Predictive factors for colonoscopy complications

Hong Kong Med J 2015 Feb;21(1):23–9 | Epub 30 Jan 2015
DOI: 10.12809/hkmj144266
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
ORIGINAL ARTICLE
Predictive factors for colonoscopy complications
Annie OO Chan, MB, BS, MD1; Louis NW Lee, MB, BS, FRCS (Edin)2; Angus CW Chan, MB, ChB, MD2; WN Ho, BHSs (Nursing)2; Queenie WL Chan, BHSs (Nursing)3; Silvia Lau, MPH, MSc4; Joseph WT Chan, MB, BS, FRCOG5
1 Gastroenterology & Hepatology Centre, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong
2 Endoscopy Centre, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong
3 Nursing Administration Department, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong
4 Medical Physics & Research Department, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong
5 Hospital Administration Department, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong
Corresponding author: Dr Queenie WL Chan (wlchan@hksh.com)
 Full paper in PDF
Abstract
Objective: To determine factors predicting complications caused by colonoscopy.
 
Design: Prospective cohort study.
 
Setting: A private hospital in Hong Kong.
 
Patients: All patients undergoing colonoscopy in the Endoscopy Centre of the Hong Kong Sanatorium & Hospital from 1 June 2011 to 31 May 2012 were included. Immediate complications were those that were recorded by nurses during and up to the day after the examination, while delayed complications were gathered 30 days after the procedure by way of consented telephone interview by trained student nurses. Data were presented as frequency and percentage for categorical variables. Logistic regression was used to fit models for immediate and systemic complications with related factors.
 
Results: A total of 6196 patients (mean age, 53.7 years; standard deviation, 12.7 years; 3143 women) were enrolled and 3657 telephone interviews were completed. The incidence of immediate complications was 15.3 per 1000 procedures (95% confidence interval, 12.3-18.4); 50.5% were colonoscopy-related, including one perforation and other minor presentations. Being female (odds ratioadjusted=1.6), use of monitored anaesthetic care (odds ratioadjusted=1.8), inadequate bowel preparation (odds ratioadjusted=3.5), and incomplete colonoscopy (odds ratioadjusted=4.5) were predictors of risk for all immediate complications (all predictors had P<0.05 by logistic regression). The incidence of delayed complications was 1.6 per 1000 procedures (95% confidence interval, 0.3-3.0), which comprised five post-polypectomy bleeds and one post-polypectomy inflammation. The overall incidence of complications was 17.8 per 1000 procedures (95% confidence interval, 13.5-22.1). The incidences of complications were among the lower ranges across studies worldwide.
 
Conclusion: Inadequate bowel preparation and incomplete colonoscopy were identified as factors that increased the risk for colonoscopy-related complications. Colonoscopy-related complications occurred as often as systemic complications, showing the importance of monitoring.
 
 
New knowledge added by this study
  •  The risks of local and systemic complications of colonoscopy are of paramount importance.
Implications for clinical practice or policy
  •  Enforcing bowel preparation and post-polypectomy care may reduce the risk of delayed complications.
 
 
Introduction
Colonoscopy is an efficient, invasive, and commonly used diagnostic tool with promising therapeutic capacity. Common colonoscopy-related complications include prolonged pain and distension, and rarely draw medical attention or lead to hospitalisation. Severe complications, including bleeding and perforation, are potentially life-threatening and require urgent management. Although death is uncommon, occurring in no more than 3 per 10 000 procedures, the incidence of post-polypectomy bleeding and perforation ranges from 1.6 to 14.8 and 0.2 to 1.0 per 1000 procedures, respectively.1 2 3 4 5 6 It is difficult to accurately benchmark direct colonoscopy-related complications due to the different outcome measure definitions used in studies. For example, some studies include immediate complications only, while others extend the complication period to 7 or 30 days, and some studies include an extensive list of complications while others include only bleeding and perforation.1 2 5 7 8 9 10 Furthermore, the efficacy and safety of the procedure vary across clinical settings and the targeted populations. With no available local data, consensus for complication incidence remains inconclusive.
 
Intravenous sedation is routinely used during colonoscopy to minimise the discomfort and pain associated with the procedure. Endoscopists are equipped to give sedatives and to monitor their side-effects, but anaesthetists are often invited to provide monitored anaesthetic care (MAC) when the patient is considered to be at high risk for complications, for instance, older patients and those with multiple co-morbidities are particularly vulnerable to complications. Systemic complications vary from prolonged drowsiness to fatal events such as cardiovascular or cerebrovascular events. Cardiovascular events following sedation, such as hypotension and myocardial infarction, during colonoscopy have been reported to range from 0.1 to 59.1 per 1000 procedures. Cerebrovascular events such as stroke range from 0.1 to 1.3 per 1000 procedures.3 6 10 The outcome variables are highly heterogeneous, for example, Nelson et al’s study3 included myocardial infarction, vasovagal event, and arrhythmia in the cardiovascular incidents, while Ma et al’s study10 recorded hypotension only.10 Some endoscopists opted to study complications related to the use of carbon dioxide (CO2) insufflation and absence of sedative use.11 12 13 This study aimed to record all complications systematically and to determine the relevant risk factors.
 
Methods
This prospective study collected data for all colonoscopies done from 1 June 2011 to 31 May 2012 at the Endoscopy Centre of the Hong Kong Sanatorium & Hospital (HKSH), which is a private hospital in Hong Kong. Prior to colonoscopy, patients were invited to give their written consent for their participation in the study, including for the 30-day follow-up telephone interview. The Hospital Management Committee involving the Research Ethics Committee of the HKSH approved the study.
 
The complications were recorded by nurses on a standard form during and immediately after the procedure. The standard audit forms for immediate and delayed colonoscopy complications were designed by a research doctor, with the most common complications based on literature review.
 
The immediate complications audit form included patients’ demographics, use of sedation/analgesic/antispasmodic, use of MAC, gross indications for colonoscopy (therapeutic or diagnostic), type of therapeutic procedures performed such as polypectomy, the reason for incomplete colonoscopy (caecum intubation failure), quality of bowel preparation (adequate – good/adequate or not – fair/poor, which was rated by the endoscopist), and the use of CO2 insufflation. Complication data were divided into systemic and colonoscopy-related complications. For systemic complications, we captured data for nausea/vomiting, hypotension (systolic blood pressure <100 mm Hg), bradycardia/tachycardia (heart rate <50 to >100 beats/min), vasovagal fainting, and other cardiovascular or cerebrovascular events. For colonoscopy-related complications, data for perforation, persistent pain/discomfort, abdominal distension, and haemorrhage were gathered.
 
Delayed complications were defined as the above events happening from the day after the initial colonoscopy to the 30th day that required readmission or admission to other hospitals. For those readmissions, we automatically inspected the records for the reasons and interventions if the readmissions were complication-related. Otherwise, trained student nurses or a research doctor telephoned all consented participants to interview for the 30-day complications using the delayed complication audit form. A participant was declared lost to follow-up after three telephone attempts. The student nurses were trained by senior nurses and the research doctor with standard instructions.
 
Data analysis was performed by the Statistical Package for the Social Sciences (Windows version 14.0; SPSS Inc, Chicago [IL], US). Descriptive statistics (mean, percentage, incidence, and/or 95% confidence interval [CI]) were used to display the characteristics of the sample. For those complications with zero events, only 95% CIs were given.14 Backward logistic regression analyses were performed to draw prediction models for immediate complications, including colonoscopy-related complications or systemic complications, and overall complications, including immediate and delayed complications, from the sample; entering variables were chosen from age, sex (male or female), use of MAC (yes or no), sufficiency of bowel preparation (adequate or not), and completion of colonoscopy (yes or no) according to the results of the univariate analyses by Pearson Chi squared tests of all potential independent variables, with a significance level set at 10%; variable inclusion in the iteration was set at P<0.1 for backward logistic regression analyses. Returning coefficients of the variables were interpreted as adjusted odds ratio (ORadjusted) with 95% CI provided. All significance levels were set at two-sided α=0.05.
 
Results
A total of 6196 colonoscopies (3143 women; mean age 53.7 years; standard deviation, 12.7 years) were done during the study period. Most patients were aged between 45 and 64 years, were in-patients, had undergone diagnostic colonoscopy, and received intravenous sedation (60.5%, 70.5%, 53.0%, and 99.4% respectively; Table 1). The data for immediate complications were complete, while the 30-day follow-up was completed for 3657 procedures (803 were lost to follow-up and 1736 refused; compliance rate 59.0%; Table 2).
 

Table 1. Demographic characteristics, sedation, and colonoscopy data (n=6196)
 

Table 2. Thirty-day follow-up, readmission, and mortality
 
Of the 6196 colonoscopies, 2912 were therapeutic with 99.7% dedicated to polypectomy (Table 1). There were 73 (1.2%) cases of incomplete colonoscopy, 18 (24.7%) of which were due to inadequate preparation. Other reasons for incomplete colonoscopy were tumour obstruction (15 of 73; 20.5%) and intention of sigmoidoscopy or stent insertion (26 of 73; 35.6%). A total of 149 patients were readmitted within 30 days after the procedure, of which six (4.0%) were related to complications. The other reasons were cancer, gastro-intestinal disease, or cardiac events (Table 2).
 
Systemic complications
Regarding the choice of sedation, midazolam and pethidine were the most used at 81.5% and 82.0%, respectively, while 15.9% of patients underwent MAC. Immediate complications reported included hypotension, vasovagal fainting, and nausea/vomiting, or a combination (6.1, 0.6, 0.3, and 0.5 per 1000 procedures, respectively; Table 3). There were no severe cardiovascular events such as heartbeat irregularity or myocardial infarction or cerebrovascular events such as stroke. Furthermore, none of the patients reported delayed systemic complications in the 30-day follow-up.
 

Table 3. Incidence of overall complications (per 1000 procedures) and their interventions
 
Modelling to study the potential risk factors showed that being female, use of MAC, and inadequate bowel preparation were the significant independent predictors for systemic immediate complications (ORadjusted=2.0, 2.6, and 3.7, respectively; all were P<0.05; Table 4).
 

Table 4. Multivariate analysis of risk predictors for complications by different models
 
Colonoscopy-related complications
Immediate colonoscopy-related complications were recorded for 48 patients (7.7 per 1000 procedures), including extensive pain/discomfort, abdominal distension, and perforation (Table 3). The only perforation was at the sigmoid-rectal junction and was due to adhesion, which might be related to previous abdominal surgery (total hysterectomy and bilateral salpingo-oophorectomy was done 10 years previously). In the 30-day follow-up, six patients reported complication-related readmissions, five of whom were for bleeding after discharge from hospital and one was for inflammation; all were caused by polypectomy.
 
Modelling was done to formulate a predictive algorithm for significant independent risk factors and outcome events (Table 4). Inadequate bowel preparation and incomplete colonoscopy were the significant predictors for immediate colonoscopy-related complications (ORadjusted=3.5 and 6.2, respectively; both were P<0.05) and for all immediate complications (ORadjusted=3.5 and 4.5, respectively; both were P<0.05). In the model for all immediate complications, being female and use of MAC were also predictors (ORadjusted=1.6 and 1.8, respectively; all were P<0.05).
 
A predictive model was also done for overall complications, including all immediate and delayed complications among those who completed follow-up at 30 days. The effect of previous significant predictors was transient in that they did not predict the overall complications occurring in the 30-day post-colonoscopy period. Monitored anaesthetic care was the only predictor during the 30-day period (ORadjusted=2.0; P=0.019).
 
Discussion
Significance of this study
Inadequate bowel preparation and incomplete colonoscopy were identified as risk factors for colonoscopy-related complications. Other complications were mostly hypotension and abdominal distension. No myocardial infarction, transient ischaemic attack, or death relating to colonoscopy was reported.
 
Contribution of individual characteristics to the complications
Colonoscopy is rarely a complication-free procedure, but a good understanding of the possible complications can help to minimise them. While experienced endoscopists, diagnostic procedures, and young patients are protective factors for colonoscopy complications, trainee endoscopists, therapeutic procedures, advanced age, female sex, obesity, co-morbidity, anticoagulant use, and previous abdominal surgery are risk factors for complications.3 5 6 10 15 16 17 The relatively low incidence of complications recorded in this study could be attributed to the fact that more than half of the procedures were diagnostic, thus reducing the potential for polypectomy-associated complications.
 
Other events—such as abdominal pain and distension, hypotension, vasovagal fainting, and nausea/vomiting—accounted for 98.9% of all immediate complications; these events were mostly reported by women (60.6%; ORadjusted=1.6; Table 4). This result is consistent with the literature.17 This effect could possibly be explained by different perceptions of somato-sensation, which could be traced back to the socio-emotional cultivation and cultural expectation of the different sexes.18
 
Hidden factors that may contribute to complications
Despite the sex effect, use of MAC, inadequate bowel preparation, and incomplete colonoscopy were all related to immediate complications. The use of MAC, in particular, requires more interpretation because it has not been found to be a risk factor in other studies and its use ought not be a cause of complications. However, MAC is designed for patients who are vulnerable to the complications of sedation and the procedure, especially those with co-morbidities and who are at an advanced age. In this study, co-morbidity was not reviewed, but patients who underwent MAC were significantly older than those who did not (mean age, 56.1 vs 53.3 years; P<0.001, t test) which may be partly contributory. However, age was not significantly associated with any of the complications after adjustment for other factors. Age might have a greater impact if co-morbidity was also considered and this may be an area for further study.
 
