In recent years, physician enthusiasm for the protection provided by newly licensed vaccines has been tempered by concerns about the pain and adverse reactions associated with additional injections. Physician and parent anxiety about multiple simultaneous injections is widespread and often leads to the withholding of scheduled vaccines.1'5 Specifically, concern about multiple injections has limited universal acceptance of hepatitis B and varicella vaccines.6,7 In addition, these injection-related worries are a significant obstacle to adding new vaccines to the immunization schedule as they are developed and licensed. Soon, new parenteral vaccines will be available to protect infants from pneumococcal and meningococcal diseases. Resistance to the addition of injections denies children the protection afforded by these advances in immunization biotechnology.
Interestingly, recent studies indicate that parents will agree to multiple injections if their child's pediatrician strongly recommends it.8,9 This suggests that promoting physician willingness to recommend simultaneous administration of all scheduled vaccines (as directed by Pediatric Immunization Practice Standard #8)10 is the key to overcoming missed opportunities to immunize during well care visits. The purpose of our article is to enhance physician knowledge about methods to reduce the pain and adverse reactions associated with vaccination. We hope that, by incorporating these techniques into routine practice, pediatricians will have less cause to withhold valuable vaccines, and children and parents will experience less distress with immunization.
REDUCTION OF ADVERSE REACTIONS
The more common adverse reactions to parenteral vaccines include fever and local injection-site pain and inflammation. Less frequent reactions of note include allergic reactions and a variety of neurologic and non-neurologic complications associated with a variety of vaccines.
Parents do consider fever and other common adverse effects in their acceptance of vaccines.11 Although fever itself should not be construed as necessarily harmful, it certainly can be discomforting to the child and distressing to the parent. Furthermore, fever from a vaccine may lead to a febrile convulsion and insinuate the vaccine as a cause of more sinister neurologic sequelae. 12,13
The main approaches to fever control with vaccination have been prevention and treatment. The mainstay of both prevention and treatment have been in the use of acetaminophen. A landmark randomized, placebo-controlled trial compared a multipledose regimen of acetaminophen given at the time of DTP vaccination and repeated every 4 hours for two additional doses. That study demonstrated a statistically significant decrease in local and systemic reactions and a halving of the rate of fever.14 The Advisory Committee on Immunization Practices recommends acetaminophen to prevent post-vaccination fever in children at risk for febrile convulsions.15 A second randomized clinical trial found similar results. In that study, acetaminophen or placebo was given at the time of vaccination and at 3, 7, 12, and 18 hours afterward.16 The investigators found that acetaminophen in a multiple-dose regimen was effective in reducing fever, pain, and fussiness. In this study, no statistically significant difference was noted on local redness and swelling. In a third trial, however, a single dose of acetaminophen did not appear to prevent fever after DTP vaccination.1'
The acellular form of the pertussis vaccine produces significantly less fever18 and thus the need for prevention may be less compelling. No studies to date have examined the impact of acetaminophen prophylaxis in those receiving acellular pertussis. Certainly studies have shown far less use of acetaminophen to treat fever following the administration of acellular pertussis-containing vaccines as contrasted with whole cell pertussis-containing vaccines.19'22 One study measured fever occurring in 31% of those having received acellular pertussis vaccine. This contrasts with an occurrence rate of 63% in those who received the whole-cell pertussis vaccine.20 Rates of fever following the administration of other vaccines are usually less than that seen with acellular and whole cell pertussis vaccines.
Experts have also proposed the use of Ibuprofen, an otherwise commonly used over-the-counter antipyretic. The Vaccine Information Statement produced by the Centers for Disease Control and Prevention (CDC) for DTP specifically suggests Ibuprofen as an equivalent alternative to acetaminophen to prevent or reduce the fever and soreness commonly associated with the vaccine. Currently, however, no published research demonstrates ibuptofen's safety or efficacy in the prevention or treatment of DTP-induced fevers. Ibuprofen has powerful vasoactive effects at the kidney, heart, and brain in neonates. The US has not licensed the use of Ibuprofen for children under 6 months. Furthermore, Ibuprofen has a relatively high rate of gastrointestinal adverse effects. Thus, in older but preverbal infants and toddlers, Ibuprofen may produce gastrointestinal discomfort that may mimic irritability from vaccination and lead to a vicious cycle of dosing.
Other Adverse Reactions
Acetaminophen has appeared to be effective in preventing local inflammation and systemic reactions other than fever with the DTP vaccine.14·16 Otherwise, the main approaches to the prevention of local injection site inflammation (pain, redness, swelling, and warmth) have focused on needle technique and site of vaccination. Using longer needles (1 inch or 25mm) rather than shorter needles (5/8 inch or 16mm) for the intramuscular injection of DTP decreased redness and swelling.23 In a study of 18-month-old children, parents viewed the reactions associated with thigh injections as more often moderate or severe than with deltoid injections.23 A study using ultrasound to examine injection depth found similarly less pain with a longer needle, which correlated with true intramuscular injection as compared with subcutaneous injection.
Along these lines, studies of granulomas formed after injection found that almost all formed in the subcutaneous tissues. These studies suggest that granuloma formation after intramuscular injection resulted from inadvertent injection of the subcutaneous tissues with an aluminum salt containing vaccine such as DTP.24'28 One should take care then to use a long enough needle to administer vaccines in a truly intramuscular fashion.29,30
Multiple vaccine-administration does increase the rate of local and systematic reactions31 but allows the child to be fully immunized at each opportunity. A significant proportion of clinicians withhold administration of multiple vaccines apparently to prevent pain, reactions, and psychological distress - more so in private practice than in public health clinics.32 Nevertheless, because the reactions are generally minor,31 these fail to provide a reason to withhold multiple vaccinations when indicated.33
The prevention of other adverse effects has depended primarily on avoiding giving vaccines to those patients who have contraindications such as previously recognized allergies to specific vaccines or vaccine constituents. Clinicians providing vaccines should remain prepared to handle anaphylaxis as well as other allergic reactions, panic, and syncope.
REDUCTION OF PAIN AND DISTRESS
Injections are among the most aversive medical procedures for children.34,35 If efforts are not made to help them cope, children may become more distressed with each procedure rather than get used to them.36 Such needle-related distress often adversely affects children's relationships with their healthcare providers. Pediatricians and parents commonly hear children ask fearfully at the outset of the pediatric visit, "Am I going to get a shot?" Consequently, we must aim to reduce pain and distress, combining nonpharmacologic and pharmacologic techniques at each child's immunization procedure.
