INTRAVENOUS ADNUXTURE 1 History of IV fluids 1605

INTRAVENOUS ADNUXTURE 1

History of IV fluids • • • 1605: (first drug iv injected) 1628: Eng. scientist Williams discover circulation 1665: Eng. scientist Richard (blood dog to dog) 1667: scientist edmo (cheap blood to human) dead 1818: scientist Jane's (blood human to human) post portum hemorrhage • 1831: cholera severe dehydration Tomas 22 years old (saline to human) • 1873 (milk caw to human) • 1901 (blood bank USA) 2

Introduction Purpose. . Intravenous admixture: is the combination of two or more parenteral products in one container 3 • The combination of drug substances in an IV. fluid can promote parenteral incompatibilities. • Hospital pharmacists can develop the expertise to prepare these solutions; recognizing their compatibility, stability problems and the potential for contamination and participate in administration of the solutions. • The complex compounding requires knowledgeable personnel making accurate calculations, compounding and having aseptic technique.

Advantages of IV admixture Convenience and time saving Drugs can be given in controlled increments Reduction in the number of injections Treating several conditions simultaneously 4

Body Fluid Compartments ü Total Body Water (TBW): 50 -70% of total body wt ü Avg. is greater for males. ü Decreases with age. ü Highest in newborn, 75 -80%. ü By first year of life TBW ~ 65%. ü Most in muscle, less in fat. ü TBW= ECF + ICF ü ICF (intracellular fluids)~ 2/3 & ü ECF (Extracellular fluids) ~ 1/3 ü ECF = Intravascular (1/3) + Interstitial (2/3) 5

Electrolyte Physiology • Primary intravascular/ECF cation is Na+ Very small contribution of K+, Ca 2+, and Mg 2+. • Primary intravascular/ECF anion is Cl- smaller contribution from HCO 3 -, SO 42 - & PO 43 -, organic acids, and protein. • Primary ICF cation is K+ Smaller contribution from. Mg 2+ & Na+. • Number of intravasc anions not routinely detected. 6 ICF ( m. Eq/L) ECF ( m. Eq/L) Cations K+ (150 -154) Na+ (6 -10) Mg ++ (40) Na+ (142) Ca ++ (5) K+ (4 -5) Mg ++ (3) Anions Organic PO 4 -3 (100 - 106) Protein (40 -60) SO 4 -2 (17) HCO 3 (10 -13) Organic acids (4) Cl(103 -105) HCO 3(24 -27) Protein (40 -60) PO 4 -3 (3 -5) SO 4 -2 (4) Organic acids (2 -5)

• • Avg water loss in stool 150 -400 ml. Avg water loss in urine 800 -1500 ml Avg insensible water loss 8 -12 ml/kg (60 -75% resp + 25 -40% skin) A pt deprived of all external access to water must still excrete a minimum of 500 -800 ml urine/day in order to excrete products of catabolism in addition to mandatory insensible loss. • These losses are increased in states of stress • Insensible losses increase with hypermetabolism, hyperventilation, and fever. 7

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• Daily fluid requirements of healthy children and adults can be estimated (35 ml/kg/d for adults). • This will vary depending on pt’s renal and cardiac function. • These requirements will increase in states of stress as fluid losses increase. • Requirements vary around what is necessary to maintain homeostasis and euvolemia 9

IV Fluid/ Electrolyte Therapy • Three key concepts in consideration of fluid and electrolyte management: • cell membrane permeability • osmolarity • electroneutrality • Cell membrane permeability refers to the ability of a cell membrane to allow certain substances such as water and urea to pass freely, while charged ions such as sodium cannot cross the membrane and are trapped on one side of it. 10

• Osmolarity is a property of particles in solution. If a substance can dissociate in solution, it may contribute more than one equivalent to the osmolarity of the solution. For instance, Na. Cl will dissociate into two osmotically active ions: Na and Cl. One millimolar Na. Cl yields a 2 milliosmolar solution. • Electroneutrality means that the overall number of positive and negative charges balances. For instance, in conditions like renal tubular acidosis where HCO 3 - is lost, chloride is retained leading to a hyperchloremic state 11

• Expected osmolarity of plasma can be calculated according to the following formula: • Concentration of sodium is the major determinant. • Normal serum osmolarity ranges from about 280 to 295 m. Osm • Maintenance fluids must be determined for basic requirements, then existing volume or electrolyte deficits must be evaluated to determine the appropriate IV fluid to use and the volume to administer. 12

Intravenous Fluids Large-volume intravenous solutions: • The injections intended for IV use, are packaged in containers holding 100 ml or more. • Other sterile large volume solutions include – Solution used for irrigation or for dialysis. These may be packaged in containers designed to empty rapidly and may contain a volume of more than 100 ml. • They are packed in single-dose units in suitable glass or plastic containers. • In addition to being sterile, they are pyrogen-free and free of particulate matter. • Bacteriostatic agents are never included, in order to avoid the toxicity due to the large volume administered. 13

