This article provides an up-to-date overview of breast cancer mammography screening and briefly discusses its history, controversies, current guidelines, practices across Asia, and future directions. An emphasis is made on shared decision-making—instead of giving just a ‘yes’ or ‘no’ answer to patients, the focus should be on providing sufficient information about the pros and cons of screening to help women make a personal, informed choice. Frontline experts, including breast surgeons, oncologists, breast radiologists, and their representative professional associations should all participate in guideline panels, with the goal of improving cancer detection, reducing mortality, and improving patient outcome.

This article provides an up-to-date overview of breast cancer mammography screening and briefly discusses its history, controversies, current guidelines, practices across Asia, and future directions. An emphasis is made on shared decision-making—instead of giving just a ‘yes’ or ‘no’ answer to patients, the focus should be on providing sufficient information about the pros and cons of screening to help women make a personal, informed choice.

The goal of mammographic screening (and other breast-cancer screening tests) is to detect breast cancer earlier than it would otherwise manifest clinically, when it is less likely to have spread. Data clearly show that detection of breast cancers at smaller sizes and lower (earlier) stages is associated with better patient outcomes, lower morbidity, and reduced breast cancer deaths.1 Reduced morbidity is likely to be related to feasibility of breast conservation and hence less extensive surgery, fewer associated complications such as lymphoedema, less chemotherapy, and hence fewer adverse effects.2 Other benefits of diagnosing screen-detected cancers at an earlier stage also include a lower cost of treatment and consequent reduced financial burden on health care resources.3

The Table summarises the mammography guidelines from selected nations.4 5 In common, all organisations emphasise that the benefits of screening outweigh the harm at all ages.3 6 They all endorse informed decision-making and the importance of informing women about both benefits and limitations of screening. However, there remain legitimate concerns about guideline differences, including the complexity of the guidelines; weak adherence to creating opportunities for informed decision-making; unreadiness of referring clinicians to discuss benefits, limitations, and harm associated with screening; and the lack of reminder systems, which results in weaker adherence to recommended screening intervals. Despite these concerns, it is widely accepted that high adherence to even the least aggressive guidelines will save more lives than the current weak adherence to regular screening programmes.4

Randomised controlled trials (RCTs) have been the gold standard for proving that early detection with mammography decreases mortality from breast cancer. Since the very first screening RCT performed in New York in the 1960s, there have been eight prospective RCTs and numerous subsequent meta-analyses published. Most well-executed RCTs demonstrated a 20% to 30% decrease in mortality from breast cancer when women were invited for screening. These results laid a solid foundation for population-based screening programmes worldwide.1 7 8

Subsequent studies that generated data from population-based screening programmes have provided further evidence of the benefits of screening mammography. The true benefit reported (in terms of mortality reduction) ranged from 38% to 49%, even higher than that shown by RCTs. This difference demonstrates that service screening studies measure the direct effect of screening on women who actually underwent mammography, and not just those who were invited to undergo mammography (as opposed to the methodology of RCTs). Service screening studies also tend to measure the effect of more recent screening practices that have benefited from improved mammography technology, better breast positioning techniques, and improved interpretive skills.1 9

One exception to the RCTs that reported unfavourable results of mammographic screening was the Canadian National Breast Screening Study (CNBSS). It was conducted between 1980 and 1985, and was divided into two parts. The first CNBSS included approximately 50 000 volunteer women aged 40 to 49 years, and determined the mortality benefit in the experimental group, who were assigned to annual screening mammography plus clinical breast examination (CBE) versus the control group who received usual care.10 The second CNBSS had almost 40 000 volunteer women aged 50 to 59 years, and compared the benefit of annual mammography plus CBE with that of yearly CBE alone.11

From the time the results were first published in 1992 and again after follow-up in 2000, 2002, and 2014, the CNBSS has been controversial, because it is the only RCT to have reported no decrease in mortality associated with an invitation to screening. The study also claimed a 22% overdiagnosis of screen-detected invasive cancer, increasing to up to 35% when cases of ductal carcinoma in situ (DCIS) were included.12 13 14 However, the credibility and scientific value of the CNBSS study have been repeatedly questioned in peer-reviewed publications.15 16 17 18 19 Most criticisms of this study are related to vulnerabilities and shortcomings in its execution, including flaws in the randomisation process, lack of statistical power, non-generalisable results, poor quality imaging, suboptimal mammographic image acquisition and interpretation by untrained personnel, and inconsistent thresholds for interpretation.

The flaws in the randomisation process principally arose from three areas. First, unlike all other RCTs, potential participants in the Canadian trials initially underwent a careful physical examination. Second, women with positive findings on physical examination, including palpable lumps, skin or nipple retraction, and even palpable axillary adenopathy, were not excluded from this ‘screening’ trial.18 Finally, randomisation was unblinded and decentralised. Because almost 80% of women with advanced palpable cancers were assigned to the screening arm in the first round of the study, there has been speculation that concerned clinicians did not follow the randomisation process, but rather assigned some symptomatic women to the study group so that they would undergo mammography.19 Whether the imbalance was due to intentional tampering or occurred by chance alone, the net effect was the same—namely, a failure to produce two equal cohorts of patients for comparison.

The CNBSS was also criticised at the time of the trial for poor quality mammography, even compared with mammographic imaging of that era.15 20 To reduce radiation dose, mammography for the trial was performed without the benefit of scatter-reducing grids despite their routine use and availability. Standard imaging for much of the trial used a straight lateral view, not a mediolateral-oblique view, which images more tissue. The combination of poor quality imaging and the investigators’ resistance to taking corrective action led two advisors’ resignation in protest. In addition, technologists who participated in the trial received no special training in performing mammography. Radiologists new to mammography also received no training in interpretation.18 There was also a lack of immediate follow-up after recommendations for biopsy had been made. Overall, about 25% of the recommended biopsies were ultimately not performed.18

The CNBSS trials are an excellent example of the need to carefully consider all facets of a large-scale screening trial before accepting its results as scientifically valid. The numerous design and execution flaws described above explain in large part why the results of the CNBSS are dramatically different from those of all other RCTs. Ultimately, on the basis of the methodology of the CNBSS, the World Health Organization excluded those results when analysing the breast-screening data in the International Agency for Research on Cancer report.21

The greatest debate on the value of breast screening arose after the publication of a highly controversial but frequently quoted meta-analysis by Gotzsche (a medical statistician and director of the Nordic Cochrane Centre) and Olsen in The Lancet in 2000. Their study concluded that there was no benefit of mortality reduction by screening, after discarding six of eight RCTs because they deemed the randomisation to be “inadequate”. The only two RCTs included in their analysis showed no benefit, including the Malmo trial and the notorious CNBSS.7 22

Gotzsche and Olsen’s critique and methodology have caused much controversy and, in turn, have been criticised heavily by leading expert breast imagers, public health clinicians, and professional bodies such as the Society of Breast Imaging.7 8 23 24 25 26 27 Gotzsche and Olsen’s use of quoted figures from cancer registries rather than actual patient data, their selective approach to studies, and in particular the ignoring of the flaws of the CNBSS, have received the harshest criticism. Many experts have commented that Gotzsche and Olsen overstated the limitations of most of the well-executed RCTs, thereby reflecting a “context-free” application of guidelines in a way that did not address the real issues relevant to the effectiveness of mammographic screening. Moreover, Gotzsche and Olsen’s recommendation to abandon screening altogether has hampered collaborative efforts to improve breast cancer detection and control.27

In February 2014, the Swiss Medical Board attempted to overturn the widespread practice of mammography screening in Switzerland by stating that new systematic mammography screening programmes should not be introduced, irrespective of women’s age, and recommended that existing programmes should be discontinued. Their main argument was that the absolute risk reduction in breast cancer mortality was low and that the adverse consequences of screening (false-positive test results, overdiagnosis, overtreatment, and high costs and expense of follow-up tests and procedures) were substantial.28 29

The Swiss Medical Board’s attempt initiated a new phase of heated arguments and debate about the benefits of screening. Expert breast cancer clinicians in both the United States and Europe (including leading cancer associations in Switzerland) rejected their report. One criticism was that the Swiss Medical Board relied heavily on the controversial work by Gotzsche and Olsen and again quoted data from the flawed CNBSS. Another criticism that attracted great attention was the questionable “expert panels” of the board: they included a medical ethicist, a clinical epidemiologist, a clinical pharmacologist, an oncology surgeon, a nurse scientist, a lawyer, and a health economist. Frontline breast imagers, with expertise in diagnosing breast diseases, were excluded from the review panels because of a “conflict of interest”.28 29

The Swiss Medical Board did not adequately consider the fact that assessment of the balance between benefit and harm involves a value judgement that each woman should make only after she is fully informed about the strengths and weaknesses of screening mammography. They also disregarded the extensive literature in support of screening mammography (RCTs and population service screening studies), making their attempt at stopping national mammography screening unjustified.

Commonly mentioned potential harms of screening include false-positive mammograms, recall for additional imaging, a false-positive biopsy, missed breast cancer, radiation dose, patient anxiety, and, above all, overdiagnosis.

Overdiagnosis is defined as the detection (and subsequent actions taken) of a cancer by screening that would not have progressed to become symptomatic in a woman’s lifetime.1 The estimation of overdiagnosis is complex, highly debated, and very difficult to measure.3 Reported figures range widely, from 0% to 50%, vary greatly in terms of methodological rigour, and testify to the inexact nature of most mathematical models.30 31 32 33 34 When appropriate adjustments for temporal trends, risk factors, and lead time are considered, the level of overdiagnosis should be low, within the range of 0% to 10%.32 Importantly, a recent study of over 5 million women (aged 50-64 years) screened by the United Kingdom’s National Health Service showed that there was a significant negative association between the detection of DCIS at screening and invasive interval cancers. In that study, Duffy and colleagues analysed the data from four consecutive screen years and the 36-month outcome after each relevant screen. For every three screen-detected cases of DCIS, there was one less interval case of invasive cancer over the next 3 years. They agreed that the policy on detection and treatment of DCIS is worthwhile and can prevent subsequent invasive cancers.35

The effect of screening on heightening a patient’s anxiety has also been long questioned by critics, but the magnitude of the effect may have been over-exaggerated. In a survey of over 1200 women with a 6-question anxiety scale to understand the short-term and long-term impact of a recall examination, women involved in the digital mammographic imaging screening trial demonstrated only a transient, limited increase in anxiety after a false-positive mammogram compared with those with a negative mammogram, and there was no difference between the two groups’ intention to undergo mammography again in the subsequent 2 years.36 Schwartz et al reported that 96% of American women who received a false-positive mammography report were glad that they underwent the test and remained supportive of screening.37 Most women agreed that the anxiety, inconvenience, and the few image-guided needle biopsies using local anaesthesia associated with a recall from screening, were minor compared with dying of breast cancer.38

To summarise, papers citing a high rate of overdiagnosis in screening (in the magnitude of 20% or higher) and claiming that false-positives are a significant cause of patient anxiety are believed by most experts to be overstating the case.

Although it is important to discuss all aspects of screening asymptomatic women (including potential harm), the harm of not attending screening is underestimated and not discussed. For instance, women who do not attend screening have significantly larger tumours, a higher stage at diagnosis, poorer overall and disease-specific survival, and higher costs of treatment.39 It has been estimated that the cost of treating advanced metastatic breast cancer exceeds USD 250 000 per patient, and the average cost of treating advanced cancer in the first year after diagnosis is almost double that of early cancers, mainly owing to the difference in costs of chemotherapy.3 40 The cost of treatment and lost productivity each year will far exceed the cost of annual screening and, additionally, do not include the indirect value of the lives saved (as a productive member of workforce).1

The incidence of breast cancer continues to increase worldwide. It remains highest in the United States and Europe, but has been increasing substantially in Asian countries over the past three decades.41 Studies that compare invasive breast cancer data from Asia with those from the United States over a 20-year period have shown that female breast cancer incidence among Asian and Western populations is more similar than expected.42 The incidence of female breast cancer in China will continue to rise, and is expected to exceed 100 per 100 000 women by 2021, giving a total of 2.5 million cases.43

According to GLOBOCAN 2012 of the International Agency for Research on Cancer, the specialised cancer research agency of the World Health Organization, almost a quarter (24%) of all breast cancers were diagnosed within the Asia-Pacific region, with the greatest number occurring in China (46%).44 The age-standardised incidence rate was highest among Taiwanese (65.9 per 100 000), followed by Singaporeans, South Koreans, and Japanese.44 In a multiracial country such as Singapore, Chinese women have been noted to have a significantly higher risk of developing breast cancer than Malays and Indians.45

The disease burden in Hong Kong is no different. Locally, the age-standardised incidence rate was 58.8 per 100 000 in 2015, with over 3900 new cases per year.46 A study of the local trend in female breast cancer incidence from 1973 to 1999 by the University of Hong Kong showed a significant yearly increase of an average of 3.6%; the increase was most marked and continued to accelerate in the younger age-groups. It was speculated that such trend changes were related to Westernisation of lifestyle.47 All these data indicate that the disease burden in Hong Kong is increasing and comparable to that of all other civilised Asian countries and cities.

