`
`A REVIEW
`of pH
`AND
`OS MOLARITY
`
`Marc Stranz, Phar110
`Infusion Services Omnicare, Inc
`Covington, Kent1uky
`
`Eric s. Kastanoo, RPh, MBA, FASHP
`Clinical IQ, LLC
`Madison, New Jersey
`
`Pharmacists have been e}.1:emporaneous(cid:173)
`ly compounding medications to meet pa(cid:173)
`tient needs for centuries. After the indus(cid:173)
`trial revolution, many compounding
`functions that had been performed by phar(cid:173)
`macists were undertaken by pharmaceuti(cid:173)
`cal manufacturers, and the pharmacist's
`role gradually became primarily that of
`dispensing commercial mass-produced
`medications to patients. During the 1970s
`and 1980s, some pharmacists comple(cid:173)
`mented dispensing with patient counseling. 1
`The demand for extemporaneously pre(cid:173)
`pared medications in oral or parenteral
`dosage forms has increased significantly.
`Historically, pharmacy as a profession has
`applied cl1e principles of secundum artem
`to ensure that only high-quality prepara(cid:173)
`tions were compounded. However, those
`principles have not adequately provided the
`most robust evidence-based decision-mak(cid:173)
`ing tools in the past.
`The delivery of pharmaceutical care re(cid:173)
`quires specialized knowledge about many
`patient-related and medication-related
`considerations such as pharmacology, vas(cid:173)
`cular access devices and their placement,
`compounding considerations (osmolarity,
`pH, stability, particulate matter), delivery
`systems, and patient management. 2 This ar(cid:173)
`ticle addresses patient morbidity and mor(cid:173)
`tality associated with the effect of osmo-
`
`larity and pH on compounded liquids for
`parenteral administration. Strategies that
`minimize the effects of osmolarity and pH
`are also presented.
`Vascular damage (phlebitis) caused by
`infusates of incorrect pH and osmolarity
`occurs frequently. The development of
`phlebitis, which increases the patient's risk
`of local cacl1eter-related infection, can be
`caused by mechanical trauma from catheter
`insertion, catheter material, catheter dwell
`time or duration of use, particulate matter,
`and chemically mediated factors. 3
`pH and OSMOLARITY
`pH
`The pH scale is a measurement of the con(cid:173)
`centration of hydrogen ions (H•) in a so(cid:173)
`lution. The scale ranges from Oto 14; 0 is
`the most acidic, 7 is neutral, and 14 is the
`most alkaline (ie, basic). It is a logariclunic
`scale based on the power of 10; a change
`of 1 pH unit equals a 10-fold change in the
`concentration of hydrogen ions. The pH
`of human blood is about 7.35 . Any changes
`in pH (even those that seem insignificant),
`effect great changes in the hydrogen
`ion concentration. In Table 1~ examples
`of common household and medication
`acids and bases and their relative pH and
`
`hydrogen ion concentrations are listed.
`Which pH values damage cells? The
`degree of cellular damage from either
`low or high pH is determined by the type
`of tissue exposed to the pH and the du(cid:173)
`ration of exposure . Phenytoin sodium
`(Dilantin) applied topically does not pro(cid:173)
`duce the same cellular toxicity as it does
`when administered parenterally. In vitro
`experiments have demonstrated that so(cid:173)
`lution pH values of 2.3 and 11 kill venous
`endothelium cells on contact. The near(cid:173)
`er the pH value is to 7 .4, the less the dam(cid:173)
`age that occurs. Limited research data,
`however, pertain to the effects of less ex(cid:173)
`treme pH conditions.
`Titratable Acidity
`Although pH is a measure of hydrogen ion
`content, titratable acidity is a measure of the
`reservoir of hydrogen ions within a solution.
`Phlebitis is more likely to be caused by a
`solution with a high titratable acidity and a
`lower pH. Venous endothelial cells at sites
`distal to the catheter tip are subject to cel(cid:173)
`lular insult because more time is required
`for the hydrogen ion content in the in(cid:173)
`fusate to be neutralized by the blood. Titrat(cid:173)
`able acidity has not been well-studied to date
`and requires further investigation.
`
`Table 1. Common Acidic and Basic Medications
`and Household Products: pH and Hydrogen Ion Concentrations.
