Review Article: Bismuth-based Therapy for Helicobacter Pylori Eradication in Children

L. Pacifico*, J. F. Osborn†, C. Anania*, D. Vaira‡, E. Olivero* & C. Chiesa§

Disclosures

Aliment Pharmacol Ther. 2012;35(9):1010-1026. 

In This Article

Methods

Studies that evaluated the efficacy of therapies with bismuth salts for H. pylori eradication in children with gastroduodenal disease between 1988 and 2011 (December) were identified using MEDLINE. The study sources included a Medline search using the key words 'Helicobacter pylori' or 'Campylobacter pylori', treatment, therapy, Bismuth, and children. Inclusion criteria for eligible studies included children (under 18 years of age) with a referral diagnosis of upper abdominal complaints but no history of previous treatment for H. pylori eradication, upper gastrointestinal endoscopy to assess H. pylori status at initial visit, and only full papers for which details were available in English regarding the medication used, study design (case series of treatment regimens including single, dual, triple therapies; comparative studies with and without randomisation), location of study subjects (nationality, in a single centre or more centres), endoscopic and/or histologic findings at baseline, and the proportion of evaluable subjects in whom H. pylori was eradicated after treatment. Studies were excluded which did not perform follow-up endoscopies with gastric biopsies or did not use the urea breath test to detect the post-treatment H. pylori status. Duplicate studies were also excluded. Duplicate data publication was identified by identical study population distributions for age, sample size, design, dosing, frequency and duration of treatment.

Analysis of H. pylori eradication efficacy was considered on an intention-to-treat basis (including all eligible patients enrolled in the study regardless of compliance with the study protocol; patients with unevaluable data were assumed to have been unsuccessfully treated) and on a per-protocol basis (excluded patients with poor adherence to therapy and patients with unevaluable data after therapy). Results on the efficacy of bismuth-containing regimens on H. pylori eradication were combined using the inverse variance method, which involves a weighted average of the effect estimates from the individual studies. The weight for each study is taken to be the inverse of the variance (one divided by the square of the standard error) of the effect estimate. Meta analyses have not been performed because the studies and trials reviewed are too different in their design and/or treatment regimens for there not to be heterogeneity between the results. A combined estimate is provided as a summary for the groups of studies, but this should not be assumed to pertain to the effects observed in the individual studies.

Pharmacological Properties of Bismuth Compounds

Bismuth compounds have been promoted for therapeutic use for over two centuries for a range of clinical conditions including dyspepsia, diarrhoea, syphilis, oral and upper respiratory tract infections, verrucae and warts. The bismuth complexes used in therapeutics have also been diverse including compounds such as bismuth subnitrate, bismuth subgallate, bismuth subcarbonate, colloidal bismuth subcitrate (CBS), bismuth subsalicylate (BSS), and more recently ranitidine bismuth citrate (RBC).[12] The use of the majority of bismuth compounds has fallen into disfavour because of their potential adverse effects, and indeed, a number of drug-regulatory authorities are actively delisting bismuth-containing products from medicinal use.[13] Nonetheless, over recent years, three bismuth compounds, CBS, BSS and RBC, have attracted renewed interest because of their newly discovered activities for conditions which respond suboptimally to existing therapies: travellers' diarrhoea, peptic ulcer disease and H. pylori-related gastroduodenal disease.

Bismuth compounds may act both locally within the gastrointestinal tract and systemically as a result of gastrointestinal absorption.[14] More than 99% of the ingested bismuth acts locally in the gastrointestinal tract and is excreted in the faeces.[15] However, substantial bismuth levels in the gastric mucus and mucosa are only observed for a few hours after administration.[12] Measurements of bismuth levels in human antral mucosa, gastric mucus and juice at different times after a single oral dose of CBS and BSS prior to endoscopy, revealed a rapid increase in mucosal levels with a peak at 30–60 min, remaining above the minimum inhibitory concentrations for eradication of H. pylori for only 3 h, and falling rapidly thereafter due to the normal turnover of mucus.[12,16] The concentrations of bismuth in gastroduodenal tissues 24 h after 4 or 8 weeks of CBS therapy were low and similar to those after single dose of therapy, suggesting no local accumulation.[17] However, there are no comparable studies in the paediatric population.