Breast screening services in Asian countries and cities are highly variable: some have advanced nationwide screening programmes and others have less developed programmes.48 South Korea and Taiwan are both well recognised for their experience in running such programmes, the former having the highest intake rate and the latter being the most well-structured.

South Korea places a very strong emphasis on screening for cancer control in general. Its national health service offers mammography and CBE every 2 years to women aged 40 or older, and at no cost to the 50% of people with the lowest incomes. Their programme is popular and widely accepted by the general public, and achieved an uptake of as high as 66% in 2014. Benefits of downstaging from screening were also observed. However, South Korea encountered a problem of potential overdiagnosis, with a noticeably higher false-positive rate when compared with other places.

Taiwan’s health authorities have been recognised for rolling-out well-organised and well-resourced screening programmes, with good support from a local randomised controlled trial showing a reduction in mortality by 40% with mammography screening.49 Since 2004, their health service has provided free breast screening to women aged 50 to 69 years, expanded in 2010 to those aged 40 to 49 years. By 2015, about 40% of the target population participated in screening. It is believed that the cause of the suboptimal participation rate was not due to capacity or outreach, but rather the Taiwanese public’s values and attitude. Nonetheless, with more resources being directed to public education and motivation, Taiwan’s health authorities are pushing their goal to 60% by 2018.

The experience of screening programmes in Singapore and Japan is more equivocal. Despite having sufficient scientific evidence to support their role in reducing mortality and reducing invasive cancer incidence, the participation rate has remained lower than expected, mostly owing to cultural barriers and paradigms, or a lack of central governing. Singapore established its national, population-wide screening programme (BreastScreen Singapore) in 2002 and now covers women aged 40 to 69 years. The participation rate has been noted to plateau at 40% since 2010, short of the target of 70%. The health promotion board believes that apart from cultural issues, costs (as screening is paid by an individual’s medical insurance account) constitute the greatest barrier to uptake.

The study of population-based screening in Japan has been complex, with scattered data owing to the lack of a single national organisation for monitoring. The participation rate remains lower than in other comparable Asian countries in the past century, again likely because of cultural paradigms. Despite these barriers, in the past decade, Japanese health officials have started designing their own methods and protocols for screening, particularly targeting the higher incidence of cancer among younger women (aged 40-49 years) and the large proportion of patients with dense breasts. After the launch of government-funded screening programmes, a clinical trial that started in 2007 (Japan Strategic Anti-cancer Randomised Trial, J-START) of over 70 000 women undergoing adjunctive ultrasonography to supplement mammography for screening showed an increased sensitivity and detection rate for early preclinical cancers.41

In China, there is no nationwide screening programme for breast cancer. A mammographic screening programme was attempted in 2005 but was abandoned because of lack of funding and concerns about false-positive diagnoses. Despite these barriers, national guidelines established in 2007 recommend annual mammography for women aged 40 to 49 years, and every 1 to 2 years for those aged 50 to 69 years. In a Beijing study of 1.46 million women (aged 35 to 59 years) who underwent screening by ultrasonography from 2009 to 2011, the cancer detection rate was 48.0 per 100 000, including 440 cases at early stage that constituted 69.7% of cases detected. The detection rate was lower than anticipated, maybe in part owing to the young age of the screened group and omission of mammography as a screening tool. Subsequently, a second-generation screening programme was initiated in 2012, after modification of the screening methods, cohort size (6 million), and target population that included women aged 35 to 64 years. The new screening procedures include parallel CBE and breast ultrasonography; women with suspicious findings from either examination are recommended to undergo mammographic imaging.50 Although the design of this screening protocol deviates from the standard practice of other countries, we believe that the programme will bring more research data and experience, and eventually lead to more comprehensive guidelines and consensus on a screening approach in China.

The awareness of breast cancer and acceptance of screening in Hong Kong is growing, but is still inadequate. According to the latest Breast Cancer Registry Report No 8 (2016), which covers 13 453 breast cancer patients diagnosed from 2006 onwards, the mean and median age of patients at diagnosis was 52.6 and 51.3 years, respectively, and about two-thirds of patients were aged 40 to 59 years. The screening habits among these patients were poor, with over 60% never having undergone mammography screening before their cancer diagnosis.51

Although to date there has been no population-based screening for women in Hong Kong, opportunistic screening has long been practised in the private sector. The largest voluntary self-financed and self-referred opportunistic screening programme is run by the Tung Wah Group of Hospitals. In a retrospective review of their performance from 1998 to 2002 involving over 46 600 screening mammograms, a breast cancer detection rate of five cases per 1000 population was noted, which was comparable to the detection rate of Western screening programmes at that time.52

Regarding the input of expertise and quality assurance, the Hong Kong College of Radiologists issued their mammographic statement in 2006 (latest revision in 2015).53 Quoting desirable goals recommended by the United Kingdom and United States as a reference the statement sets specific benchmarks for standards of mammographic machines, quality of screening mammograms, radiation dose limits, and accreditation requirements of reporting radiologists.53 Given these guidelines, together with recent advances in mammographic technology, we believe that there should be room for further local development of large-scale quality breast-screening programmes.

When planning a breast-screening programme, it is necessary to decide whom to screen (ie, at what age and the target screening population) and how to screen (ie, screening method).

For the decision of whom to screen, we should note that the mean age at diagnosis of breast cancer in Chinese women is 45 to 55 years, considerably younger than for western women.43 Starting screening at age 40 or 45 years would likely be a better fit for Chinese women than starting at age 50 years, as recommended by some western guidelines. As for the target screening population, current data favour universal screening over risk-based screening (pre-selecting patients according to risk profile). First, one should note that 80% of women with newly diagnosed breast cancer have no family history (ie, first-degree relative) or other significant previous risk factors, and therefore risk-based screening will miss a majority of screen-detected breast cancers.3 54 Second, a recent 10-year population-based cohort study of over 1.4 million asymptomatic Taiwanese women undergoing various breast-cancer screening regimens showed that universal mammography screening based only on age and sex was more effective than other screening regimens (risk-based biennial mammography screening or annual CBE alone).49 In that study, universal biennial mammography screening was associated with a 41% reduction in mortality and a rate of overdiagnosis of only 13%. In contrast, risk-based biennial mammography (pre-selecting patients according to risk profile or risk score) did not lead to any statistically significant reduction in mortality. Moreover, among all screening regimens, only universal biennial screening was associated with a clear downstaging shift in tumours (30% reduction of stage 2+ cancers), a crucial factor that can improve patient outcome.49

Regarding methods of screening, conventional screening uses standard two-view full-field digital (two-dimensional; 2D) mammography. Multiple studies have proven that screening by digital breast tomosynthesis (DBT; also called three-dimensional mammography) can increase cancer detection rates compared with 2D mammography alone, and can reduce the recall rate for benign findings (false-positives). 1 55 A retrospective analysis of over 454 000 screens showed that use of DBT was associated with relative increases of 41% in invasive cancer detection, 49% in positive predictive value (PPV) for recall, and 21% in PPV for biopsy, in addition to a 15% reduction in the overall number of recalls.56 A recent meta-analysis by a Korean group also showed that screening with DBT increased detection of early invasive cancers of <2 cm.57 The American College of Radiology Commission on Breast Imaging now recommends that mammography and DBT are “usually appropriate” for screening of average-risk women, noting that DBT addresses some limitations of standard digital mammography.58 In Hong Kong, DBT has been increasingly adopted to replace or serve as an adjunct to 2D mammography in opportunistic screening. We anticipate that the shift to DBT screening will become a global trend.

The use of whole-breast ultrasonography to screen dense breasts is also commonly adopted in Asia, including for opportunistic screening in Hong Kong. In Japan, this practice was reinforced by a government-funded RCT (J-START) that studied the use of adjunctive ultrasonography to supplement mammography in screening over 70 000 women. The J-START study showed favourable results of increased sensitivity and detection rate for early, preclinical cancers.41

Screening for high-risk women is often considered a separate entity. According to the American College of Radiology’s Appropriateness Criteria, women at high risk due to prior mantle radiation between the ages of 10 and 30 years should start mammography 8 years after radiation therapy, but not before age 25. For women with a genetic predisposition, annual screening mammography is recommended to begin 10 years earlier than the age that an affected relative had been diagnosed, but not before age 30. Annual screening by magnetic resonance imaging is recommended in high-risk women as an adjunct to mammography.59

We believe that health care in Hong Kong should have the capability and expertise to roll out quality, large-scale population-screening programmes that are comparable to those in other developed Asian countries and cities. When we examine the common themes among available guidelines, literature, and expert reviews worldwide, the global trend is to provide women with an informed choice.

In the discussion of whether breast-cancer screening is feasible, one should bear in mind that this is an emotive issue. Apart from the critical appraisal of scientific evidence, the interpretation of literature and subsequent formulation of recommendations should always account for the socioeconomic, historical, and contextual realities. The value judgement of women should also be respected.

Frontline experts, including breast surgeons, oncologists, breast radiologists, and their representative professional associations should all participate in guideline panels, with a will to end the ‘mammography wars’. Our Holy Grail should always be focused on improving cancer detection, reducing mortality, and improving patient outcome.

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49. Yen AM, Tsau HS, Fann JC, et al. Population-based breast cancer screening with risk-based and universal mammography screening compared with clinical breast examination: a propensity score analysis of 1 429 890 Taiwanese women. JAMA Oncol 2016;2:915-21. CrossRef

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Ketamine is an N-methyl-d-aspartate receptor antagonist, a dissociative anaesthetic agent and a treatment option for major depression, treatment-resistant depression, and bipolar disorder. Its strong psychostimulant properties and easy absorption make it a favourable candidate for substance abuse. Ketamine entered Hong Kong as a club drug in 2000 and the first local report of ketamine-associated urinary cystitis was published in 2007. Ketamine-associated lower–urinary tract symptoms include frequency, urgency, nocturia, dysuria, urge incontinence, and occasionally painful haematuria. The exact prevalence of ketamine-associated urinary cystitis is difficult to assess because the abuse itself and many of the associated symptoms often go unnoticed until a very late stage. Additionally, upper–urinary tract pathology, such as hydronephrosis, and other complications involving neuropsychiatric, hepatobiliary, and gastrointestinal systems have also been reported. Gradual improvement can be expected after abstinence from ketamine use. Sustained abstinence is the key to recovery, as relapse usually leads to recurrence of symptoms. Both medical and surgical management can be used. The Youth Urological Treatment Centre at the Prince of Wales Hospital, Hong Kong, has developed a four-tier treatment protocol with initial non-invasive investigation and management for these patients. Multidisciplinary care is essential given the complex and diverse psychological factors and sociological background that underlie ketamine abuse and abstinence status.

Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist, a dissociative anaesthetic agent that was first synthesised in the United States in 1962. It has been widely used in both human and veterinary medicine since 1971. It has also been used as a treatment for major depression, treatment-resistant depression, and bipolar disorder.1 However, its strong psychostimulant properties and easy absorption make it a favourable candidate for substance abuse. Ketamine abuse has become increasingly common over the past two decades. It entered Hong Kong as a club drug in 2000 and was initially used as a ‘top-up’ drug to ecstasy (3,4-methylenedioxymethamphetamine) by those aiming to elevate and redirect the ‘high’.2 It was viewed as a poor man’s version of cocaine, as it is available in powder form and can be consumed by snorting. By 2002, ketamine had become the drug of choice instead of a ‘top-up’ drug. Users self-administered ketamine to have a ‘time-out’ or ‘sit-down-to-float’ experience.2 3 Within a short period, the number of reported ketamine abusers in Hong Kong increased from 1605 in 2000 to its peak of 5280 in 2009. Ketamine remained the most popular psychotropic substance abused from 2005 to 2014 (Fig 1).4

The abuse of ketamine and its popularity nonetheless created a new medical entity. The first report of ketamine-associated urinary cystitis in Hong Kong was published in 2007.5 In the same year, Shahani et al reported a similar condition overseas.6 In the past decade, owing to the joint efforts of urologists, general surgeons, physicians, psychiatrists, pathologists, and basic scientists, we have gained a better understanding of other ketamine-associated conditions. This understanding spans from pathology to clinical management, from urological complications to upper-gastrointestinal (GI) complications, and from a mouse model to humans. We have also explored holistic ways to manage this condition in the long term, such as helping young adults to have a fresh start while living with potentially irreversible complications. This article reviews the evolution of local clinical awareness and management of these complications, with a particular focus on the work and contributions of local researchers.

Chu et al5 reported the first local case series of ketamine-associated bladder dysfunction in 2007. Ketamine-associated lower–urinary tract symptoms (LUTS) include frequency, urgency, nocturia, dysuria, urge incontinence, and occasionally painful haematuria. The exact prevalence of ketamine-associated urinary cystitis is difficult to assess because ketamine abuse and many of the associated symptoms often go unnoticed until a very late stage. A survey among 12 000 local secondary school students revealed that 18.5% of non-psychotropic substance users had LUTS, whereas 47.8% and 60.7% of psychotropic substance users and ketamine users had LUTS, respectively.7 Unpublished data from the same study showed that compared with non-psychotropic substance users, sole ketamine users were five times as likely to have LUTS, whereas concomitant users of ketamine and methamphetamine were eight times as likely to have LUTS.

In 2015, Yee et al8 reported the largest available cohort of both active and past ketamine users who had ketamine-associated uropathy. Among 463 patients, ketamine users had a significantly higher pelvic pain and urgency/frequency (PUF) score than ex-ketamine users. The PUF score is initially used to assess interstitial cystitis, and a higher PUF score correlates with worse symptoms. Among active ketamine users, a higher PUF score was found to correlate with a poorer quality of life and a smaller functional bladder capacity.8 Achieving abstinence from ketamine use and consuming smaller amounts of ketamine were factors that predicted improvement in PUF score.

As well as bladder involvement, upper–urinary tract pathology presenting as hydronephrosis and flank pain has also been reported (Fig 2). A study by Yee et al9 of 572 patients with ketamine-related LUTS found that up to 16.8% (n=96) of patients had hydronephrosis according to ultrasonography. Hydronephrosis was frequently accompanied by ureteral lesions, ureteral wall thickening, or vesicoureteral (vesicoureteric) reflux. Similarly, Chu et al10 reported that 51% (30/59) of their patients had hydronephrosis according to ultrasonography.

Although the exact mechanism of ketamine-associated cystitis remains to be explored, there is evidence that ketamine metabolites in the urine induce chemical irritation of the urothelium, thereby causing an inflammatory response.11 Severe irritation may lead to denudation of the urothelium and consequent transmural inflammation, loss of muscle thickness, fibrosis of the detrusor muscle, and ultimately poor urinary bladder compliance. Vesicoureteral reflux or urinary stasis in the ureter may occur, causing chronic ureteral inflammation and ureteral stricture. There is also evidence that both systemic and local inflammatory markers are elevated in ketamine users.10 12 In addition, the NMDA antagonist properties of ketamine may exert their effect via a central pathway.13

As ketamine is a psychostimulant, it is not surprising that it is associated with long-term neurocognitive problems. Chan et al14 found that when ketamine users were compared with healthy controls, they had impaired verbal fluency, cognitive processing speed, and verbal learning. Heavy ketamine use correlated with deficits in verbal memory and visual recognition memory. Liang et al15 also identified predominant verbal and visual memory impairment in ketamine poly-drug users. Unfortunately, these deficits persisted in ex-users. A much higher incidence of psychiatric co-morbidities, including psychosis, depression, and anxiety, was observed among ketamine users.16

Structural brain damage associated with ketamine abuse was supported by magnetic resonance imaging (MRI) by Wang et al.17 They were the first group to report patches of degeneration in the superficial white matter as early as 1 year after ketamine addiction onset. Cortical atrophy was also found in the frontal, parietal, or occipital cortices of addicts.17 Another MRI study also provided evidence of brain damage in chronic ketamine users. Reduced grey- and white-matter volumes were noted in the bilateral orbitofrontal cortex, right medial prefrontal cortex, and bilateral hippocampi. There was also significantly decreased connectivity inside the brain in chronic ketamine abusers.18

A series of studies on the neurotoxicity of ketamine suggested that ketamine could cause apoptosis of neuronal cells in both in-vitro and in-vivo models. Ketamine also potentially causes phosphorylation of tau protein, a marker of Alzheimer’s degeneration in the brain.19 20 21 22

In 2009, Wong et al23 reported ketamine-associated hepatobiliary complications for the first time. Three ketamine abusers presented with recurrent epigastric pain and dilated bile ducts mimicking choledochal cysts. Subsequently, more similar cases were identified. Fusiform dilatation of the common bile duct was also observed.24 25 26 Liver biopsy confirmed development of active liver and/or bile duct injury. A study of 297 chronic ketamine abusers with urinary tract dysfunction showed that the prevalence of liver injury was 9.8%.27 These studies and reports show the possibility and severity of damage by ketamine to the hepatobiliary and pancreatic system.

The exact mechanism of ketamine-associated bile injury is still unknown. The associated rise in C-reactive protein suggests a possible inflammatory process in the liver parenchyma, including or excluding the bile duct.27 Others have postulated that either central or direct action of ketamine on the biliary smooth muscle in turn leads to the cholestasis and biliary dilatation observed in ketamine abusers.28

In addition to urological complaints, GI problems are also frequently the symptoms for which ketamine abusers seek medical help. A review of 233 ketamine-related visits to accident and emergency departments found that 49 (21.0%) patients had abdominal pain, 23 (9.9%) had nausea or vomiting, and 41 (17.6%) had abdominal tenderness.29 Gastrointestinal complaints often co-exist with and precede the presentation of urological symptoms. Liu et al30 found that about a quarter (168; 27.5%) of 611 ketamine users who sought treatment for ketamine uropathy reported the presence of upper-GI symptoms, whereas only 42 (5.2%) of 804 non-ketamine users attending a general urology clinic reported similar symptoms (P<0.001). The majority of the symptoms reported were epigastric pain and recurrent vomiting. Nearly three-quarters of patients required hospitalisation for acute or chronic upper-GI symptoms. With the exception of acid reflux and perforated peptic ulcer, the prevalence of all the above-mentioned symptoms and hospitalisation rates were statistically significantly higher in ketamine users than in non-ketamine users. All 168 patients using ketamine had undergone oesophagogastroduodenoscopy during which biopsies were taken. Pathological findings ranged from gastritis to gastroduodenal erosions, peptic ulceration, and intestinal metaplasia.30

Liu et al30 also found that more than 80% of patients developed upper-GI symptoms before urological symptoms. Patients developed upper-GI symptoms after a mean (standard deviation) of 5.1 (3.1) years of ketamine use and developed uropathy symptoms after another 4.4 (3.0) years of ketamine use.30 Epigastric symptoms are not common in young people, but common in ketamine abusers. This difference may provide an opportunity to identify hidden ketamine abuse when assessing young patients with epigastric symptoms. The identification of ketamine use is important, as cessation of use can greatly improve GI symptoms.31 Further referral for help and counselling may improve psychological and physical health and promote long-term ketamine abstinence.

The exact pathophysiological mechanism by which ketamine produces upper-GI toxicity remains unknown but there are several postulations. First, ketamine, as an NMDA antagonist, might act on local smooth muscle or the central nervous system, thereby affecting gastric motility and leading to cramping pain. Second, microvascular damage by ketamine and its metabolites, which was believed to be a possible cause of ketamine uropathy, might also cause similar microvascular damage in the stomach and duodenum, leading to ischaemic pain and inflammation. Likewise, circulating ketamine might also trigger some unknown autoimmune responses, and thus induce interstitial inflammation in the urinary and GI tracts. Finally, as many ketamine abusers like to swallow the nasal drips occurring from ketamine inhalation, the swallowed ketamine might also induce direct cytotoxic injury to the vulnerable GI tract.30

As in the management of other substance abuse, abstinence is the key to success in overall management of ketamine use. Whereas other treatment modalities may relieve symptoms and hasten the recovery process, many ketamine abusers have complicated underlying psychosocial problems and psychiatric co-morbidities. Long-term and consistent support and encouragement from doctors, nurses, social workers, family, and friends are vital for success.

Recurrence of symptoms after resuming ketamine use highlights the importance of ketamine abstinence. Studies have shown that abstinence leads to symptomatic improvement. Compared with active ketamine abusers, those who had abstained for 1 year had significantly lower PUF scores and a larger voided volume. There was a trend towards higher voided volumes and lower PUF scores as duration of ketamine cessation increased, although neither variable was statistically significant.32 Another follow-up study of 101 participants who had abstained from ketamine and 218 active ketamine users showed that the abstinence group had a statistically significantly lower PUF score, and a higher functional bladder capacity.8 Moreover, abstinence was the only protective factor associated with fewer symptoms, larger voided volume, and bladder capacity.33

Nonetheless, abstinence does not lead to immediate and full recovery of symptoms. Gradual improvement can be expected but sustained abstinence is the key to recovery. Patience and continuous support are of paramount importance. A study showed that on admission to a drug rehabilitation centre, 90% of 40 female ex-ketamine users still had active urinary symptoms, with increased 24-hour urinary frequency, lower maximum voided volume, smaller median functional bladder capacity, and higher mean Urogenital Distress Inventory Short Form (UDI-6) and Incontinence Impact Questionnaire Short Form (IIQ-7) scores, when compared with age-matched controls who attended a general gynaecology clinic. After having stopped using ketamine for 3 months or more, mean 24-hour urinary frequency and mean UDI-6 and IIQ-7 scores decreased, and maximum voided volume increased. These scores further improved after another 3 months, although this group continued to perform more poorly in all aspects compared with controls.34

As ketamine-associated uropathy is an evolving ‘disease entity’, the exact pathophysiology remains to be elucidated. Some of the clinical features share similarities with interstitial cystitis. Protocols are being developed to cater to the needs of patients in Hong Kong. A one-stop service model has been adopted by the Youth Urological Treatment Centre at the Prince of Wales Hospital since 2011 (Fig 3). The standard treatment protocol involves four tiers of treatment, starting with an initial non-invasive investigative approach, including questionnaire assessment of symptoms and calculation of (1) functional bladder capacity by measuring voided volume using uroflowmetry and (2) residual urine using ultrasound bladder scanning. This non-invasive investigative approach helps gain patients’ trust and improve adherence to later follow-up.

