings and reduced patient expense.
METHODS
A prospective study of 15 adult patients with the
diagnosis of complex, open, infected wounds
that were treated with NPWT instillation
between January 2005 and April 2006 was
conducted. In addition, this group was com-
pared to a retrospective control group of
patients treated with our institution‘s standard
moist wound-care therapy between January
2004 and December 2005 to determine the
effectiveness of NPWT-instillation therapy.
Inclusion criteria for both groups included trunk
and extremity wounds with documented qual-
itative cultures with greater than 105 organisms,
age greater than 40 years and documented
necrotic tissue. This study was approved by
the Institutional Review Board of Loma Linda
University Medical Center. All wounds were
repeatedly sharply debrided of non viable tissue
before NPWT instillation was applied. Swab
wound cultures for all patients were taken and
submitted on the first day of hospital admission
for qualitative culture analysis.
Demographic data and type of infection
present on return of initial swab culture were

recorded for each patient (Table 1). In the three
cases of necrotising fasciitis, the patients were
monitored every 8 hours to ensure complete
resolution of the necrotic tissue before NPWT-
instillation therapy was applied on hospital
day 2. For the remaining 12 patients, NPWT
instillation was initiated as a first-line therapy
on hospital day 1, following initial surgical
debridement.
The NPWT-instillation regimen consisted of
placing a medical grade, reticulated polyure-
thane and sterile foam dressing (VAC
Granu-
Foam
; KCI, San Antonio, TX) in the entire
wound cavity and covering with a semi-occlusive
adherent drape to create an airtight seal. A
1–2 cm diameter round hole was cut into the
drape, over which a TRAC
pad with tubing
was placed. The tubing was then connected to
a fluid collection canister contained within the
computer-controlled NPWT-instillation device
(VAC Instill
; KCI, San Antonio, TX). On the
opposite side of the foam from this tubing, an
additional 1–2 cm diameter round hole was cut in
the drape and the second tube was applied. The
other end of this tubing was then connected to an
intravenous bag containing normal saline, sterile
water or silver nitrate solution for instillation.
The NPWT-instillation device was pro-
grammed to cycle through a similar regimen
for all solutions: instill the topical solution for
30–45 seconds, follow with a 1-second hold time
to allow the solution to penetrate through the
dressing to cover the wound, then deliver 2
hours of negative pressure therapy at 125
mmHg continuously. We believe that the instil-
lation time and the hold time are sufficient to
cause the hydro-debridement effect that we see
with this technology. We also believe that
activity of silver is instantaneous and there is
no need for increased hold times as this may
cause for fluid to leak out of the wound and
break the existing seal. Approximately 50–75
cm3 of solution was delivered during each instill
cycle. VAC Instill
settings are listed in Table 2.
Silver nitrate (Teva Pharmaceuticals North
America; Wales, PA; NDC 0093-9614-13) was
the antimicrobial solution of choice used in this
study with the goal of decreasing bacterial
bioburden (27–29). Silver nitrate was placed in
an empty 1 l Baxter Sterile Water bottle (Baxter:
2F7114) and covered with a special Baxter
irrigation cap (Baxter: 2C4010) and subse-
quently connected to the tubing and covered
to protect it from light as seen in Figure 1A–C.
ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc
Negative pressure wound therapy with instillation
As the solution is gravity fed, the instillation bag
must be at or slightly above the level of the
Key Points
wound. The delivered volume of solution varies • there were no statistically sig-
depending on the height of the bag. nificant differences between the
The NPWT-instillation group data were control and NPWT-instillation
groups with regard to age,
analysed and compared to a retrospective con-
wound area, pre albumin levels,
trol group of 15 adult patients with complex, diabetes history, smoking his-
infected wounds who received standard wet-to- tory and incidence of infection
moist dressings and weekly wound consults at
Loma Linda University Medical Center during
the 2004–2005 calendar years. Control patient
records were chosen by random selection and
consecutively logged into the control group if
they met appropriate inclusion criteria. A
retrospective control group was used because
of limited patient availability and length of time
of follow-up required for wet-to-moist wound
treatment. In addition, the management of these
wounds in our hands has changed because of
the positive outcomes that were seen; therefore
the treatment of the infected wounds with the
conventional therapy would be considered now
to be below the level of standard of care. The
same demographic and treatment outcome data
were recorded for this retrospective control
group as were for the NPWT-instillation group
(Table 3).
The primary endpoints of the study were total
number of days treated, days to wound closure
and days to patient discharge (Tables 1 and 3).
Categorical variables are expressed as percen-
tages and continuous variables are expressed as
the mean  SD. Analysis was performed using
the w2-test for qualitative data, two-sample
independent t-test and Wilcoxon rank sum test
for quantitative data, and Kaplan–Meier sur-
vival analysis for time-to-event outcomes to
compare the controls to the NPWT-instillation
therapy group. SPSS 12
0 (SPSS Inc., Chicago,
IL, USA) was used for data analysis. Statistical
significance was defined as P , 0
05 with a two-
tailed test (Tables 4–6).
RESULTS
There were no statistically significant differences
between the control and NPWT-instillation
groups with regard to age, wound area, pre-
albumin levels, diabetes history, smoking history
and incidence of infection (Tables 5 and 6).
Patients in the NPWT-instillation group did
differ significantly from the control group with
respect to treatment outcome endpoints
(Table 4). Compared with controls, patients in
the NPWT-instillation group required significant
401
 402
Table 1 Data for NPWT-instillation therapy group