Most bismuth salts have little or no acid-neutralising effect and do not affect acid secretion.[18] The protection conferred by bismuth compounds is thought to result from the coating of the gastric mucosa, passively defending against the digestive activity of acid and pepsin.[19] A white coating over the lining of peptic ulcers has been observed endoscopically in patients after taking CBS.[18] Koo et al. studied this coating action in rats with chronic gastric ulcers, and showed that CBS had a coating affinity for the ulcer base, but not for the adjacent normal mucosa.[20] All rats treated with CBS 1, 2, 4 and 6 h previously, but not the control rats treated with water or those treated with four other bismuth compounds, manifested a layer of bismuth that coated the ulcer base. Light and electron microscopy of CBS-treated ulcers-but not their controls – revealed an abundance of macrophages, which had ingested the bismuth. On the basis of these findings, Koo et al. suggested that this unique bismuth coat may insulate the ulcer base from acid-pepsin digestion, while the influx of macrophages may remove foreign material and expedite reparative processes.[20] In the article by Lee et al. preoperative administration of CBS resulted in a preferential accumulation of bismuth in and around chronic gastric ulcers 1–2 h after oral administration.[21] This suggests that bismuth binds to the mucus glycoprotein coating over the gastrointestinal epithelial cells. It is possible that bismuth forms a complex with other inflammatory proteins present in sites of acute and chronic ulcers, but there are no data to confirm or refute this possibility.[18] An in vitro preparation of a mucus-bismuth complex obtained by coprecipitation of gastric mucus and CBS modifies the rate of diffusion of hydrogen ions.[21] Thus, such a complex may act as an insulating barrier to the action of hydrochloric acid, allowing normal healing processes to take place. The binding of bismuth to gastric mucus depends on the concentration of both bismuth salts and mucus and on the intraluminal pH.[18] There is an exponential increase in binding affinity in an acidic environment.[22]

Other factors may also be involved in the effects of bismuth preparations in ulcer disease. Animal studies have shown that increased prostaglandin synthesis is stimulated by bismuth compounds.[23] This may be important in view of the role of endogenous prostaglandins in gastric cytoprotection.[19] In vitro studies have shown that CBS is capable of counter-acting the proteolysis of the protective gastric mucus layer by H. pylori.[24]

Data from adults have shown low, but significant, intestinal absorption of bismuth.[19] The mechanism of bismuth absorption is not clear, although most appears to be absorbed from the duodenum and the proximal small bowel.[14] A diffusely diseased gastrointestinal mucosa may lead to increased absorption.[2] Furthermore, the water soluble bismuth salts, including CBS and RBC, are better absorbed from the gastrointestinal tract than the insoluble inorganic salts such as BSS, which are absorbed in minimal amounts.[12] The study by Nwokolo et al. revealed that bismuth absorption after the oral ingestion of CBS is exceptionally rapid with a median peak plasma bismuth concentration being reached at 30 min.[25] Such a rapid absorption implies an extremely proximal site of absorption, probably in the duodenum and the proximal small bowel, a supposition that is supported by electron microscopy studies of biopsies, which show small particles of bismuth complex being endocytosed by the enterocytes of the duodenum and proximal jejunum, but no penetration of the gastric mucus barrier by bismuth particles.[26] In the same study, Nwokolo et al. also measured the individual plasma bismuth concentrations for eight male and eight female healthy volunteers (age range, 22–31 years) on the first and second study days after oral dosing with their first and third dose of CBS.[25] These authors recorded surprisingly high plasma bismuth concentrations. It is recommended in the literature that the threshold for concern about bismuth neurotoxicity is a blood concentration between 50 and 100 ng/mL ('alarm level'), and treatment should be stopped if bismuth concentrations are above 100 ng/mL ('toxicity level').[14,19,27,28] Plasma bismuth concentrations above 50 ng/mL were observed in 14 of the 16 healthy subjects receiving only 1–3 doses of CBS, and nine of the subjects had plasma bismuth concentrations above 100 ng/mL for up to 145 min.[25] However, application of these safety levels to children is not justified because of the lack of knowledge of what constitutes the normal and, more important, 'alarm', and 'toxic' values of bismuth (with current, appropriate analytic methods) across the span of childhood.[29] In the last two decades, very few studies in children of eradication therapies which include bismuth-based dual or triple therapies, have measured bismuth concentration after the intake of this heavy metal.[30–32]

Gavey et al. measured bismuth concentrations in plasma and urine before, during and after treatment of nine adult (age range, 24–66 years) patients (two with acute duodenal ulcer, and seven with H. pylori-associated gastritis) with a 6-week CBS course.[33] During treatment there was an 8.5-fold rise in median plasma bismuth concentration, and a 349-fold rise in 24 h urinary bismuth excretion. The significantly increased urinary bismuth excretion continued for at least 3 months after cessation of treatment with CBS, indicating accumulation of bismuth during treatment with this drug. Thus the study by Gavey et al. also shows that bismuth accumulates in the body during an acute course of treatment. Although none of the plasma samples measured in the study by Gavey et al. showed concentrations of bismuth above 50 ng/mL,[33] the confirmation that bismuth is absorbed during treatment must encourage caution when considering repeated or prolonged courses of treatment, especially in children.

The absorbed bismuth binds to plasma proteins and is distributed throughout all tissues. In humans and animals receiving bismuth, the concentration per gram is always highest in the kidney, and it is also retained for a long time.[14,34] However, unless the depot is exclusively in the kidney, the bismuth must pass via the plasma before renal clearance throughout all tissues. Distribution of bismuth in the organs is largely independent of the compound administered or the route of administration.[35] Concurrent administration of antacids decreases absorption of bismuth. Approximately 10% of the absorbed bismuth is detected in faeces presumably owing to biliary secretion.[12] After 14 months of administration of CBS to rats, bismuth was present in kidney, lung, spleen, liver, brain, heart and skeletal muscles, in descending order of abundance.[36] This sequestration of bismuth throughout all tissues should instill a heightened vigilance in the use of bismuth-containing compounds, particularly in children, and encourage a careful study of the excretion time in children for various courses of bismuth compounds at different daily doses to fill the information gap of the appropriate bismuth-free intervals.

The present oral use of bismuth compounds in paediatric patients is based on adult pharmacologic data. However, extrapolation of adult data to children has not been validated by clinical trials, a principle that in the future should permeate the design and conduct of efficacy studies for H. pylori eradication in children.

Bismuth Compounds for H. pylori Eradication

Heavy metals are known to possess antimicrobial properties, and bismuth is no exception to this rule. Bismuth salts have been shown to be useful in spirochetal infections for many years, and in the last decades there has been a resurgence of interest in their antibacterial properties. CBS and BSS were the first bismuth compounds shown to inhibit the growth of H. pylori in vitro. RBS is also active against H. pylori in vitro.[12] However, bismuth alone does not eradicate H. pylori but merely suppresses the organism temporarily.[37–39] Such short-term suppression of H. pylori correlates with increasing ulcer relapse rates over time.[40]

Although the mechanism of the antibacterial action of bismuth to H. pylori is not well understood, it appears that bismuth compounds have direct antibacterial action, as well as the ability to interfere with adherence of the organism to surface epithelial cells.[18,19,41,42] Ultrastructural studies of endoscopic biopsies in patients treated with CBS have shown that shortly after administration of CBS, the organism was located inside, rather than underneath, the mucus gel. This was thought to result from loss of adherence to the apical membrane of the gastric epithelial cells. Bismuth, in the form of electron-dense bodies, was seen to be deposited on the surface and within the bacterial cell. The bacterial structure was distorted by condensation and fine and gross vacuolisation of its contents. It appears that bismuth compounds have direct antibacterial action as well as the ability to interfere with epithelial attachment of the organism. The metabolic or biochemical pathways underlying this antibacterial action have not been studied. Inhibition of a number of the enzymes produced by H. pylori, including urease, catalase and lipase is observed, which may affect the local environment for the growth of the organism.[12,43] A reduction of 85–90% adherence to Hela cells was observed by preincubation of H. pylori with CBS.[12]

H. pylori resistant strains to bismuth have not been reported and presumably arise at a lower frequency than strains resistant to antimicrobial agents such as nitroimidazoles, macrolides and tetracycline.[44] In adult patients, while CBS has been suggested to decrease the development of H. pylori resistance to nitroimidazoles,[45] RBC has been suggested to help to overcome H. pylori resistance to clarithromycin.[46] There are no comparable data in children.

Helicobacter pylori Eradication Efficacy of Bismuth Salts in Children

The studies that have evaluated first-line bismuth-containing regimens for the treatment of H. pylori infection are summarised in Table 1 , Table 2 , Table 3 and Table 4 . The first attempt to eradicate H. pylori with bismuth compounds in children included monotherapy.[47] Treatment with BSS for 6 weeks resulted in the eradication of 50% of H. pylori infections ( Table 1 ). Subsequent studies included dual therapies consisting of either bismuth compounds and amoxicillin or ampicillin, or bismuth compounds and nitroimidazoles.[30,47–52] The eradication rates for these regimens ranged from 50% to 100% and from 67% to 100% according to intention-to-treat analysis and per protocol respectively ( Table 2 ). Overall, from the 117 patients treated, a mean eradication proportion of 68% (95% CI, 60%–76%) (intention-to-treat analysis) and 73% (95% CI, 64%–81%) (per protocol) was calculated. No evidence of heterogeneity was found (intention-to-treat-analysis: X2 = 9.0; degree of freedom = 6; P = 0.17; per protocol analysis: X2 = 4.52; degree of freedom = 6; P = 0.61), but the diverse characteristics of the studies would imply that it certainly exists.

Studies with triple therapy included case series[32,53,54] as well as treatment trials.[55–59] From case series involving 151 children ( Table 3 ), the tested regimen contained a combination of bismuth, clarithromycin, and nitroimidazoles, or bismuth, amoxicillin and nitroimidazoles. Eradication rates ranged from 75% to 86% and from 80% to 95% according to intention-to-treat analysis and per protocol respectively ( Table 3 ). The overall percentages of patients with successful eradication were 82% (95% CI, 76%–88%) and 86% (95% CI, 80%–92%) according to intention-to-treat analysis and per protocol respectively. There was no statistical evidence of heterogeneity for the reviewed studies (intention-to-treat-analysis: X2 = 1.99; degree of freedom = 2; P = 0.37; per protocol analysis: X2 = 3.02; degree of freedom = 2; P = 0.22).

In comparative (randomised and nonrandomised) studies involving 350 children with gastroduodenal disease, H. pylori eradication rates after therapy with bismuth, nitroimidazoles and amoxicillin or bismuth, amoxicillin and clarithromycin with or without PPI, ranged between 69% and 85% according to intention-to-treat analysis and between 74% and 96% per protocol ( Table 4 ). Very few studies have directly compared – in the same protocol – bismuth-based therapy with the alternate recommended first-line therapies.[57–59] In a retrospective study of 233 children with H. pylori infection, Choi et al. compared triple therapy containing BSS, metronidazole and amoxicillin with the standard first-line therapy (omeprazole, amoxicillin and clarithromycin).[58] On per-protocol analysis, eradication rates were 85% for bismuth containing regimen and 74% for the classic triple therapy (these differences were not statistically significant). Of note, the authors failed to report both the duration of treatment and the endoscopic and histologic findings at baseline. Two randomised studies have compared the efficacy of quadruple therapy containing bismuth, amoxicillin, metronidazole and omeprazole vs. triple therapy with omeprazole, amoxicillin and clarithromycin or omeprazole, amoxicillin-clavulanate and metronidazole, with discrepant results. The first randomised study evaluated the efficacy of quadruple therapy with bismuth subcitrate, metronidazole, amoxicillin and omeprazole and the efficacy of triple therapy using omeprazole, amoxicillin and clarithromycin.[57] The eradication rates by quadruple therapy were 68.8% and 84% for the intention-to-treat and per-protocol approaches respectively. In the triple regimen group, the eradications rates were 75.5% by the intention-to-treat analysis and 92% by the per-protocol analysis. A significantly higher eradication efficacy of triple vs. quadruple therapy was observed (P = 0.046). The second study by Delghani et al. showed that quadruple therapy containing bismuth had a higher efficacy in eradicating H. pylori infection compared with the triple regimens containing omeprazole, amoxicillin and clarithromycin, or omeprazole, amoxicillin-clavulanate and metronidazole.[59] More side effects were seen with the quadruple therapy ( Table 6 ). Differences between study populations (including geographic location), small sizes of study populations, and variation in the total daily dose, dosing frequency and duration of treatment components, as well as in time of post-treatment follow-up and methods used to assess eradication after treatment, may in part account for the conflicting findings.

Well-designed, randomised, multi-centre studies of H. pylori eradication trials in children comparing bismuth-based regimens with the alternate recommended first-line therapies are currently lacking.[11,60] The results from the paediatric European register for treatment of H. pylori (PERTH) showed that when given as first treatment, bismuth-containing triple therapies were more efficacious than those containing PPI (77% vs. 64%, P = .02, OR 1.88, 95% CI 1.1–3.3).[61] The results of this study obtained from a comparison among 27 different treatment regimens in 518 children with H. pylori infection present some limitations: the PERTH aims were to analyse the efficacy of different regimens with comparable protocols. However, efficacy of most treatment regimens were impossible to compare because of the very low number of children treated with some of them. In addition, the dosage of drugs was reported only for 141 children and only for omeprazole, the duration of treatment was different in the analysed studies (1 or 2 weeks), and only descriptive analyses were made. A comprehensive meta-analysis including 80 studies (127 treatment arms) with 4436 children showed that, among the regimens tested, 2 weeks of bismuth, amoxicillin and metronidazole as well as 2–6 weeks of nitroimidazole and amoxicillin, 1–2 weeks of clarithromycin, amoxicillin and a PPI, and 2 weeks of a macrolide, a nitroimidazole and a PPI were the most efficacious in developed countries.[62] The major limitations of this meta-analysis, however, were the poor quality of clinical trials available in the paediatric literature coupled with their small sample sizes.

Simplicity, tolerability and short duration are the most important factors of a therapeutic regimen to promote compliance in children. Conflicting data exist regarding the benefit of longer duration of therapy for first-line regimens. Efficacy was not increased by a 2 weeks' treatment course from the data collected by PERTH. In contrast, the meta-analysis by Khurana et al. suggested that longer duration of therapy was associated with improved eradication rates.[62] However, there are few randomised studies to investigate the shortest treatment duration required in children. In this respect, Cucchiara et al. failed to show a difference in efficacy between a 1-week and a 4-week course of bismuth-containing triple therapy.[55] Moreover, in a prospective randomised study comparing RBC plus amoxicillin plus clarithromycin given for 4 vs. 7 days in 206 H. pylori-infected children diagnosed by 13C-urea breath test, Tam and colleagues found that the eradication rate of 4-day treatment arm was 77.8% (both intention-to-treat and per protocol) compared with 88.8% (intention-to-treat, P = 0.036) and 89.7% (per protocol, P = 0.022) with the 7-day regimen.[63] There was no statistical difference in terms of side effects between the two groups, and the authors concluded that 7 days of treatment is an optimal duration to achieve effective eradication. It is important to stress that the majority of studied subjects were asymptomatic.

Following first-line treatment failure, a number of options are available for second-line treatment that may overcome bacterial resistance. Triple therapy, quadruple therapy and more recently levofloxacin-based therapy have been studied as second-line therapies.[64, 65, 66] Quadruple therapy with PPI ' metronidazole ' amoxicillin ' bismuth or levofloxacin-based therapy is the recommended second line therapy in the absence of primary culture and sensitivity testing in paediatric guidelines.[11] The eradication rates for these regimens after quadruple therapy containing bismuth compounds ranged from 62% to 89% (intention-to-treat analysis) and from 67% to 94% (per protocol) ( Table 5 ). More side effects were seen with the quadruple therapy ( Table 6 ).

Safety Profile of Bismuth Compounds

There are concerns about toxicity of these compounds in some countries. Recently, Ford et al. conducted a meta-analysis of adverse events resulting from a 1–2 weeks course of bismuth based H. pylori eradication therapy in H. pylori-positive adults.[67] The authors found that there was no statistically significant difference detected in individual adverse events such as abdominal pain, diarrhoea, dizziness, headache, metallic taste, and nausea and/or vomiting with bismuth compounds vs. comparison regimens. The only adverse event that occurred more frequently in patients receiving bismuth alone or in combination with antibiotics was dark stool. Diarrhoea was significantly more common with bismuth compounds when only studies using more than 1 month of therapy were included, but no statistically significant difference was detected in the incidence of other adverse events reported.[67]

From our survey of studies of children receiving H. pylori eradication therapies for gastroduodenal disease, some failed to report the safety profile of bismuth-containing regimens,[47,51] while others apparently reported no adverse effects, regardless of the duration of treatment.[30,48,49,52,57] Taking into account the small studies reporting adverse events in children with bismuth-containing regimens, side effects such as diarrhoea, dizziness, headache, metallic taste, skin rash and nausea and/or vomiting occurred with bismuth compounds as well as with comparison regimens (Table 6). However, children experiencing dark stools, urine discoloration, black tongue, burning sensation of the tongue, and marked darkness of the gums had all been treated with bismuth-containing regimens. Against that background, there is a potential scenario of serious toxic effects including neurotoxicity, nephrotoxicity, and, in children, skeletal problems.[13] Epidemics of bismuth-induced encephalopathy, the main chronic toxicity of bismuth salts, particularly among patients with ileostomies and colostomies, were reported in the 1970s in France, Britain and Australia.[19,68] As a result, some countries banned its use, while others restricted bismuth preparations to prescription only. BSS, which is currently available in many countries including the United States, is still periodically responsible for cases of encephalopathy.[19,69] A key question posed by the history of bismuth encephalopathy is why bismuth salts, used on a large scale and in very large quantities over years, should have been associated with so much toxicity within a short period in the 1970s. The slow accumulation of bismuth through long-term or high-dose usage, or both, appears plausible; the onset of epidemics in France coincided with new highs in bismuth sales.[27] However, an epidemiologic study of 942 patients showed no correlation between amount or duration of bismuth intake and neurotoxicity, and no correlation with age or gender.[70]

No case of neurotoxicity or nephrotoxicity has been apparently found in case series or in comparative studies of bismuth-based eradication therapies for H. pylori in children. It is critical that bismuth use also in children should be driven by knowledge of the lack of correlation between neurologic symptoms and age, gender, quantity of bismuth consumed or duration of therapy.[70] Likewise, no skeletal problem has been identified throughout our survey. However, the strong cause and effect relationship between bismuth administration and X-ray shadows in the growing skeleton, reported in the old paediatric literature, should not be regarded, in modern times, as of historical interest only.[13] Many decades ago, Caffey had the opportunity to study radiographically the lesions occurring directly after a single course of treatment with bismuth in antisyphilitic (intramuscular) treatment, as well as many weeks after a single course and after multiple courses during several years.[71] This author disclosed, after a single course of treatment with bismuth, bilaterally symmetrical transverse bands of increased density across the extreme ends of the shafts contiguous to the epiphysial cartilages. These transverse bands had a heavy homogeneous metallic density and sharply defined epiphysial and diaphysial borders. These lesions had developed only in the more rapidly growing portions of the skeleton, and their size varied directly with the rate of growth. They were not present before bismuth treatment or with other treatments (e.g. arsphenamine, mercury). More important, was that the transverse lines, after multiple courses of bismuth, remained stationary in the bone with respect to each other at follow-up roentgen examinations, while the ends of the bone were being progressively separated from each other because of longitudinal growth.[71] Thus the possibility that roentgen changes after bismuth administration may herald complete lack of longitudinal growth within the diaphysis of a long bone after the epyphysial cartilage has grown beyond any given level, cannot be discounted. Further support of this potential serious adverse effect is the case of bismuth poisoning recorded by Krige in a 13-month child in whom absorption took place from externally applied bismuth paste and was visible in the bony tissues after 9 weeks as dense transverse bands in areas of maximum growth such as the metaphyseal ends of the long bones.[72]

In growing dogs, analogous roentgen changes were produced by the parenteral administration of bismuth.[71] As in the human skeleton, the best-developed lesions were present at the sites of most rapid growth, and no changes were seen in nongrowing portions. The rapidity of the development of these lesions in the very young and rapidly growing dogs was demonstrated by the appearance of shadows at the ends of the bones within 8 days of the intramuscular injection of bismuth. The rapid increase in the size of the lesion was indicated by the presence of lesions 5 mm thick in the distal ends of the femurs and in both ends of the tibias only 25 days after the administration of the metal. There were marked microscopic changes in the anatomy of the metaphyses in all the bones of the experimental young dogs.[71] The most conspicuous microscopic change was an increase in the cancellated tissue which formed the internal framework of the bone in the terminal portion of the shaft next to the growing cartilage and occupied the exact location of the band of increased density seen radiographycally. The increase in the cancellous framework appeared to represent the persistence of an excessive amount of the trabeculated cartilaginous matrix which normally is destroyed early in endochondrial ossification.[71] As no change had taken place in the peritrabecular stroma in the portion of the shaft that had developed before the administration of bismuth, these observations were interpreted as signifying a bony metaplasia of peritrabecular stroma limited to the segment of bone which had grown during the administration of bismuth.[71]

Toxicity from bismuth compounds may also result from their components, particularly the salicylate moiety of BSS. During the 1950s through 1970s the drug category most frequently responsible for poisoning deaths in children in the United States was salicylates.[73] A combination of factors such as child-resistant packaging, the association of aspirin use and Reye's syndrome, decline in market share, and improved critical care have all contributed to nearly eradicating aspirin-related deaths in children after the 1990s.[73] Despite this decline in childhood deaths, poison exposures and toxicity from salicylates still persists as a common problem in all ages. Salicylate kinetics is a factor in chronic and acute-on-chronic poisonings. A small increase in dose or slowed excretion due to evolving renal dysfunction can cause a greatly prolonged elimination time, and a disproportionate increase in serum salicylate concentration with attendant severe toxicity. The serum half-life of salicylate is typically 2–4 h at low doses, approximately 12 h with anti-inflammatory doses, and can be prolonged to 15–30 h or more following overdosage. Approximately 2–30% of salicylate is excreted unchanged in the urine, with less renal excretion in acidic urine or in patients with renal dysfunction.[74] The signs and symptoms of salicylate intoxication are related to local irritation of the gastrointestinal tract, direct stimulation of the central nervous system respiratory centre, stimulation of the metabolic rate, disturbance of carbohydrate and lipid metabolism, and interference with homeostasis.[73] There are rare reports of salicylate toxicity with chronic BSS ingestion in children.[73,75] Nevertheless, caution should be exercised when BSS is administered to children, in particular those of young age, with salicylate sensitivity, or bleeding disorders, and those taking drugs that have clinically significant interactions with salicylate.

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