Pointers in Practical Pharmacology

T his a rticle r ev iews the

h istory
of hyaluronidase,
contributing factors that predispose
neonates to peripheral intravenous
Hyaluronidase for
Extravasation Management
with local anesthetic agents to
increase diffusion in spreading
the anesthetic action of agents.8
Over the next several decades,
(IV) infiltration; terms associated researchers found hyaluronidase
with inf iltration and extravasa- Michele J. Beaulieu, DNP, ARNP, NNP-BC was effective in treating a variety
tion; the mechanism of action of of conditions ranging from trau-
hyaluronidase; staging and treat- matic swelling in oral dentistry
ment of extravasated tissue, along with the economic cost to the correction of hyaluronic acid–based fillers in cosmetic
and liability associated with IV infiltrates. dermatology.9,10 Its use as an antidote was first proposed
The insertion of an IV catheter is the most common in 1976.11 In the 1980s, the study of hyaluronidase for the
invasive procedure in neonatal intensive care unit (NICU). 1 treatment of nafcillin-induced deep tissue necrosis helped
Intravenous administration of fluids and medications is a advance the use of hyaluronidase as an antidote for IV infil-
necessary treatment for many newborns in the NICU, yet tration.12 In studies using the skin of immature pigs (which
it is not without potential adverse effects. The fragile skin of resembles human skin), injection of hyaluronidase was found
the neonate places them at greater risk for alterations in skin to decrease skin necrosis and overall morbidity associated
integrity.2 Inadvertent catheter dislodgement outside of the with IV extravasation injuries.13 Additional animal model
vein with subsequent leakage of fluid into the surrounding studies showed significant reduction of areas of skin loss and
tissue can cause varying degrees of local irritation; and in the ulceration when hyaluronidase was given less than one hour
most severe cases, can cause tissue necrosis, and limb loss. from the time extravasation occurred.3 Current therapy for
It is estimated that up to 78 percent of IVs become infil- the treatment of IV infiltrates varies among institutions,
trated, and extravasation occurs in approximately 11 percent ranging from conservative to aggressive. In the most conser-
of all NICU patients, with a higher prevalence of extravasa- vative approach, the wound is exposed to air and occlusive
tion injury resulting in skin necrosis in infants with a gesta- dressings with hydrogels and nonocclusive saline dressings
tional age of 26 weeks or less.3–5 Subcutaneous injections of are used. In a more aggressive approach, administrations of
hyaluronidase in the tissue surrounding extravasation have antidotes such as hyaluronidase are used. Treatment is also
been shown to decrease tissue damage and necrosis.1 dependent on factors such as the stage of extravasation, type
of infiltrating solution, and availability of antidotes.1
HISTORICAL REVIEW
Meyer and Palmer first discovered hyaluronic acid in bovine RISK FACTORS FOR IV COMPLICATIONS
vitreous humor in 1934.6 Later, Karl Meyer introduced the REQUIRING THE USE OF HYALURONIDASE
term hyaluronidase, which included a group of enzymes Neonates can neither report pain nor advocate for them-
that was capable of degrading hyaluronic acid.7 Important selves, thus recognizing those at particularly high risk, along
to the discussion of hyaluronic acid and hyaluronidase is with vigilance in monitoring IV sites is vital. In addition
the understanding that they are not one in the same, and to gestational age and the fragile nature of a neonate’s skin
in fact, have opposing actions. Girish and Kemparaju who as risk factors, a number of factors predispose newborns to
wrote that hyaluronic acid is the “magic glue and hyaluroni- adverse outcomes of IV therapy (Table 1).
dase is its eraser” perhaps best describe the difference.7
Hyaluronic acid is readily available in many human tissues INFILTRATION VERSUS EXTRAVASATION
but most abundant in soft connective tissue with particu- The terms infiltration and extravasation are often used
larly high concentrations found in the umbilical cord, skin, interchangeably to describe displacement of an IV catheter
synovial fluid, and vitreous humor. Hyaluronic acid plays a and subsequent collection of fluid around the peripheral site.
role in many biomedical applications because of its regenera-
tive ability, including treatment for osteoarthritis, cataract Continuing Nursing Education (CNE) Credit
surgery, embryo implantation, and in cosmetic procedures, A total of 3.1 contact hours may be earned as CNE credit for reading the
to name a few. articles in this issue identified as CNE and for completing an online post-test
In the 1930s, Duran-Reynals discovered the “spreading and ­e valuation. To be successful the learner must obtain a grade of at least
80% on the test.