Days of Days to Days to

Age Wound area* NPWT-instillation infection wound Method of Days to patient
Patient (years) Diagnosis (cm2) Initial culture therapy clearance closure wound closure discharge

1 84 Abdominal necrotising fasciitis 300 Staphylococcus enterococcus 14 5 15 Primary closure 17

2 51 Necrotising fasciitis of chest and upper extremity 500 Staphylococcus, Enterococcus 9 5 10 Skin graft 15
Negative pressure wound therapy with instillation

3 71 Stage IV sacral pressure ulcer 100 VRE, MRSA 20 10 35 Secondary intention 45

4 65 Open knee joint with exposed hardware 50 Staphylococcus, Enterococcus 5 5 10 Local flap 10
5 51 Open knee joint with exposed hardware 40 Staphylococcus, Enterococcus 10 7 14 Local flap 14
6 45 Surgical wound dehiscence 300 Staphylococcus, Enterococcus 7 7 10 Primary closure 11
7 65 Lower extremity wound 40 VRE, MRSA 10 7 15 Secondary intention 15
8 60 Soft tissue loss of lower extremity 50 Staphylococcus, Enterococcus 5 5 8 Skin graft 11
9 53 Open ankle joint with exposed hardware 40 Staphylococcus, Enterococcus 5 5 5 Local flap 6
10 65 Lower extremity wound with exposed bone 50 VRE, MRSA 15 7 16 Integra/Skin graft 18
11 41 Soft tissue loss of the lower extremity 200 Staphylococcus 10 5 10 Skin graft 15
12 49 Lower extremity wound with exposed bone 30 Staphylococcus 10 7 10 Integra/Skin graft 14
13 62 Abdominal surgical wound dehiscence 100 Enterococcus 7 5 14 Secondary intention 7
14 45 Stage IV pressure ulcer 50 VRE, MRSA 14 5 14 Local Flap 15
15 50 Necrotising fascitis of the upper extremity 60 Streptococcus Enterococcus 7 5 12 Secondary intention 7

NPWT, negative pressure wound therapy; MRSA, methicillin-resistant Staphylococcus aureus; VRE; vancomycin-resistant infections.
*Post-debridement.

ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc
 Negative pressure wound therapy with instillation

Table 2 VAC
InstillTM therapy settings

NPWT-instillation settings NPWT negative pressure setting

Patient Silver nitrate Volume (cc) Instill (seconds) Dwell (seconds) Therapy (hours) mmHg continuous

1 Yes 50–75 30 1 2 125

2 Yes 50–75 30 1 2 125
3 Yes 50–75 30 1 2 125
4 Yes 50–75 30 1 2 125
5 Yes 50–75 30 1 2 125
6 Yes 50–75 30 1 2 125
7 Yes 50–75 30 1 2 125
8 Yes 50–75 30 1 2 125
9 Yes 50–75 30 1 2 125
10 Yes 50–75 30 1 2 125
11 Yes 50–75 30 1 2 125
12 Yes 50–75 30 1 2 125
13 Yes 50–75 30 1 2 125
14 Yes 50–75 30 1 2 125
15 Yes 50–75 30 1 2 125