`
`Medications5
`
`w pH Household Products
`10,000,000
`0 H ydrochloric acid
`1 Stomach acid
`1,000,000
`100,000
`2 Lemon juice
`10,000
`3 Vinegar
`1,000
`4 Soda
`5 Rainwater
`100
`6 Milk
`10
`7 Pure water
`1
`1/10
`8 Egg whites
`1/100 9 Baking soda
`1/1,000 10 Tums antacid
`1/10,000 11 Ammonia
`1/100,000 12 Mineral lime - Ca(OH )i
`1/1,000,000 13 Drano
`1/10,000,000 14 Sodium hydroxide
`H+ = Concentration of hydrogen ions compared to that in pure water.
`• Abbott Laboratories, Abbott Park, Illinois.
`
`Acid
`
`Neutral
`Base
`
`Dopamine HCl
`
`Potassium chloride•
`
`Furosemide
`
`Ganciclovir sodium
`Phenytoin sodium
`
`International Journal of Pharmaceutical Compounding
`Vol. 6 No. 3 Mtty!June 2002
`
`FRESENIUS EXHIBIT 1060
`Page 1 of 5
`
`
`
`Osmolality
`Osmosis occurs when, to produce equi(cid:173)
`librium, a substance in solution crosses
`a membrane from an area of lower
`concentration to an area of higher con(cid:173)
`centration. The concentration of parti(cid:173)
`cles dissolved in solution expressed as
`osmoles of solut e per kilogram of solvent
`is referred to as "osmolality." In human
`plasma, the concentration of dissolved
`particles is about 290 x 10-3 M; therefore,
`its osmolarity is 290 mOsm/L (285 - 3 10
`mOsm/L). Wat er, for example, flows from
`an area of low osmolarity to an area of high
`osmolarity at a rate directly proportional
`to the difference (gradient) in osmolality
`until equilibrium is reached.
`The osmotic pressure of a solution can
`be expressed as either osmolality or os(cid:173)
`molarity. Osmolality refers to the num(cid:173)
`ber of milliosmoles per kilogram of sol(cid:173)
`vent. This value can be calculated or
`determined experimentally by osmome(cid:173)
`try. Osmolarity, which is the number of
`milliosmoles per liter of solution, is wide(cid:173)
`ly used in clinical practice because it ex(cid:173)
`presses concentration as a function of
`volume. Osmolarity cannot be measured
`experimentally but must be calculated
`from osmolality by means of a conversion
`factor.
`Solutions containing the same concen(cid:173)
`tration of particles are iso-osmotic (isotonic).
`0.9% Sodium chloride solution (normal
`saline solution) is iso-osmotic with blood
`and tl1e venous endothelium; the solution
`causes no movement of water into or out
`of endothelial cells. Cellular damage does
`
`not occur when endothelial cells contact an
`iso-osmotic solution.
`Solutions with a lower osmolality (a
`lower concentration of dissolved particles)
`than 0.9% sodium chloride solution are
`considered hypotonic. 0.45% Sodium
`chloride solution and sterile water for
`injection are examples of hypotonic so(cid:173)
`lutions. Infused fluid is drawn into venous
`endothelial cells and blood cells, which
`have a relatively high osmolality. When
`those cells absorb too much water, they
`rupture or undergo hemolysis. Hypoton(cid:173)
`ic solutions such as 0.45% sodium chlo(cid:173)
`ride are used to replenish water deficits
`or to reduce the final osmolarity of cer(cid:173)
`tain drugs in solution.
`Solutions with a higher osmolality (a
`higher concentration of dissolved parti(cid:173)
`cles) than that of normal saline are con(cid:173)
`sidered hypertonic. 5 % D extrose and
`0.9% sodium chloride injection, any type
`of amino acid solution, and 50% dextrose
`injection are examples of hypertonic so(cid:173)
`lutions. The intravenous administration
`of hypertonic solutions draws fluid from
`the endothelium and blood cells, which
`causes the cells to shrink. That vascular
`insult renders cells susceptible to further
`damage. The degree and immediacy of that
`damage are determined by the osmolari(cid:173)
`ty of the infused solution. Potassium chlo(cid:173)
`ride solution (2 mEq/mL) has an ap(cid:173)
`proximate osmolarity of 4000 mOsm/L.
`Current recommendations from the
`United States Pharmacopeia for the label(cid:173)
`ing of intravenous fluids produced by phar(cid:173)
`maceutical manufacturers require that
`
`Table 2. Infusion Nursing Society Recommendations for Minimization or Prevention of
`Vascular Damage from Extremes in lnfusate pH or Osmolarity.