factor” of hyaluronidase described as the depolymerisation of
hyaluronic acid, the benefit of which aids in dispersion and Disclosure
reduction of edema. Research into the “spreading effect” dis- The author has no relevant financial interest or affiliations with any
­commercial interests related to the subjects discussed within this article.
covered by Duran-Reynals and advanced by Chain and Duthie No commercial support or sponsorship was provided for this educational
in the 1940s, led to the use of hyaluronidase in conjunction activity.

Accepted for publication June 2012.

N E O N ATA L   N E T W O R K
VOL. 31, NO. 6, NOVEMBER/DECEMBER 2012 © 2012 Springer Publishing Company 413
http://dx.doi.org/10.1891/0730-0832.31.6.413
 TABLE 1  n  Contributing Risk Factors
Mechanical Factors
Placement of catheter (e.g., areas of joint flexion)
Unstable catheter
Type of catheter
Poor securing of needle (frequent use of tape)
Poor visibility of IV site
Kinking, blocking, cracked catheter hub
Patient activity
Patient condition/length of therapy
Note: Adapted from neonatal population.25,31,32
The difference between infiltration and extravasation is prin-
cipally the type of fluid used, whereas in an infiltration the
fluid is nonirritating and with an extravasation, the fluid is
toxic to the tissues.5 Table 2 lists IV solutions and medica-
tions implicated in the development of infusion-related phle-
bitis. See the sidebar for terms related to IV infiltrations.
MANAGING IV EXTRAVASATIONS
Protocols may vary across NICU and include normal saline
washout, administration of hyaluronidase, or other antidotes
depending on the causative agent. The use of heat and/or cold
is controversial. In the immediate phase following IV infiltra-
tion and extravasation, the goal is to neutralize the substance.14
If pharmacologic treatment is chosen, positive outcomes are
dependent on timely administration within one hour.15
HYALURONIDASE: MECHANISM OF ACTION
Hyaluronidase is the generic name for a protein enzyme
that breaks down hyaluronic acid. It is used to increase the
absorption and dispersion of injected drugs by degrading
TABLE 2  n  Vesicant Drugs and Fluids
Chemotherapy agents
Antibiotics (vancomycin, amphotericin B and most b-lactams are
associated with twofold increase risk)
Solutions containing potassium, calcium
Dextrose concentrations .5%
Sodium bicarbonate
Hyperalimentation
Vasopressors (requires specific antidote*)
Barbiturates
Phenytoin
*Extravasations involving vasopressors, which cause tissue damage
by vasoconstriction and ischemia, require treatment with
alternative antidotes, such as phentolamine. Phentolamine acts
as an a-receptor blocker to relax smooth muscle and aid in the
absorption and dispersion of vasoactive drugs.16,30,33
N E O N ATA L   N E T W O R K
414  NOVEMBER/DECEMBER 2012, VOL. 31, NO. 6
Physiologic Factors Pharmacologic Factors
Decreased peripheral circulation Solutions with high pH
Poor venous circulation Hyperosmolality solutions
Reduced vessel diameter
Flexibility of subcutaneous tissue
Inability to verbalize pain
hyaluronic acid, a constituent of the normal interstitial bar-
rier.13 Hyaluronidase works by modifying the permeability
of connective tissue, temporarily decreasing the viscosity
of fluid, promoting drug absorption and rapid diffusion of
injected fluids.16 Optimal results are not achieved through IV
administration but rather through local intradermal injection
(http://www.clinicalpharmacology.com, 2010).17
U.S. Brand Names
Hyaluronidase is an antidote for the treatment of IV
extravasation. Most forms of injectable hyaluronidase are
derived from animal products, whereas only one brand is
produced from humans. Traditionally, hyaluronidase was
made from bull semen. Today, it is commercially produced
from bovine and ovine testis. In 2009, the U.S. Food and
Drug Administration approved Hylenex (rHuPH20), a
human DNA-derived hyaluronidase enzyme with up to
100 times greater purity than the animal-derived forms of
Extravasation: the leakage of a vesicant from a vein into the
surrounding tissue.4,16,29
Infiltration: the leakage of a nonvesicant fluid from a vein.4,16,29
Vesicant: fluid or medication toxic to the tissue.4
Nonvesicant: nonirritant fluids or medications such as D5W or
normal saline.30
Normal serum osmolality: the number of particles suspended
in a solution between 280 and 295 mOsm/kg.30
Hyperosmolality (hypertonic): substances with a serum
osmolality .295 mOsm/kg. Because of the high osmolality
hypertonic solutions draw fluid from endothelial cells to
the serum, causing cells to shrink.30 Hypertonic solutions
have a lower pH, making them more acidic and irritating to
the vein.16
Hypoosmolality (hypotonic): substances that have a low
serum osmolality that results in an influx of fluid into the cell
causing cell distention and possible rupture.30
TABLE 3  n  Forms of Hyaluronidase and Their Brand Names
Animal-Derived
Amphadase (Amphastar Pharmaceuticals, Rancho Cucamonga, CA): bovine testicular hyaluronidase. Concentration is 150 units/mL (contains
edetate disodium, thimerosal).