First-tier treatment includes oral non-steroidal anti-inflammatory drugs (NSAIDs) (eg, diclofenac) and anticholinergics (eg, solifenacin) or COX-II inhibitors (eg, etoricoxib) if patients cannot tolerate NSAIDS. Simple analgesics such as paracetamol and phenazopyridine are used for pain control. The Youth Urological Treatment Centre has reported the largest series of patients with ketamine-associated uropathy and their corresponding outcomes. Of 290 patients with ketamine cystitis who received first-line treatment, 202 (69.7%) reported symptom improvement and a reduction in PUF scores. Functional bladder capacity was also shown to have improved.8

The opioid group of analgesics and pregabalin are used in the next tier of pain-control treatment when first-tier treatment is insufficient for symptom relief. Sixty-two patients received second-line treatment and 42 (67.7%) responded to treatment.8

Third-tier treatment consists of a course of intravesical instillation of sodium hyaluronate (6-weekly instillations followed by 2-monthly instillations) attempting to repair the glycosaminoglycan layer. The drug is given to patients whose symptoms remain uncontrolled after second-tier treatment. Seventeen patients in the cohort received the third-tier treatment and eight completed the course. Significant improvement in voided volume was noted and five were able to reduce their oral medication usage after treatment. No significant adverse effects were reported.8

Unfortunately, for a proportion of patients with extremely refractory symptoms, surgery becomes the fourth-tier treatment of choice. In the Youth Urological Treatment Centre series, one patient in the cohort required hydrodistension and another underwent robotic-assisted laparoscopic augmentation cystoplasty. The patient with hydrodistension experienced a recurrence of symptoms post-treatment.8 Ng et al35 reported on four patients who underwent augmentation cystoplasty. Although they showed initial improvement, all patients relapsed and resumed ketamine use postoperatively. Three of the patients showed a further deterioration in renal function, secondary to new-onset ureteral strictures and/or sepsis. Therefore, patient selection, education, close follow-up, and support are vital to the success of augmentation cystoplasty.35

Given the complex and diverse psychological factors and sociological background contributing to an individual’s decision to abuse ketamine or achieve abstinence, joint multidisciplinary efforts are required to help affected young adults. Doctors, social workers, teachers, psychiatrists, psychologists, nurses, and patients’ families all need to support them on their long road to recovery, to help them rehabilitate physically and achieve sustained abstinence from ketamine.33 36 37

Since the initial discovery of ketamine-associated uropathy, the impact of this disease entity has become more prominent in Asian countries. Thanks to the joint efforts of urologists, gynaecologists, surgeons, psychiatrists, pathologists, and social workers, as well as the support of local government, the extent of medical complications has been revealed to also involve the brain, liver, and GI system. Many ketamine abusers are ‘hidden’ and can use ketamine stealthily at home for years without their family noticing. Clinicians must take the opportunity to identify hidden abusers when they consult for non-specific symptoms such as epigastric pain and LUTS. Doing so will not only enable early diagnosis of ketamine-associated uropathy, but it will also help provide appropriate medical treatment in a timely manner. In addition to medical therapy, referral for appropriate psychosocial support is essential to sustain abstinence and manage underlying psychosocial problems.

The Youth Urological Treatment Centre was developed by joint efforts of The Chinese University of Hong Kong and the Hong Kong Hospital Authority, with generous support from the Beat Drugs Fund of the Narcotics Division, Security Bureau, Government of the Hong Kong Special Administrative Region.

The authors have no conflicts of interest to disclose.

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12. Division of Urology, Department of Surgery, Princess Margaret Hospital and Tuen Mun Hospital. Research on Urological Sequelae of Ketamine Abuse. Available from: http://www.nd.gov.hk/pdf/20110307_beat_drug_fund_report.pdf. Accessed 22 Sep 2017.

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19. Yeung LY, Wai MS, Fan M, et al. Hyperphosphorylated tau in the brains of mice and monkeys with long-term administration of ketamine. Toxicol Lett 2010;193:189-93. CrossRef

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Periprosthetic joint infection (PJI) is an uncommon but serious complication after total knee arthroplasty (TKA). Treatment is often challenging and has a major impact on the patient. Multiple operations are often required and patients may suffer from a long period of disability. Moreover, PJI incurs considerable health care costs.1 2 3 Therefore, multiple strategies including antibiotic prophylaxis, body exhaust systems, and laminar airflow systems have been developed to reduce the incidence of PJI. Studies have also identified modifiable risk factors for PJI after elective total joint replacement,4 5 6 7 8 9 10 11 12 13 14 with the aim of further reducing the incidence of PJI. However, local data on the risk factors and bacteriological features associated with PJI are still lacking.

This study had several aims. First, it aimed to provide the most up-to-date local data on incidence of and risk factors for PJI, including age, sex, presence of diabetes, presence of rheumatoid arthritis, and one-stage bilateral TKA. Second, this study aimed to provide an update on the bacteriology of PJI after elective primary TKA and to examine the association between potential risk factors and bacteriology. Third, we attempted to determine which risk factors, including bacteriology, were more likely to be associated with early-onset infection after elective primary TKA.

It is hoped that risk factors can be optimised or modified to prevent infection after TKA. Furthermore, an improved understanding of local bacteriological patterns and their relationship with various risk factors can help guide antimicrobial therapy.

We reviewed 2543 elective primary TKAs performed at the Queen Mary Hospital, Hong Kong, from 1993 to 2013. Data were collected by an infection control nurse of the Department of Microbiology who was blinded to the study objectives. The cohort data were collected from the Hong Kong Hospital Authority’s Clinical Data Analysis and Reporting System, the Infection Control Team, and the hospital’s joint replacement division registry. The keywords used in the data search were ‘periprosthetic joint infection’, ‘total knee arthroplasty’, and ‘surgical site infection’. Revision arthroplasties and knee arthroplasties for malignant conditions were excluded from the study. In patients with a history of native joint infection, elective primary TKA was performed only after eradication of the infection. Patients with active bacteraemia were also precluded from elective primary TKA until they were infection-free. There were no cases of severe immunosuppression. In relation to infection control, the majority of perioperative protocols for primary TKA were the same throughout the study period. Preoperatively, intravenous antibiotic prophylaxis (1 g of cefazolin) was given within 1 h before skin incision. In patients with penicillin allergy, other antibiotics were prescribed as appropriate. Intra-operatively, laminar airflow and body exhaust systems were used. There was no routine use of antibiotic-loaded cement or postoperative antibiotics. Postoperative wound management was the same throughout the study period.

Cohort characteristics, occurrence of PJI, and bacteriological data were retrieved. Bacterial type was defined as infection with skin flora or non-skin flora. Skin flora included methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S aureus (MRSA), methicillin-susceptible coagulase-negative staphylococci (MSCNS), and methicillin-resistant coagulase-negative staphylococci (MRCNS). Other organisms were considered non-skin flora.

The following potential risk factors for PJI were analysed: age, sex, presence of diabetes, presence of rheumatoid arthritis, and one-stage bilateral TKA. They were examined by univariable analyses and then multivariable logistic regression to identify potential predictors of PJI, while controlling for confounders. We also studied the association of those potential risk factors with bacteriology and with the timing of infection onset; culture-negative PJI was excluded from these analyses. According to a working party convened by the Musculoskeletal Infection Society in 2014,15 PJI that occurs within 90 days of the index operation is considered early-onset infection, whereas PJI that occurs later is considered late-onset infection.

Both univariable and multivariable logistic regression in this study used the simultaneous entry method, with covariates of age (as a continuous variable) and sex, diabetes, rheumatoid arthritis, and one-stage bilateral TKA (as dichotomous variables). Outcomes are presented as odds ratios (ORs) with 95% confidence intervals (CIs). The regression model and data fitting were assessed using the Hosmer–Lemeshow goodness-of-fit test, and diabetes and one-stage bilateral TKA were excluded from the final model because of poor goodness-of-fit. For associations between potential risk factors and bacteriology and between potential risk factors and early onset of infection, only univariable analyses were used owing to small numbers of events. Categorical variables were compared with the chi-square test, whereas age was compared with the independent t test (two-tailed). Significance was assumed if P<0.05. All statistical analyses were conducted using SPSS version 22.0 (IBM Corporation, Armonk [NY], United States). The study was conducted in accordance with the principles outlined in the Declaration of Helsinki.

The incidence of PJI in our series was 1.34% (n=34). The incidence of early-onset infection was 0.39% (n=10) and that of late-onset infection was 0.94% (n=24). Among the cases PJI, 29.4% were early-onset infection. Early-onset infection occurred within a median of 17 days after arthroplasty (interquartile range, 9-32 days). Late-onset infection occurred within a median of 1 year and 8 months after arthroplasty (interquartile range, 7 months to 2 years and 11 months). Fifty-nine percent of infections occurred in the first year of surgery, whereas 74% occurred in the first 2 years.

The mean (standard deviation) age was 69 (9) years, with a range from 21 to 91 years; age followed a normal distribution. Overall, PJI developed in 10 males (1.9%) and 24 females (1.2%). In the one-stage bilateral TKA group, PJI occurred in 13 knees (1.2%). For the single-side TKA group, 21 knees (1.4%) developed PJI. Nine patients with diabetes (1.9%) and 25 patients without diabetes (1.2%) developed PJI. The highest rate of PJI, at 3.1%, was found in patients with rheumatoid arthritis, compared with 1.2% in patients without rheumatoid arthritis. The descriptive data are summarised in Table 1.

The most frequent causative organism was MSSA (26.5%, n=9), followed by MRSA (17.6%, n=6), Streptococcus spp (8.8%, n=3), MSCNS (5.9%, n=2), Escherichia coli (5.9%, n=2), Salmonella (5.9%, n=2), MRCNS (2.9%, n=1) and Mycobacterium tuberculosis (2.9%, n=1), The three cases of streptococcal infection comprised two Streptococcus dysgalactiae infections and one Streptococcus agalactiae infection. Culture-negative PJI comprised 23.5% of cases (n=8). Methicillin-resistant strains constituted 39% of all staphylococcal organisms. There was no significant association between the potential risk factors and skin flora infection (Table 2).

Rheumatoid arthritis was a significant risk factor of PJI in the univariable analysis, with an OR of 2.67 (95% CI, 1.15-6.20; P=0.02), as well as in the multivariable analysis, with an OR of 3.12 (CI, 1.29-7.56; P=0.01) [Table 3]. Being male (OR=1.9; P=0.11 in the multivariable analysis) and having diabetes (OR=1.54; P=0.27 in the univariable analysis) were not significantly associated with PJI.

Age (P=0.655), sex (P=0.961), diabetes (P=0.462), and rheumatoid arthritis (P=0.315) were not associated with early-onset infection (Table 4). Infection caused by skin flora was associated with early-onset infection (P=0.099), but the association was not statistically significant.

In this study, the incidence of PJI after primary TKA was 1.34% and the incidence of early-onset infection was 0.39%. The majority of PJIs (70%) were late-onset infections. The reported incidence of PJI after primary TKA ranges from 1.1% to 2.18%.16 17 18 Pulido et al16 reported the incidence of PJI after TKA to be 1.1%, of which 27% were diagnosed during the first 30 days after arthroplasty, and a majority of 65% were diagnosed in the first year after surgery. In our study, the average time to diagnosis was 431 days after the index surgery (range, 11-1699 days).

Rheumatoid arthritis was a significant risk factor for PJI after primary TKA. This finding is in keeping with the current literature.6 8 11 Although various authors have found male sex to be a risk factor for PJI,4 19 20 the association was not significant in this study. The OR of 1.9 may be of clinical importance but not significant as a result of the small number of PJIs and inadequate statistical power. The correlation between age and PJI has been a matter of controversy, with some reports mentioning young age as a risk factor for PJI4 21 and some otherwise.22 In our study, age was not associated with PJI occurrence. For one-stage bilateral TKA, age has been a controversial risk factor for PJI. Some studies16 23 have suggested that one-stage bilateral TKA is associated with an increased risk of superficial and deep infection. Hussain et al24 nonetheless reported a similar infection rate between one- and two-stage bilateral TKA. Our study did not find an association between one-stage bilateral TKA and PJI occurrence.

The local bacteriological pattern for PJI was comparable to that reported in the literature.4 16 In our study, skin flora and gram-positive bacteria were the most commonly isolated organisms, followed by gram-negative bacteria such as Escherichia coli and Salmonella. Coagulase-negative staphylococci were the most common causative organism in one study.4 In contrast, in our series, S aureus was the most common causative organism, particularly methicillin-sensitive strains. Methicillin-resistant strains were less common in our series, constituting 39% of all staphylococcal organisms.

Other authors have reported that male sex is a risk factor for PJI, which may be related to a sex difference in immune response to pathogenic bacteria. Studies6 have shown that males (compared with females) have a significantly higher likelihood of being a persistent S aureus carrier. However, our study did not support male sex as a risk factor for infection with skin flora. With regard to onset of infection, PJI caused by skin flora was positively associated with early-onset infection, although the association did not reach statistical significance (P=0.099). Direct inoculation and spread from contiguous foci of infection are more common in early-onset infection caused by wound complications and local soft-tissue conditions. In contrast, distant foci of infection, such as in bacteraemia, play a more important role in late-onset infection. Therefore, in early-onset periprosthetic joint infection with negative cultures, an empirical antibiotic regimen may provide adequate coverage against skin flora organisms.

