International journal of pharmaceutical compounding
S P E C I A L T Y
hydrogen ion concentrations are listed.
parenteral administration. Strategies that
minimize the effects of osmolarity and pH
(Dilantin) applied topically does not pro-
phlebitis, which increases the patient’s risk
duce the same cellular toxicity as it does
of local catheter-related infection, can be
when administered parenterally. In vitro
caused by mechanical trauma from catheter
insertion, catheter material, catheter dwell
lution pH values of 2.3 and 11 kill venous
time or duration of use, particulate matter,
er the pH value is to 7.4, the less the dam-age that occurs. Limited research data,
however, pertain to the effects of less ex-
The pH scale is a measurement of the con-
centration of hydrogen ions (H+) in a so-lution. The scale ranges from 0 to 14; 0 is
the most acidic, 7 is neutral, and 14 is the
content, titratable acidity is a measure of the
most alkaline (ie, basic). It is a logarithmic
reservoir of hydrogen ions within a solution.
Phlebitis is more likely to be caused by a
of 1 pH unit equals a 10-fold change in the
solution with a high titratable acidity and a
lower pH. Venous endothelial cells at sites
tient needs for centuries. After the indus-
of human blood is about 7.35. Any changes
distal to the catheter tip are subject to cel-
in pH (even those that seem insignificant),
lular insult because more time is required
functions that had been performed by phar-
effect great changes in the hydrogen for the hydrogen ion content in the in-
ion concentration. In Table 1,4 examples
fusate to be neutralized by the blood. Titrat-
cal manufacturers, and the pharmacist’s
able acidity has not been well-studied to date
acids and bases and their relative pH and
dispensing commercial mass-producedmedications to patients. During the 1970s
Table 1. Common Acidic and Basic Medications
and Household Products: pH and Hydrogen Ion Concentrations.
mented dispensing with patient counseling.1
dosage forms has increased significantly.
Historically, pharmacy as a profession has
to ensure that only high-quality prepara-
principles have not adequately provided the
considerations such as pharmacology, vas-
cular access devices and their placement,compounding considerations (osmolarity,
pH, stability, particulate matter), delivery
systems, and patient management.2 This ar-
ticle addresses patient morbidity and mor-
H+ = Concentration of hydrogen ions compared to that in pure water. a
tality associated with the effect of osmo-
Abbott Laboratories, Abbott Park, Illinois.
International Journal of Pharmaceutical Compounding
S P E C I A L T Y
not occur when endothelial cells contact an
osmolarity be stated on the product pack-
age, but there are no formal requirements
librium, a substance in solution crosses
a membrane from an area of lower lower concentration of dissolved particles)
larity.6 Osmolarity labeling requirements
mixtures do not exist. Osmolarity data for
osmoles of solute per kilogram of solvent
literature or by calculation from published
is referred to as “osmolality.” In human
lutions. Infused fluid is drawn into venous
osmolality values. The formula used to de-
termine drug-solution osmolarity calcula-
particles is about 290 x 10-3 M; therefore,
tions is not accurate and is best determined
an area of low osmolarity to an area of high
osmolarity at a rate directly proportional
ride are used to replenish water deficits
to the difference (gradient) in osmolality
or to reduce the final osmolarity of cer-
cles) than that of normal saline are con-
milliosmoles per liter of solution, is wide-
ly used in clinical practice because it ex-
causes the cells to shrink. That vascular
insult renders cells susceptible to further
of the pH of blood is between 7.35 and 7.45.
That range is necessary for the normal func-
tioning of critical metabolic processes. A
ty of the infused solution. Potassium chlo-
pH not within that range is physiologically
tration of particles are iso-osmotic (isotonic).
stabilized by three primary mechanisms: the
proximate osmolarity of 4000 mOsm/L.
action of buffer systems, respiratory con-
saline solution) is iso-osmotic with blood
trol, and renal control. Buffer systems use
United States Pharmacopeia for the label-
ing of intravenous fluids produced by phar-
phosphate mixtures. The carbonic acid-bi-
of endothelial cells. Cellular damage does
carbonate system of the body is a chemi-cal buffer mechanism that uses a weak acidand conjugate base to maintain the desired
Table 2. Infusion Nursing Society Recommendations for Minimization or Prevention of
Vascular Damage from Extremes in Infusate pH or Osmolarity.
infused, the carbonic acid-bicarbonate sys-tem releases the appropriate weak acid orconjugate base to maintain a pH near 7.4.