Hydase (Akorn, Inc., Buffalo Grove, IL): ovine testicular hyaluronidase. Concentration is 150 units/mL.
Vitrase (ISTA Pharmaceuticals, Irvine, CA): purified ovine testicular hyaluronidase, a protein enzyme.34 Concentration is 200 units/mL.
Wydase (Wyeth-Ayerst): highly purified bovine testicular hyaluronidase.31 To evaluate regulatory compliance issue, production of this product
was voluntarily stopped by the company in 2001. In 2003, the Food and Drug Administration (FDA) announced that “Wydase was not
withdrawn from sale for reasons of safety or effectiveness.”35
Human Enzyme Recombinant
Hylenex (Baxter Healthcare Corp., Deerfield, IL): 150 units/mL (contains human albumin, edetate disodium; recombinant).

hyaluronidase. Although there are no convincing reports of
allergic reaction or long-term adverse effects from animal-
derived hyaluronidase in neonates, rHuPH20 contains no
animal-derived components that may produce the risk of
allergy, nor does it transmit possible diseases carried by ani-
mals.11 Product selection is based primarily on prescriber
preference. The human form of hyaluronidase is preferred by
some health care prescribers because there may be less local
injection reactions.25 Table 3 lists the forms of hyaluronidase
and their brand names.
each skin entry to prevent bacterial contamination and mini-
mize pain. The solution is prepared by diluting 0.1 mL of
the 150 unit/mL solution in 0.9 mL of normal saline to
yield 15 units/mL.18 The dosage used may vary among
centers and may also be administered using 150 units/mL
without further dilution.19 Five 0.2 mL injections are given
either subcutaneously or intradermally into the site at the
leading edges of the infiltrate within one hour following
extravasation. The drug is not administered IV because the
enzyme is rapidly inactivated.

NEONATAL DOSING AND ADMINISTRATION ADVERSE REACTIONS

Administration of an antidote may be considered depend- Although uncommon, adverse reactions to the adminis-
ing on the stage of extravasation (Table 4). The drug is admin- tration of hyaluronidase include tachycardia, hypotension,
istered using a 27–30 gauge needle that is changed between dizziness, chills, urticarial erythema, angioedema, nausea,

TABLE 4  n  Staging of Extravasated Tissue4

Stage of Extravasation Observation Treatment Options
Stage 1 • Pain at site 1.  Remove IV cannula.
• Crying when IV cannula is flushed 2.  Elevate extremity.
• Difficulty with IV cannula flushes
• No redness or swelling
Stage 2 • Pain at site 1.  Remove IV cannula.
• Redness and slight swelling at site 2.  Elevate extremity.
• Brisk capillary refill 3.  Consider antidote.
Stage 3 • Pain at site 1. Leave IV cannula in place, and, using a 1 mL syringe, aspirate as
• Moderate swelling much fluid as possible.
• Blanching of area 2. Remove cannula unless it is needed for administration of an
antidote.
• Skin cool to touch
3.  Elevate extremity.
• Brisk capillary refill below site
4.  Consider antidote.
Stage 4 • Pain 1. Leave IV cannula in place, and, using a 1 mL syringe, aspirate as
• Severe swelling around site much fluid as possible.
• Blanching of area 2. Remove cannula unless it is needed for administration of an
antidote.