Types of (IV) re-susitation fluids Fluids contains blood cell • Whole blood • Packed RBCs Crystalloids • Electrolytes (small particles molecules pass in semipermeable membrane) saline, dextrose Colloids (large molecules ) 14 • Albumin

Types of IV Fluid Crystalloid: Balanced salt/ electrolyte solution; forms a true solution and is capable of passing through semipermeable membranes. May be isotonic, hypertonic, or hypotonic. Normal Saline (0. 9% Na. Cl), Lactated Ringer s, Hypertonic saline (3, 5 & 7. 5%), Ringer solution. However, hypertonic solutions are considered plasma expanders as they act to increase the circulatory volume via movement of intracellular and interstitial water into the intravascular space. • Free H 2 O solutions: provide water that is not bound by macromolecules or organelles, free to pass through. • D 5 W (5% dextrose in water), D 10 W, D 20 W, D 50 W, and Dextrose/ crystalloid mixes. • Blood products: whole blood, packed RBCs, FFP, cryoprecipitate, platelets, albumin. Essentially all colloids. 15

Composition of common IV fluids 16

Fluids Used for Resuscitation Na. Cl(0. 9%) RINGER'SLA CTATE Na. Cl(3)% ALBUMIN (5%) HETASTARC H (6%) DEXTRAN 70 + Na. Cl Na(m. Eq/L) 154 130 513 130 -160 154 Cl (m. Eq/L) 154 109 513 130 -160 154 K(m. Eq/L) 0 4 0 0 Osmolarity (m. Osm/L) 803 275 1025 310 310 Oncotic P (mm Hg) 0 0 00 20 30 60 Lactate (m. Eq/L) 0 28 0 0 none None 20 20 Maximum Dose (m. L/kg/24 hr) 17 Limited by serum Na+

Colloid: High-molecular-weight solutions draw fluid into intravascular compartment via oncotic pressure (pressure exerted by plasma proteins not capable of passing through membranes on capillary walls). Plasma expanders, as they are composed of macromolecules, and are retained in the intravascular space. Albumin, Hetastarch, (®Dextran. Pentastarch Pentaspan ), Plasma, Dextran 18

19 Normal Saline (0. 9% Na. Cl): Isotonic salt water. (154 m. Eq/L Na+; 154 m. Eq/L Cl-; 308 m. Osm/ L). Cheapest and most commonly used resuscitative crystalloid. High [Cl ] above the normal serum 103 m. Eq / L imposes on the kidneys an appreciable load of excess Cl that cannot be rapidly excreted. A dilutional acidosis may develop by reducing base bicarb relative to carbonic acid. Thus exist the risk of hyperchloremic acidosis. Only solution that may be administered with blood products. Does not provide free water or calories. Restores Na. Cl deficits. Lactated Ringer’s (RL): Isotonic, 273 m. Osm /L. Contains 130 m. Eq /L Na, 109 m. Eq /L Cl, 28 m. Eq /L lactate, and 4 m. Eq /L K Lactate is used instead of bicarb because it s more stable in IVF during storage. Lactate is converted readily to bicarb by the liver. Has minimal effects on normal body fluid composition and p. H. More closely resembles the electrolyte composition of normal blood serum. Does not provide calories.

D 5 W/¼NS: Hypertonic, 406 m. Osm/L. Provides 170 calories/L from 5% dextrose. Provides free water for insensible losses and some Na+ to promote renal function and excretion. With added K+ this is an excellent maintenance fluid in postop period. Prevents excess catabolism and limits proteolysis. Hypertonic Saline (3% Na. Cl): ): 1026 m. Osm/L & /513 m. Eq/L Na /Na+. Increases plasma. osmolality and thereby acts as a plasma expander, increasing circulatory volume via movement of intracellular and interstitial water into the intravascular space. Risk of hypernatremia thus careful neuro-monitoring and VS. 20

• • 21 Molality (mole/kg solvent) Molarity (mole/ liter) Osmolartity (osmole/ liter) Osmolality (osmole/kg solvent)

Additives: The additives are injections packaged in ampoules or vials, prefilled or sterile solids, the latter are reconstituted with a suitable diluent before addition to the I. V. fluid. A fresh, sterile, disposable syringe is used for each additive. Ampoules: – Not required to contain an antimicrobial preservative. – In contrast to vials, ampoules-do -not provide for dosage flexibility. – Ampoules are opened by- scoring the neck at the point of constriction with an ampoule file in order to break off the top. For larger ampoules, the opening has been made easier by prescoring or inscribing the ampoule neck with a circle of ceramic point. 22

Additives: disadvantage of the glass ampoule – the contamination of the injection by glass particles when the container is opened. – the ampoule is inconvenient to the user because the content must be transferred to a syringe prior to administration Vials: The availability of multiple-dose vials sealed with rubber closure permitted flexibility of dosage and reduced the unit cost per dose. Disadvantages – 23 increased possibility of microbial contamination with repeated withdrawal and increased particulate contamination.