Nonpharmacologic methods, which include cognitive-behavioral techniques, are the least expensive, safest, and easiest to incorporate into pediatric practice. Although they appear to be quite simple, use of these methods alone can effectively reduce the pain and distress of many pediatric procedures, including vaccination. Their effect is even further enhanced when they are combined with a pharmacologic paincontrol component.
The success of cognitive-behavioral techniques can best be explained through a brief review of the physiology of pain perception, including the gatecontrol theory of pain.37 AU pediatricians have noted that the same noxious stimulus (eg, DTP vaccination) produces markedly different pain and distress responses among children, even of the same age. Parents will recall that even for the same child, the same stimulus can prompt different reactions. The reason that the same amount of tissue injury does not produce the identical response in different individuals, or in the same individual at different times, is that the ascending pain impulses generated by the tissue injury are modulated ("gated") by other influences, including impulses descending from the brain (Figure 1). Cognitive and emotional techniques appear to work through activation of the endogenous pain inhibitory system, which dampens the effect of the noxious stimulus and lessens the degree of pain perceived. An excellent example, which parents and pediatricians will appreciate, is the immediate pain reduction provided to a toddler by a parent's kiss on a skinned knee. The toddler's belief in the power of the parent's kiss to "make it all better" actually lessens his perceived pain as it blocks ascending pain impulses from the injured knee.
Figure 1 . According to the gate control theory, pain perception is not a simple function of the amount of tissue damage, but rather is the result of active modulation of the incoming sensory input by the central nervous system. This modulation includes: 1) the "gating" of incoming nociceptive (noxious sensation) input as a function of the firing of afferent fibers in the dorsal horn of the spinal cord, and 2) modification through descending pathways from higher levels of the central nervous system, including the limbic system and the cerebral cortex, to the dorsal horn. These descending pathways are influenced by a range of cognitive (eg, attention, understanding, expectation) and affective (eg, anxiety, fear, confidence, trust) factors. Methods to reduce perceived pain from injection-related tissue injury utilize both the gating and descending inhibitory mechanisms.
Nonpharmacologic interventions include behavioral, cognitive, interactional, and physical strategies to decrease pain and distress associated with immunization. For all age groups, physical interventions should be utilized to reduce tissue damage and optimize gating of pain impulses. To limit tissue injury, injections should be performed with a rapid puncture of the skin at a 90° angle, a slow instillation of the vaccine over several seconds, and a quick, smooth withdrawal.38 Rubbing or applying firm pressure to the injection site before and after the immunization can directly reduce the sensation of pain by stimulating nerve fibers that activate a pain gating mechanism in the dorsal horn of the spinal cord.39,40 The choice of additional nonpharmacologic methods of pain control is directed by the child's developmental level.
Figure 2. A 4-year-old child, supported by his mother, practices blowing on a pinwheel while a vapocoolant-saturated cotton ball is applied to the injection site 15 seconds prior to immunization.
For infants, nonpharmacologic pain control strategies include external comfort measures such as swaddling and providing a pacifier,41 having the parent hold and soothe the infant, and offering a distracting activity. There also is evidence that newborns' procedure-related distress can be reduced by allowing them to suck pacifier dipped in a sucrose solution42 (one standard packet of table sugar dissolved in 10 cc water);43 however, use of this "sucrose analgesia" alone is less effective in children beyond the newborn period.44 In addition, attempts should be made to reduce baseline distress (hunger, fatigue) before the procedure. Infants who are already aroused will react with greater intensity to the painful stimulus than those who are calm and relaxed.43
Once children become toddlers, new possibilities exist for the nonpharmacologic management of pain. Children as young as 2 years can benefit from more formal preparation, including the provision of simple procedural and sensory information about the upcoming procedure.46·4' The information provided needs to be geared to the child's developmental level and the word "shot" avoided, lest the child think they are in fact going to be shot. Sensory words like "sting" or "prick" should be substituted for words like hurt and pain, so as not to provide the child with a self-fulfilling prophesy. Speaking to the child with hopeful language, such as "you may be surprised by how quick we get this done" may also help reduce fear and anxiety. As with infants, distraction techniques can also be helpful. Some distracting activities include having children blow bubbles, party blowers, or pinwheels, taking deep breaths while imagining they are blowing out birthday candles, having them look at pop-up or similarly involving picture books, and engaging the child in a conversation about something that is special to them like a favorite toy, pet, or story.48,49 Noting that the needle makes a hole in their skin, toddlers can become very concerned about body integrity, fearing they will bleed uncontrollably or that the vaccine will leak out. The application of an adhesive bandage can usually quell these fears, and allowing the child to choose a particular bandage design may also prove useful for reducing injectionrelated distress.
Preschool and Early School-aged Children
Several techniques have been identified as helpful in reducing vaccination-related fear and pain. In addition to the distraction techniques described above, listening to music with headphones50 or watching a cartoon videotape51 reduces distress in this age group. Parent behaviors that aim to distract the child, such as non-procedural talk and humor, as well as prompts to the child to engage in coping behaviors (eg, deep breathing), also reduce child distress.32'" In contrast, excessive parental reassurance, criticism, and apologies to the child are ineffective at reducing children's distress'6 and in some cases increase the child's distress.53'55 Because nearly all children prefer to have a parent present,57 pediatricians should give parents specific instructions in assisting their children.
Figure 3. Two available forms of vapocoolant spray, Ethyl Chloride and Fluori-Methane®, are shown. The spray is applied to the skin either directly or with a saturated cotton ball immediately prior to the injection (Photograph reproduced with permission of Gebauer Company, Cleveland, OH).
Figure 4. EMLA® Cream, shown in the 2-dose (5-gram tube) form, is applied to the skin 60 minutes prior to injection and covered with the occlusive dressing provided (Photograph reproduced with permission of Astra, USA, Inc., Westborough, MA. EMLA® is Astra's registered trademark.
