A systematic review of the non-allergic adverse reactions following benzathine benzylpenicillin injection *
(Portuguese
PDF version)
Maria do Carmo de Castro Miranda,1 Suely Rozenfeld,2 Sérgio Pacheco de Oliveira3
1.
Chemistry Department, Instituto Nacional de Controle de Qualidade em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
2. Department of Epidemiology, National School of Public Health, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
3. Department of Healthcare Planning and Administration, National School of Public Health, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
* This paper is based on the Master's dissertation of the first author.
Correspondence:
Maria do Carmo de Castro Miranda
Rua Leopoldo Bulhões, 1480 - 8º andar
CEP 21041-210 - Rio de Janeiro, RJ
Brazil
Tel: +55 (21) 3865.5128
Fax: +55 (21) 2290.0915
E-mail: docarmo@incqs.fiocruz.br
ABSTRACT
Benzathine benzylpenicillin is one of the most important drugs in the treatment of infectious diseases and prevention of cardiovascular diseases, but little is known about the extent of the severe skin reactions that it may provoke, such as necrosis and abscess. Our objective was to review the literature on local non-allergic adverse events caused by benzathine benzylpenicillin. To achieve this goal, Medline (1966-2001) database was searched with the keywords "penicillin G benzathine" and "benzylpenicillin benzathine" in order to provide studies on characteristics, causes and underlying pathophysiology of non-allergic adverse reactions. Manufacturers and international drug regulation agencies were also contacted to provide information. All kinds of epidemiological designs, reviews and letters were included. A chart was developed to help in the qualitative evaluation of data extracted from the literature, and seven experts on epidemiological methods confirmed its validity. One thousand and four hundred texts were identified, and 140 selected according to the inclusion criteria. Among them, 41 case series and case reports were included in the review. Seventy-two cases of non-allergic adverse effects were identified. The most common were vascular (42.1%) and neurological (29.1%) problems. The most common causes mentioned by the authors to explain the adverse effects were accidental intra-arterial injection (50.6%) and the inadequacy of the product (31.6%). No clinical trials dealing with non-allergic adverse effects were found. Epidemiological studies are necessary to investigate the frequency of local adverse reactions to benzathine benzylpenicillin, their ethiopathogenic patterns, and their relations with the physical, chemical and biological characteristics of the drug as well as the relation with injection techniques.
Key-words:
benzathine benzylpenicillin, review.
Palavras-chave: benzilpenicilina, revisão sistemática.
J
Vasc Br 2004;3(3):253-60
Benzathine benzylpenicillin is a β-lactam antibiotic with bactericidal action. Intramuscular benzathine benzylpenicillin is absorbed very slowly into the bloodstream from the intramuscular site. The objective is to maintain suitable and prolonged therapeutical concentrations with the minimum number of injections.1
The present paper aims to assess features, causes and mechanisms of non-allergic adverse reactions to the injection of benzathine benzylpenicillin by collecting the outcomes of published studies. A systematic qualitative review2-6 of the literature was undertaken based on an electronic database, in the Cochrane Reviewers Handbook7 and other sources.
METHOD
Data
collection
The MEDLINE electronic database was searched for the period 1966 to 2001, by typing the keywords: penicillin G benzathine and benzathine benzylpenicillin. As additional sources, manufacturers of benzathine benzylpenicillin injection and international drug regulation agencies were contacted.
Articles identification and selection
All abstracts of articles identified were read, regardless of language. Then, the following criteria for inclusion and exclusion were applied, in order to select which articles would be reviewed.
- Inclusion criteria: efficacy and effectiveness of benzathine
benzylpenicillin related to particle size in humans; accidents after
penicillin administration; warnings and recommendations concerning
the use of benzathine benzylpenicillin injection; compliance of medication
prescriptions or treatment failure; review of non-allergic adverse
reactions after the injection of benzathine benzylpenicillin; efficacy
and effectiveness assessed in randomized clinical essays or cohort
studies.
- Exclusion criteria: adverse effects of benzathine benzylpenicillin
in other presentation than injection; allergic reactions and their
adverse effects; observational or experimental studies exclusively
on the drug efficacy and effectiveness, except randomized clinical
essays and cohort studies; treatment reviews; studies which use animals.
The bibliographic references of articles selected were also examined and references considered important were identified and collected, in order to exhaust the search. When there were disagreement about the inclusion of an article, a final consensus was reached after discussion among the reviewers.