Inadequate bowel preparation, in which faeces obscure the inner lining of the colon, impedes the vision and heightens the risk for complications. Likewise, incomplete colonoscopy due to inadequate bowel preparation or unbearable discomfort inevitably increases the risk for complications. These results are consistent with other studies.2 3 10
 
A large proportion (59%) of the study population completed the study. Per protocol univariate analyses showed that use of MAC was the sole significant factor related to overall complications (Table 4).
 
Other factors
Sedation-free colonoscopy is a feasible alternative that could reduce the risk of systemic complications; use of CO2 insufflation might increase its tolerability while maintaining visibility. In this study, a sedation-free procedure was performed in only 36 patients, with no complications; CO2 insufflation was done for 647 (10.9%) patients instead of gas (room air), with only minor complications encountered (two patients reported abdominal distension and seven reported hypotension/vasovagal fainting). Insufflation with CO2 could be adopted more widely because it is non-explosive, absorbable, and does not affect the mucosal blood flow, thus minimising discomfort and the risk of colonic ischaemia. According to Bretthauer et al,19 CO2 insufflation leads to quicker recovery, and less pain and complications. These advantages are supported by other studies including local research.11 19 20 These factors might inspire greater use of CO2 insufflation and minimise use of sedation for selected patients.12 13 21
 
Inadequate bowel preparation not only hampers completion of the procedure, but also increases the risk for complications. As evidenced from the prediction models, inadequate bowel preparation significantly increases the occurrence of complications. In addition to implementing the current standardised bowel preparation protocol, enforcement of patient education, compliance, and early admission for monitored bowel preparation might help to further suppress the rate for inadequate bowel preparation.
 
Limitations
Many of the patients were lost to contact by telephone. In this study, we assumed that the pattern of missing patients was random and was not affected by whether or not the patients had complications. However, self-selection bias might exist. If patients without complications were more likely to be lost to contact, the rate of delayed complications would be overestimated. However, the rate of delayed complications would be underestimated if the patients had been admitted to other hospitals or had died. Endoscopist experience, and patient characteristics of co-morbidities and severe symptoms before the procedure were not recorded for analysis in this study. These are potential risk factors for complications. In view of the importance of monitoring the complications of colonoscopy, further study might include the missing variables of co-morbidity, endoscopist experience, symptoms at presentation and oxygen level, and explore factors such as the influence of body mass index and medical history, sedation dose, indication for colonoscopy, use of laxatives and compliance, and post-colonoscopy diagnosis/pathology that might help to minimise the variance on prediction of complications.
 
Acknowledgements
We would like to thank Dr Sheri Lim, former Administrative Officer (Medical) who proposed and developed the audit. We are grateful to Dr KM Lai, Head of Department of Anaesthesiology for his expert advice on the anaesthetic terminology; Dr Raymond Yung and Dr KN Lai, Assistant Medical Superintendents for their valuable suggestions and encouragement; Ms Grace Wong, Medical Records Manager for coordinating with different departments; and Ms Sara Fung, former Research Nurse for coordinating the project. Also, thanks to all doctors who contributed their knowledge and data, for this study would not have been accomplished without them.
 
References
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2. Gastrointestinal endoscopy, version 1. Australasian Clinical Indicator Report 2003-2010. Australian Council on Healthcare Standards; 2010.
3. Nelson DB, McQuaid KR, Bond JH, Lieberman DA, Weiss DG, Johnston TK. Procedural success and complications of large-scale screening colonoscopy. Gastrointest Endosc 2002;55:307-14. CrossRef
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11. Wong JC, Yau KK, Cheung HY, Wong DC, Chung CC, Li MK. Towards painless colonoscopy: a randomized controlled trial on carbon dioxide-insufflating colonoscopy. ANZ J Surg 2008;78:871-4. CrossRef
12. Bayupurnama P, Nurdjanah S. The success rate of unsedated colonoscopy examination in adult. Internet Journal of Gastroenterology 2010;9:2.
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14. Ho AK. When the numerator is zero: another lesson on risk. Am Biol Teach 2009;71:531-3. CrossRef
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19. Bretthauer M, Lynge AB, Thiis-Evensen E, Hoff G, Fausa O, Aabakken L. Carbon dioxide insufflation in colonoscopy: safe and effective in sedated patients. Endoscopy 2005;37:706-9. CrossRef
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Role of fine-needle aspiration cytology in human immunodeficiency virus–associated lymphadenopathy: a cross-sectional study from northern India

Hong Kong Med J 2015 Feb;21(1):38–44 | Epub 21 Nov 2014
DOI: 10.12809/hkmj144241
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
ORIGINAL ARTICLE
Role of fine-needle aspiration cytology in human immunodeficiency virus–associated lymphadenopathy: a cross-sectional study from northern India
Naveen Kumar, MD1; BB Gupta, MD1; Brijesh Sharma, MD1; Manju Kaushal, MD2; BB Rewari, MD1; Deepak Sundriyal, MD1
1 Department of Medicine, PGIMER and Dr RML Hospital, New Delhi 110001, India
2 Department of Pathology, PGIMER and Dr RML Hospital, New Delhi 110001, India
 
Corresponding author: Dr Naveen Kumar (docnaveen2605@yahoo.co.in), (2605docnaveen@gmail.com)
 Full paper in PDF
Abstract
Objective: To evaluate the role of fine-needle aspiration cytology in the diagnosis of human immunodeficiency virus (HIV)–associated lymphadenopathy.
 
Design: Case series.
 
Setting: Tertiary care teaching hospital, India.
 
Patients: Fifty consecutive HIV-positive patients, who presented with lymphadenopathy at the out-patient department and antiretroviral therapy clinic.
 
Results: Tubercular lymphadenitis was the most common diagnosis, reported in 74% (n=37) of patients; 97.2% of them were acid-fast bacilli–positive. Reactive lymphadenitis and fungal lymphadenitis were present in 10 and 1 cases, respectively. The most common cytomorphological pattern of tubercular lymphadenitis was necrotising suppurative lymphadenitis, present in 43.2% (n=16) of patients. Of eight biopsies done in reactive cases, six turned out to be tubercular lymphadenitis. Fine-needle aspiration cytology had a sensitivity of 83.7% for diagnosing tubercular lymphadenitis.
 
Conclusion: Necrotising suppurative lymphadenitis should be recognised as an established pattern of tubercular lymphadenitis. Reactive patterns should be considered inconclusive rather than a negative result, and re-evaluated with lymph node biopsy. Fine-needle aspiration cytology is an excellent test for diagnosing tubercular lymphadenitis in HIV-associated lymphadenopathy.
 
 
New knowledge added by this study
  •  Necrotising suppurative lymphadenitis should be recognised as an established pattern of tubercular lymphadenitis.
  •  In advanced human immunodeficiency virus (HIV) disease, reactive lymphadenitis should be considered inconclusive rather than a negative result, and re-evaluated with lymph node biopsy.
Implications for clinical practice or policy
  •  As lymphadenopathy is common in all stages of HIV disease, judicious use of fine-needle aspiration cytology can be helpful in diagnosing associated opportunistic infections and other pathological conditions.
 
 
Introduction
Human immunodeficiency virus (HIV) infection is an important worldwide public health problem. Developing nations, where resources are limited, are the worst affected nations. Until curative treatment for HIV infection becomes available, the crux of management is early diagnosis and treatment with highly active antiretroviral therapy.
 
As HIV is a lymphotropic virus, lymphoid tissues are the major anatomical site where the virus establishes itself during early infection. These lymphoid tissues act as reservoirs for the virus in the asymptomatic phase of infection. In the late stage, HIV disseminates from these sites to cause a full-blown acquired immunodeficiency syndrome (AIDS).1 Thus, lymph node involvement is found in all stages of infection. The cause of lymph node enlargement is often difficult to establish by history, physical examination, radiographic studies, and routine laboratory tests. Surgical biopsy is the gold standard for diagnosis. However, it has several drawbacks: costly, time-consuming, and requiring more elaborate precautions. Fine-needle aspiration cytology (FNAC) does not have any of these limitations, and is also comparatively less invasive. Furthermore, the cost of aspiration cytology is only 10% to 30% of that of surgical biopsy.2
 
We performed FNAC to establish the aetiological diagnosis in our study subjects with HIV infection. To detect false-negative results, biopsy was done in cases diagnosed as reactive lymphadenitis. The aims of the study were to assess the accuracy of FNAC and to correlate the findings with clinical and laboratory parameters like CD4 counts.
 
Methods
The study was conducted in the Departments of Medicine and Pathology, PGIMER and Dr RML Hospital, New Delhi, India, from January 2009 to December 2009. The study protocol and proforma were approved by the ethics committee of the institute. Informed written consent was obtained from all patients. Fine-needle aspiration cytology was performed in 50 consecutive HIV-positive patients presenting with lymphadenopathy at the antiretroviral clinic, or the out-patient or in-patient services. Detailed history was taken and examination of the patients was performed. Clinical stage (as per the World Health Organization [WHO] classification) and CD4 counts were recorded for all patients. Fine-needle aspiration cytology was performed by the clinician on the largest non-inguinal lymph node using standard precautions. The area was cleaned and draped. A 10-mL syringe and 23-gauge needles were used. If the sample was insufficient, another sample was taken from a different lymph node. Slides for Papanicolaou and Periodic-acid Schiff (PAS) stains were fixed with 95% ethanol immediately after preparing the smear; others were air dried. A total of six slides were prepared from each aspirate and were immediately processed by staining with Giemsa stain, Papanicolaou’s stain, Ziehl-Neelsen (ZN) stain for acid-fast bacilli (AFB), PAS stain for fungi, and Gram stain. Cases that were AFB-positive on ZN staining were diagnosed as tubercular lymphadenitis; otherwise, they were retained as suspected cases. Based on the presence or absence of granulomas, caseation (necrosis) and neutrophilic infiltration, tubercular lymph nodes were classified into four cytomorphological categories: granulomatous lymphadenitis (GL), necrotising granulomatous lymphadenitis (NGL), necrotising lymphadenitis (NL), and necrotising suppurative lymphadenitis (NSL). Lymph node biopsies were performed in cases which showed a reactive pattern or suspected tubercular lymphadenitis on FNAC. Sensitivity, specificity, and positive and negative predictive values were calculated for FNAC as a diagnostic modality compared with biopsy. Statistical analysis for association between FNAC findings and various parameters was done using univariate and multivariate logistic regression analyses. Data analysis was performed by the Statistical Package for the Social Sciences (Windows version 19.0; SPSS Inc, Chicago [IL], US). A P value of less than 0.05 was regarded as statistically significant.
 
Results
A total of 50 patients (43 men and 7 women) were included in the study. The mean age of the patients was 32.4 years. Cervical region was the most common site of lymphadenopathy (n=39; 78%) followed by axillary and inguinal regions. The lymph nodes were matted and generalised in 62% (n=31) and 48% (n=24) of cases, respectively. Generalised lymphadenopathy was present in 54% (n=20) of cases with tubercular lymphadenitis and 40% (n=4) of cases with reactive lymphadenitis. Nature of aspirate was bloody in 21 (42%) cases, caseous in 24 (48%), and mixed (with blood and caseation) in the remaining patients. The CD4 count ranged from 12 cells/µL to 353 cells/µL, with a mean count of 131 cells/µL. Most of the patients were in WHO clinical stage 3 (n=31; 62%).
 
The most common cytological diagnosis was tubercular lymphadenitis (n=37; 74%) followed by reactive pattern (n=10; 20%). Only one FNAC was diagnosed as fungal lymphadenitis showing PAS-positive spores of Histoplasma capsulatum (Fig 1). In two cases, the cytologies were suggestive of thyroid tissue and lipoma; these were treated as failed FNACs. Tubercular lymphadenitis was further categorised into four cytomorphological patterns, as shown in Table 1. All tubercular cases were AFB-positive except one which was a AFB-negative GL on FNAC. Subsequently, this was shown to be AFB-positive tubercular lymphadenitis on biopsy. Of the 10 cases reported as reactive lymph nodes on FNAC, eight gave consent for biopsy. Biopsy showed AFB-positive fibrocaseous tubercular lymphadenopathy in six out of these eight cases; in the remaining two cases, biopsy findings matched with the FNAC findings.
 

Figure 1. Histoplasma lymphadenitis: Periodic-acid Schiff–positive oval yeast cells with thick capsule (white arrow), both extracellular and intracellular (black arrow heads) in location (x 100)
 

Table 1. Cytomorphological patterns of tubercular lymphadenitis
 
All cases diagnosed as having mycobacterial disease on FNAC and those who underwent biopsy were included in the analysis. Hence 45 cases were analysed: 36 cases diagnosed as mycobacterial (tubercular) lymphadenitis on FNAC, one case of GL which was AFB-positive fibrocaseous tubercular lymph node on biopsy, and eight cases of reactive lymphadenopathy that underwent biopsy (Table 2). The sensitivity and negative predictive value of FNAC for diagnosing tubercular lymphadenitis were 83.7% and 22.2%, respectively. As AFB positivity was the requisite criterion for diagnosing tubercular lymphadenitis, it was expected that there would be no diagnosis of tuberculosis (TB) in any case which was AFB-negative on FNAC; thus, the specificity and positive predictive value were 100%.
 