School-aged and Adolescent Children
School-aged and adolescent children benefit from many of the distraction techniques mentioned above. They also can make use of additional techniques that take advantage of their cognitive maturity. For example, it is helpful to get the child's perspective on the upcoming immunization to identify and to help dispel any "catastrophizing" thoughts the child may have. Children can be encouraged to consider adaptive selfstatements whereby they silently repeat coping statements to themselves (eg, "I can do it")- This technique may be especially helpful if practiced well ahead of the planned immunization. Asking children what has helped in the past may also uncover coping strategies they already have available to them. Talking with other children who have learned to cope with immunizations can provide the child with a peer model to assist in their coping efforts.46,58
Children aged 7 and older can learn to independently engage in other pain modifying techniques such as relaxation and self-hypnosis.36 With older children, the primary nonpharmacologic intervention is helping them identify their native abilities for coping with pain, offering them new skills or strategies as indicated, and prompting them to use them.
As described earlier, nonpharmacologic techniques are effective when used alone, but their effect will be further enhanced when combined with one of the pharmacologic components discussed below.
Local cooling has been used extensively for relief of acute and chronic pain, especially pain that is musculoskeletal in origin. It is inexpensive, has few side effects, and may be applied with ice, gel packs, or volatile liquid spray.59 Volatile refrigerant liquids, known as "vapocoolant sprays", provide cutaneous anesthesia by lowering the skin temperature through their rapid evaporation. Possible mechanisms of action include desensitized pain receptors60 or lowtemperature specific gating of the pain message.61
Vapocoolant spray was first described as a pain reduction method for injections in 1955 by Travell.62 Subsequently, vapocoolants have been shown to effectively reduce injection pain in infants and early school-aged children undergoing vaccination.63,64 We recently demonstrated in a study of 4- to 6-year-old children that, when combined with distraction (a pinwheel), vapocoolant spray is equally effective as EMLA cream in reducing vaccination pain, and both are superior to distraction alone.65
We have found that the advantages of vapocoolant spray include the low cost (less than $0.50 per child), rapid onset, and ease of application. Although the volatile liquid may be sprayed directly on the injection site, its fine, forceful spray may be perceived as noxious. Instead, we apply a liquid-saturated cotton ball to the skin, using forceps to avoid cooling the nurse's fingers. After holding the cotton ball firmly on the site for 15 seconds, the liquid is allowed to evaporate (1-2 seconds). The skin will be maximally cooled for only 1 to 2 minutes, so care is taken to quickly clean the site with alcohol and administer the injection. Vapocoolant also is easily complemented by a nonpharmacologic cognitive approach. For optimal effect as well as improved acceptance of the cold liquid, children may be asked to think of their favorite cold things (eg, ice cream, snow balls) while the vapocoolant is applied. Older children respond favorably when they learn that vapocoolant is often used for professional athletes who are injured to help them "get back in the game." Such positive associations enhance the pain reduction effect and help the child achieve a sense of mastery with the immunization procedure.
Figure 5. The Numby Stuff® system, including the drug delivery and ground electrodes and the battery-powered electronic unit, provides effective local anesthesia in approximately 10 minutes (Photograph reproduced with permission of IOMED, Inc., Salt Lake City, Utah).
Adverse reactions to vapocoolant spray are reported to include skin sensitivity if the vapocoolant spray is applied repeatedly. In addition, the time of exposure should be limited to approximately 15 seconds because freezing of the skin may occur if the liquid is applied to the skin for an excessive amount of time. Environmental concerns also should be considered. Ethyl chloride, the liquid used in the original study by Travell, is flammable. Currently, the common alternative nonflammable liquid, Fluori-Methane® (Gebauer Company, Cleveland, Ohio), contains fluorocarbons. A new nonflammable, fluorocarbon-free compound is currently under development by the manufacturer.
The introduction of EMLA cream (Eutectic Mixture of Local Anesthetics, Astra Pharmaceutical Products, Inc., Westborough, MA) in the late 1980s represented a breakthrough in delivery of local anesthetics . Prior to its conception, topical anesthetics were applied by injection, as transdermal absorption (ie, via intact skin) was limited. EMLA's name indicates the process by which its components, 2.5% lidocaine and 2.5% prilocaine, achieve enhanced transdermal absorption. In this eutectic mixture, the lidocaine -prilocaine combination has a lower melting point than either component has independently, allowing it to be a liquid at room temperature. Created as an oil- in- water emulsion, EMLA achieves higher effective concentration of the anesthetics, stimulating improved absorption at lower total drug concentrations. EMLA cream has been shown to penetrate to a depth of 5mm, effectively reducing pain in numerous pediatric procedures, including injections.66-69
Despite its proven efficacy, EMLA has not been widely accepted for pain reduction for routine vaccination. The most likely reasons are inconvenience and expense. To provide adequate anesthesia, EMLA cream must be applied to each injection site at least 60 minutes prior to the procedure, which may prolong the office visit. Parents may be trained to apply EMLA cream at home prior to the visit, but explicit instructions are necessary to ensure that the correct sites are treated and that the cream is not left in contact with the skin for a longer time than prescribed. The cost of EMLA is also a consideration. The pharmacy charge is approximately $15.00 for a 2 -dose tube ($7.50/dose). Although this cost may be covered by insurance for some families, EMLA may be prohibitively expensive to adopt as part of the standard immunization routine.
Pain Reduction Methods for Immunization Injections
Common side effects of EMLA cream include transient blanching and erythema of the treated skin, which resolves in 1 to 2 hours. In addition, children may complain about the sensation of the occlusive adhesive dressing (6 cm x 7 cm) that covers the cream, especially at the time of its removal. It is important that parents ensure that children do not inadvertently traumatize the anesthetized area by scratching or rubbing, until sensation returns (1 to 2 hours after removal of the cream). Finally, there are patients for whom the use of EMLA is contraindicated: infants younger than 1 month, children taking class I antiarrhythmic drugs, and children at increased risk of prilocaine-induced methemaglobinemia (children with rare congenital or idiopathic methemoglobinemia, and infants younger than 12 months or children with G6PD taking methemoglobinemia- inducing agents, eg, sulfonamides).
Figure 6. The Biojector 2000*. a handheld, C02-powered device used for immunization. The sterile, disposable cartridge shown in the foreground is filled manually with vaccine prior to insertion into the device (Photograph reproduced with permission of Bioject, Inc., Portland, OR, USA).
Iontophoresis is a mode of transdermal drug delivery in which a mild electric current drives ionized substances across the epidermis. During the passage of the painless electric current, positively or negatively charged drug particles (ions) are repelled into the skin by an identical charge on the electrode surface placed over it.70
The total amount of drug delivered is related to the amount of drug available for transport, the surface area of the drug delivery electrode, and the total delivery current (expressed in mA-min).71 This method can be used to deliver many medications into and across the skin, including topical anesthetics.