Sterile solid: drugs supplied by the manufacturer in solid form must be reconstituted before use. Prefilled syringes: Some injectable products are packaged in pre-filled syringes with or without special administration devices. Each prefilled unit contains a dose of medication with an attached sterile needle. After administration, the cartridge-needle unit is discarded, the injection is reusable. 24

Intravenous administration systems IV fluids are available in glass and plastic containers. They are singledose and should be discarded after opening even if not used. The plastic containers made from either a flexible or semirigid plastic material and nonvented. – – 25 Plastic is less expensive and is less dangerous if a hanging bottle fall. the plastic containers should be translucent and require very careful inspection concerning solution-container interactions, stability, freedom from particulate matter. Plastic containers have-eyelet openings or plastic-straps for attachment to IV- poles. flexible plastic systems don't require air introduction in order to function. Atmospheric pressure pressing on the container forces the fluid to flow.

Intravenous administration systems 26

IV fluid systems utilizing glass bottles – – – operate by gravity flow with room air replacing the lost volume of fluid administered. The bottles are graduated at 20 -ml increments scales that permit the volume in container determined either from upright or inverted position. Glass containers have aluminum and plastic bands for hanging. Fluids for IV are available from 3 sources viz Baxter, Mc. Gaw and Abbott/Cutter. – – 27 The major difference between the various manufactures of IV fluid systems utilizing glass bottles is the presence of an airway in the bottle. As mentioned, all IV fluids flow by gravity and the fluid empties from the bottle replaced by air from surrounding atmosphere.

Baxter and Mc. Gaw systems • utilize a plastic airway tube that extends from the rubber stopper above the level of the fluid when the bottle is hanging for administration. • Due to the airway the air that comes into the bottle does not pass through the fluid and this reduces the danger of oxidation the drugs in the fluid. disadvantage of this system • the airway does not contain any mechanisms for filtering. • Both companies counter this idea with the fact that any contaminants which might entrance to the bottle will lay on the top of the solution and remain there throughout the period of fluid therapy since there is some amount of fluid in the bottle and the administration set that is not administered, these contaminants will remain in the bottle and not administered to the patient. The Abbott /Cutter systems • both utilize a filtered airway on the administration set for the admission of air to the bottle. This filter has the capability of filtering some microorganisms from the air before the air the fluid. 28

Each administration set (Baxter and Mc. Gaw or Abbott / Cutter) consists of several parts: – an airway for admitting air into the bottle (in the Baxter/Mc Gaw systems this is not an-integral part of set), – a drip chamber for counting the drops to determine the flow rate and also to act as a reservoir to insure continuous flow, – a length of tubing of sufficient length to reach from hanging bottle to patient arm, – a flow control meter – an injection site for adding medications to the bottle of fluid – a site for the attachment of the needle or other auxiliary equipment, e. g. , final filters, small scallp vein sets, to the administration set. These various parts are presented in the following diagram 29

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Administration methods Both Volume-control sets or piggyback methods 1. Volume-control systems • Allow IV. fluids to be diluted further and administered at a slower rate. • have a cost advantage compared with piggyback systems. • require manual readjustment to restart the flow of the main IV. solution when the medication in the chamber has been completely infused. • Disadvantages of volume-control sets – catheter occlusion- or drug dilution may result. – drug incompatibility and instability, and assuring proper dilution 31

2. Piggyback systems This system with special administration sets overcome the deficiencies of the volume-control sets. – Flow of the IV. fluid automatically resumes after the pre-diluted dose of the drug has been infused completely. Disadvantages of this methods: • The flow of the primary I. V. fluid resumes at the rate established for the piggyback solution which may be more rapid. • The cost: requires addition of a minibag or minibottle for each dose increasing the hospitals costs. 32

Authors studied the rates of contamination, costs and efficiency of four intermittent intravenous infusion systems 1. Inline burette system 2. Piggyback with minibag system 3. Tandem piggyback with inline burette and system 4. Piggyback with manufacturer's drug container, 33

System I: Inline Burette: – The drug was injected into a calibrated chamber and diluted IV fluid. – The flow from the main solution was shut off and the solution in the calibrated chamber was infused fully. – After the fluid in the chamber was infused, flow of the main IV fluid was restarted manually. System 2: piggyback with minibag: – The drug was added to a separated small IV container which was hung higher than the primary container. – The minibag formed a 2 ry pathway for the administration of the content of the minibag. – The flow from the secondary set interrupted the flow of the primary IV fluid to allow infusion of the full contents of the secondary container. After complete infusion of the secondary solution, flow from the primary IV fluid automatically resumed. 34