Table 2. Analysis of 45 cases
 
We performed logistic regression analysis with tubercular lymphadenitis as the dependent variable and four parameters as covariates. On univariate analysis, CD4 count (P=0.016), nature of aspirate (P=0.013), and matted nodes on examination (P=0.028) were associated with tubercular aetiology on FNAC; lymph node distribution did not show any such association (P=0.401). However, in multivariate analysis, none of these factor was associated with tubercular aetiology on FNAC. Moreover, none of these factors was associated with the severe form (NL or NSL) of tubercular lymphadenitis either on univariate or multivariate analysis.
 
Discussion
Lymphadenopathy in HIV patients is very common; it can be a presenting feature in about 35% of patients with AIDS.3 Causes can be varied, depending on the stage of the disease, and may include persistent generalised lymphadenopathy, lymphoid malignancies, and opportunistic infection. All these can be easily and efficiently diagnosed by aspiration study of these lymph nodes. These causes of lymphadenopathies are important causes of death in AIDS patients. In this study, we aimed to investigate the performance of FNAC for the accurate diagnosis of lymphadenopathies. We also compared our results with those from similar Indian and western studies (Table 3 1 4 5 6 7 8 9 10 11 12 13 14 15 16).
 

Table 3. Comparison of our FNAC results with those from previous studies1 4 5 6 7 8 9 10 11 12 13 14 15 16
 
Tuberculosis is the most frequent opportunistic infection in HIV patients.17 18 Lymph nodes are the commonest site of extra-pulmonary TB in patients with AIDS.19 20 Using FNAC as the diagnostic modality, we also found tubercular lymphadenitis to be the most common cause of lymphadenopathy, present in 74% of our patients. Similar conclusion was drawn in other Indian studies; however they reported a prevalence of 34.2% to 60% (Table 3). The high prevalence of tubercular lymphadenitis in our series may be related to the low immunity of the majority of patients; 41 out of 50 patients had CD4 counts of <200 cells/µL.
 
There are two specific pathological criteria for diagnosing tubercular lymphadenitis—caseation and granuloma formation. Both are less likely to be present in tubercular lymphadenitis associated with advanced HIV disease. This is because T-cell function, which is suppressed in advanced HIV disease, is required for granuloma formation. On the basis of these two findings, tubercular lymphadenitis is classified into three categories21 22: GL, NGL, and NL.
 
The GL pattern can occur due to several causes. However, in a country like India, where TB is very common, this pattern is considered to be due to TB until proven otherwise. We found this pattern in 5.4% (2 out of 37 cases with tubercular lymphadenitis) of TB cases, a finding similar to that in other previous studies where it ranged from 4.3% to 28.5% (Table 4).6 9 11 12 16 23 The NGL pattern, with both caseation and epithelioid granulomas, is the most typical pattern of tubercular lymphadenitis. It was present in 18.9% (7 out 37 cases of tubercular lymphadenitis) of our cases; other studies have reported it in the range of 26.6% to 74% (Table 4).9 11 12 16 23 Necrotising lymphadenitis represents the most severe cytomorphological pattern of tubercular lymphadenitis. There is complete necrosis with only ‘acellular’ debris. It is not labelled as ‘purulent’ because there are no degenerated polymorphonuclear cells. Complete necrosis reflects impaired cell-mediated immunity in this group of patients. Cases of NGL can be wrongly labelled as NL if material is aspirated from that part of the node which contains only caseation. This was the second most common pattern reported in our study (32.4%; 12 out of 37 cases of tubercular lymphadenitis). In other studies, the reported prevalence rates range from 8.6% to 57.1% (Table 4).6 9 11 12 16 23
 

Table 4. Cytomorphological patterns in tubercular lymphadenitis: comparison with previous studies6 9 11 12 16 23
 
The NSL pattern of tubercular lymphadenitis (Fig 2) was the most common cytomorphological picture, seen in 43.2% (16 out of 37 cases of tubercular lymphadenitis) of patients. This pattern was reported in 20% and 13% cases of tubercular lymphadenitis by Nayak et al11 and Shenoy et al,12 respectively (Table 4). Jayaram and Chew6 reported this pattern in 67% of their TB cases in Kuala Lumpur, Malaysia. Although reported in these case series, unlike the other three patterns, the NSL pattern is not yet a well-recognised cytomorphological type of tubercular lymphadenitis. However, this pattern is important, especially in HIV patients. If ZN staining is not done, the thin caseation commonly present in these cases can be mistaken for pus, and the case wrongly labelled as pyogenic lymphadenitis. Similar observations have been made in some studies.6 11 12 24
 

Figure 2. Liquefied necrotic material (black arrow head) with infiltration of polymorphs (white arrow), giving impression of suppurative lymphadenitis. No epithelioid cells or giant cells are seen (Giemsa staining, x 40)
 
Studies have shown that FNAC is more sensitive for the diagnosis of TB in HIV-positive patients than in seronegative patients.25 In our series, AFB positivity rate in TB cases was 97.2% (n=36/37), which was higher than that in previous studies (43.4% to 95.2%).6 9 11 12 16 This could be due to the fact that the disease was quite advanced in our group of tubercular lymphadenitis patients (mean CD4 count of 108 cells/µL). Moreover, as the cytomorphological pattern deteriorated and necrosis appeared, AFB positivity increased from 50% to 100%. This was in agreement with data from earlier studies.6 9 11 12 16 Chances of detecting AFB were least in lymph nodes showing GL pattern: four out of five studies6 9 11 12 16 did not report any AFB-positive case with this pattern of lymphadenopathy. Further, although TB is very common in HIV subjects, Mycobacterium avium complex (MAC) is not frequently seen in India. Its chance further decreases by adding MAC prophylaxis of azithromycin to the patient’s treatment regimen.
 
A reactive lymphadenitis was observed in only 20% of cases in our study. Most of the western studies reported it as the most common lymph node pathology, observed in 25.6% to 59.6% of cases (Table 3). One case of histoplasmosis was detected in our study (Fig 1). On Giemsa staining, the lymph node showed reactive lymphoid cells, histiocytes, areas of granuloma formation, along with sheets of Histoplasma capsulatum organism, located both extracellularly and intracellularly, which were positive on PAS staining. Hence, although the finding of GL without AFB in HIV-infected patients in India is taken as TB unless proven otherwise, causes like fungal infection (by PAS staining) should be excluded, especially if the CD4 count is low.
 
We performed a lymph node biopsy in 18% of our cases (Table 5). Among these, the findings were different from those in FNAC in 77.8% of the cases. False-negative rate in our study was 16.3% (7 out of 43 cases of TB; Table 2). The false-negative rate in other studies ranges from 2% to 9.2%.1 4 7 8 Of these seven false-negative cases, six were diagnosed as reactive nodes on FNAC which later showed fibrocaseous nodes on biopsy. Possible reasons for discordance could be focal tubercular involvement of the nodes. On FNAC, the tubercular area could have been missed and, hence, wrongly labelled as reactive cases. Also, different nodes in the same area can enlarge due to different pathologies. Hence, a report of reactive pattern in advanced disease, like in our group of patients (mean CD4 in reactive group being 196 cells/µL), does not have much value, and should not be the end of further assessment. It should be considered an inconclusive result rather than a negative one. It emphasises the importance of performing a biopsy in this group of patients.
 

Table 5. Comparison of lymph node biopsy results with those from previous studies1 4 7 8
 
A falling CD4 count in our group of patients was associated with increasing risk of tubercular lymphadenitis. However, CD4 counts did not predict the severity of cytomorphological forms of tubercular lymphadenitis. Of note, 41 out of 50 patients had CD4 counts of <200 cells/µL. Hence, we did not have a group of patients with higher CD4 counts in whom less severe forms of tubercular lymphadenitis were more common. This association should be studied further by recruiting patients with a wide range of CD4 counts.
 
In univariate analysis, a matted lymph node on examination (P=0.028) and caseous material (P=0.013) on aspiration were found more often in TB cases versus reactive cases. Hence, apart from routine cytology stains, these observations guide us for ordering special staining like ZN staining. However, their association with cytomorphological pattern of TB was not significant on univariate analysis, as the whole spectrum of pattern can have caseation on aspiration (except GL) and matted nodes on examination, although cytomorphologically these are of increasing severity.
 
Conclusion
Tuberculosis is the most common aetiology of HIV-associated lymphadenopathy in India. Acid-fast bacilli positivity is very high in HIV-associated tubercular lymphadenitis. We recommend routine AFB staining for all lymph nodes undergoing FNAC in HIV patients. Lymph nodes showing AFB-negative GL pattern on FNAC should be stained for fungus, especially if CD4 count is low. If a patient’s CD4 count is low, a reactive FNAC pattern should be taken as an inconclusive result and is an indication for biopsy. All lymph nodes showing NSL pattern on FNAC should undergo ZN staining in HIV-positive patients. It should be recognised as a tubercular cytomorphological pattern, especially in patients with low immunity like those with AIDS. Fine-needle aspiration cytology of lymph nodes is a valuable test for diagnosing tubercular lymphadenitis in HIV-associated lymphadenopathy.
 
References
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2. Kaminsky DB. Aspiration biopsy for community hospital. In: Johnston WW, editor. Masson monograph in diagnostic cytopathology. New York: Masson Publication; 1981: 12-3.
3. Guidelines for prevention and management of common opportunistic infection/malignancy among HIV-infected adult and adolescents. NACO. Ministry of Health & Family Welfare. Government of India; May 2007.
4. Martin-Bates E, Tanner A, Suvarna SK, Glazer G, Coleman DV. Use of fine needle aspiration cytology for investigating lymphadenopathy in HIV positive patients. J Clin Pathol 1993;46:564-6. CrossRef
5. Shapiro AL, Pincus RL. Fine-needle aspiration of diffuse cervical lymphadenopathy in patients with acquired immunodeficiency syndrome. Otolaryngol Head Neck Surg 1991;105:419-21.
6. Jayaram G, Chew MT. Fine needle aspiration cytology of lymph nodes in HIV-infected individuals. Acta Cytol 2000;44:960-6. CrossRef
7. Reid AJ, Miller RF, Kocjan GI. Diagnostic utility of fine needle aspiration (FNA) cytology in HIV-infected patients with lymphadenopathy. Cytopathology 1998;9:230-9. CrossRef
8. Bottles K, McPhaul LW, Volberding P. Fine-needle aspiration biopsy of patients with acquired immunodeficiency syndrome (AIDS): experience in an outpatient clinic. Ann Intern Med 1988;108:42-5. CrossRef
9. Llatjos M, Romeu J, Clotet B, et al. A distinctive cytologic pattern for diagnosing tuberculous lymphadenitis in AIDS. J Acquir Immune Defic Syndr 1993;6:1335-8.
10. Lowe SM, Kocjan GI, Edwards SG, Miller RF. Diagnostic yield of fine-needle aspiration cytology in HIV-infected patients with lymphadenopathy in the era of highly active antiretroviral therapy. Int J STD AIDS 2008;19:553-6. CrossRef
11. Nayak S, Mani R, Kavatkar AN, Puranik SC, Holla VV. Fine-needle aspiration cytology in lymphadenopathy of HIV-positive patients. Diagn Cytopathol 2003;29:146-8. CrossRef
12. Shenoy R, Kapadi SN, Pai KP, et al. Fine needle aspiration diagnosis in HIV related lymphadenopathy in Mangalore, India. Acta Cytol 2002;46:35-9. CrossRef
13. Saikia UN, Dey P, Jindal B, Saikia B. Fine needle aspiration cytology in lymphadenopathy of HIV-positive cases. Acta Cytol 2001;45:589-92. CrossRef
14. Gill PS, Arora DR, Arora B, et al. Lymphadenopathy. An important guiding tool for detecting hidden HIV-positive cases: a 6-year study. J Int Assoc Physicians AIDS Care (Chic) 2007;6:269-72. CrossRef
15. Shobhana A, Guha SK, Mitra K, Dasgupta A, Neogi DK, Hazra SC. People living with HIV infection / AIDS—a study on lymph node FNAC and CD4 count. Indian J Med Microbiol 2002;20:99-101.
16. Vanisri HR, Nandini NM, Sunila R. Fine-needle aspiration cytology findings in human immunodeficiency virus lymphadenopathy. Indian J Pathol Microbiol 2008;51:481-4. CrossRef
17. Harries AD. Tuberculosis and human immunodeficiency virus infection in developing countries. Lancet 1990;335:387-90. CrossRef
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19. Shafer RW, Kim DS, Weiss JP, Quale JM. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine (Baltimore) 1991;70:384-97. CrossRef
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21. Das DK, Pant JN, Chachra KL, et al. Tuberculous lymphadenitis: correlation of cellular components and necrosis in lymph-node aspirate with A.F.B. positivity and bacillary count. Indian J Pathol Microbiol 1990;33:1-10.
22. Das DK. Fine needle aspiration cytology in diagnosis of tuberculous lesion. Lab Med 2000;31:625-32. CrossRef
23. Rajasekaran S, Gunasekaran M, Jayakumar DD, et al. Tuberculous cervical lymphadenitis in HIV positive and negative patients. Indian J Tuberc 2001;48:201-4.
24. Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1999;340:367-73. CrossRef
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Effectiveness of a new standardised Urinary Continence Physiotherapy Programme for community-dwelling older women in Hong Kong

Hong Kong Med J 2015 Feb;21(1):30–7 | Epub 7 Nov 2014
DOI: 10.12809/hkmj134185
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
ORIGINAL ARTICLE
Effectiveness of a new standardised Urinary Continence Physiotherapy Programme for community-dwelling older women in Hong Kong
BS Leong, MSc, BScPT1,2; Nicola W Mok, PhD1
1 Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hunghom, Hong Kong
2 Elderly Health Service, Department of Health, Hong Kong
 
Corresponding author: Dr Nicola W Mok (nicola.mok@polyu.edu.hk)
 Full paper in PDF
Abstract
Objective: To examine the effectiveness of a standardised Urinary Continence Physiotherapy Programme for older Chinese women with stress, urge, or mixed urinary incontinence.
 