Fan et al20 reported 479 TKAs and rates of 1.9% for superficial wound infection, 0.2% for early deep infection (n=1), and 0.6% for late deep infection (n=2). Methicillin-sensitive S aureus and coagulase-negative staphylococci were causative organisms. Lee et al25 reviewed 1133 primary TKAs and found a 0.71% incidence of PJI. The most common causative organisms in descending order were methicillin-sensitive S aureus, coagulase-negative staphylococci, methicillin-resistant S aureus, and Pseudomonas aeruginosa. This finding is in keeping with our data. Among risk factors identified by Lee et al25 were young age, diabetes, anaemia, thyroid disease, heart disease, lung disease, and long operating time. However, the researchers identified limitations of having only a small number of patients with infection (n=8) and insufficient power for analysis. In addition, multivariable analysis should have been performed to account for the effect of confounders among the multiple risk factors. They also reported the limitation that the mean follow-up duration was only 2 years. A short follow-up period may underestimate the occurrence of late-onset infection.

Our study has several limitations. The number of PJI-positive cases was small and thus subgroup analysis was limited. This study included subjects treated at a single centre in Hong Kong; multicentre studies may improve the representativeness of local data. In addition, perioperative management for elective TKA has evolved over the past 20 years, including the introduction of an MRSA-screening programme in 2011. In the screening programme, a nasal swab is taken from all elective joint-replacement patients. Patients with a positive result are prescribed 5 days of decolonisation therapy including a daily chlorhexidine bath. Furthermore, intravenous vancomycin is now administered for prophylaxis instead of cefazolin.26

There are many potential risk factors for PJI documented in the literature. Nonetheless, only a limited number were included in this study, most of which are not be modifiable. Thus, it may not provide the necessary guidance for preoperative optimisation. Furthermore, the exclusion of some potential risk factors may have led to inadequate control for potential confounding factors. Inclusion of more risk factors with better characterisation is needed to provide a more comprehensive understanding and to better account for the confounding effect of other variables.

The incidence of PJI after elective primary TKA in our institution over two decades from 1993 to 2013 was 1.34%. Rheumatoid arthritis was a significant risk factor for PJI in this series. In the early-onset infection group, PJI was caused by skin flora, but this was not statistically significant. It is hoped that this study has updated the local data for PJI after primary TKA and serves as a model for future related studies.

We thank colleagues from the Department of Orthopaedics and Traumatology and the Infection Control Team at the Queen Mary Hospital for their assistance in data collection, and those who advised on this project to make its publication possible.

The authors have no conflicts of interest to disclose.

1. Kurtz SM, Lau E, Watson H, Schmier JK, Parvizi J. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty 2012;27(8 Suppl):61-5.e1. CrossRef

2. Lamarsalle L, Hunt B, Schauf M, Szwarcensztein K, Valentine WJ. Evaluating the clinical and economic burden of healthcare-associated infections during hospitalization for surgery in France. Epidemiol Infect 2013;141:2473-82. CrossRef

3. Nero DC, Lipp MJ, Callahan MA. The financial impact of hospital-acquired conditions. J Health Care Finance 2012;38:40-9.

4. Crowe B, Payne A, Evangelista PJ, et al. Risk factors for infection following total knee arthroplasty: a series of 3836 cases from one institution. J Arthroplasty 2015;30:2275-8. CrossRef

5. Meller MM, Toossi N, Johanson NA, Gonzalez MH, Son MS, Lau EC. Risk and cost of 90-day complications in morbidly and superobese patients after total knee arthroplasty. J Arthroplasty 2016;31:2091-8. CrossRef

6. Zmistowski B, Alijanipour P. Risk factors for periprosthetic joint infection. In: Springer BD, Parvizi J, editors. Periprosthetic Joint Infection of the Hip and Knee. New York: Springer; 2014: 15-40. CrossRef

7. Jämsen E, Huhtala H, Puolakka T, Moilanen T. Risk factors for infection after knee arthroplasty. A register-based analysis of 43,149 cases. J Bone Joint Surg Am 2009;91:38-47. CrossRef

8. Wilson MG, Kelley K, Thornhill TS. Infection as a complication of total knee-replacement arthroplasty. Risk factors and treatment in sixty-seven cases. J Bone Joint Surg Am 1990;72:878-83. CrossRef

9. Namba RS, Inacio MC, Paxton EW. Risk factors associated with deep surgical site infections after primary total knee arthroplasty: an analysis of 56,216 knees. J Bone Joint Surg Am 2013;95:775-82. CrossRef

10. Pruzansky JS, Bronson MJ, Grelsamer RP, Strauss E, Moucha CS. Prevalence of modifiable surgical site infection risk factors in hip and knee joint arthroplasty patients at an urban academic hospital. J Arthroplasty 2014;29:272-6. CrossRef

11. Chesney D, Sales J, Elton R, Brenkel IJ. Infection after knee arthroplasty: a prospective study of 1509 cases. J Arthroplasty 2008;23:355-9. CrossRef

12. Moucha CS, Clyburn T, Evans RP, Prokuski L. Modifiable risk factors for surgical site infection. J Bone Joint Surg Am 2011;93:398-404.

13. Peersman G, Laskin R, Davis J, Peterson M. Infection in total knee replacement: a retrospective review of 6489 total knee replacements. Clin Orthop Relat Res 2001;392:15-23. CrossRef

14. Rasouli MR, Restrepo C, Maltenfort MG, Purtill JJ, Parvizi J. Risk factors for surgical site infection following total joint arthroplasty. J Bone Joint Surg Am 2014;96:e158. CrossRef

15. Parvizi J, Gehrke T; International Consensus Group on Periprosthetic Joint Infection. Definition of periprosthetic joint infection. J Arthroplasty 2014;29:1331. CrossRef

16. Pulido L, Ghanem E, Joshi A, Purtill JJ, Parvizi J. Periprosthetic joint infection: the incidence, timing, and predisposing factors. Clin Orthop Relat Res 2008;466:1710-5. CrossRef

17. Tsaras G, Osmon DR, Mabry T, et al. Incidence, secular trends, and outcomes of prosthetic joint infection: a population based study, Olmsted County, Minnesota, 1969-2007. Infect Control Hosp Epidemiol 2012;33:1207-12. CrossRef

18. Tande AJ, Patel R. Prosthetic joint infection. Clin Microbiol Rev 2014;27:302-45. CrossRef

19. Herwaldt LA, Cullen JJ, French P, et al. Preoperative risk factors for nasal carriage of Staphylococcus aureus. Infect Control Hosp Epidemiol 2004;25:481-4. CrossRef

20. Fan JC, Hung HH, Fung KY. Infection in primary total knee replacement. Hong Kong Med J 2008;14:40-5.

21. Meehan JP, Danielsen B, Kim SH, Jamali AA, White RH. Younger age is associated with a higher risk of early periprosthetic joint infection and aseptic mechanical failure after total knee arthroplasty. J Bone Joint Surg Am 2014;96:529-35. CrossRef

22. Berbari EF, Osmon DR, Lahr B, et al. The Mayo prosthetic joint infection risk score: implication for surgical site infection reporting and risk stratification. Infect Control Hosp Epidemiol 2012;33:774-81. CrossRef

23. Luscombe JC, Theivendran K, Abudu A, Carter SR. The relative safety of one-stage bilateral total knee arthroplasty. Int Orthop 2009;33:101-4. CrossRef

24. Hussain N, Chien T, Hussain F, et al. Simultaneous versus staged bilateral total knee arthroplasty: a meta-analysis evaluating mortality, peri-operative complications and infection rates. HSS J 2013;9:50-9. CrossRef

25. Lee QJ, Mak WP, Wong YC. Risk factors for periprosthetic joint infection in total knee arthroplasty. J Orthop Surg (Hong Kong) 2015;23:282-6. CrossRef

26. Cheng VC, Tai JW, Wong ZS, et al. Transmission of methicillin-resistant Staphylococcus aureus in the long term care facilities in Hong Kong. BMC Infect Dis 2013;13:205. CrossRef

Elderly patients have multiple co-morbidities and they are consequently prone to multiple medication use. Inappropriate medication use is common among hospitalised older adults. The number of drugs taken is one of the important determinants of risk for receiving an inappropriate medication.1 There is a high prevalence of unnecessary drug use in frail older people. In one hospital study, 44% of patients were prescribed at least one unnecessary drug, with the most common reason being lack of indication.2 The most commonly prescribed unnecessary drug classes were gastrointestinal, central nervous system, and therapeutic nutrients/minerals.2 Appropriate use of drugs is particularly important in the frail older people who are especially at risk of adverse drug reactions.3 It has been shown that implementation of a clinical pharmacist service has a positive effect on medication use and health care service utilisation among hospitalised patients.4 5 A local study in a geriatric hospital demonstrated the effectiveness of a drug rationalisation programme with involvement of a clinical pharmacist in reducing the incidence of polypharmacy and inappropriate medications.6 Interacting with the health care team on patient rounds, interviewing patients, reconciling medications, and providing patient discharge counselling and follow-up all resulted in improved outcomes.7 It is for this reason that patient safety strategies encourage the use of medication reconciliation and clinical pharmacists in health care systems to reduce adverse drug events.8 9 10

There is not much information about the effectiveness of a medical review programme among hospitalised elderly patients in Hong Kong. Two recent local reports that examined the effects of a clinical pharmacist–led medication review on hospital readmissions showed conflicting results and did not specifically address elderly patients.11 12 We therefore conducted a prospective controlled study to investigate the effectiveness of a comprehensive pharmacist intervention on medication use and hospital readmission among a group of geriatric in-patients in Hong Kong.

This prospective controlled study was conducted in the geriatric unit of a regional hospital in Hong Kong. The unit has 38 in-patient beds and admits older people aged 65 years or above who are transferred from an acute hospital after initial stabilisation of medical and/or geriatric problems. The unit admits more than 1000 patients per year and provides medical treatment, rehabilitation, and discharge planning services by a multidisciplinary team composed of a geriatrician, residents, nurses, physiotherapists, occupational therapists, and medical social workers. All patients admitted to the unit during December 2013 to September 2014 were included. Patients were excluded if they refused to participate, were terminally ill with a life expectancy of less than 3 months, or if they had already received pharmacist intervention in another hospital prior to this admission. Eligible subjects were assigned to an intervention or control group according to the admission day of the week. Those who were admitted on Monday through Thursday were assigned to the intervention group, and those admitted on Friday through Sunday to the control group. This arrangement was to ensure that pharmacist intervention could be initiated promptly within 48 hours of patient admission. Demographic data, functional status, co-morbidities, and number of drugs on admission were collected at admission.

The intervention was conducted by a pharmacist who was present in the unit from Monday to Saturday. The pharmacist provided pharmaceutical care from admission to discharge. Interventions performed by the pharmacist consisted of the following:

(1) Medication reconciliation on admission to identify unintended discrepancies between medications prescribed on admission and the usual medications prior to admission—sources to assist medication reconciliation included: electronic patient record; patient’s ward case notes; interview with patient and/or patient carer. The number and type of unidentified discrepancies were recorded.

(2) Medication review to check for medication appropriateness on admission and also at discharge—medication appropriateness was assessed by the Medication Appropriateness Index (MAI).13 There are 10 criteria to assess for appropriateness, namely indication, effectiveness, dosage, correct direction, practical direction, drug-drug interaction, drug-disease interaction, duplication, duration, and expense. For a drug item coded as ‘inappropriate’, relative weights for each criterion would apply. A sum of MAI scores could then be calculated to give a score ranging from 0 to 18. The higher the score, the more inappropriate the drug. Recommendations from the pharmacist after the reconciliation and medication review in the intervention group were then communicated to the in-charge doctor via a written note in the medical records. Recommendations were reinforced verbally if deemed appropriate by the pharmacist.

(3) Pharmacist counselling on admission and also at discharge was provided to improve patients’ drug knowledge to ensure proper use of drugs and compliance after discharge. A discharge counselling service was provided for all patients who returned home. The counselling included any changes to drug regimen; an explanation of each drug’s indication; any untoward effects that might occur and when to seek medical advice; and drug storage and administration instructions. To ensure patient understanding, written information such as patient information leaflets were given to patients and their carers to remind them of the correct drug regimen. If the patient was illiterate, a simple diagram was drawn on drug labels to demonstrate the time of day and number of tablets to be taken. If necessary, individualised pictorial schedules with drug images and administration instructions could be produced for patients and their carers. The assistance of a family member or external care services such as a community nurse was enlisted if the patient was found to have compliance issues.