For pre-injection iontophoresis (commercially available as Numby Stuff [lomed, Salt Lake City, UT]), a drug delivery electrode hydrated with lcc of lidocaine is placed on the site to be anesthetized, and a second ground electrode is placed more than 4 inches from the first. Both electrodes are attached to the small battery powered electronic unit. A low level direct current (approximately 3 mA) is applied for 7 to 10 minutes to achieve a dose approximately 30 mA/min. Iontophoretic delivery of lidocaine has been shown to effectively reduce the pain of injections,72,73 but it has not specifically been studied for immunization injections.
The cost of Numby Stuff is equivalent to EMLA cream ($7.50/dose), if large quantities are purchased ( 1 power unit provided without charge for each 150 dosekits purchased). Adverse reactions of lidocaine iontophoresis are similar to EMLA cream, including transient erythema and blanching, as well as paresthesias during the application of the electric current. Although lidocaine iontophoresis offers the advantages of more rapid onset (10 minutes) and greater penetration (up to 10 mm) than EMLA cream, it may be more cumbersome to set up multiple power units for simultaneous injections. However, its rapid absorption makes iontophoresis attractive for other painful procedures, such as intravenous cannulation.71
For all three pharmacologic methods discussed above, vapocoolant spray, EMLA cream, and iontophoresis, no data have been published regarding the impact, if any, on the immunogenicity of vaccines administered through treated skin.
NEEDLE-FREE JET INJECTION
Another means of avoiding needle phobia is to eliminate the needle drugs can be administered parenterally by shooting through the skin a fine stream of liquid under high pressure through a small orifice. The technique originated as aquapuncture in France in the 1860s and was revived in the late 1940s with the introduction of the first commercial, needle-free jet injector device designed to reduce the discomfort and needle phobia of insulin injections for diabetic children.74'78 Over the years, numerous other needle-free devices for self-administration of insulin were developed,79,80 and current models now occupy an established niche in this market. Among needle-free insulin jet injectors on the US market in 1998 were the Advantajet® and Gentlejet® (Health-Mor Personal Care Corporation, Bradley, IL), the Medi-Jector Choice™ (Medi-Ject Corporation, Minneapolis, MN), and the Vitajet® (Laguna Hills, CA).
High-Workload Jet "Guns" for Mass Immunization
Beginning in the 1950s, needle-free injectors achieved wide-scale application on the development of "high-workload" devices to vaccinate large numbers of persons in short periods of time. These jet "guns" are capable of administering several hundred vaccine doses per hour, often using fjigger-operated, hydraulically powered pistons to fill a chamber from stock vaccine vials as large as 50 doses.78,81,82 Recycling time between spring- or gas-powered injections can be as fast as every 5 to 15 seconds. Originally designed under military specifications, these high-workload devices are solidly built, relatively heavy (the hand-held components can weigh up to 1.2 kg [2.6 pounds]), and have a high capital cost (currently US $2,000-3,000). They require specialized training for routine maintenance and repair, but they are capable of delivering tens of thousands of injections before major overhaul of parts. Thus, they can reduce amortized costs to less than $0.01 per injection over their useful lifetime. Since the 1950s, they have been used to administer hundreds of millions of vaccine doses in military induction centers, epidemic situations, and mass immunization campaigns around the world.78 High-workload jet injectors available in recent years include the Am-O-Jet™ (American Jet Injector, Inc., Lansdale, PA), Med-E-Jet™ (Med-E-Jet Corporation, Cleveland, Ohio), and Ped-O-Jet™ (Keystone Industries, Cherry Hill, NJ).
Concern Over Multiple-Use Nozzle Devices
In the mid-1980s, an outbreak of hepatitis B was caused by noncompliant use of one high-workload model (Med-E-Jet™) in a weight loss clinic.83,84 Laboratory study of the device suggested blood on the nozzle surface and crevices could contaminate subsequent injections, even with the routinely recommended alcohol swabbing of the nozzle between injections. This raised concern that perhaps other jet injectors in which the same nozzle is used for multiple vaccine recipients may pose a risk of bloodbome pathogen transmission.85,86 Despite the extensive use of jet injectors, no other case of bloodborne disease transmitted between vaccinées has ever been documented. However, Mycobacterium chelonae contaminating a jet injector disinfectant solution infected eight patients in a pediatric clinic.87
Low- Workload Injectors for Routine Immunization
In contrast to high-workload jet injectors, smaller, lighter, less-costly devices have been developed that are more practical for routine clinical use. These "low-workload" devices generally use hand-wound springs or small CO2 gas cylinders for power and usually require more time to prepare between doses, because many do not reload automatically from multidose vials. They are commonly used to inject lidocaine for dental anaesthesia88 and have been used to administer antibiotics,77 corticosteroids,89 erythropoietin,90 growth hormone,91 heparin,92 local anesthetic and nerve blocks,93,94 morphine,92 preoperative pediatric sedation,95 tuberculin,96 and vitamins,97 as well as vaccines.
As with current high-workload models, some lowworkload jet injectors use the same permanent nozzle and distal fluid pathway for sequential injections, raising doubt as to their suitability for immunization clinics, where sterilizing nozzles between patients would be impractical.
New Generation Devices with Disposable Cartridges
A new generation of jet injector devices with a disposable fluid path to satisfy concerns about the safety of injectors with multiple-use nozzles are now coming on the market. The nozzle, with orifice, medicine chamber, and fluid piston, is disposed after each injection, and some are automatically damaged to prevent reuse. The Biojector™ 2000 (Bioject Inc., Portland, OR 97224, www.bioject.com/) is now used for immunization by a number of public and private clinics in the United States. Its disposable vaccine cartridges are filled manually just before vaccination. At a street price of about $550, plus the cost of disposables and maintenance, its overall amortized cost for each injection was estimated to be about $0.62.98
Another new-generation device (Mini-Imojet®, Pasteur-Mérieux Serums et Vaccins, Lyon, France)not yet marketed - uses a novel factory-prefilled vaccine vial (Imule®, Pasteur-Mérieux Serums et Vaccins, Lyon, France), which becomes the injector cartridge with its own disposable orifice and piston.99 Another inventive prototype (MEDi VAX™, Vitajet Corporation (Program for Appropriate Technology in Health, Seattle, WA), still in development, combines the advantages of disposable cartridges with the ability to fill them automatically from multidose vials, yielding a capacity of up to 1000 injections per day that rivals traditional highworkload devices.