`
`Vessel
`Superior
`vena cava
`
`Subclavian vein and/or
`proximal axillary vein
`
`Cephalic and basilic veins
`in tl1e upper arms
`
`Blood Flow
`(ml/min)8
`
`0smolarity
`(m0sm/ L)
`
`Solution pH
`
`2000
`
`800
`
`> 900
`
`< 5 or> 9
`
`500 - 900
`
`< 5 or> 9
`
`40 - 95
`
`< 500
`
`5 - 9
`
`SPECIALTY
`
`osmolarity be stated on the product pack(cid:173)
`age, but there are no formal requirements
`for the determination of solution osmo(cid:173)
`larity.6 Osmolarity labeling requirements
`for pharmacy-prepared intravenous ad(cid:173)
`mixtures do not exist. Osmolarity data for
`admixtures can be obtained only from the
`literature or by calculation from published
`osmolality values. The formula used to de(cid:173)
`termine drug-solution osmolarity calcula(cid:173)
`tions is not accurate and is best determined
`by direct measurement via osmometry. 2
`INFUSION NURSING
`SOCIETY RECOMMENDATIONS
`To minimize or prevent vascular dam(cid:173)
`age from extreme infusate pH or osmo(cid:173)
`lari ty, the Infusion Nursing Society
`(INS) has published recommendations
`based on a number of factors, including
`the physiologic location of the venous
`access device. In Table 2,7 those recom(cid:173)
`mendations are presented.
`METHODS of COMPENSATION
`Buffering Capacity
`As mentioned earlier, the normal range
`of tl1e pH of blood is between 7.35 and 7 .45.
`That range is necessary for the normal ftmc(cid:173)
`tioning of critical metabolic processes. A
`pH notwitl1in that range is physiologically
`stabilized by three primary mechanisms: the
`action of buffer systems, respiratory con(cid:173)
`trol, and renal control. Buffer systems use
`proteins, hemoglobin, and bicarbonate(cid:173)
`phosphate mixtures. The carbonic acid-bi(cid:173)
`carbonate system of the body is a chemi(cid:173)
`cal buffer mechanism that uses a weak acid
`and conjugate base to maintain the desired
`pH range. When acidic or basic drugs are
`infused, the carbonic acid-bicarbonate sys(cid:173)
`tem releases the appropriate weak acid or
`conjugate base to maintain a pH near 7.4.
`As the infusate leaves the catheter tip, the
`pH is neutralized by the carbonic acid-bi(cid:173)
`carbonate system. The time required for
`neutralization of the pH is a function of
`the strength of tl1e acid or base and its titrat(cid:173)
`able acidity. The respiratory and renal pH
`control systems of the body monitor and
`compensate for pH via a series of complex
`processes.
`
`International Journal of Pharmaceutica l Compounding
`2
`
`FRESENIUS EXHIBIT 1060
`Page 2 of 5
`
`
`
`S P E C I A L T V
`
`Laminar Flow
`"Laminar flow" refers to the movement of air or fluid in layers
`and without fluctuation or turbulence. Pharmacists are familiar
`with the concept of laminar flow because they use specialized equip(cid:173)
`ment to create aseptic working environments for the preparation
`of parenteral products. Laminar flow can be applied to the infu(cid:173)
`sion of solutions into the bloodstream.
`According to the principle of laminar flow, infusate leaving the
`catheter travels in a layer parallel to but separate from the sur(cid:173)
`rounding blood flow. Neutralization occurs during the slow dif(cid:173)
`fusion of blood at the contact surface between the laminar blood
`flow and the laminar flow of the infused solution. As the infusate
`slows to the rate of blood flow, the infusate and blood mingle dis(cid:173)
`tal to the catheter tip. At that point, venous endothelial cells are
`exposed to the irritating solution, especially in smaller veins in
`which the amount of blood flow cannot further minimize the lo(cid:173)
`cal effects of the infusate.