Due to the vein graft occlusion, a 6-mm extraanatomic dacron graft was
inserted from the right external iliac to the left internal iliac artery
(Figure 2). On the first postoperative day, the patient presented pain
relief with ABI of 0.58. After 5 months, there was total lesion recovery,
and non-limiting claudication.
Information retrieval and data analysis
In order to keep the integrity of information and to minimize errors, a chart for qualitative evaluation (CQA) was created, thus it was possible to standardize the retrieval of information and records.
The creation of the CQA was based on the theoretical considerations
of Oxman & Guyatt8 about the development of criteria for the assessment
of quality of biomedical scientific literature. The char was composed
of six sections: paper identification, methodological features of the
study; general characteristics of samples; specific characteristics
of adverse reactions, specific characteristics of factors associated
to adverse reactions; and observations. Seven specialists (professors
of the Epidemiology Department of Escola Nacional de Saúde Pública
of FIOCRUZ) assessed the face/content validity of the chart, which reached
a global mean of 75.4% (between 64.3 and 89.6%, depending on the questionnaire
item). This was considered satisfactory according to the cut-point suggested
by Streiner & Norman.9
Two reviewers read all the papers that composed the final list, and they filled the CQA as they read the documents. Information were compared and launched in a database. For data analysis, three interconnected databases were created in Epi-Info version 6.04d.
RESULTS
The bibliographical search
The bibliographic search included all kinds of epidemiological design, as well as review articles, comments and letters on the issue of non-allergic adverse reactions. After reading 10% of abstracts, articles suggested that the randomized clinical essays were basically about the drug efficacy, and non-allergic adverse reactions. That is the reason why our evaluation includes only case reports and case series.
As for information provided by manufacturers, despite our commitment to preserve confidential data on product and producers, thus trying not to inhibit them, none of the 22 manufacturers sent any piece of information on local adverse reactions. Twenty-four percent said not to have records of complaints or that they did not manufacture the product.
The international drug regulation agencies did not answer the request. Only the Coordinator of Pharmacovigilance from Cuba sent the notifications of adverse reactions to benzathine benzylpenicillin administration received between January 2000 and September 2001. There were a total of 182 notifications, where 14.3% were presumably associated to ischemic damage, which is a non-allergic reaction in the injection site.
One thousand and four hundred articles were identified, from these, 1,390 were selected through the electronic search and 10 were bibliographic references cited in those articles. From articles identified in the electronic search, 133 were selected and 124 were available. Among these, 52 were case reports or case series (41.9%), 16 were excluded because they were not case reports of non-allergic adverse reactions, but case reports of treatment failure and inefficacy. The bibliographic references of the 36 papers selected pointed to other 10 papers; of which seven were selected and five were available. Therefore, 41 papers were submitted to the methodological approach of the systematic review.
Seventy-two papers were excluded: three review articles, 10 comments and letters, 16 observational studies, and 43 experimental studies. By reading the abstracts of experimental studies we could observe that their major aim was to assess efficacy and effectiveness of the active principle, outlines of treatment, therapeutic indication and treatment follow-up. The majority did not focus on adverse reactions, a few papers made some references to pain.
Journals, articles and institutions
Most of articles were published in the United States of America (34%), followed by Germany (12%) and Italy (7%). Language distribution was as follows: English (20), German (seven), French (three), Spanish (three), Italian (two), Romanian (two), Polish (two), Slovenian (one), and Portuguese (one). Articles publication dates were 1980 (43.9%), 1970 (24.4%) and 1960 (24.4%), in 40 different periodicals mostly in the areas of pediatrics and internal medicine. Almost half of the selected papers were produced in teaching and research institutions and four of them did not mention any institutional affiliation.
Features of non-allergic adverse reaction cases
Seventy-two cases were identified, mean and median age 15.2 and 5 years respectively (2 months to 83 years of age); 25% of cases were children under 2 years-old and 25% were adults. Sex distribution was balanced: 48.6% male and 38.9% female; 12.5% of cases did not mention sex, and 97.2% of cases were given intramuscular injections.
The most frequent therapeutic recommendations were infections (24.1%), upper respiratory tract infections (16.7%), rheumatic fever (16.7%), syphilis (16.7%), cardiopathy (14.8%), inflammation in the upper respiratory tract (3.7%) and tuberculosis (1.8%); 5.5% did not mention indications.