Design: A controlled trial.
 
Setting: Six elderly community health centres in Hong Kong.
 
Participants: A total of 55 women aged over 65 years with mild-to-moderate urinary incontinence.
 
Interventions: Participants were randomly assigned to the intervention group (n=27) where they received eight sessions of Urinary Continence Physiotherapy Programme for 12 weeks. This group received education about urinary incontinence, pelvic floor muscle training with manual palpation and verbal feedback, and behavioural therapy. The control group (n=28) was given advice and an educational pamphlet on urinary incontinence.
 
Results: There was significant improvement in urinary symptoms in the intervention group, especially in the first 5 weeks. Compared with the control group, participants receiving the intervention showed significant reduction in urinary incontinence episodes per week with a mean difference of -6.4 (95% confidence interval, -8.9 to -3.9; t= –5.3; P<0.001) and significant improvement of quality of life with a mean difference of -3.93 (95% confidence interval, -5.08 to -2.78; t= –6.9; P<0.001) measured by Incontinence Impact Questionnaire Short Form modified Chinese (Taiwan) version. The subjective perception of improvement, measured by an 11-point visual analogue scale, was markedly better in the intervention group (mean, 8.7; standard deviation, 1.0; 95% confidence interval, 8.4-9.1) than in the control group (mean, 1.4; standard deviation, 0.7; 95% confidence interval, 1.2-1.7; t=33.9; P<0.001). The mean treatment satisfaction in the intervention group was 9.5 (standard deviation, 0.8) as measured by an 11-point visual analogue scale.
 
Conclusions: This study demonstrated that the Urinary Continence Physiotherapy Programme was effective in alleviating urinary symptoms among older Chinese women with mild-to-moderate heterogeneous urinary incontinence.
 
 
New knowledge added by this study
  •  This standardised Urinary Continence Physiotherapy Programme is effective in improving various types of urinary incontinence of mild-to-moderate severity.
  •  The superior exercise compliance and treatment outcome in this study are likely attributed to the palpation and verbal feedback provided by physiotherapists during pelvic floor muscle training.
Implications for clinical practice or policy
  •  A standardised urinary continence programme consisting of education, supervised pelvic floor muscle training with palpation, and behavioural therapy is an effective first-line management for various types of urinary incontinence in a community setting.
 
 
Introduction
Urinary incontinence (UI), defined as “the complaint of any involuntary leakage of urine”,1 is a major clinical problem, and a significant cause of disability and dependency in the aged population. It is a condition with heterogeneous pathology and commonly classified as stress urinary incontinence (SUI), urge urinary incontinence (UUI), and mixed urinary incontinence (MUI) depending on the symptom behaviour. While the prevalence of UI in older women, globally, is estimated to range from 15% to 30%,2 the reported prevalence rate of UI in Hong Kong ranges from 20% to 52%.3 It has been acknowledged that UI is associated with profound adverse impact on the quality of life (QoL) of the sufferers.3 4 The impact of UI is so substantial that community-dwelling elderly with UI reported inferior physical and mental health, worse self-perceived health status, greater disability, and more depressive symptoms.5 In addition, the extent of the impact was shown to be associated with the severity of UI. Therefore, it is important to investigate a safe and effective treatment strategy in this population, especially in a community setting.
 
Conservative management has been recommended as the first-line management for UI. It is acknowledged that a variety of conservative management strategies which require patient’s active participation shows promising results for patients with UI. These include pelvic floor muscle training (PFMT),6 7 vaginal cones,8 bladder training (BT),9 and even combination of PFMT and general lumbopelvic mobilisation exercises.10 A recent Cochrane review7 suggested that PFMT, the ‘knack’ manoeuvre (a voluntary counterbracing type of contraction during physical stress), and BT are effective strategies in the management of UI in general. In particular, a combination of PFMT and BT was shown to have superior outcome than BT alone for the management of UUI and MUI.9 However, to date, there is insufficient conclusive evidence on the best approach for PFMT.11 In addition, the applicability and effectiveness of PFMT and BT for treating UI have not been properly evaluated in the elderly Chinese population, especially in randomised controlled studies. The aim of this study was to evaluate the effectiveness of a Urinary Continence Physiotherapy Programme (UCPP), which is a comprehensive programme involving education and exercise (PFMT and BT) components for managing SUI, UUI, and MUI in older Chinese women in a community setting.
 
Methods
A total of 60 subjects were recruited for screening by convenience sampling from six Elderly Health Centres (EHCs), Department of Health, Hong Kong. Inclusion criteria were Chinese females aged 65 years or older who had a clinical diagnosis of SUI, UUI, or MUI (with reference to the definition from International Continence Society1) of a mild-to-moderate severity (based on the scoring system by Lagro-Janssen et al12) which is made by the EHC medical officers in-charge. Exclusion criteria were active urinary tract infection, patients on diuretic medication, presence of bladder pathology or dysfunction due to genitourinary fistula, tumour, pelvic irradiation, neurological or other chronic conditions (eg diabetes mellitus, Parkinson’s disease), previous anti-incontinence surgery, significant cognitive impairment assessed by the Cantonese version of Mini-Mental State Examination Score (CMMSE13 with cutoffs of: ≤18 for illiterate subjects, ≤20 for those who had had 1 to 2 years of schooling, ≤22 for those who had had more than 2 years of schooling out of a maximum score of 30), obesity (body mass index [BMI] of >30 kg/m2), and use of concomitant treatments during the trial.
 
Randomisation was performed prior to the study by an off-site investigator using a computerised randomisation programme with allocation concealment by sequentially numbered, opaque, and sealed envelopes. After taking consent, grouping of the individual participants was revealed to the principal investigator by phone. Overall, 55 eligible participants were assigned to the intervention (n=27) or control (n=28) groups. The trial period lasted for 12 weeks. The study was approved by the Institutional Medical Research Ethics Committee and was conducted in accordance with the Declaration of Helsinki.14
 
Intervention protocol
One physiotherapist was responsible for delivering assessment and treatment to all subjects during the trial period of 12 weeks, and she was not blinded to the intervention.
 
The intervention group received a 30-minute individual training session at a pre-decided time of the day, once weekly for the first 4 weeks; and then once bi-weekly for the remaining 8 weeks. A total of eight treatment sessions were given to each recipient. There were three major components in the UCPP: education (anatomy of the pelvic floor muscle [PFM] and urinary tract, urinary continence mechanism, and bladder care), PFMT with the aid of vaginal palpation, and BT. Pelvic floor muscle training included Kegel exercise programme and neuromuscular re-education (the ‘knack’).15 Bladder training involved strategies to increase the time interval between voids by a combination of progressive void schedules, urge suppression, distraction, self-monitoring, and reinforcement.
 
Four stages of Kegel’s PFMT programme were adopted in this study, including (1) muscle awareness, (2) strengthening, (3) endurance, and (4) habit building and muscle utilisation.16 The exercise regimen was designed to progressively strengthen both type I and type II muscle fibres of the pelvic floor. In the first 2 weeks (muscle awareness phase), one set of 10 (week 1) and 15 (week 2) slow submaximal contractions for 5 seconds each and five fast maximal contractions with a 10-second relaxation between contractions was performed in lying down position. In the strengthening phase (weeks 3 to 4), the muscle-strengthening element was reinforced by gradually increasing the number of submaximal contractions to 25 per session with an increment of five repetitions per week in gravity-dependent position including sitting and standing. The number of fast maximal contractions (5) remained the same as in the awareness phase. In the endurance phase (weeks 5 to 8), the training was more focused on improving the performance of slow and sustained contractions of PFMs by increasing the contraction time to 10 seconds with submaximal contraction while keeping the exercise position and number of both submaximal and maximal contractions as in week 4. In the habit-building and muscle utilisation phase (weeks 9 to 12), the learnt neuromuscular re-education technique (the ‘knack’) and urge suppression strategies were reinforced. In this period, one set of 30 slow submaximal contractions for 10 seconds each and 10 fast maximal contractions with a 10-second relaxation between contractions was practised. Participants were asked to perform three sets of the above-mentioned exercise at specific periods as part of the home programme.
 
The control group was given advice and received an educational pamphlet with information about management of UI at baseline. Participants were given an appointment for a follow-up visit in 12 weeks.
 
Outcome measures
A number of indicators were employed to assess different aspects of outcomes. First, the number of UI episodes in the previous 7 days (UI7) was examined using a weekly bladder diary log sheet, which was also the primary outcome measure of this study. Information for UI7 was collected at baseline and then weekly until the end of the programme (12 weeks). Second, a validated condition-specific QoL assessment tool—Incontinence Impact Questionnaire Short Form (IIQ-7) Chinese (Taiwan) version17—was used to study the impact of UI on QoL and its change with the intervention after minor modifications were made to align with the local culture. Content validation was made by a panel of doctors who reviewed the instrument and determined if the questions satisfied the content domain. Seven items were included in the questionnaire to examine if the subjects were suffering from urine leakage under those specific situations. The questionnaire was administered by the same physiotherapist and the subjects were asked to choose the most appropriate response to those 7 items on a 4-point ordinal scale, with 0 meaning “not at all affected”, 1 “slightly affected”, 2 “moderately affected”, and 3 “greatly affected”. The maximum score of 21 indicated a great impact of UI on QoL. Third, subjective perception of improvement was assessed with a 10-cm visual analogue scale (VAS) rated from 0 to 10, with 0 suggesting “no improvement” and 10 “complete relief” at the end of the intervention period. Fourth, another VAS was used to assess subjects’ satisfaction to treatment (on a 0 to 10 rating), with 0 being “totally dissatisfied” and 10 “totally satisfied”. The IIQ-7 was collected at baseline and at the end of the programme. Compliance with treatment in the intervention group was evaluated from two perspectives: attendance and compliance with home exercises. Attendance was reviewed by calculating the proportion of sessions that were attended by an individual. Compliance with home exercises was also reviewed by calculating the reported frequency of exercises being executed. Any drawbacks and adverse effects during the intervention period were also monitored.
 
Statistical analysis
The sample size calculation based on the power estimation and results of a similar study,18 with a power of 0.8 and α = 0.05 and an attrition rate of 30%, revealed that a recruitment sample of 60 participants (30 participants in each group) was required. Statistical analysis was performed with the Statistical Package for the Social Sciences (Windows version 13.0; SPSS Inc, Chicago [IL], US). Any missing data were treated with “the last observation carried forward” approach. Independent t tests (for parametric data) or Mann-Whitney test (for nonparametric or non-normally distributed data) and Chi squared tests (for nominal/ordinal data) were used to compare the demographic data and outcome variables between the intervention and control groups at baseline. Pairwise comparisons with the P value adjusted using Bonferroni correction was used to examine for the differences in UI7 between week 1 and the subsequent time points during the intervention period (eg between week 1 and 2, week 1 and 3, etc). The results were presented as mean (standard deviation [SD]).
 
Results
The demographics and baseline measurements for the participants are shown in Table 1. Of the 60 participants recruited for screening, three did not turn up for assessment, one declined to participate in the study, and one was excluded due to impaired mental status (Fig 1). The majority of the participants were in their 70s with a mean (± SD) age of 74.3 ± 4.6 years. There was no significant difference between the groups in terms of age, BMI, parity, education level, mental status (CMMSE), and the characteristics of UI at baseline.
 

Table 1. Characteristics of subjects at baseline
 

Figure 1. CONSORT flowchart indicating flow of subjects in the study
 
Number of urinary incontinence episodes in 7 days
There was a significant interaction between time and groups in UI7 (F(1,53) = 33.14; P<0.001). A significant reduction in UI7 was noted only in the intervention group. There was significant difference between the control and intervention groups (t = –5.3; P<0.001) at 12 weeks with a mean difference of -6.4 (95% confidence interval [CI], -8.9 to -3.9). The mean numbers of UI7 for intervention and control groups were 1.0 ± 1.9 (95% CI, 0.3-1.7) and 7.4 ± 6.2 (95% CI, 5.0-9.8), respectively, at 12 weeks (Table 2). When comparing the percentage reduction ([pre-treatment frequency – post-treatment frequency] / [pre-treatment frequency] x 100%) in UI7, the intervention group demonstrated a mean of more than 90% reduction versus 7.2% in the control group. A similar trend of improvement was shown in subjects with SUI, UUI, and MUI; however, statistical analysis was not performed due to insufficient power (Fig 2). Post-hoc pairwise comparisons (a total of 11) suggested a significant improvement from week 1 to week 5 and onwards (P<0.001) in the intervention group.
 

Table 2. Results of outcome measures in the two groups before and after treatment
 

Figure 2. Progress of urinary incontinence episodes in the previous 7 days in subjects in the intervention group with various types of incontinence
 
Incontinence Impact Questionnaire Short Form modified Chinese (Taiwan) version
A significant interaction between time and groups was noted (F(1,53) = 54.56; P<0.001). As IIQ-7 was non-normally distributed, Mann-Whitney test was used and revealed a significant reduction of IIQ-7 (ie improvement in QoL) only in the intervention group (P<0.001), with a mean difference of -3.9 (95% CI, -5.1 to -2.8) at 12 weeks (Table 2).
 