`Animal studies9 have shown evidence of venous lumen damage
`distal to the catheter tip. That finding is supported by studies in(cid:173)
`dicating that increasing the infusion rate of irritating solutions
`reduces the potential for the development of phlebitis;
`cephalosporins and other antibiotics are irritating to peripheral
`veins but can be administered in an intravenous "push" without
`producing an increased incidence of phlebitis. 10- 12 Attempts have
`
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`International Journal of Pharmaceutical Compounding
`Vol. 6 No. 3 Mtty!June 2002
`
`been made to use the ratio of the infusion rate to the blood flow
`rate to estimate the risk of phlebitis caused by irritating intrave(cid:173)
`nously administered solutions. Because the blood and the infusate
`flow in a laminar manner, the neutralization process and achiev(cid:173)
`ing osmotic equilibrium may take longer than expected. If that
`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.
`CHEMICAL PHLEBITIS In VIVO
`Animal Models
`To date, the effects of pH and osmolarity have been studied most
`effectively in animal models. According to Kuwahara et al, 13 the
`effects of infusions of solutions at various pH values and infusion
`times were studied. When the effects of 6 -hour infusions through
`peripheral vessels were compared, a solution with a pH of 4.5 re(cid:173)
`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(cid:173)
`imal subjects, a pH of 6.3 caused mild damage in 20% of those
`subjects, and a pH of 6.5 caused no significant damage. When the
`pH value was 6.5, extending the duration of the infusion did not
`produce phlebitis.
`Other trials 14• 15 have indicated that a solution with a pH of 3 to
`11 did not induce phlebitic changes when drugs were adminis(cid:173)
`tered over a few minutes. When the same acidic solution volume
`was infused over 5 hours, 1 hour, or 30 minutes, fewer inflam(cid:173)
`mation-related changes were noted after the more rapid infusions.
`No trials have studied the effect of slowing the infusion of high(cid:173)
`ly acidic or basic infusates to increase dilution.
`Both pH and titratable acidity must be considered when the ad(cid:173)
`ministration of peripheral parenteral nutrition is required.16 An(cid:173)
`imal studies 16• 17 indicate that the higher the titratable acidity of
`an infusate, the greater the proximal and distal phlebitic changes.
`When the principles of laminar flow were applied, tolerance to
`osmolarity in peripheral veins was demonstrated in animal mod(cid:173)
`els. When other factors were controlled, those studies indicated
`that the peripheral tolerance was directly related to the osmolarity
`and duration of the infusion. The faster the infusion of hyper(cid:173)
`tonic infusates, the greater the vein tolerance, which was 820
`mOsm/kg for 8-hour infusions, 690 mOsm/kg for 12 -hour infu(cid:173)
`sions, and 550 mOsm/kg for 24-hour infusions.
`Human Models
`H uman tolerance of pH and osmolarity has not been as well re(cid:173)
`searched (or understood) as it has been in animal models; how(cid:173)
`ever, human tolerance to pH and osmolarity is similar to that of
`animals. There is a direct relationship between the pH and os(cid:173)
`molarity of an infusate and the development of phlebitis. The in(cid:173)
`cidence of phlebitis increases as infusate pH and osmolarity in(cid:173)
`crease, and it decreases according to the baseline pH and
`osmolarity of blood. The exact point at which osmolarity and pH
`become significant risk factors in humans is not known.
`The outcomes of human studies of osmolarity-induced phlebitis
`have been inconsistent. Gazitua et al 18 classified three risk levels
`of phlebitis caused by infusate osmolarity. The lowest risk of phlebitis
`occurred when a solution osmolarity lower than 450 mOsm/Lwas
`used, a moderate risk occurred at 450 to 600 mOsm/L, and the
`highest risk occurred when the solution osmolarity exceeded 600
`
`FRESENIUS EXHIBIT 1060
`Page 3 of 5
`
`
`
`mOsm/L. That study provided evidence(cid:173)
`based science used by the INS to define an
`osmolarity of 500 mOsm/L as the outer lim(cid:173)
`it of peripheral vein tolerance. The abil(cid:173)
`ity to tolerate different levels of infusate
`pH and osmolarity varies significantly
`among patients.
`Few human trials have been conducted
`to measure the effect of pH on peripheral
`veins. Some studies 18-21 indicate that neu(cid:173)
`tralizing the pH of the infusate to 7 to 7.4
`significantly reduces the incidence of
`phlebitis. To date, no trial of human patients
`has identified a pH range that corresponds
`to the potential for the development of
`phlebitis. The physiochemical properties
`of medication indicate that very few drug
`infusions are stable at pH 7. The accept(cid:173)
`ed pH range of 5 to 9 for solutions infused
`peripherally represents clinically significant
`variances from the ideal pH of 7 .4. How(cid:173)
`ever, factors such as blood Bow, infusion rate,
`venous access device, catheter tip location,
`and variations in patient tolerance to the
`pH of the infusate influence the occurrence
`of pH-induced phlebitis in spite of the
`challenges posed by the pH value of final
`drug admixtures.