Adverse reactions
Three-hundred and fifty-eight symptoms were mentioned in the literature (Table 1). The vascular reactions were the most frequent (42.1%), presenting color changes (19.2%) such as redness, violaceous color, cyanosis, exanthema, petechiae, skin discoloration, ecchymosis and erythema. Some of these symptoms (redness, exanthema, petechiae and erythema) were described as signs of venous occlusion, although these are not specific signs. As an example, we cite the case described by Stiehl,10 in which the extremities presented a mottled appearance and 28 hours after benzylpenicillin injection the patient underwent cardiac arrest and died. The autopsy proved the presence of thrombus in the arteries of lower extremities, where injuries were the same size and dimension as crystals of the penicillin salt. According to the authors, the accidental intravascular injection may have been the cause, and the fact that the suspension is opaque may have prevented the visualization of blood on aspiration.
 Table
1 - Frequency distribution of signs and symptoms of adverse reactions
following benzathine benzylpenicillin injection
 |
| Sign/Symptom
|
Frequency
|
Percentage |
|
| Vascular
complications |
151
|
42.1 |
| Color
changes * |
69
|
19.2 |
| Pallor
|
29
|
8.1 |
| Local
edema |
20 |
5.6 |
| Pulse
(absent/diminished) |
17
|
4.7 |
| Cold
extremities |
15 |
4.2 |
| Ischemia |
1 |
0.3 |
| Neurological
complications |
104
|
29.1 |
| Muscles
reflex alterations |
26
|
7.3 |
| Atony/hypotonia
|
22 |
6.1 |
| Altered
sensibility |
19 |
5.3 |
| Injured
rectum/bladder |
18
|
5.0 |
| Neurological
paralysis |
11 |
3.1 |
| Paraplegia |
7 |
2.0 |
| Drop
foot |
1 |
0.3 |
| Systemic
complications |
67 |
18.7 |
| Pain |
30 |
8.4 |
| Fever
|
15
|
4.2 |
| Respiratory
problems † |
8
|
2.2 |
| Excessive
sweating |
4
|
1.1 |
| Cardiac
arrest |
2
|
0.6 |
| Tachycardia
|
2
|
0.6 |
| Itching
|
2
|
0.5 |
| Sleepiness |
2 |
0.5 |
| Shivering |
1 |
0.3 |
| Headache |
1 |
0.3 |
| Central
neurological involvement |
36
|
10.1 |
| Excitement
|
14
|
3.9 |
| Loss
of consciousness |
11
|
3.1 |
| Illusions/delirium |
6 |
1.7 |
| Convulsion |
3 |
0.8 |
| Coma |
1 |
0.3 |
| Dizziness |
1 |
0.3 |
| Total
|
358
|
100.0 |
|
*
Erythema, discoloration, violaceous color, cyanosis, exanthema, petechiae.
† Dyspnea.
The second most frequent alterations were in the neurological group (29.1%). The interpretation of most authors is that the sciatic nerve may have been damaged in these cases.
Thirdly there were the general systemic alterations (18.7%), with different types of signs and symptoms and also various degrees of severity. The most frequent symptom was pain (8.4%).
The group with central neurological alterations had the least frequency of adverse reactions, which was 10.1%.
With relation to evolution and sequelae, cases of necrosis and gangrene were the most frequent: 33.3% (24) of cases, in which nine required legs, feet, toes, or digits amputation. Other sequelae were three cases with difficulty walking, and three cases with urinary and/or rectal incontinence. The most serious cases presented with paraplegia (three) and death (two). Autopsy of one death case proved the presence of thrombus in the lower limbs arteries, and the examination confirmed the presence of crystals.10
Causes of non-allergic adverse reactions
Table 2 lists the causes of non-allergic adverse reactions mentioned by the authors in the literature reviewed.
Table
2 - Frequency of probable causes for non-allergic adverse reactions
|
| Probable
cause |
Frequency
|
Percentage |
|
| Accidental
injection (intra-arterial) |
45 |
50.6 |
| Inadequacy
of product |
28 |
31.6 |
| Injection
site |
4 |
4.6 |
| High
dosage toxicity |
2 |
2.25 |
| Accidental
injection (intravenous) |
2 |
2.25 |
| Vasculitis |
2 |
2.25 |
| Perineural-sciatic
injection |
2 |
2.25 |
| Application
procedure |
1 |
2.25 |
| Toxic
effect caused by the drug |
1 |
1.12 |
| Vessels
irritation from blood products |
1 |
1.12 |
| Cerebral
microthrombosis |
1 |
1.12 |
| Total
|
89
|
100 |
|
Inadvertent direct intra-arterial injection was the most probable cause of non-allergic adverse reactions with 50.6% of cases, although the authors say the administration was correct.
The second most frequent cause of non-allergic adverse reactions was related to the viscous aspect of the product, the crystalline aspect of suspension and the dimension of penicillin crystals. Only two papers, Duverne11 and Fiocchi,12 concluded that adverse reactions were caused by a defective lot, because many cases in the same period and place were reported.
The site of application was mentioned as cause of adverse reaction only in four cases. It is considered13-16 that in children under 2 years-old, benzathine benzylpenicillin should be preferably administrated in the midlateral aspect of the thigh, which is free of blood vessels and not dangerously close to the sciatic nerve.
Only one paper15 mentioned the injection procedure as the cause for non-allergic adverse reaction, and authors suggest that application should be with the needle inclined and at a slow rate, although they do not explain why.
Justification of causes and description of adverse reaction mechanisms cited were embolism caused by the drug crystals; product viscosity, which may prevent the visualization of blood on aspiration if a blood vessel is entered; vasospasm due to constriction of blood vessels due to irritation from the blood products.
DISCUSSION
Importance for public healthcare
Non-allergic adverse reactions were mostly frequent in infants and children under 5 years of age (50%). This explains why most of the journals e found were specialized in pediatrics and calls the attention for the importance of this problem in terms of public healthcare and rational drug use.
Description of evolution and sequelae make evident the seriousness of these non-allergic adverse reactions, and the fact that they are mostly frequent in children makes the situation even more dramatic, although the incidence of cases is low.
Action mechanisms
Vascular alterations were the most frequent signs and symptoms recorded. They varied from slight vasomotor disturbance to serious ischemic lesions, including gangrene of limbs. Some authors have used the term Nicolau's Syndrome to describe ischemic alterations following injections. It was firstly used in 1924 after adverse reactions of intramuscular injections of bismuth salts routinely used for the treatment of syphilis.15
According to the authors,10,13,15,17-23
neurological involvement occurs because embolus or clots in the vessels
of the buttocks (site of injection) formed, due to retrograde flow,
reach the internal iliac artery and the vertebral canal through the
blood flow and go to the lower limbs, causing arterial occlusion and
sciatic nerve injury, distal vasa nervorum lesion and direct
trauma lesion.
Systemic complications result from the previous, and pain is the most frequent one (45%). It seems to be generally accepted, even in the medical practice, that penicillin injections are painful. In the present review we identified some epidemiological studies that approached this symptom, as well as studies on the use of pain-relief anesthetic drugs such as lidocaine, or different treatment outlines using benzathine benzylpenicillin and procaine benzylpenicillin. However, our review has shown that pain may be also an indication of inadvertent intra-arterial injection, which causes serious injuries.
Symptoms and signs characterized as central neurological complications have been termed Hoigne's syndrome and they are more related with procaine benzylpenicillin than with benzathine benzylpenicillin, once procaine benzylpenicillin is more soluble and has a toxic effect, with depression of the myocardium and central nervous system.24
Regarding vascular complications again, although there are convergent opinions on the fact that inadvertent intra-arterial injection is a probable cause of reactions, the explanation of the lesion mechanism remains obscure and was not scientifically proven yet.
The articles we analyzed raise some hypothesis for possible causes of vessels walls lesions. The most significant and frequent seemed to be the embolic occlusion of small arteries or arterial vasospasm. Some authors10,14,21,25-28 consider lesions as a result of vessels occlusion by penicillin crystals, which would form clots that would reach the sciatic nerve or distal arteries of upper limbs by retrograde flow, starting from the injection site. Others17,22,29-31 consider an arterial vasospasm as cause of the lesion, as it provokes clot formation by vessels walls irritation. And there are some authors who consider the irritation of tissues19,32 and the inadequate particle size23,33,34 the cause for vessels lesion. The majority agrees that as the benzathine benzylpenicillin injectable suspension is viscous and opaque it would hint the visualization of blood on aspiration if a blood vessel were inadvertently entered. These features would facilitate an accidental intravascular injection, mainly in the buttocks region, which has many blood vessels and is next to the sciatic nerve.