The control group received routine clinical services. Records of the control group were retrospectively reviewed by the pharmacist after patient discharge to check for medication appropriateness on admission and also at discharge. The primary outcome measure was the appropriateness of prescription as measured by the MAI. Secondary outcomes included the acceptance rate by physicians, number of subjects with unintended discrepancies, patient satisfaction with the programme (for those home-living only), and unplanned hospitalisations 1 and 3 months after discharge.

A sample size of 98 patients per group was required to have 85% power to detect an effect size of 0.9 on the MAI. Our sample size was finally set at 210 patients to account for loss of participants due to dropout or death. This sample size was comparable with a study by Spinewine et al14 in which MAI was used as one of the tools to assess appropriateness of prescribing in an acute geriatric care unit and 203 patients were recruited. Our study included 212 patients and was expected to have adequate statistical power to detect differences between groups. Descriptive analyses were performed and included the number and types of unintended discrepancies, MAI score upon admission and at discharge, types of drug-related problems, number of interventions made by pharmacists, and number of recommendations accepted by doctors and implemented. Outcomes for the two groups before and after the programme were compared using the t test and Chi squared test. The Statistical Package for the Social Sciences (Windows version 17.0; SPSS Inc, Chicago [IL], United States) was used and a P value of <0.05 was regarded as statistically significant. The study was approved by the Cluster Research Ethics Committee of the Hospital Authority Hong Kong West Cluster. Written consent was obtained from the patient or their caregiver. The absence of pharmacist intervention in the control group was considered acceptable because a pharmacy service was not a part of routine care at the institution.

Figure 1 summarises the patient flow from recruitment to hospital discharge, the components of the medication review programme, and the planned outcome measures. A total of 212 patients were recruited. There were 108 subjects in the intervention group and 104 in the control group (Fig 2). There were no statistical differences in the baseline characteristics of patients (Table 1).

On admission, 51.9% (56/108) of the intervention group and 58.7% (61/104) of the control group had at least one drug classified as inappropriate (P=0.319). Overall, 1996 drug items were reviewed by a pharmacist on admission of which 1020 were from the intervention group and 976 from the control group. Among them, 9.3% and 11.1% of the drugs, respectively, were classified as inappropriate (P=0.282). In the intervention group, 93 recommendations were made by the pharmacist of which 60 (64.5%) were accepted by the physicians and implemented. The mean (± standard deviation) MAI score per patient was 2.19 ± 3.03 in the intervention group and 2.28 ± 3.09 in the control group (P=0.841). The mean MAI score per drug was 0.23 ± 0.30 in the intervention group and 0.25 ± 0.31 in the control group (P=0.628) [Table 2].

After the program and at discharge, the proportion of subjects with inappropriate medications in the intervention group was significantly lower than that in the control group (28.0% vs 56.4%; P<0.001). Among the 1999 drug items reviewed by the pharmacist on patient discharge, 3.5% (37 of 1048) of the intervention group and 9.7% (92 of 951) of the control group were classified as inappropriate (P<0.001). The intervention group also had a significantly lower MAI score per patient (0.95 ± 2.02 vs 2.02 ± 2.53; P<0.001) and MAI score per drug (0.09 ± 0.17 vs 0.24 ± 0.30; P<0.001) implying a significant reduction in medication inappropriateness after the pharmacist medication review (Table 2).

Types of inappropriateness according to the MAI in the two groups are illustrated in Figure 3. In both the intervention and control groups, the common causes were indication, effectiveness, dosage, practical direction, duration, and expense. After the programme, there was a significant reduction in the number of these drug-related problems in the intervention group.

Among the 108 subjects in the intervention group, 19.4% had at least one unintended discrepancy in medications, involving a total of 43 drug factors. The majority (90.7%) of these factors were omission of drugs, and 4.6% were due to inappropriate dosages. Of all the drug factors involved, 69.8% involved prescribed drugs from hospitals, 25.6% were from a private clinic, and 4.6% were over-the-counter drugs. Overall, 41 recommendations were made, of which 32 (78.0%) were accepted by physicians and implemented.

Contact was made with 50 of the 90 non-institutionalised subjects 1 month after discharge to assess satisfaction with the programme. Of those contacted, 98.0% were satisfied with the programme and only one (2.0%) patient expressed a neutral opinion.

There were no statistical differences in the length of hospital stay, in-patient mortality, or mortality at 1 month or 3 months after discharge. There was also no statistical difference in the number of attendances at the accident and emergency department 1 month or 3 months after discharge or in the unplanned hospital readmission rate at 3 months after discharge. The unplanned hospital readmission rate 1 month after discharge, however, was significantly lower in the intervention group than that in the control group (13.2% vs 29.1%; P=0.005) [Table 3].

To the best of our knowledge, this is the first local prospective controlled study to investigate the effectiveness of a pharmacist-led medication review programme on medication appropriateness and clinical outcomes among geriatric in-patients in Hong Kong. This study has demonstrated superior outcomes that favour a pharmacist-led intervention. There was a substantial reduction in the use of inappropriate medications and all-cause unscheduled readmissions 1 month after hospital discharge. Nonetheless, analysis of length of hospital stay, number of all-cause emergency department visits, and mortality rate favoured neither the intervention nor the usual pharmacist care.

This study showed that one in five geriatric in-patients had an unintended medication discrepancy on admission. This figure was slightly higher than that found in a group of 3317 hospitalised medical patients (13%) over 1 year in an acute hospital in Hong Kong by Kwok et al.15 Subjects in our study were all elderly patients, whereas those in Kwok et al’s study were adults of all ages. Elderly subjects tend to have polypharmacy and thus are more vulnerable to unintended medication discrepancy when they move in and out of hospital or are transferred to another health care unit for further care. Unjustifiable medication discrepancies account for more than half of the medication errors that occur during transition of care and up to one third have the potential to cause harm.16 17 This does not bode well for our elderly patients with multiple co-morbidities.

Up to 30% of the discrepancies in our study involved medications that had been prescribed by private practitioners or purchased over-the-counter. Unlike medications prescribed from the Hospital Authority, these medications might be overlooked unless the admitting doctor specifically asks for a detailed drug history from the patient. Knowing the medication history and hence resuming these medications are important if new health problems are to be prevented. Pharmacist-led medication reconciliation is therefore a critical process that can enhance patient medication safety by compiling a complete and accurate medication list for patients in hospital.

This study revealed that more than half of the subjects (55.2%) received inappropriate medications. The majority of reasons for inappropriateness related to effectiveness, dosage, practical directions, and expense as reflected by the MAI. The inappropriate dosage and the questionable effectiveness might lead to not only failed pharmacological effects, but also potentially an untoward adverse drug reaction, especially in elderly individuals with pre-existing organ dysfunction.18 When a medication is not used according to the practical directions, it may lead to patient non-compliance. Optimising outcomes while reducing costs are the keys for medication management in today’s health care environment.19 Often there are several choices of drugs available to treat a disease or health condition and some are more expensive than others. The involvement of a ward-based pharmacist to review medication can enhance the use of appropriate medications in hospitalised patients and potentially reduce medication costs.

Following the medication review (60/93) and medication reconciliation (32/41), there were 92 recommendations that were accepted by the physician. The overall acceptance rate by physicians and the implementation of pharmacist recommendations in our study was 68.7% (92/134). This figure ranged from 39% to 100% in a previous systematic review of 32 studies.4 Our study did not specifically record recommendations accepted by physicians but not implemented. Hence the acceptance rate in our study may be underestimated. Nevertheless, the clinical pharmacist is encouraged to discuss the medication-related problems in person with the physician as well as contacting the patient in order to enhance the implementation rate.4

Pharmacy departments within the public hospital system in Hong Kong have strived to implement the aforementioned patient safety strategies in different specialties. Nonetheless, this is not a standard practice simply because of insufficient pharmacist staffing resources. In some hospitals, a pharmacist service is provided in wards, but this does not apply in all cases and is not standardised. Experience of a pharmacist-led medication reconciliation service from an acute teaching hospital in Hong Kong showed promising results over a 1-year trial run with high acceptance and recognition by other health care professionals.16 It is hoped that the clinical role of clinical pharmacists in patient medication management in hospitals can be encouraged. Another local study has demonstrated a positive impact on medication safety in patients with diabetes by pharmacists’ intervention in collaboration with a multidisciplinary team.20 The feasibility of incorporating a pharmacist as part of a multidisciplinary team of health care professionals must be explored in geriatric wards in Hong Kong. With increasing life expectancy, the expanding elderly population will equate to an increase in morbidity and mortality owing to drug-related problems where the need for trained health care professionals to perform medication reviews will be in even greater demand. To enhance safe drug use with limited resources, a systematic approach must be adopted to cover all aspects that affect drug therapy.

In terms of the impact on health care services utilisation, a recent systematic review and meta-analysis of the effectiveness of a pharmacist-led medication reconciliation programme revealed a substantial reduction in the rate of all-cause readmissions (19%), all-cause emergency department visits (28%), and adverse drug event–related hospital visits (67%).21 Our study revealed a significant reduction in unplanned hospital admissions (all-cause admission) at 1 month but not at 3 months. This implication might be due to an inadequate sample size to show the difference at 3 months. Alternatively, it might also imply that pharmacist intervention needs to be continued after patient discharge in order to have a sustained effect. This is supported by a study by Schnipper et al22 in which pharmacist intervention after patient discharge was associated with a lower rate of preventable adverse drug events 30 days after hospital discharge.

During the pharmacist review, cost-effectiveness of drug use was assessed through MAI. Alternative options such as less-expensive formulations or drugs but of the same quality would be recommended to the doctor in-charge. This was a means of encouraging cost-effective use of drugs in a hospital. Furthermore, the reduction in unscheduled hospital readmissions in the intervention group implies a potential saving in hospital costs. Although a detailed analysis was not performed in this study, a rough estimation is that nearly HK$2 million may be saved annually as a result of lower drug costs and reduced hospital admissions, even after considering the cost of employing a pharmacist. The estimation was based on the following calculations. The estimated drug saving as a result of a switch to a more cost-effective alternative was HK$7500 among the 108 patients in the intervention group. This can be projected to a saving of about HK$69 500 in a unit that admits 1000 patients annually. In the current study, there were 16 fewer readmissions in the intervention group compared with the control group. Assuming a daily cost of an acute hospital bed is HK$4680 and the mean length of hospital stay is 3 days, this equates to a potential saving of about HK$2 080 000 per year in a unit that admits 1000 patients annually. If it is assumed that a pharmacist spends 30 minutes for each patient at an hourly salary of HK$433, the projected cost of an additional pharmacist to run the intervention would be HK$216 500 per year. The net annual saving of this programme to serve 1000 patients in this unit would thus still be close to HK$2 million.

This study had several limitations. First, a substantial proportion (35%) of all the admitted patients were not screened by a pharmacist on admission. This was due to a temporary pause in subject recruitment when patients were admitted on public holidays, when the pharmacist was on holiday or when she had to relieve another pharmacist in the hospital. Moreover, a substantial proportion (44%) of eligible subjects were not included owing to no consent or refusal. These factors might have resulted in selection or self-selection bias. Second, subject recruitment was not randomised, but done according to the day of admission. This might be a source of bias. Nevertheless, this would have minimal influence on the outcomes, as the baseline characteristics of the intervention and control groups were comparable. Third, the pharmacist who carried out the review and data extraction was not blinded to the study hypothesis and the group status of the subjects. This could potentially lead to information bias, although this might be partially offset by the fact that the majority of the information or data on the outcome measures were taken with reference to a well-established and validated tool. Fourth, this study was performed in a single unit, so generalisation to other settings is not possible. Fifth, MAI is an implicit tool that is subjective. A single pharmacist as the rater might limit the reliability of the assessment results. Nevertheless, the more explicit tools of STOPP/START criteria23 had also been referred to in addition to the MAI during the review process. Sixth, this study only addressed appropriateness of drug use, whereas underuse of drugs was not investigated. Finally, this study could not conclude a causal relationship between the reduction in inappropriate medications and the reduction in unscheduled hospital readmissions because there were several components in the intervention that included a medication review, medication reconciliation, and discharge counselling. It is difficult to be certain which of these components alone or in combination gave rise to the positive outcome of this study.