Deposition and Immunogenicity
Drug or vaccine administered by jet injection spreads along paths of least resistance in a conical distribution - with apex at the injection site - and is generally more widespread than that achieved with needle injection.75100 Although fascia is harder to penetrate, deposition into muscle can be achieved depending on the thickness of the skin and the amount it is stretched taut, the angle of injection, and the force and width of the jet stream.74'76 However, these latter factors are not easily adjusted in most devices. Thus, jet injectors cannot, unlike needles, target precisely the deposition of the dose, some of which will remain in subcutaneous tissues and dermis. Nevertheless, studies with a variety of both live vaccines (eg, BCG,101 measles,102 smallpox,102,103 and yellow fever102,104) and inactivated ones (eg, cholera, diphtheria-tetanus-pertussis,99·105 hepatitis A,99,106 hepatitis B,107 influenza,81,99,108 plague, polio,109 tetanus,99 and typhoid99,110) have demonstrated that jet injectors produce immunogenic responses that are equivalent to and often higher than those produced by needle and syringe.
Needle-Phobia and Pain
Obviously, jet injectors eliminate the object of fear and avoidance among patients, and are thus reassuring.81'92 Various controlled and uncontrolled studies in adults and children generally report that a few patients describe no pain at all, a substantial proportion of subjects rate the pain of these devices to be less than with needles, and other subjects find no difference.74,76·81,97,109 Pain from jet injectors may correlate directly with increasing pressure of the jet, greater size of the orifice, larger volume of the dose, and higher chemical irritability of the vaccine.76,95,110
Jet injector orifice diameters usually vary from 0.08 mm - about the size of a mosquito proboscis75 - to 0.2 mm. This is several times smaller than a 2 5 -gauge needle (about 1.0 mm) and may account for the decreased pain compared with needles. Inactivated vaccines often contain somewhat irritating alum adjuvants, which is why they are recommended for intramuscular administration. Clinical trials and experience with jet injection of inactivated vaccines, however, indicate satisfactory tolerance and safety for this indication.
Adverse Events and Complications
Jet injection of inactivated adjuvanted vaccines do tend to produce somewhat higher rates of delayed local soreness or edema compared with control needle injections.99110 Jet injectors also result in slightly higher frequencies of blood appearing at the injection site, and subsequent ecchymosis74,76,78,81,91,92,95,99,109 or redness.106 If the limb moves in relation to the device during injection, laceration can result from the cutting effect of the jet stream.74,78,81 Other injuries have been reported,89,111 but probably at no greater frequency than trauma caused by needle and syringe.
Additional advantages of needle-free injection
Needles and syringes have other drawbacks besides inducing fear and pain in children (and some adults) and the effect on compliance with recommended immunizations: In many developing countries they are often improperly disposed of and are sometimes reused unsterile. Everywhere, they cause needlestick injuries. Needles and syringes are also not practical for vaccinating large populations quickly, a feature needed for epidemic control or global disease eradication programs. New-generation jet injector devices with disposable nozzles and cartridges to satisfy concerns over the safety of previous jet injectors are now coming on the market. Further improvements to increase the speed and convenience of loading these new devices, and studies to determine if reduced dose volumes would work, might increase their advantages over needle and syringe.
Anxiety about the excessive pain and adverse reactions associated with multiple immunization injections causes children to miss scheduled vaccines, and limits the acceptance of newly developed vaccines. Fortunately, many methods exist to reduce the injection-related pain and reactions that worry physicians and parents. These include administration techniques (such as proper needle length), nonpharmacologic and pharmacologic pain control interventions, and improved injection devices (such as needle-free jet injectors). Optimally, a combination of these methods will be chosen, based on the individual child, family, and staff needs, and applied at each vaccination. By adopting these techniques, pediatricians can enhance immunization protection of their patients, while reducing much of the unnecessary distress of children and parents.
1. Szilagyi PG. Rodewald LE. Humiston SG, et al. Immunization practices oí pediatricians and family physicians in the United States. Pediatrics. 1994;94:517-523.
2. Madlon-Kay D]. Haper PG. Too many shots.': Parent, nurse, and physician attitudes toward multiple simultaneous childhood vaccines. Ardi Fam Med 1994;3:610-61 3.
3. Woodin KA. Rodewald LE. Humiston SG. Carges MS, Schaff« SJ, Szilagyi PG Physician and parent opinions: Are children becoming pincushions from immunizations.' Ardi Pediatr Adoiesc Med. 1995;149:845-849.
4. Zimmerman RK. Schlesselman JJ. EWd AL, Mieczkowski TA. A national review to understand why physicians limit childhood immunizations. Ardi Pediatr Adoiesc Med. 1997:151*57-664.
5. Reis EC. Multiple scheduled injections contribute to missed opportunities to immunize during well care visits. Ambulatory Child Health. 1997:3(1, pan 2): 1 72
6. Freed GL, Borley WG Clark SJ, Konrad TR. Universal hepatitis B immunization of infants: Reactions iA pediamcians and family physicians over time. Pediatrics. 199453:747-751.
7. Reis EC. Introducing Varivax: parental pain concerns mav limit compliance Ardi Pediatr Adoiesc Med. 1996;150:P7C.
8 Kolisa M. Bisgard K. Prevoo R. et al. IPV or OPV: Will parents accept the new poliovirus vaccination recommendation? Pediatric Res. 1997:41:95A.
9. Melman ST, Nguyen TT, Weingast R, Schorr MD, Anbar RD. Parental compliance with multiple immunization injections. Ambulatory Child Health. 1997:3:162.
10. US Department of Health and Human Services, Public Health Service. Standards for Pediatric Immunization Practices. Atlanta. GA: National Immunization Program, Centers for Disease Control and Prevention; 1996.
11. Wischnack LL. Jacobson RM, Poland GA, Jacobsen SJ, Harrison JM, Murtaugh PA. The surprisingly high acceptability of low-efficacy vaccines for otitis media: a survey of parents using hypothetical scenarios. Pediatrics. 1995;95:350-354
12. Blumberg DA, Lewis K, Mink CM, Christeruon PD, Chatfield P, Cherry JD. Severe reactions associated with diphtheria-tetanus-pertussis vaccine: detailed study of children with seizures, hypotonic-hyporesponsive episodes, high fevers, and persistent crying (see comments]. Pediatrics. 1993;91:1 158-1 165.