• Skin cool to touch
3.  Elevate extremity.
• Area of skin necrosis or blistering
4.  Consider antidote.
• Prolonged capillary refill time (.4 s)
5. If swelling of the site is tense and skin is blanched, edematous area
• Decreased or absent pulse can be punctured many times with a needle to allow free-flow
drainage of infiltrating solution, decrease swelling, and prevent
necrosis.
Adapted from Montgomery et al., 1999 and Ramasethu, 2003.36,37

N E O N ATA L   N E T W O R K
VOL. 31, NO. 6, NOVEMBER/DECEMBER 2012  415
vomiting, and localized edema in the adult population.
In rare instances, anaphylactic-like reaction can occur.
CONTRAINDICATIONS
Known hypersensitivity to hyaluronidase or any com-
ponent is a contraindication to use, although no systemic
adverse effects have been reported in the neonatal popula-
tion. Additionally, injections in or around infected, inflamed,
or cancerous areas is contraindicated.
Hyaluronidase should not be used for dopamine and alpha
agonist drug infiltrates because it can potentiate the vasocon-
strictive effect of the drug.18 Rather, phentolamine, a potent
a-adrenergic blocker, should be given when infiltrates occur
from vasoactive drug administration. Phentolamine has been
shown to reverse the ischemic effects of vasoactive drugs such
as norepinephrine and dopamine.5
OTHER USES OF HYALURONIDASE
Among several other uses, during local anesthesia,
hyaluronidase is injected locally to decrease the anesthetic
onset of action. Hyaluronidase is also used in the manage-
ment of vitreous hemorrhage to help liquefy the vitreous and
improve the clearance of blood from vitreous.17
Because the cervix is a fibrous organ and composed prin-
cipally of hyaluronic acid, cervical injection of hyaluronidase
has been previously proposed as a mechanism to ripen the
cervix to augment the induction of labor.20 The administra-
tion of human recombinant hyaluronidase (rHuPH20) has
recently been proposed as an alternative to IV fluid adminis-
tration for the treatment of mild to moderate dehydration by
subcutaneous infusion “hypodermoclysis” in pediatric and
adult populations. Hypodermoclysis is the process of inject-
ing isotonic fluids subcutaneously to treat or prevent dehydra-
tion and is considered to be safe, less invasive than IV fluid
administration and provides an alternative to IV rehydration
in patients with difficult IV access. 21–23 Additional studies
evaluating the safety and efficacy of subcutaneous infusions
of hyaluronidase for the treatment of infiltrates or other uses
are currently underway.24
LIABILITY ISSUES AND IMPLICATIONS
FOR NURSING PRACTICE
More than 2 percent of injury claims from 1970 to 2001
were related to peripheral IV catheter infiltrates involving
skin sloughing, necrosis, swelling, inflammation, infection,
nerve damage, and scarring.25 Increasingly, nurses are being
named in malpractice suits involving administration of IV
fluids and medications with claimants being awarded up to
$10 million per claim. Failure to monitor, assess the patient’s
clinical status, or protect the patient from avoidable injury is
subject to litigation.16
Increasing health costs are a concern for every institution.