As the infusate leaves the catheter tip, the
pH is neutralized by the carbonic acid-bi-
neutralization of the pH is a function of
the strength of the acid or base and its titrat-
able acidity. The respiratory and renal pH
compensate for pH via a series of complexprocesses.
International Journal of Pharmaceutical Compounding 217 S P E C I A L T Y
been made to use the ratio of the infusion rate to the blood flow
“Laminar flow” refers to the movement of air or fluid in layers
rate to estimate the risk of phlebitis caused by irritating intrave-
and without fluctuation or turbulence. Pharmacists are familiar
nously administered solutions. Because the blood and the infusate
with the concept of laminar ﬂow because they use specialized equip-
flow in a laminar manner, the neutralization process and achiev-
ment to create aseptic working environments for the preparation
ing osmotic equilibrium may take longer than expected. If that
of parenteral products. Laminar flow can be applied to the infu-
method of determining the risk of phlebitis is used, the location
of the catheter tip and blood ﬂow in the infused area must be known.
According to the principle of laminar flow, infusate leaving the
catheter travels in a layer parallel to but separate from the sur-rounding blood flow. Neutralization occurs during the slow dif-
fusion of blood at the contact surface between the laminar blood
To date, the effects of pH and osmolarity have been studied most
flow and the laminar flow of the infused solution. As the infusate
effectively in animal models. According to Kuwahara et al,13 the
slows to the rate of blood flow, the infusate and blood mingle dis-
effects of infusions of solutions at various pH values and infusion
tal to the catheter tip. At that point, venous endothelial cells are
times were studied. When the effects of 6-hour infusions through
exposed to the irritating solution, especially in smaller veins in
peripheral vessels were compared, a solution with a pH of 4.5 re-
which the amount of blood flow cannot further minimize the lo-
sulted in a 100% incidence of severe phlebitic changes, a pH of
5.9 caused mild-to-moderate phlebitic changes in 50% of the an-
Animal studies9 have shown evidence of venous lumen damage
imal subjects, a pH of 6.3 caused mild damage in 20% of those
distal to the catheter tip. That finding is supported by studies in-
subjects, and a pH of 6.5 caused no significant damage. When the
dicating that increasing the infusion rate of irritating solutions
pH value was 6.5, extending the duration of the infusion did not
reduces the potential for the development of phlebitis;
cephalosporins and other antibiotics are irritating to peripheral
Other trials14,15 have indicated that a solution with a pH of 3 to
veins but can be administered in an intravenous “push” without
11 did not induce phlebitic changes when drugs were adminis-
producing an increased incidence of phlebitis.10-12 Attempts have
tered over a few minutes. When the same acidic solution volumewas infused over 5 hours, 1 hour, or 30 minutes, fewer inflam-mation-related changes were noted after the more rapid infusions. No trials have studied the effect of slowing the infusion of high-ly acidic or basic infusates to increase dilution.
Both pH and titratable acidity must be considered when the ad-
ministration of peripheral parenteral nutrition is required.16 An-imal studies16,17 indicate that the higher the titratable acidity ofan infusate, the greater the proximal and distal phlebitic changes. When the principles of laminar flow were applied, tolerance toosmolarity in peripheral veins was demonstrated in animal mod-els. When other factors were controlled, those studies indicatedthat the peripheral tolerance was directly related to the osmolarityand duration of the infusion. The faster the infusion of hyper-tonic infusates, the greater the vein tolerance, which was 820mOsm/kg for 8-hour infusions, 690 mOsm/kg for 12-hour infu-sions, and 550 mOsm/kg for 24-hour infusions.