13. Wentz KR, Marcuse EK. Diphtheria-tetanus-pertussis vaccine and serious neurologic illness: an updated review of the epidemiologic evidence. Pediatrics. 1991;87:287-297.
14. Ipp MM, Gold R, Greenberg S, Goldbach M, Kupfert BB. Lloyd DD, Maresky DC, Saunders N, Wise SA. Acetaminophen prophylaxis of adverse reactions following vaccination of infants with diphtheria-pertussis-tetanus toxoids-polio vaccine. Pediatr Infect Dis J. 1987;6:721-725.
15. Recommendations of the Immunization Practices Advisory Committee (ACIP): Pertussis immunization: Family history of convulsions and use of antipyretics. - supplementary ACIP statement. MMWR. 1987;36:281-282.
16. Lewis K, Cherry JD, Sachs MH, Woo DB, Hamilton RC, Tarie JM, Overturf GD. The effect of prophylactic acetaminophen administration on reactions to DTP vaccination. AmJDis Chili 1988;142:62-65.
17. Uhari M, Hiérala J, Viljanen MK. Effect of prophylactic acetaminophen administration on reaction to DTP vaccination. Acta Paediatr Scarni. 1988;77:747-751.
18. Schmitt-Grohe S, Stehr K, Cherry JD, Heininger U, Überall MA, Laussucq S, Eckhardt T. Minor adverse events in a comparative efficacy trial in Germany in infants receiving either the Lederle/Takeda acellular pertussis component DTP (DTaP) vaccine, the Lederle whole-cell component DTP (DTP) or DT vaccine. The Pertussis Vaccine Study Group. Developments m Biological Standardization. 1997;89:113-118.
19. Feldman S, Perry CS, Andrew M, Jones L, Moffitt JE, Lamb D, Meschievitz C. Primary immunization series for infants: comparison of two-component acellular and standard whole-cell perrussis vaccines combined with diphtheria-tetanus toxoids. South Med J. 1993;86:269-275,284.
20. Marcinak JF. Ward M, Frank AL, Boyer KM, Froeschle JE, Hosbach PHt. Comparison of the safety and immunogenicity of acellular (BIKEN) and whole-cell pertussis vaccines in 15- to 20-month-old children [erratum appears in Am J Dis Child 1993 Jun;147(6):626]. AmJ Dis Child. 1993;147:290-294.
2 1 . Englund JA. Glezen WP, Barrero L. Controlled study of a new five-component acellular pertussis vaccine in adults and young children. J Infect Dis. 1992:166:14361441.
22. Auerbach BS, Wilson ME, Lake AM, Deforest A, Steinhoff M. Halsey NA. Doseresponse to acellulat pertussis vaccine and comparison with whole cell pertussis vaccine at 15-24 months and 4-6 years of age. Acellular Pertussis Vaccine Study Team. Vaccine. 1992;10:14-20.
23. Ipp MM, Gold R. Goldbach M, Maresky DC. Saunders N, Greenberg S, Davy T Adverse reactions to diphtheria, tetanus, pertussis-polio vaccination at 18 months of age: effect of injection site and needle length [see comments). Pediatrics. 1989;83:679-682.
24. Miliauskas JR, Mukherjee T, Dixon B. Postimmunization (vaccination) injectionsite teactions. A report of four cases and review of the literature [see comments]. AmJ Surg Path. 1993;17:516-524.
25. Hendrick MJ, Dunagan CA. Focal necrotizing granulomatous panniculitis associated with subcutaneous injection of rabies vaccine in cats and dogs: 10 cases (19881989). J Am Vet Med Assoc. 1991;198:304-305.
26. Fawcett HA, Smith NP. Injection-site granuloma due to aluminum. Arch Dermatol. 1984;120:1318-1322.
27. Mrak RE. Muscle granulomas following intramuscular injection. Muscle & Nerve. 1982;5:637-639.
28. Haramati N, Lorans R, Lunvin M, Kaleya RN. Injection granulomas. Incramuscle or intrafat? Arch Fam Med. 1994;3:146-148.
29. Poland GA, Borrud A, Jacobson RM. McDermott K, Wollan PC, Brakke D, Charboneau JW. Determination of delroid fat pad thickness. Implications for needle length in adult immunization. JAMA. 1997;277:1709-1711.
30. Hick JF, Charboneau JW, Brakke DM, Goergen B. Optimum needle length fot diphtheria-tetanus-pertussis inoculation of infants. Pediatrics. 1989;84:136-137.
31. Falvo C, Horowitz H. Adverse reactions associated with simultaneous administration of multiple vaccines to travelers. J Gen Intern Med. 1994;9:255-260.
32. Askew GL, Finelli L, Lutz J, DeGraaf J, Siegel B, Spitalny K. Beliefs and practices regarding childhood vaccination among urban pediatric providers in New Jersey. Pediatrics. 1995;96:889-892.
33. Anonymous. General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 1994:43:138.
34. Schechtet NL. Management of pain associated with acute medical illness. In: Schechter NL, Berde, C, Yaster, M., ed. Pam m infants, children and adolescents. Baltimore: Williams & Wilkins, 1993:537-546.
35. Jay SM. Invasive medical procedures: Psychological intervention and assessment. In: Routh DK, ed. Handbook of Pediatric Psychology. New York: Guilford, 1998.401425.
36. Kutner L. A Child m Pom. Point Roberts. WA: Hartley & Marks, 1996.
37. Melzack R, Wall PD. Pain mechanisms: A new theory. Science. 1965;1 50-971-979.
38. Schecter NL. Common pain problems in the general pediatric setting. Pediatric Annals. 1995;24:139-146.
39. Melzack R, Wall PD. The Challenge of Pain. New York: Basic Books, 1983.
40. Barnhill BJ, Holbert MD, Jackson NM, Erickson RS. Using pressure to decrease the pain of intramuscular injections. J Pain Symptom Manage. 1996;12:52-58.
41. Campos RG. Soothing pain-elicited distress in infants with swaddling and pacifiers. Child Del. 1989:781-792.
42. Blass EM, Hofrmeyer LB. Sucrose as an analgesic for newborn infants. Pediatrics. 1991;87:215-218.
43. Stang HJ, Snellman LW, Condon LM, et al. Beyond dorsal penile nerve block: A more humane circumcision. Pediatrics. 1997;100:e3
44. Barr RG, Young SN, Wright JH, et al. "Sucrose analgesia" and diptheria-tetanuspertussis immunizations at 2 and 4 months. J Dev Behav Pediatr. 1995;16:220-225.