NPWT, negative pressure wound therapy; VAC, vacuum-assisted closure.

fewer hospital days of wound treatment (36
5 
13
1 versus 9
9  4
3 days, P , 0
001). The
NPWT-instillation-treated wounds cleared of
clinical infection (based on qualitative cultures)
earlier (25
4  6
6 versus 6
0  1
5 days, P ,
0
001), were closed earlier (29
6  6
5 versus
13
2  6
8 days, P , 0
001) and were discharged
earlier (39
2  12
1 versus 14
7  9
2 days, P ,
0
001). The Kaplan–Meier survival analysis
confirmed highly significant (P , 0
001) shorter
duration of treatment for the NPWT-instillation
group compared with the control group for
wound clearance of clinical infection, wound
closure, treatment and discharge (Figure 2).
A regression analysis comparing the associa-
tion between wound infection clearance and
wound closure is shown in Figure 3. The best-fit
line equation yielded a strong linear relation-
ship between infection clearance and days to
wound closure showed by the high R2-value of
0
96 for the control group. As the NPWT-
instillation wounds cleared of infection within
a relatively short time span (6
0  1
5 days), an
association was difficult to find among these
patients and the best-fit line equation yielded
a weaker association as indicated by the R2-
value of 0
60. The equation y ¼ 0
9748x þ 4
8409
where y is ‘days to wound closure’ and x is ‘days
to wound infection clearance’ may provide
a useful guide to predicting length of treatment
necessary for infection clearance using standard
wet-to-moist wound treatment.
In the NPWT-instillation group, all 15
wounds cleared the bacteria bioburden, versus

Figure 1. Vacuum-Assisted Therapy (VAC
InstillTM) therapy set-up for irrigation of silver nitrate. All tubing and bottles are
covered by dark bags or aluminium foil.

ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc 403
 404
Table 3 Data for moist wound-healing control group

Days of
Age Wound area* wet-to-moist Days to infection Days to Method of Days to
Patient (years) Diagnosis (cm2) Initial culture treatment clearance wound closure wound closure patient discharge

1 56 Stage IV sacral pressure ulcer 150 Staphylococcus, Enterococcus 56 Not cleared Not closed Secondary intention 56
2 62 Stage IV sacral pressure ulcer 250 Staphylococcus, Enterococcus 34 Not cleared Not closed Secondary intention 34
Negative pressure wound therapy with instillation

3 48 Necrotising fasciitis of chest and upper extremity 400 Staphylococcus, Enterococcus 28 22 28 Skin graft 30
4 81 Stage IV sacral pressure ulcer 75 VRE, MRSA 45 Not cleared Not closed Secondary intention 45
5 49 Open knee joint with exposed hardware 75 MRSA 35 28 30 Local flap 35
6 51 Open knee joint with exposed hardware 45 Staphylococcus, Enterococcus 20 18 24 Local flap 26
7 49 Abdominal necrotising fasciitis 350 Enterococcus, MRSA 34 30 34 Primary closure/Skin graft 36
8 60 Open tibial wound with exposed hardware 50 MRSA 40 35 40 Local flap 45
9 50 Necrotising fasciitis of chest and upper extremity 250 MRSA 22 18 22 Skin graft 25
10 75 Stage IV sacral pressure ulcer 100 VRE, MRSA 50 Not cleared Not closed Secondary intention 55
11 64 Open tibial wound with exposed hardware 50 MRSA 28 25 28 Local flap 32
12 52 Necrotising fasciitis of chest and upper extremity 350 Enterococcus, MRSA 21 18 21 Primary closure/Skin graft 26
13 59 Open knee joint with exposed hardware 100 Enterococcus 39 35 39 Local flap 43
14 63 Open tibial wound with exposed hardware 100 Staphylococcus, Enterococcus 30 25 30 Local flap/Skin graft 35
15 72 Stage IV sacral pressure ulcer 250 Enterococcus 65 Not cleared Not closed Secondary intention 65

MRSA, methicillin-resistant Staphylococcus aureus; VRE; vancomycin-resistant infections.

*Post-debridement.

ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc
 Negative pressure wound therapy with instillation

Table 4 Treatment outcomes

Key Points
Control group (n ¼ 15) NPWT-instillation therapy group (n ¼ 15) P-value
• the goal of surgical debride-
Days treated* 36
47  13
07 9
87  4
31** ,0
001 ment is to excise the wound
Infection cleared 66
7% 100%** 0
042 until only normal, soft and well
Day wound cleared of clinical infection* 25
40  6
57 6
00  1
46** ,0
001 vascularised tissue remains
• the importance of removing the
Wound closed 66
7% 100% 0
042
local inhibitory wound-healing
Wound closure method (%) 0
606
factors is also one of the factors
Primary 13
3 13
3 by which negative pressure
Secondary intention 33
3 26
7 wound therapy can successfully
Skin graft 13
3 33
3 convert chronic wounds to
Local flap 40
3 26
7 healthy healing wounds
Days to wound closure* 29
60  6
54 13
20  6
75** ,0
001
Days to patient discharge* 39
20  12
07 14
67  9
18** ,0
001

NPWT, negative pressure wound therapy.

*Mean  SD.
**P , 0
05 compared with control group.

10 of 15 for the control group. The reason these
five control wounds remained colonised
throughout care is unknown and the patients
have since been lost to follow-up. Eleven of the
15 NPWT-instillation-treated wounds pro-
gressed to the point where they could be
surgically closed; two of these cases are
described in figures 4 and 5. Four wounds were
left open to be closed by secondary intention. In
the control group, 9 of the 15 wounds pro-
gressed to the point of surgical closure and 6
were left to be closed by secondary intention.
DISCUSSION
The goal of treating any type of wound is to
create an environment that is conducive to
normal and timely healing. To achieve this goal,
one first has to address and evaluate the
underlying issue (disease) to optimise healing.
Secondly, most wounds require some form of
debridement, if appropriate. Debriding an acute
wound enables it to go through the normal
wound-healing phases, assuming that systemic
and local factors are functioning normally (35).
However, aggressively debriding a chronic
wound helps convert it into an acute wound,
so that it can progress through the normal
phases of wound healing.
The goal of surgical debridement is to excise
the wound until only normal, soft and well-
vascularised tissue remains. Frequent debride-
ments regularly remove inhibitors of wound
healing (metalloproteases, including the colla-
genases matrix metalloproteinase 1 and 8 and
elastases) and allow growth factors to function
more effectively (36–38). The importance of
removing the local inhibitory wound-healing
factors is also one of the factors by which
negative pressure wound therapy can success-
fully convert chronic wounds to healthy healing
wounds (14,15).
Whether debridement is with non surgical
modalities [maggots (Phaenicia sericata), enzy-
matic] or surgical, it is defined as removing
necrotic tissue, foreign material and bacteria
from an acute or chronic wound. This environ-
ment impedes the body’s attempt to heal and
allows bacteria to proliferate. The development
of an infected wound is an ‘exponential pro-
gression’ that starts with sterility, followed by

Table 5 Pre-treatment status

NPWT-instillation therapy
Control group (n ¼ 15) group (n ¼ 15) P-value

Age (years)* 59
40  10
29 57
13  11
64 0
576

Wound area (cm2)* 173
00  123
73 127
33  137
87 0
098
Albumin* 2
364  0
325 2
350  0
823 0
441

NPWT, negative pressure wound therapy.

*Mean  SD.

ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc 405
 Negative pressure wound therapy with instillation

Table 6 Pre-treatment history

Key Points
Control group (n ¼ 15)(%) NPWT-instillation therapy group (n ¼ 15)(%) P-value
• NPWT instillation combines the
mechanisms of action of stan- Diabetes* 40 53
3 0
715
dard NPWT with timed, inter- Smoking history* 20 33
3 0
682
mittent delivery of an instilled Staphylococcus** 33
3 60 0
272
topical solution
Enterococcus** 60 60 1
000
• at our hospital, NPWT instilla-
VRE** 13
3 26
7 0
651
tion has played a crucial role in
treating wounds that benefit MRSA** 53
3 26
7 0
264
from continuous hydro-debride-
NPWT, negative pressure wound therapy; MRSA, methicillin-resistant Staphylococcus aureus; VRE; vancomycin-resistant
ment, such as in acute trau-
infections.
matic wounds or acutely *Percentage that is diabetic or have smoking history based on medical record.
debrided wounds because of **Percentage testing positive from culture test.
infected hardware or soft tissue
• NPWT instillation actively re-
moves exudate and microscopic contamination, colonisation, critical colonisation tant to topical and systemic antibacterials unless
debris to an extent that we
have not experienced with
and infection. All stages are linked and if it is violated by debridement modality.
other wound-care modalities attempts are not made to stop the progression NPWT instillation was introduced to the
at any level, bacteria will continue to replicate United States acute care market in 2004 as an
and produce a polymeric matrix (glycocalyx), evolutionary product to standard NPWT. It
which is adherent to any inert or living surface, combines the mechanisms of action of standard
and allows bacteria to live in an otherwise NPWT with timed, intermittent delivery of an
hostile environment (39). This biofilm is resis- instilled topical solution.