Perception of improvement, treatment satisfaction, attendance, exercise compliance, and attrition rate
The results of the subjective perception of improvement and level of satisfaction with treatment after 12 weeks are shown in Table 2. The majority of the participants in the intervention group were satisfied with the interventions and perceived a subjective improvement. The mean attendance and exercise compliance rates in the intervention group were 97.7% ± 5.0% and 99.4% ± 1.9%, respectively. The attrition rate was zero in both groups during the whole study period. No adverse effect or discomfort was reported during the intervention period.
 
Discussion
In line with results from previous studies, this study further confirms that PFMT is an effective and safe treatment for women suffering from various types of UI. However, we observed a mean of >90% reduction in UI episodes which is noticeably higher than that reported in previous similar studies (32% to 73% reduction).18 19 Although recommendation of PFMT for women with UI is strongly supported by previous research findings,7 the best approach of PFMT programme continues to remain unclear.11 One possible explanation for the superior outcome in this study might be the combination of a few effective features in this programme, including programme duration of 12 weeks with gradual exercise progression, combination of PFMT and BT, manual vaginal palpation, and one-on-one supervised training session. First, the design of this UCPP incorporated some important concepts of exercise therapy. The training period of this study was 12 weeks, which could optimise the effect of the neural adaptation (recruitment of efficient motor units and frequency of excitation) and muscle hypertrophy according to the recommendations made by the American College of Sports Medicine.20 In addition, a recent systematic review7 also revealed that implementation of PFMT programme for at least 3 months (ie around 12 weeks) is more likely to result in greater treatment effect versus that lasting for <12 weeks. This programme also adopted the concepts raised by Kegel16 in which the progression of the exercise regimen is designed according to different stages, namely muscle awareness, strengthening, endurance, habit building, and muscle utilisation. Previous studies suggested a negative correlation between increased PFM strength and UI symptoms.21 22 The improvement of UI7 at the end of the UCPP might be a direct result of the muscle training programme, although PFM strength was not measured in this study. Theoretically, skeletal muscle strengthening should be facilitated by using additional resistance20 and, therefore, it is questionable whether muscle strength could be increased by UCPP using only maximal voluntary contractions. However, a previous study has indicated muscle strength improvement with daily practice of voluntary PFM contraction without resistance,20 and absence of extra improvement in UI patient groups with intravaginal resistance as compared with the group without resistance.23
 
Second, a combination of PFMT and BT was used in this UCPP. Although PFMT has been recommended as first-line management, even for women with UUI and MUI,7 there is some evidence suggesting superior outcome with combined PFMT and BT in this population.9 The result of this study confirmed these suggestions as a similar pattern of improvement was observed across the three groups (UUI, SUI, and MUI), although statistical analysis of the difference between subgroups was not performed due to the small sample size.
 
Third, vaginal palpation was used to facilitate and ensure correct PFM contraction. It was reported that approximately 30% of women are unable to perform isolated pelvic floor contractions with only written or verbal instructions.21 We consider the extra proprioceptive cue and specific verbal feedback are an integral part of the PFMT, and consider these to play a crucial role, especially in the initial (muscle awareness) stage. Ensuring feedback may also increase exercise adherence and compliance, apart from improving the treatment outcomes.
 
Fourth, the exercise sessions were conducted on a one-on-one basis for 30 minutes each. It has been reported that the amount of contact with health care professionals is positively correlated with reported cure and improvement (eg perception of change and incontinence-specific QoL) in patients with UI.11 It is argued that women receiving more attention may overestimate their improvement to please the treatment provider (ie experimenter effect),11 and it is strongly suggested to include more ‘objective’ data such as leakage episode outcomes in all PFMT trials. The result of this study revealed improvement in UI7 as well as other subjective measures (IIQ-7, perception of improvement, and treatment satisfaction), which could be considered as additional evidence base.11
 
The subjects’ compliance with the treatment programme was excellent, as reflected by the high compliance rate with exercise regimens, high attendance rate, and zero dropouts; the dropout rates reported in previous studies were relatively high, ranging from 12% to 41%.6 18 24 A possible explanation for such good compliance might be the significant improvement in the early stage of the protocol, which in turn increased the participants’ motivation for and confidence in adhering with the PFMT programme. Regular meetings (weekly or bi-weekly) with the same physiotherapist, who offered continuity of care, could be another possible explanation for the favourable compliance.
 
Study limitations
The main limitations in this study were: (1) potential selection bias due to use of convenience sampling, (2) absence of assessor blinding, (3) possibility of over-reporting, and (4) the use of the modified IIQ-7 Chinese (Taiwan) version. It has been acknowledged that convenient sampling might not be representative of the whole population suffering from UI. On the other hand, our subject group might have similar care-seeking behaviour as the client group in clinical practice. Although statistically insignificant, the data showed a small difference in some aspects of the demographic characteristics. In general, the control group tended to be slightly older (75.4 years vs 73.0 years), more likely to be illiterate, and have milder severity, and shorter duration of UI versus the intervention group. As these slight differences in the demographics might induce confounding, their effects warrant further investigation. Nevertheless, interpretation of the results of this study deserves some caution. In this study, five participants recruited for screening did not join the programme due to various reasons (one denied, three failed to turn up, and one due to impaired mental status). Although the specific reason for the absence of three participants was not investigated, the possibility of self-selection bias should be considered. In addition, all involved parties (the assessor, treatment provider, and the participants) were not blinded to the intervention, as opposed to the ideal experimental setup. However, it is widely acknowledged that given the nature of the treatment programme, it is difficult and often impossible to blind the treatment provider and participants during treatment.11 Due to resource limitation, it was not possible to include an independent, blinded assessor for outcome assessment. We were well aware of the possible ‘experimenter effect’, and therefore used UI7 as our primary outcome measure which is considered a more objective measure to minimise the possible effect of over-reporting of subjective improvement,11 although its ‘objectivity’ remains controversial. In addition, a significant proportion of participants (approximately 44%) required assistance for completing the outcome questionnaires due to illiteracy. This could possibly lead to over-reporting of improvement. Furthermore, the possibility of over-reporting of compliance by participants using self-reported weekly exercise diary should not be overlooked. There is, however, no better measure available to monitor the performance of this type of exercise accurately. A recent randomised controlled trial25 reported that severity of SUI symptoms at baseline and extent of PFM strength improvement, rather than exercise adherence, were correlated with symptom reduction for women with SUI. The result suggested a complex interaction between subject’s health condition, exercise compliance and treatment effectiveness, which warrant further investigation. Therefore, we intended not to account the improvement observed in our intervention group to the high self-reported compliance rate. Finally, a modified Chinese (Taiwan) version of IIQ-7 was used in this study. We are aware of the fact that this version has not been properly validated. However, we do not believe this affects our results as the modification was minor and the version was highly comparable with the Hong Kong version which was validated subsequent to the current study.
 
This study examined the immediate effectiveness of the verbally instructed UCPP just after cessation of supervised training. No follow-up data were collected. It is recommended that the long-term effectiveness of UCPP be explored, especially in the light of fairly extensive literature which reported poor long-term adherence and relapse at 3 to 5 years following pelvic floor rehabilitation programme.26
 
Conclusions
This study demonstrated that a structured 12-week programme of PFMT with gradual exercise progression, BT with urgency suppression, and enhanced education is likely to improve episodes of urinary leakage and QoL in older Chinese women with various kinds of UI in a community setting.
 
References
1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:167-78. CrossRef
2. Klausner AP, Vapnek JM. Urinary incontinence in the geriatric population. Mt Sinai J Med 2003;70:54-61.
3. Pang MW, Leung HY, Chan LW, Yip SK. The impact of urinary incontinence on quality of life among women in Hong Kong. Hong Kong Med J 2005;11:158-63.
4. Cheung RY, Chan S, Yiu AK, Lee LL, Chung TK. Quality of life in women with urinary incontinence is impaired and comparable to women with chronic diseases. Hong Kong Med J 2012;18:214-20.
5. Aguilar-Navarro S, Navarrete-Reyes AP, Grados-Chavarria BH, Garcia-Lara JM, Amieva H, Avila-Funes JA. The severity of urinary incontinence decreases health-related quality of life among community-dwelling elderly. J Gerontol A Biol Sci Med Sci 2012;67:1266-71. CrossRef
6. Fan HL, Chan SS, Law TS, Cheung RY, Chung TK. Pelvic floor muscle training improves quality of life of women with urinary incontinence: a prospective study. Aust N Z J Obstet Gynaecol 2013;53:298-304. CrossRef
7. Dumoulin C, Hay-Smith J. Pelvic floor muscle training versus no treatment, or inactive control treatments, for urinary incontinence in women. Cochrane Database Syst Rev 2010;(1):CD005654.
8. Pereira VS, de Melo MV, Correia GN, Driusso P. Long-term effects of pelvic floor muscle training with vaginal cone in post-menopausal women with urinary incontinence: a randomized controlled trial. Neurourol Urodyn 2013;32:48-52. CrossRef
9. Wallace SA, Roe B, Williams K, Palmer M. Bladder training for urinary incontinence in adults. Cochrane Database Syst Rev 2004;(1):CD001308.
10. Kim H, Yoshida H, Suzuki T. The effects of multidimensional exercise treatment on community-dwelling elderly Japanese women with stress, urge, and mixed urinary incontinence: a randomized controlled trial. Int J Nurs Stud 2011;48:1165-72. CrossRef
11. Hay-Smith EJ, Herderschee R, Dumoulin C, Herbison GP. Comparisons of approaches to pelvic floor muscle training for urinary incontinence in women. Cochrane Database Syst Rev 2011;(12):CD009508.
12. Lagro-Janssen TL, Debruyne FM, Smits AJ, van Weel C. Controlled trial of pelvic floor exercises in the treatment of urinary stress incontinence in general practice. Br J Gen Pract 1991;41:445-9.
13. Chiu HF, Lee HC, Chung WS, Kwong PK. Reliability and validity of the Cantonese version of Mini-Mental State Examination: a preliminary study. J Hong Kong Coll Psych 1994;4:25-8.
14. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013;310:2191-4. CrossRef
15. Miller JM, Sampselle C, Ashton-Miller J, Hong GR, DeLancey JO. Clarification and confirmation of the Knack maneuver: the effect of volitional pelvic floor muscle contraction to preempt expected stress incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:773-82. CrossRef
16. Kegel AH. Physiologic therapy for urinary stress incontinence. J Am Med Assoc 1951;146:915-7. CrossRef
17. Tsai CH. The effectiveness of a pelvic floor muscle rehabilitation program in managing urinary tract incontinence among Taiwanese middle age and older women [dissertation]. Pittsburgh: University of Pittsburgh; 2001.
18. Castro RA, Arruda RM, Zanetti MR, Santos PD, Sartori MG, Girao MJ. Single-blind, randomized, controlled trial of pelvic floor muscle training, electrical stimulation, vaginal cones, and no active treatment in the management of stress urinary incontinence. Clinics (Sao Paulo) 2008;63:465-72. CrossRef
19. Zahariou A, Karamouti M, Georgantzis D, Papaioannou P. Are there any UPP changes in women with stress urinary incontinence after pelvic floor muscle exercises? Urol Int 2008;80:270-4. CrossRef
20. Garber CE, Blissmer B, Deschenes MR, et al. American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med Sci Sports Exerc 2011;43:1334-59. CrossRef
21. Bø K. Pelvic floor muscle strength and response to pelvic floor muscle training for stress urinary incontinence. Neurourol Urodyn 2003;22:654-8. CrossRef
22. Dannecker C, Wolf V, Raab R, Hepp H, Anthuber C. EMG-biofeedback assisted pelvic floor muscle training is an effective therapy of stress urinary or mixed incontinence: a 7-year experience with 390 patients. Arch Gynecol Obstet 2005;273:93-7. CrossRef
23. Herbison GP, Dean N. Weighted vaginal cones for urinary incontinence. Cochrane Database Syst Rev 2013;(7):CD002114.
24. Hay-Smith EJ, Bø Berghmans LC, Hendriks HJ, de Bie RA, van Waalwijk van Doorn ES. Pelvic floor muscle training for urinary incontinence in women. Cochrane Database Syst Rev 2001;(1):CD001407.
25. Hung HC, Chih SY, Lin HH, Tsauo JY. Exercise adherence to pelvic floor muscle strengthening is not a significant predictor of symptom reduction for women with urinary incontinence. Arch Phys Med Rehabil 2012;93:1795-800. CrossRef
26. Bø K, Hilde G. Does it work in the long term?—A systematic review on pelvic floor muscle training for female stress urinary incontinence. Neurourol Urodyn 2013;32:215-23. CrossRef
 
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Comparison between fluorescent in-situ hybridisation and array comparative genomic hybridisation in preimplantation genetic diagnosis in translocation carriers

Hong Kong Med J 2015 Feb;21(1):16–22 | Epub 24 Oct 2014
DOI: 10.12809/hkmj144222
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
ORIGINAL ARTICLE
Comparison between fluorescent in-situ hybridisation and array comparative genomic hybridisation in preimplantation genetic diagnosis in translocation carriers
Vivian CY Lee, FHKAM (Obstetrics and Gynaecology); Judy FC Chow, MPhil; Estella YL Lau, PhD; William SB Yeung, PhD; PC Ho, MD; Ernest HY Ng, MD
Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
Corresponding author: Dr Vivian CY Lee (v200lee@hku.hk)
 Full paper in PDF
Abstract
Objectives: To compare the pregnancy outcome of the fluorescent in-situ hybridisation and array comparative genomic hybridisation in preimplantation genetic diagnosis of translocation carriers.
 