45. Campos RG. Comfort measures for infant pain. Zero to Three. December I988;6-13
46. Peterson L, Schultere K, Ridley-Johnson R, Miller DJ, Tracy K. Comparison of three modeling procedures on the presurgical and postsurgical reactions of children. Behavior Therapy. 1984;15:197-203.
47. Peterson L, Ridley-Johnson R, Tracy K, Mullins LL. Developing a cost-effective presurgical preparation: A comparative analysis. J Pediatr Psychol. 1984:439-455.
48. Kuttner L. Helpful strategies in working with preschool children in pediatric practice. Pediatric Armais. 1991;20:120-127.
49. French GM, Paints EC, Coury DL. Blowing away shot pain: a technique for pain management during immunization. Pediatrics. 1994;93:384-388.
50. Fowler-Kerry S, Lander JR. Management of injection pain in children. Pom. 1987;30:169-175.
5 1 . Cohen LL, Blount RL, Panopoulos G. Nurse coaching and cartoon distraction: An effective and practical intervention to reduce child, parent, and nurse distress during immunization. J Pediatr Psychol. 1997;22:355-370.
52. Gonzalez JC, Routh DK, Armstrong FD. Effects of maternal distraction versus reassurance on children's reactions to injections. J Pediatr Psychol. 1993;18:593-604.
53. Blount RL, Sturges JW, Powers SW. Analysis of child and adult behavioral variations by phase of medical procedure. Behavior Therapy. 1990;21:33-48.
54. Blount RL, Corbin SM, Sturges JW, Wolfe W, Prater JM. James LD. The relationship between adult's behavior and child coping and distress during BMA/LP procedures: A sequential analysis. Behavior Therapy. 1989;20:585-601.
55. Bush JP, Meiamed BG. Sheras PL, Greenbaum PE. Mother-child patterns of coping with anticipatory medical stress. Health Psychology. 1986;5:137-157.
56. Blount RL, Coen LL, Frank NC, et al. The Child-Adult Medical Procedure Interaction Scale-Revised: An assessment of validity. J Pediatr PsychoL 1997:22:7388.
57. Ross DM, Ross SA. Childhood pain. Baltimore: urban 7 Schwarzenberg, 1988.
58. Pinto RP, HoUandsworth JG. Using videotape modeling ro prepare children psychologically for surgery: Influence of parents and costs versus benefits of providing preparation services. Health Psychology. 1989;8:79-95.
59. Ebner CA. Cold therapy and its effect on procedural pain in children. Issues Compr Pediatr Nurs. 1996;19:197-208.
60. Kunesch E, Schmidt R, Nordin M, Wallin U, Hagbarth KE. Peripheral neural correlates of cutaneous anaesthesia induced by skin cooling in man. Acta Physiol Scand. 1987;129:247-257.
61. Yamitsky D, Ochoa JL. Release of cold- induced burning pain by block of cold-specific afferent input. Brom. 1990;I13(Pt4):893-902.
62. Travell J. Factors affecting pain of injection. JAMA. 1955;158:368-371.
63. Maikler VE. Effects of a skin refrigerant/anesthetic and age on the pain responses of infants receiving immunizations. Res Nurs Health. 1991;12:397-403.
64. Abbott K, Fowler-Kerry S. The use of topical refrigerant anesthetic to reduce injection pain in children. J Pain Symptom Manage. 1995;10:584-590.
65. Reis EC, Holubkov R. Vapocoolant spray is equally effective as EMLA cream in reducing immunization pain in school-aged children. Pediatrics. 1997;100:e5.
66. Hopkins CS, Buckley CJ, Bush GH. Pain-free injection in infants. Anaesthesia. 1988;43:198-201.
67. Taddio A, Robieux 1, Koren G. Effect of lidocaine-prilocaine cream on pain from subcutaneous injection. CIm Pharmacol. 1992;11:347-349.
68. Koren G. Use of the eutectic mixture of local anesthetics in young children for procedure-related pain. J Pediatr. I993;122:S30-S35.
69. Steward D. Eutectic mixture of local anesthetics (EMLA): What is it? What does it do? J Pediatr. 1993;122:S21-S23.
70. Li LC, Scudds RA. Iontophoresis: An overview of the mechanisms and clinical application. Arthritis Care Res. 1995;8:51-61.
71. Ashbum MA, Gauthier M, Love G, Basta S, GaylotrJ B, Kessler K. Jontophoretic administration of 2% lidocaine HCl and 1 : 1 00,000 epinephrine in humans. CIm J Pain. 1997;13:22-26.
72. Maloney JM, Bezzant JL, Stephen RL, Petelenz TJ. Iontophoretic administration of lidocaine anesthesia in office practice. J Dermatol Surg Oncol. 1992;18:937-940.
73. Petelenz T, Axenti I, Petelenz TJ, Iwinski J, Dubel S. Mini set for iontophoresis for topical analgesia before injection. Ira J CIm Pharmacol Ther Toxicol. 1984:22:152155.
74. Hingson RA, Hughes JG. Clinical studies with jet injection. A new method of drug administration. Current Researches m Anesthesia and Analgesia. 1947;26:221-230.
75. Figge FHJ, Bamett DJ. Anatomic evaluation of a jet injection instrument designed to minimize pain and inconvenience of parenteral therapy. Am Pract. 1948;3:197206.
76. Hughes JG, Jordan RG, Hill FS. Jet injection in pediatric practice. Pediatrics. 1949;3:801-811.
77. Hireh HL, Welch H, Milloff B.Katz S. Administration of penicillin and streptomycin by means of the Hypospray apparatus (jet injection); absorption, toxicity, and stability. J Loh Clin Med 1948;33:805-810.
78. Hingson RA, Davis HS, Rosen M. The historical development of jet injection and envisioned uses in mass immunization and mass therapy based upon two decades' experience. Military Medicine. 1963;128:516-524.
79. Denne JR, Andrews KL, Lees DV, Mook W. A survey of patient preference for insulin jet injectors vetsus needle and syringe. Diabetes Educ. May/June 1992;18:223-227.