Figure 2. Kaplan–Meier survival graphs showing proportion of patients over time for days to wound infection clearance (A), days
to wound closure (B), days of treatment (C) and days to discharge (D). The negative pressure wound therapy (NPWT) installation
therapy group had highly significantly (P , 0
001) less time to endpoint compared with the control therapy group.

406 ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc
 Negative pressure wound therapy with instillation

Infection clearance vs. Wound closure

NPWT Instillation Control
100

90
y = 3.5667x - 8.2
80 R2 = 0.5978
Days to woeund closure

70

60

50

40

30
y = 0.9748x + 4.8409
20 R2 = 0.9601

10

0
0 5 10 15 20 25 30 35 40
Days to wound infection clearance
Figure 3. Regression analysis of ‘days to wound infection clearance’ and ‘days to wound closure’. The regression line is significant
(P , 0
001) for predicting rate of wound closure for the control therapy group. NPWT, negative pressure wound therapy.

From our initial experience with NPWT
instillation, we have found the addition of an
instilled irrigating fluid to NPWT provides
a unique autolytic and mechanical debridement
effect that appears to enhance wound healing
over our traditional standard of care for these
complex, infected wounds. We have found it to
be efficacious in treating wounds with high
levels of exudate and slough content. At our
hospital, NPWT instillation has also played
a crucial role in treating wounds that benefit
from continuous hydro-debridement, such as in
acute traumatic wounds or acutely debrided
wounds because of infected hardware or soft
tissue. The hydro-debridement plays an important
role in inhibiting glycocalyx formation and
therefore decreasing the biofilm in these open
wounds.
NPWT instillation actively removes exudate
and microscopic debris to an extent that we have
not experienced with other wound-care modal-
ities. Wolvos determined that the addition of

Figure 4. Case 1. An 84-year-old male with abdominal necrotising fasciitis (A). The necrotic tissue was resolved in 24 hours and
negative pressure wound therapy instillation was initiated on day 2 with normal saline solution for irrigation. Following confirmation
of positive cultures, silver nitrate irrigation was started. On day 5, healthy granulation tissue was present and the wound was
noticeably contracted (B). On day 14 (C), the patient was taken to the operating room and the wound was primarily closed. The
patient was discharged back to his nursing home facility on day 17 with a closed wound (D).

ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc 407
 Negative pressure wound therapy with instillation
Key Points
• Bernstein and Tam published
a case series of five diabetic
foot wounds that were treated
with NPWT instillation
• in the three cases of necrotising
fasciitis and systemic infection,
intravenous antibiotics were
administered to treat the inva-
sive infection
Figure 5. Case 2. A 65-year-old male with infected open right knee joint with exposed hardware (A). Infection present for 3
months following an open reduction with internal fixation procedure. Negative pressure wound therapy instillation was initiated (B)
with normal saline irrigation, and followed on day 3 with silver nitrate irrigation. By day 5, the wound culture returned negative, and
the knee was closed via local flap on day 10. (C) illustrates the granulating knee the day it was closed and (D) shows the knee
closed and viable at 6-month follow-up.
instilled solutions appears to enhance viscosity
of the wound fluid, which allows more efficient
removal into the canister (40). It should be noted
that NPWT instillation is a low-pressure deliv-
ery system for wound irrigation. Wounds with
significant debris and bacterial contamination
can be irrigated when needed at higher pres-
sures (fluid delivered at 0
6–0
8 kg cm2 psi such
as with a 35-ml syringe and a 19-gauge
angiocatheter) during dressing changes (41,42).
Once the wound exudate and slough levels
are controlled and minimised, the therapy can
be switched to either granufoam or granufoam
silver, depending on the need for antimicrobial
delivery.
An initial paper describing the combined
effect of NPWT and instillation of antiseptics or
antibiotics was published by Fleischmann et al.
in 1998 (43). Fleischmann is generally credited
for pioneering the NPWT-instillation technique
in orthopaedic medicine. Among the 27 patients
with acute infections of bone and soft tissues,
chronic osteomyelitis or chronic wounds treated
with NPWT instillation, the authors found only
one instance of recurrence of infection in
a patient with chronic osteomyelitis in 3–14
months of follow-up (43,44).
Two additional case series describing NPWT
instillation and its uses have been previously
published. Wolvos describes his experiences
with NPWT instillation through a retrospective
analysis of five cases (41). Wolvos used NPWT
instillation to simultaneously provide pain con-
408 ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc
trol and treat grossly contaminated and infected
wounds. He reported favourable outcomes in
infection and pain control through topical
intermittent instillation of a diluted lidocaine
solution mixed with antibiotic solutions (41).
Bernstein and Tam published a case series of
five diabetic foot wounds that were treated with
NPWTinstillation (45). The authors compared the
use of NPWT instillation to standard NPWT and
other historical delivery methods of local anti-
biotics in post-surgical wounds and found
a reduced length of stay with NPWT instillation.
Based on the authors’ initial experience, NPWT
instillation was recommended in cases of diffuse
or extensively treated osteomyelitis, large areas of
post-debrided exposed bone or joint and where
standard NPWT cannot be tolerated because of
pain that may be heightened during dressing
changes. Bernstein and Tam also recommend
NPWT instillation in cases of critical bacterial
colonisation levels and as an alternative to
antibiotic-impregnated beads when needed (45).
In the three cases of necrotising fasciitis and
systemic infection, intravenous antibiotics were
administered to treat the invasive infection. In
these situations, literature supports that topical
agents alone are not sufficient to reduce infec-
tion and culture-specific systemic antibiotics
should be prescribed (46). In each of these three
cases, intravenous antibiotics were adminis-
tered for 1 week and then discontinued for the
remainder of therapy. In our experience, sys-
temic antibiotics were not necessary once the