System 3. Tandem piggyback and inline burette: – The drug was injected into a calibrated chamber which was attached to a secondary LV solution used for dilution of the drug. – The LV, line from the calibrated chamber (considered the secondary solution) was connected in a piggyback manner to the IV, set of the primary IV fluid. – The flow from the secondary line interrupted the flow from the primary IV, fluid to allow infusion of the full contents of the calibrated chamber. – After complete infusion of the secondary solution, flow from the primary automatically resumed. 35

System 4. Piggyback with drug manufacturer’s container: – The dose of drug was diluted in its original container. An administration set was inserted directly into the drug container and then connected in a piggyback manner to the IV. set of the primary IV. fluid to allow complete infusion of the secondary solution. – After complete infusion of the secondary solution; flow from the primary solution automatically resumed. It was found that although system I had the lowest total costs, these were only slightly lower than those of system 4 which was mechanically superior. – Thus, system 4 is preferred. System 3 is a suitable alternative to system 4 when the dose of drug required is not available in a manufacturer's container. 36

Flow Rates of intravenous infusion fluids The rate of flow of IV fluids is determined by the physician whose judgment is based on variety of factors such as: – patient's body surface area and age; and – fluid composition. – The rate of administration and total volume are often limited by the patient's ability to assimilate the fluid. Patient with congestive heart failure or pulmonary difficulties can react adversely to infusion fluids. Extreme caution is exercised when administering fluids to patients with renal impairments. The physician, may prescribe his order in a number of ways: 1) 2) 3) 4) 37 100 ml every 8 hour, 1000 ml at 50 ml/h, 30 drops/min or Keep the Vein Open (KVO).

Flow Rates of intravenous infusion fluids Gravity Flow: The majority of infusion fluids are administered by the gravity method. – In this method the container must be supported above the patient in order the solution to flow. – Flow will not begin until the clamp is opened and air is a 11 owed to enter the container. For a plastic infusion container air is not required for the solution to flow. – The rate can be adjusted by counting the drops that enter the drip chamber. The clamp on the tubing is then adjusted to regulate flow. However, reported that iv fluid delivery via gravity-flow IV is highly inaccurate. – To insure appropriate fluid delivery, the electronic infusion control devices is recommended. 38

Flow Rates of intravenous infusion fluids Pumps and controllers: – There are different types of pumps such as syringe pumps, peristaltic pumps and volumetric pumps. – Volumetric pumps will be used as an aid for the infusion of the following types of solutions: parenteral nutrient: low-dose insulin infusion, lidocaine drips; dopamine, heparin infusion, intravenous fats, small volume administration, nitroprusside, magnesium infusion, blood (emergency only) and elemental diets. . 39

Techniques for preparation of admixtures: Admixture preparation requires strict attention to the three factors – maintenance of sterility, – avoiding particulate contamination and – prevention of incompatibility. a) Maintenance of sterility: The National Coordinating Committee on Large Volume parenteral (NCCLVP) recommended – – The availability of clear work area with laminar air flow hood (class 100). correct aseptic technique and correct use of hood. The use of LF work area incorporating a HEPA filter. Pre-filtered air delivered through the HEPA filter which filters about 99. 79% or all particles 0. 3 µg or larger, which includes airborne bacteria. – The flow of air may be in either a horizontal or vertical pattern. 40

b) Avoiding particulate contamination: – the hazard of introducing particulate matter and microbial contamination by this route presents a serious problem. – Particulate matter (the mobile un-dissolved substances) present in parenteral product (rubber, glass, metal, plastic) – bacterial contamination, particles can be introduced into iv fluids and drug containers at the time of manufacture or during preparation and use. – Hence the use of inline filters in the IV administration system has been suggested to reduce the complication of infection and increase patient safety. – researchers studied the effect of filtration on the particulate matter and drug conc. of solutions of cefazolin sodium in 0. 9% Nacl and dextrose 5% in water. They found that no change of cefazolin conc. – It was found that reconstituted amphotericin B "solutions" contain large numbers of particles less than 3 µm in size. Filtrations through a membrane filters were studied: It was found that filtration did not reduce the in vitro antimicrobial activity or alter the concentration of the drug. 41

c) Compatibility and stability: – The increasing number of injectable drugs and solutions increases the possibility of incompatibilities. – Incompatibilities can be divided into three categories: therapeutic, physical and chemical. Therapeutic incompatibilities occur when two or more drugs are administered concurrently in antagonistic or synergistic pharmacology action. Physical incompatibility occurs when the combination of two or more drugs in solution results in a change in the appearance of the solution. However, degradation of drugs in solution resulting from the combination of parenteral dosage forms is called "chemical incompatibility". 42