Human tolerance of pH and osmolarity has not been as well re-
searched (or understood) as it has been in animal models; how-ever, human tolerance to pH and osmolarity is similar to that ofanimals. There is a direct relationship between the pH and os-molarity of an infusate and the development of phlebitis. The in-cidence of phlebitis increases as infusate pH and osmolarity in-crease, and it decreases according to the baseline pH andosmolarity of blood. The exact point at which osmolarity and pHbecome significant risk factors in humans is not known.
The outcomes of human studies of osmolarity-induced phlebitis
have been inconsistent. Gazitua et al18 classified three risk levelsof phlebitis caused by infusate osmolarity. The lowest risk of phlebitisoccurred when a solution osmolarity lower than 450 mOsm/L wasused, a moderate risk occurred at 450 to 600 mOsm/L, and thehighest risk occurred when the solution osmolarity exceeded 600
International Journal of Pharmaceutical Compounding
S P E C I A L T Y
based science used by the INS to define an
osmolarity of 500 mOsm/L as the outer lim-
it of peripheral vein tolerance. The abil-
greater volumes of fluid to affect solution
ity to tolerate different levels of infusate
fected; their formulation must result in a
ing pH-induced effects. A solution that acts
The effect of pH on solubility is best il-
as a buffer must affect the titratable acid-
lustrated in parenteral nutrition solutions
ity of a medication by contributing either
to measure the effect of pH on peripheral
in which calcium salts (calcium gluconate
veins. Some studies18-21 indicate that neu-
tralizing the pH of the infusate to 7 to 7.4
phates. The lower the pH of the final so-
ride injection has an inherent buffering ca-
pacity; therefore the pH of the final in-
phlebitis. To date, no trial of human patients
has identified a pH range that corresponds
and not the base solution. Final osmolar-
ity can be altered by using other base so-
of medication indicate that very few drug
lutions such as lactated Ringer’s solution,
infusions are stable at pH 7. The accept-
osmotic or of neutral pH. Stability is the
ed pH range of 5 to 9 for solutions infused
peripherally represents clinically significant
tions. Premade frozen medications (eg, cer-
tain antibiotics) are formulated with ster-
ever, factors such as blood ﬂow, infusion rate,
ile water or dextrose injection to produce
venous access device, catheter tip location,
and variations in patient tolerance to thepH of the infusate influence the occurrenceof pH-induced phlebitis in spite of thechallenges posed by the pH value of finaldrug admixtures.
osmolarity cannot be easily explained. Cer-tain isotonic, pH-neutral infusates (eg, am-photericin B, cladribine, erythromycin,foscarnet, imipenem, meropenem, pamid-ronate, nafcillin, oxacillin, chemothera-peutic drugs) cause phlebitis, perhaps be-cause they can produce a direct cellular insultto the endothelial cells.
medications is adjusted with either hy-drochloric acid and/or sodium hydroxideto ensure drug stability and a long shelf life. The solubility of weakly acidic or basic med-ications is a direct function of solutionpH, which controls both the portion of med-ication that is in an ionized form (eg, thatis metabolically active) and the solubilityof the nonionized form of the medication.6
methotrexate) are considered weak acidsand must be formulated at a high pH toensure solubility. If, during the prepara-tion of a solution, the pH is lowered, the
International Journal of Pharmaceutical Compounding 219 S P E C I A L T Y
mOsm/L. Parenteral nutrition solutions usually have a much high-
venous access device and tip. Additional research on the princi-
er final osmolarity because of the number of cations and anions
ple of laminar flow must be conducted to identify methods (such
as the intravenous push of antibiotics) of administering highlyacidic or highly alkaline infusates.
The osmolarity of drug solutions should not be the primary con-
sideration in the prevention of infusion-related phlebitis. Many
RidgeRx Compounding. Available at: http://www.RidgeRx.com/story.ntml.
approaches can be used to ensure that the osmolarity of an infusate
(with the exception of parenteral nutrition solutions) remains be-
Kastango ES, Hadaway L. New perspectives on vancomycin use in home
low the recommended INS guideline of 500 mOsm/L.
care. Part 1. IJPC 2001;6:465-469.