It is important to note that intra-arterial injection does not need
to be given in a large-caliber vessel to cause injuries. Smaller vessels,
when entered by the needle, may allow suspension to enter the arterial
circulation. The injection high pressure and the short period of administration
may have a fundamental role in the progression of the suspension in
the artery against the flow of the arterial bloodstream. When suspension
reaches a bifurcation, the suspension would enter the bloodstream of
the main arterial branch and then would follow the normal flow until
it causes the occlusion of smaller vessels. This may explain the incidence
of arterial obstruction distal to the injection site, such as upper
limbs after a deltoid application, and lower limbs and sciatic nerve
after an injection in the buttock. A reason for the damage on the sciatic
nerve could be the retrograde flow after an accidental intra-arterial
injection in the buttock. The suspension would follow the iliac artery
muscular branches up to other branches of the same area, reaching the
origin of vasa nervorum vessels, which would be linked to the
sciatic nerve.
Limitations and future studies
In this review, the search for articles on non-allergic adverse reactions after the injection of benzathine benzylpenicillin tried to be as exhaustive as possible. However, some limitations should be mentioned. A thorough compilation would require an additional effort for acquisition, translation, analysis and most importantly, the importation of articles cited in the bibliographic references. Yet, it has been noticed that information displayed in articles is sometimes described in a confusing and loose manner. In case reports and case series, the authors describe adverse reactions in a very personal and varied way, what prevents the good systematization of information. In order to complete these data, it would be necessary to contact each author personally, what would be problematic in respect to articles published some time ago. We believe, however, that the additional effort to overcome these limitations would not bring different data from those we showed here.
As for the search strategy and keywords used, the evaluation of the overall collection of papers suggests that the comprehensive search is the best option. Even considering that we could analyze only part of papers in the present study, the identification of others will be useful for future studies.
The strategy we intended to follow to minimize bias of publication35-38 was the contact with and request for information to manufacturers and drug regulation agencies, however it was not well succeeded, as we did not obtain any answer. This fact confirms the importance and interference of this type of bias in a review study, as it is suggested that there is no interest in publishing studies that report negative results or that are against the interests of the pharmaceutical industry.
The value of the systematic review is directly related to the collection of all studies on the topic. In this work there was an extra effort to overcome some critical factors, such as obtaining papers published in non-indexed journals, importing papers not available in Brazil, and translating those who were in languages other than those we domain. This seems to have prevented a language bias, as none paper was excluded for language reasons, and authors limitations counted on the add of skilled professionals.
There seems not to have been interference of selectors, because criteria were very well defined and disagreement between reviewers was thoroughly discussed.
We believe that papers considered "classic" or "historic" in the area were included in this review. Fourteen papers included in this study were bibliographic references in at least three other papers, one of them19 was cited in 14 papers and other21 in 12. The paper by Weir39 is a case review on adverse reactions to benzathine benzylpenicillin. It presents data reported to the Food and Drug Administration Agency (FDA) and data published in the United States. Ten of the eleven papers analyzed by Weir entered the present study.
All these findings may bring a lot of contribution to future studies and for the daily clinical practice in healthcare services. We consider that the injection procedures should be carefully handled, as well as the choice for the injection site, especially in the case of children. The early diagnosis and treatment of adverse reactions should also be considered.
The outcomes of this systematic review reinforce the need for urgently finding definitive solutions, due to the seriousness of adverse reactions and the importance of benzathine benzylpenicillin in treatments. As previewed by Schanzer,40 if any change in the product manufacturing is made that would enable a safer use of this suspension, more accidents may happen.
Our proposal is that experimental and observational studies should be carried out and systematically analyzed. Epidemiological studies in the public healthcare system (SUS, in Brazil) should be also considered, for the assessment of the occurrence of non-allergic adverse reactions following the injection of benzathine benzylpenicillin, its etiology and the relationship with physical, chemical, and biologic features of the product, as well as injection procedures.
The increase in the number of syphilis cases and other sexually transmitted diseases also bring to light the importance of the problem, although such diseases prevail in young adults and adults.
ACKNOWLEDGMENTS
Authors thank Luis Antonio Camacho and Evandro Coutinho for their suggestions to the manuscript; professors of the Epidemiology and Quantitative Methods Department of Escola Nacional de Saúde Pública (DEMQS/ENSP) for the data collection chart evaluation; Ana Célia P. da Silva, Christina Zackiewicz, Fátima Pivetta, Isabella F. Delgado, Milena P. Duchiade and Thomas Manfred Krauss for papers translation; and Abrantes da Silva Filho for the database development.
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