Design: Historical cohort.
 
Setting: A teaching hospital in Hong Kong.
 
Patients: All preimplantation genetic diagnosis treatment cycles performed for translocation carriers from 2001 to 2013.
 
Results: Overall, 101 treatment cycles for preimplantation genetic diagnosis in translocation were included: 77 cycles for reciprocal translocation and 24 cycles for Robertsonian translocation. Fluorescent in-situ hybridisation and array comparative genomic hybridisation were used in 78 and 11 cycles, respectively. The ongoing pregnancy rate per initiated cycle after array comparative genomic hybridisation was significantly higher than that after fluorescent in-situ hybridisation in all translocation carriers (36.4% vs 9.0%; P=0.010). The miscarriage rate was comparable with both techniques. The testing method (array comparative genomic hybridisation or fluorescent in-situ hybridisation) was the only significant factor affecting the ongoing pregnancy rate after controlling for the women’s age, type of translocation, and clinical information of the preimplantation genetic diagnosis cycles by logistic regression (odds ratio=1.875; P=0.023; 95% confidence interval, 1.090-3.226).
 
Conclusion: This local retrospective study confirmed that comparative genomic hybridisation is associated with significantly higher pregnancy rates versus fluorescent in-situ hybridisation in translocation carriers. Array comparative genomic hybridisation should be the technique of choice in preimplantation genetic diagnosis cycles in translocation carriers.
 
New knowledge added by this study
  •  Fluorescence in-situ hybridisation (FISH) has been widely used in preimplantation genetic diagnosis (PGD) in translocation carriers. However, array comparative genomic hybridisation (aCGH) has largely replaced FISH since its development due to the advantages of testing all 24 chromosomes and improved pregnancy rates. This is the first study to show the use of aCGH in Hong Kong. Compared with FISH, aCGH was associated with significantly higher rate of ongoing pregnancy in translocation carriers (both reciprocal and Robertsonian translocations).
Implications for clinical practice or policy
  • Array CGH should be the technique of choice for PGD in translocation carriers.
 
 
Introduction
Since the report of first live-birth after preimplantation genetic diagnosis (PGD) published in 1990,1 more than 21 000 cycles have been performed worldwide, based on the data from ESHRE (European Society of Human Reproduction and Embryology) PGD consortium in the past two decades.2 Fluorescent in-situ hybridisation (FISH) has been used for PGD in translocation carriers. This technique uses chromosome-specific DNA probes in metaphase chromosomes or interphase nuclei. For PGD in translocation carriers, the usual approach is to use commercially available centromeric, locus-specific and subtelomeric probes depending on the translocated segments.3
 
However, FISH itself carries technical difficulties of fixation and spreading of nucleus, with the reported error rate of 7% to 10%.4 5 6 Another problem is that in translocation carriers, there is interchromosomal effect so that the proportion of embryos having aneuploidies is higher than those without translocations.7 Segmental loss or gain is also a frequent event in human embryos.8 9 Fluorescent in-situ hybridisation would not be able to detect these chromosomal abnormalities, which could be the cause of low success rates of PGD in translocation carriers as most of these embryos would result in implantation failure or miscarriages.10
 
With the development of comparative genomic hybridisation (CGH), it is possible to detect abnormalities in all 24 chromosomes and its application on single blastomere biopsy was first reported in 1996.11 Comparative genomic hybridisation is a DNA-based technique, employing comparative hybridisation of differentially labelled DNA samples to normal metaphase chromosome on a microscope slide.4 The ratio of fluorescence reveals the gain or loss of the tested samples. However, the turnover time is about 4 days, which does not fit into the strict time frame of treatment for PGD, and cryopreservation of embryos is mandatory, unless polar body biopsy is used.12 Array CGH (aCGH), employing DNA probes affixed directly to a microscope slide, solves this problem as the turnover time is about a day, which makes fresh transfer after blastomere biopsy or trophectoderm biopsy possible.13 It has been demonstrated that using aCGH in translocation carriers is beneficial.9
 
Our centre used the FISH technique for translocation carriers since our team developed the technique of PGD in 2001 which resulted in the first live-birth in Hong Kong.14 We acquired the platform of aCGH in April 2012. This retrospective analysis aimed to compare the pregnancy outcomes using FISH and aCGH for the treatment cycles of PGD in translocation carriers.
 
Methods
Study population
Data from all treatment cycles performed for PGD in the Department of Obstetrics and Gynaecology, Queen Mary Hospital/The University of Hong Kong from 2001 till 2013 June were retrieved. Only PGD cycles in translocation carriers were included in the present study, which was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster.
 
Treatment regimen
The details of the long protocol of ovarian stimulation regimen, gamete handling, cryopreservation of embryos, and frozen embryo transfer have been previously described.15 The details of PGD have also been previously described.16 In short, embryo biopsy was performed on day 3 at 6-to-8-cell stage. Two blastomeres were tested from 2001 to 2005 and one blastomere was routinely tested from 2006 onwards. The blastomere was fixed for FISH analysis. Commercially available FISH probes were chosen to flank the break point. For aCGH, the blastomere was transferred into a polymerase chain reaction tube and whole genome amplification was performed (SurePlex; BlueGnome, Cambridge, UK). Array CGH was performed using 24sure V3 (BlueGnome) for Robertsonian translocation carrier or 24sure+ (BlueGnome) for reciprocal translocation carrier. All results were interpreted separately by two laboratory staff.
 
Outcome measures
The primary outcome measures of the study were clinical and ongoing pregnancy rates. Clinical pregnancies were defined by the presence of one or more gestation sacs or the histological confirmation of gestational product in case of early pregnancy failures. Ongoing pregnancies were those pregnancies beyond 8 to 10 weeks of gestation, at which stage the patients were referred for antenatal care. The secondary outcome measures were miscarriage rate and cancellation rate. Cancellation rate was defined as the percentage of treatment cycles with no embryo transfer after oocyte retrieval.
 
Statistical analysis
The Kolmogorov-Smirnov test was used to test the normal distribution of continuous variables. Results of continuous variables were expressed as mean ± standard deviation if normally distributed, and median (range) if not normally distributed. Statistical comparison was carried out by Student’s t test, Mann-Whitney U test, and/or Wilcoxon signed rank test for continuous variables and Chi squared test or Fisher’s exact test for categorical variables, as appropriate. Statistical analysis was performed using the Statistical Package for the Social Sciences (Windows version 20.0; SPSS Inc, Chicago [IL], US). The two-tailed value of P<0.05 was considered statistically significant. Binary logistic regression using enter method was used to calculate the prediction of the pregnancy rate in PGD cycles.
 
Results
There were 339 PGD cycles, of which 101 treatment cycles were performed in translocation carriers during the study period: 77 cycles for reciprocal translocation and 24 cycles for Robertsonian translocation. The two techniques, FISH and aCGH, were used in 78 and 11 cycles, respectively (Table 1). The overall cancellation rate was 39.6% (40/101). Four cycles were cancelled due to high risk of ovarian hyperstimulation syndrome; eight cycles due to poor ovarian responses or poor embryo qualities; and 28 cycles due to no normal embryo after PGD with either technique (Table 1). The cancellation rate using FISH technique due to abnormal signals for all embryos was significantly higher than that using aCGH (34.6% vs 9.1%, respectively).
 

Table 1. Information on preimplantation genetic diagnosis cycles
 
The demographic and clinical data of women who underwent PGD with FISH and aCGH are presented in Table 2. Women in the aCGH group were significantly younger than those in the FISH group, and the serum oestradiol concentration on ovulation trigger day in the aCGH group was significantly higher than that in the FISH group. The total dosage of gonadotropin, the number of follicles larger than or equal to 16 mm, and the number of oocytes retrieved were comparable between the two groups. The demographic and clinical data of cycles for couples with reciprocal and Robertsonian translocation were all comparable (data not shown).
 

Table 2. Demographic and clinical data of subjects included in treatment cycles for preimplantation genetic diagnosis using fluorescent in-situ hybridisation and array comparative genomic hybridisation
 
The pregnancy rates per cycle and per transfer were all significantly higher in cycles performed using aCGH. The miscarriage rates were similar between the two groups (Table 3). A subgroup analysis of cycles performed from 2006 to 2013 showed similar results in all the above comparisons with significantly higher clinical and ongoing pregnancy rates per initiated cycle and per transfer in cycles using aCGH than those using FISH, but with comparable miscarriage rates (data not shown). Figures 1 and 2 show PGD results with FISH and aCGH, respectively.
 

Table 3. Pregnancy rates
 

Figure 1. Preimplantation genetic diagnosis by fluorescent in-situ hybridisation
 

Figure 2. Results of array comparative genomic hybridisation (aCGH)
 
Logistic regression revealed that the method of testing (FISH or aCGH) was the only factor that significantly affected the ongoing pregnancy rate; age of the women, the type of translocation, or other clinical information including number of oocytes retrieved, the gonadotropin dosage used, and the oestradiol concentration on the day of human chorionic gonadotropin administration did not affect the outcome. The method of testing remained a significant factor after controlling for the age of women and type of translocation (Table 4).
 

Table 4. Logistic regression of variables associated with ongoing pregnancy rate for PGD in translocation carriers
 
Figure 3 shows the results of aCGH in embryos produced from reciprocal translocation carrier. Array CGH can detect segmental changes in translocated chromosomes (embryo 18) and other chromosomes (embryo 3). It can also detect whole chromosome aneuploidy (embryo 16). Embryo 7 was replaced and resulted in an ongoing pregnancy.
 

Figure 3. Array comparative genomic hybridisation (CGH) of embryo biopsy
The mother was a reciprocal translocation carrier, 46,XX,t(3;4)(q29;q32). Array CGH could detect segmental changes unrelated to translocation chromosomes (embryo 3), whole chromosome aneuploidy (embryo 16), and unbalanced reciprocal translocation (embryo 18)
 
Discussion
The present study showed that PGD using aCGH was associated with significantly higher pregnancy rates (both per initiated cycle or per embryo transfer) versus FISH. The testing method, ie using aCGH or FISH, was the only significant factor affecting the ongoing pregnancy rate in logistic regression.
 
Couples carrying balanced reciprocal or Robertsonian translocations are well-known to produce a high percentage of unbalanced gametes and embryos,17 resulting in high miscarriage rates and a variable chance of unbalanced offspring with multiple congenital anomalies and mental retardation.18 The high percentage of unbalanced gametes can be explained by the segregation modes and behaviours of translocations during meiosis.19 Not only the direct effect of the translocations on the meiosis, but also the interchromosomal effect exerted by the translocations increases the percentage of aneuploidies in the gametes and embryos of couples carrying translocations.7 20 21 22 It further decreases the number of normal/balanced euploid embryos, including those suitable and feasible for transfer. It was reported that only up to 16% of preimplantation embryos were normal/balanced and euploid in translocation carriers.9
 
In the past decade, FISH was commonly employed to detect the unbalanced chromosome rearrangement of embryos using probes depending on the translocated segments.23 Fluorescent in-situ hybridisation is technically challenging, especially with regard to fixation and spreading.3 5 24 The error rate of FISH was reported to be up to 10%.5 6 25 As PGD using FISH in translocation carriers only employs fluorescent DNA probes for the translocated segments, aneuploidies and segmental rearrangements which are not related to the translocated segments will be missed.3 Even in aneuploidy screening, only up to five chromosomes can be tested in one round of FISH, and so, usually up to half of all chromosomes can be tested in repeated rounds. However, repeated rounds were related to the decrease in diagnostic accuracy.4 Therefore, using FISH would miss a proportion of aneuploidies and abnormal embryos, which may result in misdiagnosis, implantation failure, or miscarriages.10 This is probably the major reason for the unfavourable results in a systematic review on the use of PGD in translocation carriers26 and the meta-analysis of preimplantation genetic screening.27 The cancellation rate, ie no embryo transfer after oocyte retrieval, was higher after FISH than that after aCGH, probably due to technical difficulties.
 
The development of CGH makes it possible to test for all 24 chromosomes, while the development of aCGH makes it feasible to use the technique in the restricted time frame of PGD. Several groups of investigators have reported success with using aCGH for PGD in translocation carrier couples to improve their reproductive outcomes9 28; we have shown similar results in this local study.
 
Figure 3 shows the result of PGD in a patient with reciprocal translocation. Array CGH detected unbalanced reciprocal translocated segments in embryo 18. It also picked other segmental changes (1q and 9q21.11-qter) not related to translocated chromosomes in embryo 3. It could also detect whole chromosome aneuploidy (monosomy 22) in embryo 16. In FISH, probes flanking the translocation breakpoints are used and, therefore, the abnormalities in embryo 3 and embryo 16 cannot be detected. Furthermore, the average probe density of aCGH used for Robertsonian translocation is 10 Mb while that of one used for reciprocal translocation is 5 Mb. Increase in resolution allows us to easily pick a small abnormality in the embryo. Array CGH offers a more comprehensive way of PGD in translocation carriers and this results in a significant increase in the pregnancy rate compared with FISH.
 