80. Jovanovic-Peterson L, Sparks S, Palmer JP, Peterson CM. Jet-injected insulin is associated with decreased antibody ptoduction and postprandial glucose variability when compared with needle-injected insulin in gestational diabetic women. Dio6etes Care. 1993;16:1479-1484.
81. Anderson EA, Lindberg RB, Hunter DH. Report of large-scale field trial of jet injection in immunization for influenza. JAMA. 1958;167:549-552.
82. Neufeld PD, KaR L. Comparative evaluation of three jet injectors for mass immunization. Can J PuMic Health. 1977:68:5 1 3-5 16.
83. Centers for Disease Control. Hepatitis B associated with jet gun injection - California. MMWR. 1986;35:373-376.
84. Canter J1 Mackey K. Good LS, Roberto RR, Chin J. Bond WW, Alter MJ, Horan JM. An outbreak of hepatitis B associated with jet injections in a weight reduction clinic. Ardi Intern Med. 1990;150:1923-1927.
85. de Souza Brito G; Chen RT; Stefano IC-, Campos AM; Oselka C. The risk of transmission of HlV and other blood-bom diseases via jet injectors during immunization mass campaigns in Brazil. 10th International Conference on AIDS, Yokohama, 712 August 1994;10:301 (abstract no. PC0132).
86. Lindsay L. Assessing the Safety of Multidose Jet Injectors for die Administration of Vaccines. Atlanta: Emory University; 1996. Thesis.
87. Wenger JD, Spika JS, Smirhwick RW1 et al. Outbreak of mycobacterium chelonae infection associated with use of jet injectors. JAMA. 1990;264:373-376.
88. Lambrianidis T, Rood JP, Sowray JH. Dental anesthesia by jet injection. Br J Oral Surg. 1980;17:227-231.
89. Martins JK, Roedl EA. Medijector - A new method of corticostefoid-anesthetic delivery. JOccup Med. 1979;21:821-824.
90. Suzuki T, Takahashi 1, Takada G. Dally subcutaneous erythropoietin by jet injection in pediatric dialysis patients. Nephron. 1995;69:347.
91. Bareille P, MacSwiney M, Albanese A, De Vile C, Stanhope R. Growth hormone treatment without a needle using the Preci-Jet 50 transjector. Arch Dis Child. 1997;76:65-67.
92. Baer CH, Bennett WM, Folwick DA, Erickson RS. Effectiveness of a jet injection system in administering morphine and heparin to healthy adults. Am J Crìi Care. 1996;5:42-48.
93. Seddon SJ, Clayton KC. Intercostal nerve block by jet injection. Anaesthesia. 1984;39:484-486.
94. Gerbere J, Bums S, Liedtke LL- Anesthesia blocks of the lower extremity - comparing the Biojector® with needle and syringe. J Am Pediatric Med Assoc. 1996;86:195-204.
95. Greenberg RS. Maxwell LG, Zahurak MS, Yaster M. Preanesthetic medication of children with midazolam using the Biojectot jet injector. Anesthesiology. 1995;83:264-269.
96. Luby JP, Kaiser RL, Herring LL, Dull HB. Jet injector tuberculin skin testing: a comparative evaluation. Quantitative aspects. Am Rev Resprr Do. 1968;97:46-53.
97- Kutscher AH, Hyman GA, Zegarelli EV, Dekis J, Piro JD. A comparative evaluation of the jet injection technique (Hypospray) and the hypodermic needle for the parenteral administration of drugs: a controlled study. Am J Med Sci. 1962;54: 418-420.
98. Dodson K, Risk of blood-bome pathogen transmission for ier injectors and needles and syringes in parenteral immunizations and a comparison of the direct and indirect costs associated with their use. (Report submitted in partial fulfillment for the degree of Master of Public Health). Atlanta: Department of International Health, Rollins School of Public Health, Emory University, August, 1997:1-43.
99. Parent du Châtelet I, Lang J, Schlumberger M, et al. Clinical immunogenicity and tolerance studies of liquid vaccines delivered by jet-injector and a new single-use cartridge (lmule®): comparison with standard syringe injection. Vaccine. 1997;15:449-458.
100. Bennett CR, Mundell RD, Monheim LM. Studies on tissue penetration characteristics produced by jet injection. J Am Dent Assoc- 1971;83:625-629.
101. Parker V Jet Gun or Syringe? A trial of alternative methods of BCG vaccination. Public Health London. 1984;98:315-320.
102. Meyer HM, Hostetier DD, Bernheim BC1 et al. Response of Volta children to jet inoculation of combined live measles, smallpox and yellow fever vaccines. Bull World Health Organ. 1964;30:783-794.
103. Neff JM, Millar JD, Roberto RR. Wulff H. Smallpox vaccination by intradermal jet injection. Evaluation in a well-vaccinated population. Bull World Health Organ. 1969;41:771-778.
104. Jackson J, Dworkin R, Tsai T, McMullen R, Kuchmak N. Comparison of antibody response and patient tolerance of yellow fever vaccine administered by the Biojector® needle-free injection system versus conventional needle/syringe injection. International Society of Travel Medicine Conference, Paris, 1993.
105. Stanfield JP, Bracken PM. Waddell KM, Gall D. Diphtheria-tetanus-pertussis immunization by intradermal jet injection. Br Med J. 1972;2:197-199.
106. Hoke CH Jr, Egan JE1 Sjogren MH, et al. Administration of hepatitis A vaccine to a military population by needle and jet injector and with hepatitis B vaccine. J IrrftctDis. 1995;17USuppl I):s53-s60.
107. Lemon SM, Scott RM, Bancroft WH. Subcutaneous administration of inactivated hepatitis B vaccine by automatic jet injection. J Med ViroL 1983;12:129-136.
108. Davies JW, Simon WR. Antibody response to influenza immunization by jet injection. Canadian J Public Health. 1969:60:104-108.
109. Lipson MJ, Carver DH, Morton GE, Hingson RA, Robbins FC. Antibody response to poliomyelitis vaccine administered by jet injection. Am J Public Health. 1958;48:599-603.
110- Edwards EA, Johnson DP, Pierce WE, Peckinpaugh RO. Reactions and serologic responses to monovalent acetone-inactivated typhoid vaccine and heat-killed TAB when given by jet injection. BuU World Health Organ. 1974;51:501-505.
111. Salanga VD, Hahn JF. Traumatic ulnar neuropathy from jet injection: Case report. J Trauma. 1979;19:283-284.
Pain Reduction Methods for Immunization Injections