`Exceptions to the Rules
`Some exceptions to the rules of pH and
`osmolarity cannot be easily explained. Cer(cid:173)
`tain isotonic, pH-neutral infusates (eg, am(cid:173)
`photericin B, cladribine, erythromycin,
`foscarnet, imipenem, meropenem, pamid(cid:173)
`ronate, nafcillin, oxacillin, chemothera(cid:173)
`peutic drugs) cause phlebitis, perhaps be(cid:173)
`cause they can produce a direct cellular insult
`to the endothelial cells.
`Secundum Artem
`During manufacturing, the pH of many
`medications is adjusted with either hy(cid:173)
`drochloric acid and/or sodium hydroxide
`to ensure drug stability and a long shelflife.
`The solubility of weakly acidic or basic med(cid:173)
`ications is a direct function of solution
`pH, which controls both the portion of med(cid:173)
`ication that is in an ionized form (eg, that
`is metabolically active) and the solubility
`of the nonionized form of the medication.6
`Sodium salts (phenobarbital, phenytoin,
`methotrexate) are considered weak acids
`and must be formulated at a high pH to
`ensure solubility. If, during the prepara(cid:173)
`tion of a solution, the pH is lowered, the
`
`SPECIALTY
`
`aqueous solubility of the medication may
`be exceeded and the potential for pre(cid:173)
`cipitation exists . Medications that are
`considered weak bases are similarly af(cid:173)
`fected; their formulation must result in a
`low pH to ensure solubility.
`The effect of pH on solubility is best il(cid:173)
`lustrated in parenteral nutrition solutions
`in which calcium salts (calcium gluconate
`or calcium chloride) interact with phos(cid:173)
`phates. The lower the pH of the final so(cid:173)
`lution, the more stable the formulation,
`because the calcium and phosphate ions
`remain ionized. As the pH increases, the
`ions become less ionized, and precipita(cid:173)
`tion can occur. Ready-to-use formula(cid:173)
`tions of medications are not always iso(cid:173)
`osmotic or of neutral pH. Stability is the
`principle concern with those formula(cid:173)
`tions. Premade frozen medications (eg, cer(cid:173)
`tain antibiotics) are formulated with ster(cid:173)
`ile water or dextrose injection to produce
`better solution tonicity.
`
`Diluting medications that are extreme(cid:173)
`ly acidic (vancomycin hydrochloride) or
`extremely alkaline (phenytoin sodium) in
`greater volumes of fluid to affect solution
`pH is not an effective method of mediat(cid:173)
`ing pH-induced effects. A solution that acts
`as a buffer must affect the titratable acid(cid:173)
`ity of a medication by contributing either
`carbonic acid or hydroxide. Neither 5%
`dextrose injection nor 0.9% sodium chlo(cid:173)
`ride injection has an inherent buffering ca(cid:173)
`pacity; therefore the pH of the final in(cid:173)
`fusate containing those substances is
`determined by the pH of the medication
`and not the base solution. Final osmolar(cid:173)
`ity can be altered by using other base so(cid:173)
`lutions such as lactated Ringer's solution,
`5% dextrose injection, dextrose 5% in
`lactated Ringer's injection (D5LR), or
`0.45% sodium chloride injection.
`The osmolarity of most parenteral med(cid:173)
`ication solutions (antibiotics, antineo(cid:173)
`plastics, etc) is usually less than 400
`
`International Journal of Pharmaceutica l Compounding
`2
`
`FRESENIUS EXHIBIT 1060
`Page 4 of 5
`
`
`
`S P E C I A L T V
`
`mOsm/L. Parenteral nutrition solutions usually have a much high(cid:173)
`er final osmolarity because of the number of cations and anions
`in solution.
`CONCLUSION
`The osmolarity of drug solutions should not be the primary con(cid:173)
`sideration in the prevention of infusion-related phlebitis. Many
`approaches can be used to ensure that the osmolarity of an infusate
`(with the exception of parenteral nutrition solutions) remains be(cid:173)
`low the recommended INS guideline of 500 mOsm/L.