In our cohort, the age of women for whom aCGH was employed was younger than that of women for whom FISH was employed. This can probably explain the higher oestradiol concentration after ovarian stimulation of in-vitro fertilisation treatment, along with the non-significant, higher number of follicles and oocytes retrieved in the aCGH group. In order to reveal the effect of the testing method on pregnancy rate, we controlled the women’s age, type of translocation, and other data of the stimulation including the total dosage of gonadotropin and number of oocytes retrieved in multivariate logistic regression; the testing method remained the only significant factor affecting the ongoing pregnancy rate. This indicates that, after controlling for all the possible confounding factors, PGD cycles using aCGH were associated with a significantly higher ongoing pregnancy rate than those using FISH.
 
It has been controversial whether PGD can improve the reproductive outcomes compared with natural conception in translocation carriers. A systematic review reported adverse effects on the pregnancy rates after PGD in translocation carriers compared with natural conception.26 However, all the PGD cycles included in this review were performed with FISH. Moreover, the case reports and case series of PGD included had a small number of subjects; in 16 out of 21 studies, the sample size was only one to three cases. Larger systematic reviews on the use of aCGH in translocation carriers are urgently needed.
 
This study is retrospective in nature and there may be some confounding factors such as differences in embryo biopsy techniques and culture conditions which were not controlled for and which might have affected the pregnancy outcomes. As we started using aCGH approximately one and a half year ago, the number of cases was smaller than that using FISH. Despite the small sample size, the ongoing pregnancy rate revealed a significant increase after employing aCGH in translocation carriers. This serves to further strengthen our argument in favour of PGD programme using aCGH.
 
It is well known that two-blastomere biopsy is more detrimental to pregnancy than one-blastomere biopsy.22 Our team employed two-blastomere biopsy when we first developed our PGD programme. We then switched to one-blastomere biopsy in 2006. Therefore, a subgroup analysis was performed on those cycles between 2006 and 2013. The ongoing pregnancy rate per initiated cycle remained significantly higher in the group using aCGH than that using FISH.
 
Conclusion
Use of aCGH can improve the pregnancy outcomes of PGD in translocation carriers compared with FISH. Array CGH should be the technique of choice for PGD in translocation carriers.
 
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9. Fiorentino F, Spizzichino L, Bono S, et al. PGD for reciprocal and Robertsonian translocations using array comparative genomic hybridization. Hum Reprod 2011;26:1925-35. CrossRef
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11. Wells D, Delhanty J. Evaluating comparative genomic hybridisation (CGH) as a strategy for preimplantation diagnosis of unbalanced chromosome complements. Eur J Hum Genet 1996;4:125.
12. Wells D, Escudero T, Levy B, Hirschhorn K, Delhanty JD, Munné S. First clinical application of comparative genomic hybridization and polar body testing for preimplantation genetic diagnosis of aneuploidy. Fertil Steril 2002;78:543-9. CrossRef
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15. Ng EH, Yeung WS, Lau EY, So WW, Ho PC. High serum oestradiol concentrations in fresh IVF cycles do not impair implantation and pregnancy rates in subsequent frozen-thawed embryo transfer cycles. Hum Reprod 2000;15:250-5. CrossRef
16. Chow JF, Yeung WS, Lau EY, et al. Singleton birth after preimplantation genetic diagnosis for Huntington disease using whole genome amplification. Fertil Steril 2009;92:828.e7-10.
17. Munné S. Analysis of chromosome segregation during preimplantation genetic diagnosis in both male and female translocation heterozygotes. Cytogenet Genome Res 2005;111:305-9. CrossRef
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Improving the emergency department management of post-chemotherapy sepsis in haematological malignancy patients

Hong Kong Med J 2015 Feb;21(1):10–5 | Epub 10 Oct 2014
DOI: 10.12809/hkmj144280
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
ORIGINAL ARTICLE
Improving the emergency department management of post-chemotherapy sepsis in haematological malignancy patients
HF Ko, MB, BS, FHKAM (Emergency Medicine)1; SS Tsui, APN1; Johnson WK Tse, APN, BSN HD (Nursing)1; WY Kwong, MB, ChB1; OY Chan, MB, BS2; Gordon CK Wong, MB, BS, FHKAM (Emergency Medicine)1
1 Accident and Emergency Department, Queen Elizabeth Hospital, Jordan, Hong Kong
2 Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
 
Corresponding author: Dr HF Ko (frankhko@hotmail.com)
 Full paper in PDF
Abstract
Objective: To review the result of the implementation of treatment protocol for post-chemotherapy sepsis in haematological malignancy patients.
 
Design: Case series with internal comparison.
 
Setting: Accident and Emergency Department, Queen Elizabeth Hospital, Hong Kong.
 
Patients: Febrile patients presenting to the Accident and Emergency Department with underlying haematological malignancy and receiving chemotherapy within 1 month of Accident and Emergency Department visit between June 2011 and July 2012. Similar cases between June 2010 and May 2011 served as historical referents.
 
Main outcome measures: The compliance rate among emergency physicians, the door-to-antibiotic time before and after implementation of the protocol, and the impact of the protocol on Accident and Emergency Department and hospital service.
 
Results: A total of 69 patients were enrolled in the study. Of these, 50 were managed with the treatment protocol while 19 patients were historical referents. Acute myeloid leukaemia was the most commonly encountered malignancy. Overall, 88% of the patients presented with sepsis syndrome. The mean door-to-antibiotic time of those managed with the treatment protocol was 47 minutes versus 300 minutes in the referent group. Overall, 86% of patients in the treatment group met the target door-to-antibiotic time of less than 1 hour. The mean lengths of stay in the emergency department (76 minutes vs 105 minutes) and hospital (11 days vs 15 days) were shorter in those managed with the treatment protocol versus the historical referents.
 
Conclusion: Implementation of the protocol can effectively shorten the door-to-antibiotic time to meet the international standard of care in neutropenic sepsis patients. The compliance rate was also high. We proved that effective implementation of the protocol is feasible in a busy emergency department through excellent teamwork between nurses, pharmacists, and emergency physicians.
 
 
New knowledge added by this study
  •  A well-written, easily available treatment protocol together with stocking of antibiotics in the emergency department can effectively shorten the door-to-antibiotic (DTA) time from 300 minutes to 47 minutes.
  •  In this study, 86% of patients met the target DTA time of less than 1 hour.
Implications for clinical practice or policy
  •  Orchestrated efforts between nurses, pharmacists, and physicians are crucial for implementation of the protocol in one of the busiest emergency departments in the region.
 
 
Introduction
Cancer patients receiving chemotherapy sufficient to cause myelosuppression and adverse effects on the integrity of gastro-intestinal mucosa are at high risk of invasive infections. Patients with profound, prolonged neutropenia are at particularly high risk of serious infections. Prolonged neutropenia is most likely to occur in patients undergoing induction chemotherapy for acute leukaemia. More than 80% of those with haematological malignancies will develop fever during more than one chemotherapy cycle.1 Since neutropenic patients are unable to mount a strong inflammatory response to infections, fever may be the only sign. Infection in neutropenic patients can progress rapidly, leading to serious complications and even death with a mortality rate ranging from 2% to 21%.2 3 It is critical to recognise neutropenic fever patients early and initiate empirical, broad-spectrum antibiotics. Major international guidelines advocate early administration of empirical antibiotics within 1 hour of emergency department (ED) presentation, sometimes even without cytological proof of neutropenia.4 5 6 7 However, management of febrile neutropenic patients varies across different EDs, and even among different physicians. A recent audit performed in the EDs of the United Kingdom showed that only 26% of the audited patients received intravenous antibiotics within the target time of 1 hour.8 Another study in French EDs showed that management of febrile neutropenia was inadequate and severity was under-evaluated in the critically ill.9 In order to improve and standardise the care of post-chemotherapy sepsis in haematological malignancy patients, the Accident and Emergency Department (A&E) and Department of Medicine of Queen Elizabeth Hospital (QEH) initiated a treatment protocol in 2011. This is the first hospital in Hong Kong to implement such a treatment protocol. It included febrile patients with haematological malignancy who had received chemotherapy within 1 month of ED visit. These patients were identified at triage station and provided with a fast-track consultation. The ED physician would verify the history and perform a thorough physical examination and targeted investigations. Empirical antibiotics were administered after taking appropriate culture samples aiming at a door-to-antibiotic (DTA) time of less than 1 hour (Fig).
 

Figure. Protocol for empirical antibiotic treatment in the emergency department for post-chemotherapy febrile haematological malignancy patients
 
Local publication on post-chemotherapy patients mainly focused on solid tumour patients, in-patient management and their outcomes.10 There is a paucity of literature concerning the initial ED management of haematological malignancy patients. The objective of this study was to examine the protocol compliance rate among ED physicians, the DTA time before and after implementation of the protocol, and the impact of the protocol on A&E and hospital services. It also serves to provide invaluable epidemiological data regarding the haematological malignancy patients in Hong Kong.
 
Methods
This is a before-and-after study of the impact of a protocol on the management of post-chemotherapy sepsis in haematological malignancy patients. A 2-year retrospective chart review was conducted. The first chart review was performed from June 2010 to May 2011. These patients were admitted through ED to the haematological ward prior to implementation of the protocol and served as historical referents. Data were retrieved from the admission book of the haematology ward. A diagnosis of post-chemotherapy fever or neutropenic fever was shortlisted. Cases that were admitted through ED were analysed. The second year started from June 2011. The intervention group included patients recruited in the protocol. There were two patients who fulfilled the inclusion criteria but were excluded from the study since they refused any investigation or treatment in ED despite explanation. The charts were reviewed by two emergency physicians and two senior nurses. Any discrepancy was resolved by discussion among investigators. The protocol was implemented on a 24-hour basis. According to the protocol, fever was defined by a single measurement of oral temperature of >38.3°C either at the triage station or self-reported at home. Neutropenia was defined as absolute neutrophil count (ANC) of <1 x 10-9 /L. Sepsis was defined by Bone criteria11 (ie >2 out of 4 of the following: leukocyte count <4 or >12 x 10-9 /L, respiratory rate >20/min, oral temperature >38°C or <35°C, pulse >90 beats/min). Door-to-antibiotic time was charted in the medical record. Lengths of stay in the A&E and hospital were retrieved from the Clinical Data Analysis and Reporting System. The primary outcome was mean DTA time. Secondary outcomes included compliance of the ED physician with the protocol, mean ED length of stay, mean hospital length of stay, and the adverse outcome rate. Adverse outcomes included occurrence of a serious medical complication or death during index admission; these criteria are commonly cited in oncology literature.12 Adverse outcome was charted from patients’ medical record during the index admission.
 
Chi squared tests were performed when comparing categorical parameters between the protocol and referent groups. Student’s t tests were performed for parametric variables. All statistical analyses were performed using the Statistical Package for the Social Sciences (Windows version 17; SPSS Inc, Chicago [IL], US). A P value of less than 0.05 was regarded as statistically significant.
 
The study was conducted in the A&E of QEH, Hong Kong, a tertiary referral centre for haematological malignancy patients. The A&E of QEH is an urban ED with a daily attendance of 500 and is one of the busiest EDs in Hong Kong. This study was approved by the chief of service of the department.
 
Results
A total of 69 patients were recruited; 19 patients were referents while 50 belonged to the protocol group. Baseline demographic data are shown in Table 1. Overall, 49% of the patients were male. Their mean age was 56 years (range, 20-81 years). Leukaemia was the most commonly encountered haematological malignancy, accounting for 51% of cases (n=35/69). Among these, acute myeloid leukaemia was the most prevalent subtype. Lymphoma was the second most common haematological malignancy, making up 42% (n=29/69) of the cases. The mean duration of the last chemotherapy dose to ED visit was 12 days in both groups of patients. At least one co-morbidity was present in 47% of patients in the referent group and in 52% of patients in the protocol group (P=0.18).
 

Table 1. Baseline characteristics of study patients
 
During the index ED visit, the mean door-to-consultation time was 15 and 12 minutes in referent group and protocol group, respectively (P=0.40). Overall, 88% (n=16/19 in referent and n=45/50 in protocol group) of the patients fulfilled the sepsis criteria; 64% (n=44/69) had ANC of <1 x 10-9 /L, although the result was not known at the time of consultation. All protocol group patients received antibiotics after blood cultures were taken during their ED stay compared to none in the control group. Tazobactam-piperacillin (Tazocin; Pfizer, Taiwan) was the most commonly prescribed antibiotic in ED. The mean DTA time in the protocol group was 47 minutes compared to 300 minutes in referent group (P<0.05). Overall, 86% (n=43/50) of protocol group patients could achieve the target DTA time of less than 1 hour (P<0.05). The shortest time required for antibiotic administration in the referent group was 70 minutes. The mean length of stay in ED was 105 minutes in the referent group versus 76 minutes in the protocol group (P=0.46). The major outcomes are shown in Table 2.
 

Table 2. Comparison of outcomes of patients with post-chemotherapy fever between the protocol and referent groups
 
The duration of fever, which was defined as oral temperature of >38°C for 24 hours, was 4 days in the referent group and 3 days in the protocol group (P=0.09). One patient from the referent group suffered from septic shock and required intensive care unit (ICU) admission; no patient from this group died. Six patients in the protocol group had adverse outcomes; three had septic shock requiring inotropic support, one of them required ICU admission, while three patients died during index admission. Adverse event rate was 5% in the referent group versus 14% in the protocol group (P=0.45). Overall, 25% (n=17/69) of patients had bacteraemia. Escherichia coli was recovered in five samples of which two were extended-spectrum beta-lactamase (ESBL)–producing bacteria. Streptococcus mitis was the second most common pathogen and was found in four samples. Overall, 43% (n=30/69) of the patients had microbiologically documented infection. The mean length of hospital stay was 15 days in the referent group compared with 11 days in the protocol group (P=0.15).
 