On the other hand, there were several strengths in this study. This was the first prospective controlled study of the effect of a pharmacist-led medication review programme on medication use and health services utilisation involving over 200 Chinese elderly patients in Hong Kong. Second, a well-validated tool was used to assess medication appropriateness. The use of the MAI tool focused on the patient and the entire medication regimen. Third, there was a comprehensive review of outcomes including quality of prescribing, health services utilisation, mortality, length of hospital stay, and patient satisfaction.

This study supported the role of a hospital-based clinical pharmacist to enhance appropriate medication use among elderly Chinese in-patients. A systematic medication review programme in a geriatric unit resulted in a reduced number of drug omissions and fewer inappropriate medications. The service provided by the clinical pharmacist and supported by geriatricians was welcomed by patients and their carers. Together with the potential to reduce hospital readmissions and their associated cost, it is hoped that an in-hospital pharmacist-led medication review programme can be recognised as one of the important strategies to enhance the safety and quality of prescription among elderly patients in hospitals. It is strongly recommended that these programmes be standardised and implemented in all medical and geriatric wards in Hong Kong. Future studies should recruit a larger sample size in a randomised controlled design in other geriatric hospital settings to reiterate our findings. Furthermore, these studies might consider including adverse drug event–related hospital visits as one of the outcome measures.

All authors have disclosed no conflicts of interest.

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2. Hajjar ER, Hanlon JT, Sloane RJ, et al. Unnecessary drug use in frail older people at hospital discharge. J Am Geriatr Soc 2005;53:1518-23. CrossRef

3. Routledge PA, O’Mahony MS, Woodhouse KW. Adverse drug reactions in elderly patients. Br J Clin Pharmacol 2004;57:121-6. CrossRef

4. Graabaek T, Kjeldsen LJ. Medication reviews by clinical pharmacists at hospitals lead to improved patient outcomes: a systematic review. Basic Clin Pharmacol Toxicol 2013;112:359-73. CrossRef

5. Gillespie U, Alassaad A, Henrohn D, et al. A comprehensive pharmacist intervention to reduce morbidity in patients 80 years or older: a randomized controlled trial. Arch Intern Med 2009;169:894-900. CrossRef

6. Chan FH, Pei CK, Chiu KC, Tsang EK. Strategies against polypharmacy and inappropriate medication—are they effective? Australas J Ageing 2001;20:85-9. CrossRef

7. Kaboli PJ, Hoth AB, McClimon BJ, Schnipper JL. Clinical pharmacists and inpatient medical care: a systematic review. Arch Intern Med 2006;166:955-64. CrossRef

8. The ACHS EQuIP5 (5th edition of the ACHS Evaluation and Quality Improvement Program) clinical standard 1.5, criterion 1.5.1.: Medication are managed to ensure safe and effective consumer/patient outcomes. Sydney: The Australian Council on Health Care Standards; 2010.

9. Medication reconciliation. Patient Safety Network. Agency for Healthcare Research and Quality. US Department of Health & Human Services. Available from: http://psnet.ahrq.gov/primer.aspx?primerID=1. Accessed 11 Jun 2017.

10. Gurwitz J, Monane M, Monane S, Avorn J. Polypharmacy. In: Morris JN, Lipsitz LA, Murphy K, Bellville-Taylor P, editors. Quality care in the nursing home. St. Louis, MO: Mosby-Year Book; 1997: 13-25.

11. Wong CY, Lee TO, Lam MP. Pharmacist discharge intervention programme to reduce unplanned hospital use in patients with polypharmacy. Hong Kong Pharm J 2017;24(Suppl 1):S18.

12. Chan HH. To reduce avoidable readmission of patients who are categorized as high risk by 30-day hospital readmission model at medical ward of United Christian Hospital through medication reconciliation and discharge counseling. Hong Kong Pharm J 2017;24(Suppl 1):S21.

13. Hanlon JT, Schmader KE, Samsa GP, et al. A method for assessing drug therapy appropriateness. J Clin Epidemiol 1992;45:1045-51. CrossRef

14. Spinewine A, Swine C, Dhillon S, et al. Effect of a collaborative approach on the quality of prescribing for geriatric inpatients: a randomized, controlled trial. J Am Geriatr Soc 2007;55:658-65. CrossRef

15. Kwok CC, Mak WM, Chui CM. Implementational experience of medical reconciliation in Queen Mary Hospital. Hong Kong Pharm J 2009;16:50-2.

16. Rozich JD, Howard RJ, Justeson JM, Macken PD, Lindsay ME, Resar RK. Standardization as a mechanism to improve safety in health care. Jt Comm J Qual Saf 2004;30:5-14. CrossRef

17. Cornish PL, Knowles SR, Marchesano R, et al. Unintended medication discrepancies at the time of hospital admission. Arch Intern Med 2005;165:424-9. CrossRef

18. Cameron KA. Caregivers’ guide to medications and aging. National Center on Caregiving, Family Caregiver Alliance 2004. Available from: https://www.caregiver.org/caregiver%CA%BCs-guide-medications-and-aging. Accessed 11 Jun 2017.

19. Splawski J, Minger H. Value of the pharmacist in the medication reconciliation process. P T 2016;41:176-8.

20. Chung AY, Anand S, Wong IC, et al. Improving medication safety and diabetes management in Hong Kong: a multidisciplinary approach. Hong Kong Med J 2017;23:158-67. CrossRef

21. Mekonnen AB, McLachlan AJ, Brien JA. Effectiveness of pharmacist-led medication reconciliation programmes on clinical outcomes at hospital transitions: a systematic review and meta-analysis. BMJ Open 2016;6:e010003. CrossRef

22. Schnipper JL, Kirwin JL, Cotugno MC, et al. Role of pharmacist counseling in preventing adverse drug events after hospitalization. Arch Intern Med 2006;166:565-71. CrossRef

23. Lam MP, Cheung BM. The use of STOPP/START criteria as a screening tool for assessing the appropriateness of medications in the elderly population. Expert Rev Clin Pharmacol 2012;5:187-97. CrossRef

A variety of exotic animals are kept as ‘pets’ including fish, amphibians, reptiles, and arthropods. The keeping of exotic, and sometimes venomous pets, is becoming increasingly common worldwide. Some of these exotic pets are capable of causing injury to or even life-threatening envenomation of their owners.1

Reptiles are the most popular exotic pets worldwide. It has been estimated that 1.5 to 2.0 million households in the United States (US) own one or more pet reptiles. Snakes account for approximately 11% of the imported reptiles in the US, and up to 9% of these are venomous.2 Envenomation by exotic pets, particularly snakes, is an increasing cause for concern in both the US and Europe.3 In a study of exotic snake envenomation in the US, data from the National Poison Data System database revealed 258 cases of exotic snakebites involving at least 61 unique exotic venomous species between 2005 and 2011. Among these, 40% of bites occurred in a private residence.4 Another study of bites and stings by exotic pets in Europe reported 404 cases in four poison centres in Germany and France from 1996 to 2006. Exotic snakebites from rattlesnakes, cobras, mambas, and other venomous snakes were the cause of approximately 40% of envenomations.5 Another survey conducted in the United Kingdom reviewed the data from the National Health Service Health Episode Statistics from 2004 to 2010. A total of 709 hospital admissions associated with injuries from exotic pets were reported and approximately 300 hospital admissions were related to contact with scorpions, venomous snakes, and lizards.6 Nonetheless, no such epidemiological study has been conducted in Hong Kong. According to the thematic household survey report in 2006, 286 300 households in Hong Kong kept pets at home, of which 5% were pets other than dogs, cats, turtles, tortoises, birds, hamsters, and rabbits.7 The number of imported pet reptiles into Hong Kong has increased rapidly in recent years. In 2016, the Agriculture, Fisheries and Conservation Department (AFCD) recorded that almost 1 000 000 pet reptiles were imported into Hong Kong (Table 1).

The knowledge of local emergency physicians about the management of injuries by these exotic animals is limited. Since 2005, the Hong Kong Poison Information Centre (HKPIC) has provided a 24-hour telephone consultation service (tel: 2635 1111) for health care professionals in Hong Kong, offering poison information and clinical management advice. The objectives of this study were to use HKPIC records to describe the variety of reported exotic species and the clinical features and outcomes of injuries and envenomation caused by exotic pets.

This was a case series based on the database of the HKPIC. It included cases encountered by clinical frontline staff and surveillance data from routine reporting of poisoning cases by all accident and emergency departments (AEDs) under the Hospital Authority (HA). Cases of injuries and envenomation by exotic pets recorded by the HKPIC from 1 July 2008 to 31 March 2017 were retrospectively retrieved. Demographic data of the patients—including the involved species, clinical presentations, and outcomes—were reviewed from the patient electronic Health Record. This study was done in accordance with the principles outlined in the Declaration of Helsinki.

The severity of injuries and the effects of envenomation were defined as major (life-threatening or resulting in significant residual disability or disfigurement), moderate (pronounced, prolonged, or systemic signs and symptoms), or mild (minimal and rapidly resolving signs and symptoms).

During the study period, 15 cases of injuries and envenomation by exotic pets were reported to the HKPIC. Among the 15 patients, nine consulted the HKPIC for management advice and one was managed by the toxicology team of the AED. Local zoologists were consulted in five cases for species identification and opinion about the venomous nature of the species. All bites and stings were unintentional and occurred in a private household. The mean age of the exotic pet owners was 28.2 (range, 14-59) years and the majority (73%) were male. There were six cases of snakebite, four cases of fish sting, two cases of scorpion sting, two cases of lizard bite, and one case of turtle bite. The severity of injury and envenomation effect are summarised in Table 2.

All major effects occurred in patients with snakebite. A 16-year-old boy was bitten by a short-tailed mamushi (Gloydius blomhoffii brevicaudus; Fig 1a) on his left middle finger. The short-tailed mamushi is not native to Hong Kong but was being kept as a pet. The patient had a history of snakebite by a bamboo snake (Trimeresurus albolabris) that required antivenom treatment, sustained while attempting to catch the snake in the suburbs. Following the bite by the short-tailed mamushi, the patient developed severe local envenomation over his left hand and required admission to the intensive care unit for close observation of the rapidly progressing local envenomation. No systemic envenomation was observed. A local zoologist was consulted for snake identification. A total of three vials of antivenom for Agkistrodon halys were administered as treatment but ischaemia due to compartment syndrome developed in the left hand. Debridement and fasciotomy were eventually performed. The patient had a residual flexion contraction deformity of his left middle finger 2 months later. He recovered with full movement of the left middle finger 6 months after the injury. Another boy, aged 15 years, was bitten by a bamboo snake on his left thumb. The snake had been caught by the patient in the suburbs and kept as a pet. He developed severe local envenomation and was given three vials of antivenom for Agkistrodon halys and three vials of antivenom for green pit viper. The patient developed tenosynovitis of his left thumb and required emergency surgery for debridement. Another four patients were bitten by ‘nonvenomous’ snakes including a rainbow boa (Epicrates cenchria; Fig 1b), corn snake (Pantherophis guttatus), and eastern hognose snake (Heterodon platirhinos; Fig 1c). All snakes were kept as pets. An 18-year-old girl was accidentally bitten by a rainbow boa on her left hand but had no signs of local or systemic envenomation after the injury. Another patient developed a wound infection after being bitten by a corn snake 2 weeks previously (Fig 1d). She recovered after a course of antibiotic therapy. Two young men were bitten by hognose snakes. One developed local envenomation with progressive swelling over the injured hand (Fig 1e). The local envenomation resolved with conservative management. The HKPIC was consulted in all cases, of which three required consultation with a zoologist.

Injuries from reptiles other than snakes were also recorded. There were two cases of lizard bite. In one case, a 22-year-old man was bitten by a common iguana (Iguana iguana) on his left wrist. In the other case, a 41-year-old man presented to the AED approximately 2 hours after being bitten on his right hand by a Gila monster (Fig 2a). He developed intense pain and local swelling over the site of injury. The pain lasted for about 12 hours and then gradually improved. His haemodynamic state remained stable and no airway oedema or neurological symptoms were observed during his stay in the emergency medicine ward. He was eventually discharged. A young woman attended the AED because of a turtle bite over her left face with consequent minor physical injury.

Stings by aquarium fish were the second most common injuries by exotic pets. Four cases were recorded, including one sting by a blue tang fish and three by freshwater stingrays (Fig 2b). All patients developed severe pain over the site of injury that responded to immersion in hot water. One of the patients with a freshwater stingray sting developed a wound infection that required emergency surgery for wound exploration and irrigation.

Two male patients were stung by their pet scorpions: a thick-tailed scorpion (Parabuthus transvaalicus; Fig 2c) and a cave-claw scorpion (Pandinus cavimanus; Fig 2d). No systemic envenomation was observed. The patient with the cave-claw scorpion sting developed a local wound infection (Fig 2e) that recovered after a course of antibiotics.

The characteristics and management of the 15 cases are summarised in Table 3.

Injuries by a variety of exotic pets were encountered in this study. More than half of the injuries (9/15) were inflicted by reptiles. Reptiles are becoming increasingly popular to keep as pets in Hong Kong. According to the records of the AFCD over the past 5 years, the top 10 most common reptile species imported to Hong Kong are the European pond turtle (Emys orbicularis), razor-backed musk turtle (Sternotherus carinatus), common snapping turtle (Chelydra serpentina), red-bellied cooter (Pseudemys nelsoni), yellow-spotted Amazon River turtle (Podocnemis unifilis), Hermann’s tortoise (Testudo hermanni), African spurred tortoise (Geochelone sulcata), leopard tortoise (Stigmochelys pardalis), common iguana (Iguana iguana), and ball python (Python regius). Commonly imported pet snakes include the ball python (Python regius), king snake (Lampropeltis getula), corn snake (Pantherophis guttatus), rat snake (Elaphe obsoleta), milk snake (Lampropeltis triangulum), and western hognose snake (Heterodon nasicus). With the exception of the hognose snake, which is a mildly venomous species, they are all nonvenomous. Nonetheless, a much wider variety of species, including venomous reptiles, may be sold on the black market. Bites may occur during the care and handling of these exotic animals.3 Envenomation by exotic venomous species is an uncommon but often serious medical emergency.

The keeping of venomous snakes is common in the US.4 Amateur collectors are at risk of bites and envenomation and fatalities have been reported.8 Although envenomation from exotic snakes is rarely encountered in Hong Kong, it poses a great challenge to emergency physicians owing to their lack of experience and limited supplies of antivenom, as illustrated by our case of bite by a short-tailed mamushi. Currently, the HA stocks principally snake antivenom for local venomous species (Table 4). Bites by nonvenomous pet snakes may also result in local envenomation and complications; for instance, although the hognose snake is known as a nonvenomous species, one patient developed local envenomation after being bitten. Another patient developed a wound infection after being bitten by a corn snake.

As well as snakes, lizards are popular as pets. Bites by large species such as the common green iguana (Iguana iguana) can result in serious injury.9 Envenomation from lizard bites is rare in Hong Kong. Two lizards are well known to be venomous: the Gila monster (Heloderma suspectum)10 and the Mexican beaded lizard (Heloderma horridum).11 12 Both have venom-secreting glands and bites. The Gila monster is native to the southwestern US extending into Mexico, whereas the beaded lizard is native only to Mexico. The Gila monster is listed in the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) as a protected species.13 Captive-bred Gila monsters are traded in international pet markets. Venom of the Gila monster consists of a variety of proteins including gilatoxin, a kallikrein-like protease that can hydrolyse kininogen and produce bradykinin.11 14 The common envenomation effects are intense pain at the injured site, oedema, paraesthesia, weakness, dizziness, and nausea. Hypotension occurs in severe envenomation.15 The intense pain, oedema, and hypotension are likely due to the bradykinin-mediated effects. Airway oedema has been reported regardless of the site of bite and may occur up to 12 hours after the bite.14 Nevertheless, severe envenomation from the Gila monster occurs in only a minority of patients. In a retrospective study of all cases of Gila monster bite reported to the two Arizona poison control centres from 2000 to 2011, 105 cases of human exposure to Gila monsters were recorded and 70 cases were referred to health care facilities for medical treatment. Eleven cases required admission to hospital and five required care in an intensive care unit. Six patients developed airway oedema and three required emergent airway management including one cricothyrotomy.14 Treatment of Gila monster bites is mainly supportive. Intravenous crystalloid infusion and vasopressors may be required for treatment of hypotension in severe envenomation. Radiographic assessment is needed to look for retained teeth and subcutaneous air due to the chewing-like action during the bites.16 No antivenom to Gila monster is commercially available.17 Observation for at least 12 hours after the bite for delayed-onset airway oedema is recommended.14

Among all the reptiles, tortoises and turtles are the most popular in pet markets. All species of tortoises and turtles are nonvenomous although some, such as the alligator snapping turtle (Macrochelys temminckii) and the common snapping turtle (Chelydra serpentina), are aggressive and can grow to a very large size. Bites by these large species can result in severe limb injuries.18

Stings by aquarium fish contributed to the second largest group of injuries in our case series. The most commonly encountered aquarium fish was freshwater stingray. Freshwater stingrays (Potamotrygon species) are native to South America. They are regarded as dangerous by the native people of the Amazon and frequent sting during fishing season.19 Freshwater stingrays are not aggressive by nature; stings frequently occur when people step on them or handle them improperly. Different species of freshwater stingrays have different colour patterns on their body. They are popular aquarium fish as they are easy to keep although stings may result in severe envenomation.20 The most common feature of envenomation from freshwater stingrays is intense local pain. Systemic manifestations are rare. Skin necrosis is frequently observed in victims wounded by large freshwater stingrays in the wild.21 In addition, skin necrosis is more commonly observed in victims injured by freshwater stingrays than marine stingrays. A study of tissue extracts from the stingers of freshwater and marine stingrays showed that both tissue extracts had gelatinolytic, caseinolytic, and fibrinogenolytic activity but hyaluronidase activity was detected only in the extracts from freshwater stingrays.22 In our case series, no patient injured by a freshwater stingray developed skin necrosis. The risk of developing skin necrosis is likely related to the venom load. Larger stingrays possess a much larger venom load in their stingers. Small freshwater stingrays are commonly kept in an aquarium and skin necrosis as a result of their sting is uncommon. Hot water immersion is effective in controlling acute pain but does not prevent skin necrosis.21 Wounds caused by freshwater stingray stings such as the Aeromonas species can be complicated by severe secondary infection with virulent bacteria.23 Prophylactic antibiotic is often required.

Apart from freshwater stingrays, the stinging catfish (Heteropneustes fossilis) is another commonly reported freshwater aquarium fish that can cause injuries and envenomation. It possesses venom in the sting that is located in front of the soft-rayed portion of the pectoral and dorsal fins. Apart from intense local pain, systemic envenomation including weakness and hypotension can result from a sting.24 25 There was no case reported to the HKPIC of injury by this venomous catfish during the study period. Coral reef fish are also popular pets in Hong Kong. Some coral reef fish, such as the lionfish (Pterois volitans), are venomous.26 Nonetheless, injuries by aquarium coral reef fish were rarely encountered in the AED of Hong Kong.

Exotic pet owners also enjoy keeping arthropods such as scorpions and spiders. There are approximately 2000 species of scorpion in the world but only a few (30 to 40) are highly venomous and able to cause severe envenomation in humans.27 Scorpion envenomation is reported throughout the world, mainly in subtropical and tropical regions.28 The majority of scorpion stings cause mild or no envenomation. Species that cause serious medical problems mainly belong to the Buthidae family. The genera of the Buthidae family include Centruroides, Tityus, Leiurus, Androctonus, Buthus and Parabuthus.29 Scorpions have a special venom apparatus, the telson, that produces venom. Scorpion venom comprises numerous toxins including several neurotoxins. Unlike snake venom, scorpion venom generally lacks enzyme activity. The main molecular targets of scorpion neurotoxins are the voltage-gated sodium channels and the voltage-gated potassium channels. Scorpion α-toxin, one of the most medically important neurotoxins in the scorpion venom, acts on the voltage-gated sodium channels. Once the toxin binds to voltage-gated sodium channels, it inhibits inactivation of the channel with consequent prolonged depolarisation and, hence, neuronal excitation. The autonomic centres, both sympathetic and parasympathetic, are stimulated. In most situations of scorpion envenomation, the sympathetic nerves are predominantly affected. Scorpion envenomation is characterised by relatively similar neurotoxic excitation syndromes, irrespective of the species. Parasympathetic effects tend to occur early and then sympathetic effects persist due to the release of catecholamines that are responsible for the severe envenomation. Parasympathetic (cholinergic) effects include hypersalivation, diaphoresis, lacrimation, miosis, diarrhoea, vomiting, bradycardia, hypotension, increased respiratory secretion, and priapism. Sympathetic (adrenergic) effects are manifested as tachycardia, hypertension, mydriasis, hyperthermia, hyperglycaemia, and agitation. Fatal effects of scorpion envenomation are largely due to cardiovascular effects. Various cardiac conduction abnormalities have been reported in patients with scorpion envenomation as well as catecholamine-induced cardiomyopathy, pulmonary oedema, and cardiogenic shock. Other manifestations of systemic envenomation include vomiting, abdominal pain, abnormal oculomotor movements, muscle fasciculation, and spasms of the face and limbs.29 Pancreatitis is also a well-reported complication of envenomation by certain species, such as Leiurus quinquestriatus.30 Nonetheless, severe local envenomation is generally uncommon. Differences in the clinical manifestations of systemic envenomation exist in some species. Delayed localised necrosis has been reported in patients stung by an Iranian scorpion (Hemiscorpius lepturus).31 Patients with envenomation from the thick-tailed scorpion (Parabuthus transvaalicus) in Zimbabwe have been reported to develop predominant symptoms from parasympathetic nerve system stimulation, including profuse sialorrhoea, sweating, and urinary retention, in the absence of sympathetic stimulation.32

Scorpion stings and envenomation are uncommon in Hong Kong. Most of the locally reported cases of scorpion sting occurred while patients were handling langsat, a type of tropical fruit from South-East Asia. The Chinese stropped bark scorpion (Lychas mucronatus) hides in the fruit and is subsequently imported into Hong Kong.33 Scorpions are also sold as fish food in aquarium shops in Hong Kong. People use scorpions to feed arowana, which are popular aquarium fish. Importation of endangered scorpion species (CITES-listed species) for commercial purposes is regulated by the Protection of Endangered Species of Animals and Plants Ordinance Cap. 586 in Hong Kong.34 According to the data from the AFCD for importation of CITES-listed scorpions, more than 1000 heads of emperor scorpion (Pandinus imperator) have been imported as pets to Hong Kong each year for the last 4 years. The emperor scorpion is a nonvenomous species and is native to the rainforests and savannas of West Africa. Most scorpions in the pet trade, such as the forest scorpion (Heterometrus species), have no potential for dangerous envenomation. Nonetheless venomous species may also be kept by hobbyists and severe envenomation may occur after stings.

Management of scorpion stings includes local wound care and supportive care for systemic envenomation. Expert opinion should be sought from a zoologist for species identification and to determine the venomous nature of the species. Patients with severe systemic envenomation may require antivenom therapy. Specific antivenom (Scorpifav; Sanofi Pasteur, France) for Androctonus australis, Buthus occitanus, and Leiurus quinquestriatus is currently available in the HKPIC.

Spiders, such as tarantulas, are popular exotic pets and are common in the pet trade in Hong Kong. Nonetheless, inexperienced owners may be unaware of the potential risk of ocular injury from the barbed urticating hairs on the abdomen of the tarantulas. Eye injuries occur when the barbed hairs come into contact with the eyes, either directly from the tarantula’s ejection or when the owners rub their eyes after handling the spider.35 Embedment of the hairs in the cornea can result in severe complications, including ophthalmia nodosa, iritis, and even permanent visual impairment.36 37

The diversity of pets is changing and keeping exotic animals is increasingly popular. Injuries from these exotic pets are expected to increase and envenomation may result from stings or bites from some species. In our case series, reptiles, scorpions, and fish were responsible for human injuries, and all cases of major envenomation were inflicted by snakes. Emergency physicians need to be aware of the appropriate management of injuries and envenomation by these exotic animals. The HKPIC plays an important role in the provision of expert advice about management of these special toxicological cases.

The authors would like to thank AFCD for providing the data of imported reptiles, scorpions, and spiders.

All authors have disclosed no conflicts of interest.

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