Complications related to IV therapy can significantly impact
health care costs as well as patient morbidity and ­mortality.16
With the changes in reimbursement for “vascular infections
N E O N ATA L   N E T W O R K
416  NOVEMBER/DECEMBER 2012, VOL. 31, NO. 6
that result from improper use of catheters,” hospitals are
being held accountable for preventing complications and
decreasing hospital stays.5 In the absence of randomized con-
trolled trials and consistency in unit protocols, identifying
the subgroup of neonates at the highest risk of experiencing
an IV infiltrate and closely monitoring IV infusions (particu-
larly vesicants) that are more likely to cause the most injury
will help in promoting patient safety and preventing IV com-
plications. Through proper documentation and following
treatment protocols, nurses can decrease patient injury and
help prevent complications of IV therapy and risk of mal-
practice liability. Although treatment for IV infiltrations and
extravasations have not been standardized, some institu-
tions have developed a kit which includes specific protocols,
management algorithm, documentation forms, antidotes
with specific instructions for diluting and reconstituting,
and necessary equipment for the treatment of extravasa-
tions, ­including a tape measure to determine the size of the
involved area.25
FUTURE RESEARCH
There is a paucity of research regarding treatment for
I V inf iltration/extravasation, and protocols may vary
among institutions. A review of the Cochrane Database by
Gopalakrishnan and colleagues failed to identify random-
ized controlled trials comparing the use of saline irriga-
tion with or without hyaluronidase for the management
of extravasation injuries in neonates. 26 Although no stan-
dardized approach to IV infiltration and extravasation has
been agreed upon, and Centers for Medicare and Medicaid
Services (CMS) considers IV infiltrates as reasonably pre-
ventable events and thus have discontinued reimbursement
for complications that result from improper use of catheters,
a new approach to the management of IV infiltrates in pedi-
atric and neonatal patients has been proposed. A planned
quantitative study is pending institutional approval. 5 The
new protocol includes a modification of the staging of infil-
trates. Millam first presented criteria for scaling IV infiltra-
tions in 1988, which was primarily based on the amount of
swelling and discoloration related to the infiltration (stages
from I–IV).27 In 2006, the Infusion Nurses Society (INS)
developed a grading scale more specifically measuring the
extent of edema and recommended that infiltrates involving
vesicants be automatically considered a Grade IV (based on
a scale of I–IV), which is considered the most severe type of
infiltrate.28 In 2007, Thigpen adapted the grading scale from
Montgomery and colleagues, which closely resembles that of
the INS scale of IV infiltrations and also includes treatment
options and interventions (see Table 4).4
The authors of the proposed study, published in the
Journal of Infusion Nursing, have presented a modified
grading scale based on the number of joints involved, rather
than the amount of measurable swelling and have changed
the scale from previous authors’ grading or staging from I–IV
to degrees of infiltrations 1st, 2nd, and 3rd. First degree is
 defined as swelling ,2 cm from the site of ,1 joint involved;
2nd degree is defined as swelling .2 cm from the site or
blanched skin/involvement of one to two joints; and 3rd
degree is defined as swelling involving more than two joints
or any localized tissue damage. The authors suggest that
this proposed scale more accurately represents the degree
of severity relative to the patient’s size and “corrects for
­misunderstandings inherent to scales based on set distances”
(p. 245). Treatment changes have also been proposed based
on the fact that traditional treatment with hyaluronidase
still requires multiple punctures and tissue modification to
the already fragile neonatal skin. The newly proposed treat-
ment focuses more on wound management than adminis-
tration of antidotes. The treatment is less invasive than the
administration of hyaluronidase and involves the use of a
compression wrap and warm packs for a first-degree IV infil-
trate (swelling); and a combination of Bacitracin, Vigilon,
and cast padding dressing for the treatment of second-degree
(swelling and redness) and third-­degree (swelling beyond
the joint/vesicant) IV infiltrations. 5 The cast padding is a
type of bandage whose function is to compress the limb,
which forces the infiltrated f luid to move and be subse-
quently drained from the site of infiltration. This technique
is used only for infiltrations associated with extremities. For
second- and third-degree infiltrates, the site is evaluated for
signs of improvement each morning. Staff gently debride the
site with normal saline and soft gauze or cotton-tipped appli-
cator, then apply a topical collagenase and soft gauze cover
followed by cast padding. In the evening, staff then applies
bacitracin, Vigilon, and cast-­padding dressing. The twice-
a-day therapy continues until there is improvement; and, if
there are no signs of improvement, reconsultation with the
surgical team or plastic surgeon is recommended.
SUMMARY
Hyaluronidase has a long history of reliable use in coun-
teracting the effects of hyaluronic acid in a variety of condi-
tions. It has earned a place in the NICU where peripheral
IVs are commonplace and treatment to reduce tissue damage
and necrosis in certain stages of IV infiltration and extravasa-
tion may be necessary. Less invasive treatments such as occlu-
sive hydrocolloid dressings have emerged as a replacement,
or concomitant therapy, with hyaluronidase; but research to
date does not support one type of treatment over the other.
Newer therapies, such as the one described by Amjad and
associates, are on the horizon. Prevention of infiltration and
extravasation remains the primary goal for patients in the
NICU who require IV therapy. In 2007, the Association
of Women’s Health, Obstetric and Neonatal Nurses
(AWHONN) released the second edition of evidence-based
guidelines for neonatal skin care (see http://www.guidelines
.gov/content.aspx?id=24063 for details). Identifying those
patients at highest risk and understanding the treatment
options is the responsibility of those providing IV therapy
to neonates.