According to data from anecdotal clinical practice and exten-
Pearson ML. Guideline for prevention of intravascular device-related in-fection. US Department of Health and Human Services, Centers for Dis-
sive studies of animal and human subjects, pH is the most signif-
ease Control and Prevention, Atlanta, Georgia. Available online:
icant cause of phlebitis. Current INS standards state that an in-
http://www.cdc.gov/ncidod/hip/iv/iv.htm. 1999. Accessed January 12, 2002.
fusate pH of 5 to 9 can be tolerated by peripheral veins. Animal
Carpi A. Acids and bases: An introduction. Available at: http://www.
and human data also suggest that variance from a pH of 7.4 caus-
es damage to venous endothelium tissue. Other unknown mitigating
factors prevent phlebitis from occurring in a large percentage
Trissel LA. Handbook of Injectable Drugs. 11th ed. Bethesda, MD:Ameri-
can Society of Health-System Pharmacists; 2001.
CmcIssues: Consulting services for the pharmaceutical industry Website.
The best method of preventing patient morbidity and mortal-
Available online: http://www.cmcissues.com/Methods/osmolarity.htm.
ity caused by infusion therapy is to consider all primary and sec-
ondary factors that cause phlebitis, such as the dilution of the
Intravenous Nurses Society. Intravenous nursing standards of practice.
medication, the composition of the base infusate solution, the
J Intraven Nurs 2000;23(suppl):S37-S38.
rate of infusion, and the type, size, material, and location of the
Kokotis K. Preventing chemical phlebitis. Nursing 98. Available at: http://www.springnet.com/ce/p118a.htm. Accessed May 28, 2001.
Kuwahara T, Asanami S, Tamura T, et al. Effects of pH and osmolarity onphlebitic potential of infusion solutions for peripheral nutrition. J ToxicolSci 1998;23:77-85.
10. Poole SM, Nowobilski-Vasilios A, Free F. Intravenous push medications
in the home. J Intraven Nurs 1999;22:209-215.
11. Nowobilski-Vasilios A, Poole SM. Development and preliminary outcomes
of a program for administering antimicrobials by IV push in home care. Am J Health Syst Pharm 1999;56:76.
12. Vickery TR, Hatheway JG, Edgar SP, et al. Concentrated vancomycin and
administration via central venous catheters in the alternate-care setting. Poster presented at: ASHP Midyear Clinical Meeting; 1990; Las Vegas, NV.
13. Kuwahara T, Asanami S, Kawauchi Y, et al. Experimental infusion phlebitis:
Tolerance pH of peripheral veins. J Toxicol Sci 1999;24:113-121.
14. Simamora P, Pinsuwan S, Alvarez JM, et al. Effect of pH on injection phlebitis.
15. Hessov I, Bojsen-Mooller M. Experimental infusion thrombophlebitis. Im-
portance of the infusion rate. Eur J Intensive Care Med 1976;2:103-105.
16. Kuwahara T, Asanamia T, Kubo S. Experimental infusion phlebitis: Impor-
tance of titratable acidity on phlebitic potential of infusion solution. ClinNutr 1996;15:129-132.
17. Kuwahara T, Asanamia T, Kubo S. Experimental infusion phlebitis: Toler-
ance osmolarity of peripheral venous endothelial cells. Nutrition 1998; 14:496-501.
18. Gazitua R, Wilson K, Bistrian BR, et al. Factors determining peripheral vein
tolerance to amino acid infusions. Arch Surg 1979;114:897-900.
19. Fonkalsrud E, Pederson BM, Murphy J, et al. Reduction of infusion throm-
bophlebitis with buffered glucose solutions. Surgery 1968;63:280-284.
20. Eremin O, Marshall V. Complications of intravenous therapy: Reduction by
buffering of intravenous fluid preparation. Med J Aust 1977;2:528-531.
21. Fujita M, Hatori N, Shimizu M, et al. Neutralization of prostaglandin E1 in-
travenous solution reduces infusion phlebitis. Angiology 2000;51:719-723. Address correspondence to: Marc Stranz, Phar mD, 100 E. River Center Boulevard, Suite 1700, Covington, KY 41011. E-mail: [email protected]■
International Journal of Pharmaceutical Compounding
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