`According to data from anecdotal clinical practice and exten(cid:173)
`sive studies of animal and human subjects, pH is the most signif(cid:173)
`icant cause of phlebitis. Current INS standards state that an in(cid:173)
`fusate pH of 5 to 9 can be tolerated by peripheral veins. Animal
`and human data also suggest that variance from a pH of 7.4 caus(cid:173)
`es damage to venous endothelium tissue. Other unknown mitigating
`factors prevent phlebitis from occurring in a large percentage
`of patients who receive infusions.
`The best method of preventing patient morbidity and mortal(cid:173)
`ity caused by infusion therapy is to consider all primary and sec(cid:173)
`ondary factors that cause phlebitis, such as the dilution of the
`medication, the composition of the base infusate solution, the
`rate of infusion, and the type, size, material, and location of the
`
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`INNOVAT ORS IN C LEAN AIR TeCHNOlOGY
`
`1 International Journal of Pharmaceutical Compounding
`Vol. 6 No. 3 Mtty!June 2002
`
`7.
`
`venous access device and tip. Additional research on the princi(cid:173)
`ple oflaminar flow must be conducted to identify methods (such
`as the intravenous push of antibiotics) of administering highly
`acidic or highly alkaline infusates.
`References
`1. RidgeRx Compounding. Available at: http://www.RidgeRx.com/story.ntml.
`Accessed January 12, 2002.
`2. Kastango ES, Hadaway L. New perspectives on vancomycin use in home
`care. Part 1. IJPC2001;6:465-469.
`3. Pearson ML Guideline for prevention of intravascular device-related in(cid:173)
`fection. US Department of Health and Human Services, Centers for Dis(cid:173)
`ease Control and Prevention, Atlanta, Georgia. Available online:
`http://www.cdc.gov/ncidod/hip/iv/iv.htm. 1999. Accessed January 12, 2002.
`4. Carpi A. Acids and bases: An introduction. Available at: http://www.
`vision learning.com/Ii bra ry/sc ien ce/chemistry-2/CH E2.2-a cid_base.
`htm. 2000.
`5. Trissel LA. Handbook of Injectable Drugs. 11th ed. Bethesda, MD:Ameri(cid:173)
`can Society of Health-System Pharmacists; 2001.
`6. Cmclssues: Consulting services for the pharmaceutical industry Website.
`Available on line: http://www.cmcissues.com/ Methods/osmolarity.htm.
`Accessed on January 10, 2002.
`Intravenous Nurses Society. Intravenous nursing standards of practice.
`J lntraven Nurs 2000;23{suppl):S37-S38.
`8. Kokotis K. Preventing chemical phlebitis. Nursing 98. Available at: http://
`www.springnet.com/ce/p118a.htm. Accessed May 28, 2001.
`9. Kuwahara T, Asanami S, Tamura T, et al. Effects of pH and osmolarity on
`phlebitic potential of infusion solutions for peripheral nutrition. J Toxicol
`Sci 1998;23:77-85.
`10. Poole SM, Nowobilski-Vasilios A, Free F. Intravenous push medications
`in the home. J lntraven 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, Kawauch i Y, et al. Experimental infusion phlebitis:
`Tolerance pH of peripheral veins. J Toxicol Sci 1999;24:113-121.
`14. Simamora P, Pinsuwan $,Alvarez JM, et al. Effect of pH on injection phlebitis.
`J Pharm Sci 1995;84:520-522.
`15. Hessov I, Bojsen-Mooller M. Experimental infusion thrombophlebitis. lm(cid:173)
`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(cid:173)
`tance of titratable acidity on phlebitic potential of infusion solution. Clin
`Nutr 1996;15:129-132 .
`17. Kuwahara T, Asanamia T, Kubo S. Experimental infusion phlebitis: Toler(cid:173)
`ance osmolarityof 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(cid:173)
`bophlebitis with buffered glucose solutions. Surgery 1968;63:280-284.
`20. Eremin 0, 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 prostag land in E1 in(cid:173)
`travenous solution reduces infusion phlebitis. Angio/ogy2000;51:719-723.
`
`Address correspondence to: Marc Stranz , PharrnD, I 00 E.
`River Center Bonlevard, Suite 1700, Cov ington, KY 4 JO I I.
`E-rnail: marc.stranz@ornnicare.com. ■
`
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