N E O N ATA L   N E T W O R K
VOL. 31, NO. 6, NOVEMBER/DECEMBER 2012  417
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8. Headquarters address: 11 W 42nd St, 15th Fl, New York, NY 10036
9. Publisher: Springer Publishing Company, 11 W 42nd St, 15th Fl, New York, NY 10036
Editor: Deb Fraser, Athabasca University, 1 University Drive, Athabasca, AB, Canada,
T9S 3A3
Managing Editor: Megan Hughes, Springer Publishing Company, 11 W 42nd St, 15th Fl,
New York, NY 10036
10. Owner: Springer Publishing Company, 11 W 42nd St, 15th Fl, New York, NY 10036
11. Known bond holders: None
12. Nonprofit purpose, function, status: Has Not Changed During Preceding 12 Months
13. Publication name: Neonatal Network: The Journal of Neonatal Nursing
14. Issue date for circulation data below: Nov 2012
N E O N ATA L   N E T W O R K
418  NOVEMBER/DECEMBER 2012, VOL. 31, NO. 6
34. Vitrase. Drugs.com. 2012. http://www.drugs.com. Accessed April 19,
2012.
35. Food and Drug Administration. Determination that hyaluronidase
for injection was not withdrawn from sale for reasons of safety or
effectiveness. 2003. http://www.wais.access.gpo.gov. DOIfr06no03-57.
Accessed April 18, 2012.
36. Montgomery LA, Hanrahan K, Kottman K, Otto A, Barrett T, Hermiston
B. Guideline for i.v. infiltrations in pediatric patients. Pediatr Nurs.
1999;25(2):167–169, 173–180.
37. Ramasethu J. Management of extravasation injuries. In: MacDonald MG,
Ramasethu J, eds. Atlas of Procedures in Neonatalogy. 3rd ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2003:149–151.
Association of Women’s Health, Obstetric and Neonatal Nurses (AWHONN).
Neonatal Skin Care: Evidence-Based Clinical Practice Guideline. 2nd
edition. Washington, DC: Association of Women’s Health, Obstetric and
Neonatal Nurses; 2007.
About the Author
Dr. Beaulieu is a board-certified practicing NNP at All Children’s
Hospital/Member of Johns Hopkins Medicine. She has been an NNP for
more than 25 years and earned her doctorate in nursing practice from
Case Western Reserve University Frances Payne Bolton School of Nursing,
Cleveland, Ohio, in 2007. Dr. Beaulieu is a member of several nursing
organizations, including the Academy of Neonatal Nursing (ANN),
Sigma Theta Tau Delta Beta Chapter, National Association of Neonatal
Nurses (NANN), American Academy of Pediatrics (AAP), Association
of Women’s Health, Obstetric and Neonatal Nurses (AWHONN), and
the Florida Association of Neonatal Nurse Practitioners (FANNP).
For further information, please contact:
Michele J. Beaulieu, DNP, ARNP, NNP-BC
E-mail: nnpdoctor@gmail.com
15. Extent & nature of circulation:
Avg. no. copies Act. no. copies of
each issue during single issue pub.
preceding nearest to
12 months filing date
A. Total no. copies 8950 9150
B. Paid circulation
1. Paid/Requested outside-co. etc 8203 7935
2. Paid in-county subscriptions 0 0
3. Sales through dealers, etc 0 0
4. Other classes mailed USPS 0 0
C. Total paid circulation 8203 7935
D. Free Distribution by Mail
1. Outside-county as on 3541 50 50
2. In-county as stated on 3541 0 0
3. Other classes mailed USPS 0 0
E. Free Distribution Other 183 700
F. Total free distribution 263 780
G. Total distribution 8466 8715
H. Copies not distributed 484 435
I. Total 8950 9150
Percent paid circulation 96.89% 91.04%
16. This statement of ownership will be printed in the vol. 31.6 issue of this
­publication.
17. I certify that all information furnished on this form is true and complete. I under-
stand that anyone who furnishes false or misleading information on this form or
who omits materials or information requested on the form may be subject to crimi-
nal sanctions (including fines and imprisonment) and/or civil sanctions (including
multiple damages and civil penalties). James Costello, Vice President . . . . . 9/27/12
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.