local soft tissue was surgically controlled and
treated with continuous topical irrigation. In
the remaining 12 of 15 NPWT-instillation
patients, we were able to reduce the bacterial
bioburden and expedite wound closure
through continuous topical irrigation with
silver nitrate and without the need for systemic
antibiotics.
Historical control patients were used in this
study to ensure sufficient medical record data
with all patients receiving standard moist
wound-care therapy. Prior to conducting this
study, it was determined that at least 15 patients
needed to be enrolled into each study group to
ensure reasonable statistical power and repre-
sentation of both groups. This was based on
power and sample size calculations using pilot
study results of treatment outcomes with a ¼
0
05 and b ¼ 0
80. Standard moist wound-care
therapy was the treatment for the control group
per historical patient treatment at our facility. As
the positive outcomes with the antimicrobial
installation and VAC therapy, we did not feel
that it was appropriate to enrol patients in the
conventional wet-to-moist dressing changes
group, as it is considered for us to be inferior
to the current standard of care at our facility.
The resurgence of interest in silver products
for wound care stems from the increase in the
level of bacterial resistance to traditional anti-
biotics. For example, rates of methicillin-
resistant Staphylococcus aureus (MRSA) increased
steadily over the past decade from about 30% in
1989 to approximately 40% in 1997 among
intensive care units (ICU) patients (47). Unlike
traditional antibiotics, ionic silver has multiple
mechanisms of action, such as inhibiting
cellular respiration, denaturing nucleic acids
and altering cellular membrane permeability
(48,49). An adequate concentration of silver
coupled with its various mechanisms of action
make it difficult for micro-organisms to
develop resistance because they would have
to undergo several mutations to develop
defence mechanisms against silver‘s multi-
pronged attack (46).
Silver nitrate has long been a choice as
a topical antimicrobial based on clinical studies
that substantiate its merits in treating wounds
(50–53). Silver is a broad-spectrum antimicro-
bial with claims for efficacy in the elimination of
Gram-positive and Gram-negative bacteria,
yeasts/fungi, MRSA and vancomycin-resistant
infections (VRE) (46). In this NPWT-instillation
ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc
Negative pressure wound therapy with instillation
patient study, silver nitrate was effective in
clearing all cases of MRSA (n ¼ 4) and VRE
Key Points
(n ¼ 4) within 10 days. • in our experience, systemic
The silver nitrate irrigation fluid used in this antibiotics were not necessary
study was purchased in a 0
5% ready-made once the local soft tissue was
surgically controlled and trea-
solution (1
25 g per 250 cm3 of water). On
ted with continuous topical
purchasing the solution, it was transferred to irrigation
a dry evacuation container for storage. Because • we were able to reduce the
of silver nitrate’s sensitivity to light, all the bacterial bioburden and expedite
tubing, including the tubing that connects wound closure through continu-
ous topical irrigation with silver
directly into the foam dressing, and bottles were
nitrate and without the need for
covered by dark bags or aluminium foil, with systemic antibiotics
bags being the quickest and easiest method of
coverage (Figure 1C). The irrigating bag of
silver nitrate was changed every other day with
each dressing change to minimise any effects of
light exposure.
Silver nitrate is contraindicated for those with
a silver allergy or hypersensitivity to silver.
Leucopenia, bone marrow toxicity and renal or
hepatic damage through silver deposition are
other complications reported from the use of
silver nitrate, but they are rare and probably of
marginal significance (54). As silver nitrate can
stain bedding and devices, the NPWT-instillation
device should be at least 5 minutes into the
negative pressure cycle so as to remove all
free-floating silver nitrate fluid from the tubing
before removing dressing. Once the silver nitrate
is pulled through the dressing tubing and the
clamp is closed, leaking is minimised.
Application of topical antibiotics and anti-
septics to wounds continues to be a controversial
subject in wound care. The strongest argument
against the topical use of antimicrobial agents,
such as nanocrystalline silver and silver nitrate
on wounds is that they have been found, by
primarily using in vitro models, to be cytotoxic
to cells essential to the wound-healing process,
such as fibroblasts, keratinocytes and leucocytes
(55,56). As in vitro results are not always
predictive of what may happen in vivo, numer-
ous studies have been conducted on animal and
human models. Drosou et al. (2) performed
a literature review of relevant animal studies
and clinical trials examining the effects of
commonly used topical antibiotics and found
despite cytotoxicity data, in most of clinical
trials (50,57,58) topical antibiotics appeared to
be safe and were not found to negatively
influence wound healing.
Wright et al. noted a higher frequency of
apoptosis and reduced levels of matrix metal-
loproteinase in a porcine model of contaminated
409

Key Points
• because of the significantly
shorter wound closure rates
observed for the NPWT-instilla-
tion group, we hypothesised
that the combined effect of
silver nitrate and NPWT in
reducing bacterial bioburden
had a correlated effect on the
rate of wound closure
• in this pilot study, the mean
number of days of wound
treatment for the control group
was 36
5 days versus 9
9 days
for the NPWT-instillation group,
yielding a total difference in
wound treatment time of 26
6
days between the two groups
410
Negative pressure wound therapy with instillation
wounds treated with silver (59). The results
suggest that silver may help to alter or compress
the inflammatory events in wounds, thus
facilitating the early phases of wound healing
(59). Differing effects of silver seen in the lab
versus clinical practice may best be explained by
the organic and inorganic materials in wound
fluid that bind ionic silver and render it inactive.
This level of reactivity cannot be duplicated in
vitro, which typically results in a higher con-
centration of silver that can be cytotoxic to
viable cells in vitro (54).
In our practice, we have historically observed
favourable results in wound healing with the
use of silver nitrate. For this study, we did not
quantitatively measure cytotoxity levels of
silver nitrate for any of these wounds. However,
we observed anecdotally that the net effect of
the silver nitrate had a positive effect on wound
healing. In each of the 15 NPWT-instillation
cases, we continued with the silver nitrate
instillation past the point of bacterial bioburden
clearance because of consistently observed pro-
gression towards closure with each dressing
change.
The silver nitrate appeared to provide an
effective barrier against further bacterial pene-
tration (60). There were no incidences of
recurrent infection or odour during dressing
changes for any of the patients throughout the
length of therapy. Additionally, we noted an
even distribution of silver effect to the entire
wound surface at each dressing change, which,
we suspect, is because of the dressing‘s confor-
mance to the contours of the wound. There was
noticeable odour reduction as well as decreased
pain with dressing changes. Clearly other
antiseptics can also be used; however, our
clinical experience with silver with its polymi-
crobial coverage has been successful. In addi-
tion, this is also a solution that is cleared by the
Food and Drug Administration for topical
instillation.
Because of the significantly shorter wound
closure rates observed for the NPWT-instillation
group, we hypothesised that the combined
effect of silver nitrate and NPWT in reducing
bacterial bioburden had a correlated effect on
the rate of wound closure. To test this probable
correlation, we conducted a regression analysis.
An equation was fit to the number of ‘days to
wound infection clearance’ and the ‘days to
wound closure’ summarised by the model y ¼
0
9748x þ 4
8409 where y is the ‘days to wound
ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd and Medicalhelplines.com Inc
closure’ and x is ‘days to wound infection
clearance’.
The results showed a statistically significant
association between decrease of bacterial bio-
burden and wound closure for the control
group. The association was very strong (R2 ¼
0
96 and P , 0
001) and suggests that approx-
imately 96% of the variation in the time to
wound closure can be explained by the time it
takes for wound infection to clear. The P-value
indicates that the day infection was cleared is
a highly significant predictor of days to wound
closure. As the NPWT-instillation therapy
wounds decreased of bacterial bioburden
within a relatively short time span (6
0  1
5
days), an association was difficult to evaluate
within the NPWT-instillation group and the
equation yielded a weaker association as indi-
cated by the R2-value of 0
60. The results of both
relationships are shown in Figure 5.
The high costs of treating infections are
primarily driven by antibiotic treatment costs,
patient care and prolonged hospital stays,
including time spent in ICUs. It has been
reported that patients with a surgical site
infection have a 2
2-fold increased risk of dying,
a 60% increased risk of being admitted to an ICU
and a twofold increased hospital length of stay
compared with uninfected patients (61).
In this pilot study, the mean number of days of
wound treatment for the control group was 36
5
days versus 9
9 days for the NPWT-instillation
group, yielding a total difference in wound
treatment time of 26
6 days between the two
groups. Most wound-care patients of both
groups were treated in the medical surgical ward.
The high correlation between the decrease in
bioburden and wound closure and the significant
difference in treatment endpoints may indicate
overall cost reduction for the NPWT-instillation
group versus the control group.
CONCLUSION
The use of VAC therapy with silver instillation
has changed the management of complicated
infected or colonised wounds and has become
the standard of care at our facility. It has enabled
surgeons to perform less complex reconstruc-
tive procedures for major soft tissue defects and
it saves donor site morbidity and decreases
anaesthesia time. Patzakis et al. and Patzakis
and Zalavras have shown that only 18% of
infections after open fractures are caused by an
organism initially cultured from the traumatic

wound, suggesting that many of the infections
after open fractures are nosocomial acquired,
making the broad-spectrum treatment of these
wounds in even more crucial (62,63). Although
early coverage is important, at times this is not
possible because of the severe oedema, an
unstable patient or indistinct zone of injury of
the extremity. Therefore temporising wounds
with VAC therapy and supplying the broad-
spectrum antimicrobial instillation (silver
nitrate) is an optimal bridge to final closure.
In this pilot study, NPWT instillation showed
a significant decrease in the mean time to
bioburden reduction and wound closure, com-
pared with traditional wet-to-moist wound
care. Outcomes from this study analysis suggest
that the use of NPWT instillation may result in
overall cost savings and decreased in-patient
care requirements for these complex, infected
wounds. We believe patient tolerance and
compliance with the therapy is enhanced with
the decreased time to closure and sooner
hospital discharge. The improved outcomes
also affect indirect costs such as loss of work
days, recovery time and mortality. However,
this study has all the limitations of a retrospec-
tive study and caution should be used in the
interpretation of the data. Additional studies
with larger patient samples are needed to
further substantiate the results of this novel
wound treatment therapy.
ACKNOWLEDGEMENTS
The authors wish to thank Karen Beach, BS, for
her editorial assistance (funded by KCI). Finan-
cial disclosures: Subhas Gupta, MD, PhD,
FRCSC, FACS no financial interests or commer-
cial associations; Allen Gabriel, MD is a member
of the speakers bureau and clinical advisory
panel of Kinetic Concepts, Inc.; the remaining
authors have no financial interests or commer-
cial associations.
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