Discussion
Chemotherapy-induced sepsis is a medical emergency that requires urgent assessment and treatment with antibiotics. Our study shows that 88% of post-chemotherapy febrile patients fulfilled the sepsis criteria. Overall, 25% of patients had bacteraemia, a rate similar to that reported in the literature.4 Hence, prompt identification and early administration of broad-spectrum empirical antibiotics is the cornerstone of management. In a retrospective study of 2731 patients with septic shock (only 7% of whom were neutropenic), each hour delay in initiating effective antimicrobials decreased survival by around 8%.13 Another cohort study showed that the in-hospital mortality among adult patients with severe sepsis or septic shock decreased from 33% to 20% when time from triage to appropriate antimicrobial therapy was ≤1 hour compared with >1 hour.14 Our protocol suggested Tazocin as the first-line antibiotic, in accordance with the 2010 Infectious Diseases Society of America guideline.4 However, the rising trend of ESBL E coli infection may raise concern of antibiotic resistance. A larger-scale cohort study should be carried out to update the local microbiology prevalence and amend the empirical antibiotic recommendations accordingly.
 
Implementation of the protocol in our department could significantly reduce the mean DTA time from 300 minutes to 47 minutes (P<0.05). Furthermore, 86% of patients could achieve the target DTA time of <1 hour. The result was satisfactory when compared with similar studies conducted in Europe and North America where reported median DTA ranged from 154 minutes to 3.9 hours.15 16 17 Audits from the UK report that only 18% to 26% of patients receive initial antibiotic within the target DTA of 1 hour.8 According to the authors, the most common reasons for failure to comply with this time frame included failure to administer the initial dose of the empirical antibacterial regimen until the patient has been transferred from ED to the inpatient ward, prolonged time between arrival and clinical assessment, lack of awareness of the natural history of neutropenic fever syndrome and its evolution to severe sepsis and shock, failure of the ED to stock appropriate antibacterial medications, and non-availability of neutropenic fever protocols in the ED for quick reference.8 The last two points were further supported by studies. A chart review of 201 febrile neutropenic patients in Canada showed that the electronic clinical practice guideline could decrease the DTA time by 1 hour (3.9 hours vs 4.9 hours).16 Another retrospective observational study of timeliness of antibiotic administration in severely septic patients presenting to a US community ED showed that storing key antibiotics could decrease the mean DTA time by 70 minutes (167 minutes vs 97 minutes).18 The percentage of severely septic patients receiving antibiotics within 3 hours of arrival to the ED increased from 65% pre-intervention to 93% post-intervention.18 Before the implementation of this protocol, multiple briefing sessions were held with nurses and physicians to increase awareness about prompt treatment of post-chemotherapy fever. Antibiotics were stocked in the ED and were readily available. The protocol could be easily downloaded from the department website. Regular collaboration existed between the nursing manager and the pharmacist to replenish the antibiotic stock. Thus, successful implementation of the protocol involved a joint effort by different parties.
 
There was a trend towards reducing the duration of fever and length of hospital stay in the intervention group. Although this does not imply causation, especially in view of the small sample size, the correlation makes one ponder whether a delay in antibiotic delivery indeed increases the length of hospital stay. Similar correlation was demonstrated in a UK review.15 However, we could not demonstrate an impact on mortality and adverse outcome. The reason may partly be related to the small sample size, heterogeneous nature of haematological malignancies, and overall low incidence of mortality (4%) in our study as compared to 49.8% in-hospital mortality rate reported in an 11-year review.19 Our result shows that the length of ED stay was similar between control and intervention groups, thus, demonstrating that this protocol did not add further burden to the overcrowding ED.
 
This study has two limitations that need to be discussed. First, the study used a retrospective chart review design and there were inherent challenges with missing information and poor documentation. Second, prior to implementation of the protocol, the febrile haematological malignant patients were often instructed to either attend the day ward or A&E; this partly explains the relatively small case number in the control group. In addition, we relied on the diagnosis coding for case identification in the control group; some cases might have been missed as a result of error in coding. Even if they attended ED, the lack of awareness and reluctance of physicians to prescribe antibiotics led to a significant delay in administration of the first dose of antibiotic. Although the number of control cases was small, mean DTA time of 300 minutes echoed the same in a similar study performed overseas.16 Efforts were made to use accepted chart review methods to assess outcomes that were automatically recorded in the electronic ED information systems, and to examine the nurse records of antibiotic administration.
 
Conclusion
Implementation of a treatment protocol in post-chemotherapy febrile haematological malignancy patients can significantly shorten the mean DTA time to <1 hour, which is now the standard of care worldwide. The key to effective implementation lies in orchestration of efforts between administrators, physicians, nurses, and pharmacists. We can prove that the protocol is feasible even in a busy urban ED.
 
Acknowledgement
We would like to thank Ms Kelly Choy for statistical analysis.
 
Declaration
No conflicts of interests were declared by authors.
 
References
1. Klastersky J. Management of fever in neutropenic patients with different risks of complications. Clin Infect Dis 2004;39 Suppl 1:S32-7. CrossRef
2. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of recommendations for the use of white cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24:3187-205. CrossRef
3. Herbst C, Naumann F, Kruse EB, et al. Prophylactic antibiotics or G-CSF for the prevention of infections and improvement of survival in cancer patients undergoing chemotherapy. Cochrane Database Syst Rev 2009;(1):CD007107.
4. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:e56-93. CrossRef
5. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580-637. CrossRef
6. Bate J, Gibson F, Johnson E, et al. Neutropenic sepsis: prevention and management of neutropenic sepsis in cancer patients (NICE Clinical Guideline CG151). Arch Dis Child Educ Pract Ed 2013;98:73-5. CrossRef
7. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2013;31:794-810. CrossRef
8. Clarke RT, Warnick J, Stretton K, Littlewood TJ. Improving the immediate management of neutropenic sepsis in the UK: lessons from a national audit. Br J Haematol 2011;153:773-9. CrossRef
9. Andr&eacute S, Taboulet P, Elie C, et al. Febrile neutropenia in French emergency departments: results of a prospective multicentre survey. Crit Care 2010;14:R68. CrossRef
10. Hui EP, Leung LK, Poon TC, et al. Prediction of outcome in cancer patients with febrile neutropenia: a prospective validation of the Multinational Association for Supportive Care in Cancer risk index in a Chinese population and comparison with the Talcott model and artificial neural network. Support Care Cancer 2011;19:1625-35. CrossRef
11. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644-55. CrossRef
12. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer Risk Index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038-51.
13. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589-96. CrossRef
14. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010;38:1045-53. CrossRef
15. Sammut SJ, Mazhar D. Management of febrile neutropenia in an acute oncology service. QJM 2012;105:327-36. CrossRef
16. Lim C, Bawden J, Wing A, et al. Febrile neutropenia in EDs: the role of an electronic clinical practice guideline. Am J Emerg Med 2012;30:5-11, 11.e1-5.
17. Nirenberg A, Mulhearn L, Lin S, Larson E. Emergency department waiting times for patients with cancer with febrile neutropenia: a pilot study. Oncol Nurs Forum 2004;31:711-5. CrossRef
18. Hitti EA, Lewin JJ 3rd, Lopez J, et al. Improving door-to-antibiotic time in severely septic emergency department patients. J Emerg Med 2012;42:462-9. CrossRef
19. Legrand M, Max A, Peigne V, et al. Survival in neutropenic patients with severe sepsis or septic shock. Crit Care Med 2012;40:43-9. CrossRef
 
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Disease spectrum and treatment patterns in a local male infertility clinic

Hong Kong Med J 2015 Feb;21(1):5–9 | Epub 2 Jan 2015
DOI: 10.12809/hkmj144376
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
ORIGINAL ARTICLE
Disease spectrum and treatment patterns in a local male infertility clinic
KL Ho, FRCSEd (Urol), FHKAM (Surgery); James HL Tsu, FRCSEd (Urol), FHKAM (Surgery); PC Tam, FRCSEd (Urol), FHKAM (Surgery); MK Yiu, FRCS (Edin), FHKAM (Surgery)
Division of Urology, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
Corresponding author: Dr KL Ho (hokwanlun@gmail.com)
 Full paper in PDF
Abstract
Objective: To review disease spectrum and treatment patterns in a local male infertility clinic.
 
Design: Case series.
 
Setting: Male infertility clinic in a teaching hospital in Hong Kong.
 
Patients: Patients who were seen as new cases in a local male infertility clinic between January 2008 and December 2012.
 
Intervention: Infertility assessment and counselling on treatment options.
 
Main outcome measures: Disease spectrum and treatment patterns.
 
Results: A total of 387 new patients were assessed in the male infertility clinic. The mean age of the patients and their female partners was 37.2 and 32.1 years, respectively. The median duration of infertility was 3 years. Among the patients, 36.2% had azoospermia, 8.0% had congenital absence of vas deferens, and 48.3% of patients had other abnormalities in semen parameters. The commonest causes of male infertility were unknown (idiopathic), clinically significant varicoceles, congenital absence of vas deferens, mumps after puberty, and erectile or ejaculatory dysfunction. Overall, 66.1% of patients chose assisted reproductive treatment and 12.4% of patients preferred surgical correction of reversible male infertility conditions. Altogether 36.7% of patients required either surgical sperm retrieval or correction of male infertility conditions.
 
Conclusions: The present study provided important local data on the disease spectrum and treatment patterns in a male infertility clinic. The incidences of azoospermia and congenital absence of vas deferens were much higher than those reported in the contemporary literature. A significant proportion of patients required either surgical sperm retrieval or correction of reversible male infertility conditions.
 
 
New knowledge added by this study
  •  The present study provided important local data on the disease spectrum and treatment patterns in a male infertility clinic.
  •  The incidences of azoospermia and congenital absence of vas deferens in the present study were much higher than those reported in the contemporary literature.
Implications for clinical practice or policy
  •  The present study may help to increase public awareness of the contribution of male factors in infertility assessment and treatment.
  •  The study provides a background for future research into azoospermia and congenital absence of vas deferens in the locality.
 
 
Introduction
Infertility is defined by the inability to conceive after 1 year of regular unprotected sexual intercourse, and it affects 15% of couples worldwide.1 Male factors contribute to about 50% of infertile couples. Clinically significant varicocele is present in 40% of infertile men and is the commonest surgically reversible condition. As many as 10% to 15% of infertile men have azoospermia.2 According to the report of the Council on Human Reproductive Technology in 2012, male factor infertility contributes to 50% of women receiving reproductive technology treatment.3 Local data on male factor infertility, however, have been scarce. The objective of the present article was to review the disease spectrum and treatment patterns in a local male infertility clinic.
 
Methods
All consecutive new patients seen in a local teaching hospital (Queen Mary Hospital) male infertility clinic from January 2008 to December 2012 were included in this retrospective study. The clinical records were reviewed and the demographics of the patients and their female partners, aetiologies of male factor infertility, semen analyses, and treatment were analysed.
 
All patients underwent two separate semen analyses and hormonal profiles (including morning serum testosterone, and follicle-stimulating and luteinising hormones) before being seen in the clinic. A detailed urological and reproductive history was taken, followed by a focused physical examination. The fertility history was ascertained and female factors of age and gynaecological history were taken into consideration. Clinical diagnoses were made and possible aetiologies were postulated based on the above information. The patients’ semen results were classified as azoospermia (no sperms were identified after examination of the post-centrifugation pellet), abnormal (in concentration, motility, morphology, or any combination according to the contemporary World Health Organization standards4), or normal. The exact analysis of semen parameters was beyond the scope of the present study. Patients with azoospermia were classified clinically as having obstructive (normal-sized testes and hormonal profiles) and non-obstructive (small testes and elevated follicle-stimulating hormones) disorder. Genetic studies, including karyotyping and Y chromosome microdeletion, were offered to patients with non-obstructive azoospermia or severe oligospermia. Only grade 2 (palpable) or 3 (visible) varicoceles when standing were considered clinically significant in the assessment. Diagnosis of congenital absence of vas deferens was made by physical examination and occasionally supplemented with transrectal ultrasound for unclear cases. For patients with a history of mumps after puberty and no other identifiable causes of male infertility, mumps was quoted as the main cause. Depending on the clinical scenarios, the couples were counselled on different treatment options, including surgical or assisted reproductive treatments (ART), donor insemination, adoption, and conservative treatment.
 
Results
From January 2008 to December 2012, 387 patients had been seen in the male infertility clinic as new cases. The mean age of the patients and their female partners was 37.2 and 32.1 years, respectively. The median duration of infertility was 3 years. Of the patients, 140 (36.2%) had azoospermia, of whom 67 and 71 patients had obstructive and non-obstructive causes, respectively, and two had both components of azoospermia. A total of 187 (48.3%) patients had abnormalities in one or more semen parameters (Table 1).
 

Table 1. Demographics and semen parameters of patients attending the male infertility clinic (n=387)
 
The commonest causes of male factor infertility were unknown (idiopathic), clinically significant varicoceles, congenital absence of vas deferens, mumps after puberty, and erectile or ejaculatory dysfunction (Table 2). For patients with obstructive azoospermia, common pathologies included congenital absence of vas deferens and genital tract infection. For patients with non-obstructive azoospermia, no causes were identified in most patients. A history of mumps and endocrinopathies were implicated in some non-obstructive azoospermic patients (Table 3).
 

Table 2. