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Sterile Dosage
Forms
Nahla S. Barakat, Ph.D
King Saud University
College of Pharmacy
Dept. of Pharmaceutics
1432-1431
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The course topics
Introduction and characteristics of sterile dosage
forms.
Methods of sterilization
Composition of Sterile Dosage Forms.
Large Scale preparation of Sterile Products.
Handling and Administration.
Large Volume Sterile Solutions.
IV Admixtures and incompatibilities.
Ophthalmic preparations.
Reference:
Sterile dosage forms, preparation, clinical application. Salvatore Turco.
1996
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Sterile products:
Sterile dosage form refers to a product of a general group of
pharmaceuticals having in common the characteristic of
sterility, i.e., freedom from living microorganism
The sterile dosage forms in general use:
- Injections
- Infusion fluids
- Radiopharmaceuticals
- Sterile solids
- Sterile suspensions
-Ophthalmic solutions, suspensions, and ointments
-Solution for irrigation
- Diagnostic agents
- Peritoneal dialysis solutions
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Parenteral products are dosage forms intended for
administration by injection, infusion or implantation.
Major routes of Parenteral administration:
Intradermal
Subcutaneous
Intramuscular
Intravenous
Intra-arterial
Intraspinal
Intra-articular
Hypodermoclysis
Intracardiac
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Subcutaneous (21)
Intravenous (21)
Intradermal (23)
Intramuscular (20)
Intra arterial (20-22)
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Official Types of Injections:
1. Solutions of Medicinal
Example: Codeine Phosphate Injection
Insulin Injection
2. Dry solids or liquid concentrate does not contain diluents
etc.
Example: Sterile Ampicillin Sodium
3. If diluents present, referred to as.....for injection
Example: Methicillin Sodium for injection
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4. Suspensions
"Sterile....Suspension"
Example: Sterile Dexamethasone Acetate Suspension
5.Dry solids, which upon the addition of suitable vehicles yield
preparations containing in all respects to the requirements for
sterile suspensions.
Title: Sterile....for Suspension
Example: Sterile Ampicillin for Suspension
6. Injectable Emulsions:
Example: Propofol injection
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•
Formulation of Parenteral:
1. Therapeutic agents
2. Vehicles
i. Water
ii. Water miscible vehicles
iii. Non- aqueous vehicles
3. Added substances (Additives)
i. Antimicrobials
ii. Antioxidants
iii. Buffers
iv. Bulking agents
v. Chelating agents
vi. Protectants
vii.Solubilizing agents
viii.Surfactants
ix. Tonicity- adjusting agents
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Commonly Used IV Abbreviations
Fluids
IV Component
Abbreviation
2.5% dextrose in water
D2.5W
5% dextrose in water
D5W
5% dextrose and lactated Ringer’s solution
D5RL or D5LR
10% dextrose in water
D10W
5% dextrose and normal saline
D5NS
2.5% dextrose and 0.45% normal saline
D2.5½ NS
5% dextrose and 0.45% normal saline
D5 ½ NS
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Commonly Used IV Abbreviations:
Fluids
IV Component
Abbreviation
Normal saline
NS
0.45% normal saline
0.45%NS or ½ NS
lactated Ringer’s solution
RL or LR
sterile water for injection
SWFI
bacteriostatic water for injection
BWFI
sterile water for irrigation
SW for irrigation
normal saline for irrigation
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NS for irrigation
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Commonly Used IV Abbreviations:
Electrolytes
IV Component
Abbreviation
potassium chloride
KCl
potassium phosphate
K phos or KPO4
potassium acetate
K acet
sodium phosphate
Na phos or NaPO4
sodium chloride
NaCl
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Commonly Used IV Abbreviations:
Additives
IV Component
Abbreviation
multivitamin for injection
MVI
trace elements
TE
zinc (a trace element)
Zn
selenium (a trace element)
Se
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Liquid drugs are supplied in prefilled syringe, heat-sealed
ampoules, vials sealed with rubber closure.
• Ampoules are intended for single dose only, do not provide
dose flexibility.
 A 5 micron filter needle should be used when drawing the
contents of an ampoule into a syringe since glass particles
may have fallen inside the ampoule when the top was
snapped off.
 It is useful to wrap an alcohol wipe or small piece of gauze
around the top of the ampoule before breaking it.
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2
1
3
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• Vials may be designed for single-dose or multi-dose use (contain
preservative). Glass or plastic container
 Advantages:
 The product is easier to remove from vials than form ampoules.
 The vials can hold multiple doses.
 Eliminate the risk of glass particles contamination during opening.
 Some drugs are not stable in liquid form and so are put into the
powder form and reconstituted before use.
 Disadvantages:
 The rubber stopper can become cored
causing a small bit of rubber to enter the solution.
 Possible error in dose calculation
 Increased waste
 Increased microbial contamination
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1
2
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Double chambered
vials
Mix-O-Vial (Upjohn)
• Can be used to package a sterile powder with its vehicle.
• The top chamber contain sterile water for injection, is separated from the
bottom chamber holding the sterile powder by a rubber plug located at the
constriction of the container.
•
External pressure is applied to the outer rubber closure to dislodge the
inner closure and mix the contents of the components. Ex.: Solu-Cortef,
kefzol.
• A convenient way to separate unstable drug from the diluent
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Prefilled disposable cartridge or syringes:
• Are designed for maximum convenience. The injection is
filled into a glass cartridge with needle attached and
administered with a reusable stainless steel or plastic holder.
• The other type of prefilled syringe consists of a glass tube
closed at both ends with rubber stoppers. The prefilled tube is
placed into a specially designed syringe that has needle
attached to it.
• After using this type of prefilled syringe, all of the pieces are
discarded.
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Advantages:
Ease of administration,
reduction of medication error,
increase assurance of sterility,
good control of drugs (narcotics),
adequate labeling save nurses' time.
Emergency drugs as:
Sodium bicarbonate, epinephrine,
Ca chloride, lidocaine, atropine are available for
use as IV in this type of prefilled syringe.
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i
ii
Syringe tips:
i- Luer-Lok Tip
ii- Luer-Slip Tip
iii- Eccentric Tip
iv- Catheter Tip
iv
iii
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Intravenous Access Devices
Syringes: are devices for injection, withdrawing fluids.
Syringes
consist
with
of
a
glass
tight-fitting
or
plastic
plunger
barrel
and
tip
provides the point of attachment for a
needle.
The barrel is graduated in milliliters.
Glass reusable, glass disposable, plastic disposable.
Syringe volume: 1-60 ml
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• Insulin syringe is graduated in units of insulin (40,
80, 100 unit/ml)
• Tuberculin syringes have capacity of 1 ml, a volume
of 0.05 ml can be measured with accuracy.
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The Needle:
Transfer needle
16 and 19 gauge thin-wall needles for fluid transfer
from a unit-of-use vial to a bag or evacuated IV bottle
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Different bevels:
are slanting edges cut into needle tips
Regular bevel: used for IM and
SC
Short bevel: used for IV and
intraspinal
True short bevel: used for
intradermal administration
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• Various needle lengths are available: range from 1/4 to 6
inches (in).
• The choice depends on the site of administration, the depth of
penetration into the body.
• Compounding parenteral 1 1/4 in
• IM
• I.D , SQ
1-2 in
1/4 - ⅝ in
• IV infusion 11/4 - 2 1/2 in
• Intracardiac 3 1/2 in
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• Needle gauge: is the outside diameter of the needle shaft.
• Gauge in common range from 13-to 27.
• The choice of gauge depends on the viscosity of the fluid to
be injected or withdrawn.
• Intradermal require 24-26 G
• S.Q require 24-25 G (insulin)
• IM require 19-22 G
• Compounding Parenteral 18-20 G
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The French catheter scale or "French units" (F) is commonly
used to measure the outside diameter of needles, catheters,
and other cylindrical medical instruments.
In the French system, the diameter in millimeters of the
catheter can be determined by dividing the French size by 3.
D(mm) = F/3 or F = D(mm) * 3
For example,
if the French size is 9, the diameter is 3 mm.
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IV Sets
An IV administration set is a sterile, pyrogen-free disposable
device used to deliver IV fluids to patients
The set may be sterilized before use by means of radiation or
ethylene oxide
 The set come in sterile packaging and a sealed plastic wrap
 Sets carry expiration dates
 Sets carry the following legend:
“Federal law restricts this device to sale on the order of a
physician.”
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Each unit is supplied in packaging that ensures the maintenance of
sterility
Flanges and other rigid parts of an IV set are molded from tough
plastic
Most of the length of the tubing is molded from a polyvinyl chloride
(PVC)
PVC sets should not be used for
nitroglycerin, which is absorbed by the tubing
IV fat emulsions, which may leach out of the tubing
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The length of sets varies from 6-inch extensions up to 110- to
120-inch sets used in surgery
the priming of tubing depends on the length of the set
Standard sets have a lumen diameter of 0.28 cm
varying the size of the lumen diameter achieves different flow
rates
regulation of flow rates is critical in neonates and infants
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Intravenous administration set:
 Plastic spike to pierce the rubber closure or plastic seal on the IV
container
 A drip chamber to trap air and permit adjustment of flow rate
 150-450 cm length polyvinyl chloride tubing terminating in
 A gum-rubber injection port ending with rigid needle or catheter
adapter
 An adjustable clamp (screw or roller type) on the tubing to regulate
flow
 Air-inlet filters designed as part of the administration set (used with
glass container that have no air tubes ).
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• The most convenient site is often the arm, especially the veins
on the back of the hand, or the median cubital vein at the
elbow, but any identifiable vein can be used.
• Often it is necessary to use a tourniquet which restricts the
venous drainage of the limb and makes the vein bulge.
• Once the needle is in place, it is common to draw back slightly
on the syringe to aspirate blood, thus verifying that the needle
is really in a vein. The tourniquet should be removed before
injecting to prevent extravasation of the medication.
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Different Types of IV Containers
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Preparing IV solutions
•
Preparation should always be done under the
supervision of a licensed pharmacist
• Medication that is prepared by the technician must be
reviewed and approved by the pharmacist
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• Begin any IV preparation by washing your hands thoroughly
using a germicidal agent such as chlorhexidine gluconate or
povidone-iodine
• All jewelry should be removed from the hands and wrists
before scrubbing and while making a sterile product
• Wear gloves during procedures
• Laminar airflow hoods are normally kept running
• The exterior surfaces of the hood should be disinfectant
weekly with 70% isopropyl alcohol.
• Before making the product, thoroughly clean all interior
working surfaces using sterile gauze with 70% isopropyl
alcohol
• Prefilters in the laminar -airflow hood will be cleaned
monthly.
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• Eating, drinking, talking, or coughing is prohibited in the
laminar airflow hood
• Working in the laminar flow hood should be free from
interruptions
• Gather all the necessary materials for the operation and
make sure they are:
– not expired
– free from particulate matter such as dust
– check for leaks by squeezing plastic solution containers
• Only essential objects and materials necessary for product
preparation should be placed in the airflow hood.
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• Work in the center of the work area within the laminar airflow
hood
– at least six inches inside the edge of the hood
– make sure nothing obstructs the flow of air from the highefficiency particulate air (HEPA) filter over the preparation
area
– nothing should pass behind a sterile object and the HEPA
filter.
– Minimize hand movements within the hood.
– Swab all surfaces require puncture with 70% isopropyl
alcohol or betadine solution.
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• Follow proper procedure for handling sterile devices and
medication containers
• Remember that the plunger and tip of the syringe are sterile
and must not be touched
• For greatest accuracy, use the smallest syringe that can hold
the desired amount of solution
– syringe should not be larger than twice the volume to be
measured
– Examine all formulations before removing them from the
hood
– Place all syringes and needles in puncture-proof
containers
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• Follow proper procedure for handling sterile devices and
medication containers
• Remember that the plunger and tip of the syringe are sterile
and must not be touched
• For greatest accuracy, use the smallest syringe that can hold
the desired amount of solution
– syringe should not be larger than twice the volume to be
measured
– Examine all formulations before removing them from the
hood
– Place all syringes and needles in puncture-proof
containers
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• Follow proper procedure for handling sterile devices and
medication containers
• Remember that the plunger and tip of the syringe are sterile
and must not be touched
• For greatest accuracy, use the smallest syringe that can hold
the desired amount of solution
– syringe should not be larger than twice the volume to be
measured
– Examine all formulations before removing them from the
hood
– Place all syringes
proof containers
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NEVER TOUCH
Tip or Plunger
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• Peripheral IV injection
• This is the most common intravenous access method in both
hospitals and pre-hospital services.
• A peripheral IV line consists of a short catheter (a few
centimeters long) inserted through the skin into a peripheral
vein (any vein that is not inside the chest or abdomen). Ex.
Arms and hand veins are typically used.
• The scalp veins are sometimes used in infants
• This is usually preferred for drugs that don’t irritate the veins
• Patients require short-term IV therapy
• Administration of isotonic solutions.
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• Peripheral venous catheters
problems 20 to 50% of patients
will
likely
cause
– pain
– irritation
– infiltration
• Infiltration is a breakdown or collapse of a vein that
allows the drug to leak into tissues surrounding the
catheter site, causing edema and/or tissue damage
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Venflon intravenous cannula
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Parts of I.V. cannula
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• Special consideration:
The size of cannula effects four factor;
• Needle guage
• External diameter of cannula i.e. its catheter
• Length of catheter
• Flow rate i.e. ml/min
• As the gauge number increases the cannula size decreases
(14 largest and 24 smallest)
• Larger the gauge number is (24G) smaller the
cannula/diameter is (0.7mm)
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Butterfly catheter — a metal needle with flexible plastic ‘wings’ and a
short length of tubing. The ‘wings’ assist in placement and facilitate
fixation with tape.
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Central IV lines
• Central IV lines flow through a catheter with its tip within a
large vein, usually the superior vena cava or inferior vena
cava, or within the right atrium of the heart.
This has several advantages over a peripheral IV:
• It can deliver fluids and medications that would be overly
irritating to peripheral veins because of their concentration or
chemical composition.
• These include some chemotherapy drugs and total parenteral
nutrition.
• It is used when patients require long-term IV therapy.
• Multiple medications can be delivered at once.
• Medications reach the heart immediately, and are quickly
distributed to the rest of the body.
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• Central IV lines carry risks of bleeding, infection, gangrene,
thromboembolism and gas embolism.
• They are often more difficult to insert correctly as the veins are
not usually palpable and rely on an experienced clinician
knowing the appropriate landmarks and/or using an ultrasound
probe to safely locate and enter the vein.
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Methods of IV administration
Injection
Infusion
Continuous
Intermittent
Piggyback
Partial fill
Manufactured reconstituted
Frozen
Liquids
prefilled piggyback
Mini-infusion
Volume control set
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• Methods of IV administration
• Continuous drip infusion: is the slow primary-line infusion
of an IV preparation to maintain a therapeutic drug level or
provide fluid and electrolyte replacement.
• This method achieve continuous, constant blood levels of the
drug.
• In many instances, drug therapy is accomplished initially by
IV push and then maintained slowly and constantly by IV
infusion.
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• Direct IV push (Bolus): The drug solution is administered in
a short time directly into a vein. The injection time is a matter
of minutes and varies with different drugs .
• Many drugs are given by IV push and are diluted further with
the vehicle to reduce the irritability on the vein.
• Not all drugs may be pushed IV
• Phenytoin and diazepam injections must be given by IV push
• They much be pushed at a specified rate that is slow enough
to prevent toxicity.
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• Intermittent infusion: allows drug administration at
specific intervals (e.g., every 4 h). has a "high"
infusion rate, alternating with a low programmable
infusion rate to keep the cannula open.
• The timings are programmable. This mode is often
used to administer antibiotics, or other drugs that can
irritate a blood vessel.
• Total parenteral nutrition usually requires an infusion
curve similar to normal mealtimes.
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• A piggyback is a small-volume parenteral admixture
that is attached to an existing IV line
• The piggybacked solution is infused into the tubing of
the running IV
– usually over a short time, from 30 minutes to 1 hour
• Some IV piggybacks are prepared in 250 mL solution
because they contain a medication that is irritating to
the veins
• In some cases, syringes are used instead of piggyback
containers to deliver medication into a running IV
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Figure 2: Hang primary solution
lower than secondary piggyback
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Automatic piggyback set with built-in
check valve
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Benefits of intermittent infusion:
The method is suitable for patients who don not
require administration of large amounts of IV fluids.
 It permits greater patient ambulation, as the
intermittent infusion injection devices do not require
continuous attachment to an IV bottle or bag.
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Prefilled partial-fill containers:
• Underfills, Mini-bottles: Partial-fill containers used for piggybacking are
250 ml capacity infusion bottles or bags underfilled with 50 or 100 ml of
5% D/W or normal saline solution.
• The drug is first reconstituted in its original vial and then added by needle
and syringe to the underfill which receives an administration set complete
with needle.
• The needle is inserted into the Y-site or gum rubber injection port of a
hanging primary infusion set.
• Flow of the primary IV fluid is stopped while the drug solution in the
partial fill container is administered (30-60 min).
• The primary fluid is reestablished.
• When the next dose of drug is required, the piggyback procedure is
repeated
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Prefilled piggyback units
• A mini-bottle (100 ml capacity) prefilled with a specific amount of dry drug
(antibiotic).
• The piggyback solution is administered through the gum rubber injection
site or Y-type facility of an existing IV system.
• Reconstitution of drug in a piggyback unit requires only addition of small
volume of diluent.
• No drug transfer is involved, transfer syringe and additional IV containers
are not necessary
• Great ease in handling, reduction in cost, patient safety, reduced
potential for solution contamination.
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Premixes
• Frozen drug products packaged in PVC containers.
• The frozen products are stored in a freezer in the hospital
pharmacy and thawed and used when needed
• Ex: Cefazolin, Cephalothin, cimetidine, cefotaxime.
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• Rate of flow of IV fluids is based on variety of factors:
• Patient’s body area and age
Nomograms are used to calculate body SA
• Composition of the fluid to be administered
• Patient’s ability to assimilate the fluid.
• The usual flow rate of low-viscosity isotonic solutions is app. 125ml/h or
1L / 8h
• Highly hypertonic solutions are administered at a rate not exceeding
1L /8 h or 3L /24 h. (exception, blood loss, shock, the rate > 1L /1 ½ h)
• Order is written as KVO (keep vein open), i.e. the rate of administration
would be slow (5ml/h).
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• Pumps An IV pump is a medical device used to deliver
intravenous fluids and medicines, via a catheter, to patients in
hospitals, ambulances, clinics, ambulances, and other
healthcare environments.
• IV pumps are used throughout hospitals, including emergency
rooms, intensive care units, surgery suites, and pediatric
units.
• IV pumps are also used in home healthcare environments by
personal users.
• IV pumps can deliver antibiotics, pain medicines, and
nutrients, chemotherapy, cardiac medications and blood
products.
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• Types of pump
• There are two basic classes of pumps.
• Large volume pumps can pump nutrient solutions large
enough to feed a patient.
• Small-volume pumps infuse hormones, such as insulin, or
other medicines, such as opiates.
• Within these classes, some pumps are designed to be
portable, others are designed to be used in a hospital.
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Benefits of pumps:
• They maintain a constant, accurate flow rate
• They detect infiltration, occlusions and air
• Pumps decrease the time of a nurse spends
dispensing medications
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Types of pumps:
• 1- Volumetric pump: are used for intermittent infusion of
medications such as antibiotics, also used for continuous
infusion of IV fluid, Parenteral nutrition
• 2- Syringe pump: are used to administer intermittent or
continuous infusion of medication in concentrated form
• 3- Mobile infusion pump: is small device designed for
ambulatory and home patients, used for chemotherapy, and
opiate medications
• 4- Implantable pump: are infusion device surgically placed
under the skin to provide a continuous release of medication,
typically an opiate, this type has a lower index of infection
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• 5-patient-controlled analgesia (PCA), in which repeated small
doses of opioid analgesics are delivered on demand, with the
device coded to stop administration before a dose that may
cause hazardous respiratory depression is reached.
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 The National IV Therapy Association (NITA) has published
standards of care to minimize all IV-related complications.
 Strict aseptic technique should
cannulation, during admixture.
be
followed
during
 If hair removal is necessary, it should be cut with scissors and
not shaved.
 The insertion site must be prepared with disinfectant prior to
cannulation (70% alcohol, povidone iodine).
 The cannula should be securely anchored to prevent
mechanical irritation.
 The puncture should be covered with a sterile dressing
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 Injection port should be disinfectant immediately prior to
use.
 All peripheral IV cannula should be changed every 48-72 h.
 All IV solution containers should be used or discarded after
24 h.
 All IV tubing and component parts should be changed every
24-48 h
 All insertion sites should be checked every 8 h. The site
should be palpated to detect any tenderness, edema, redness.
 The site should be changed immediately at the first site of
any complication.
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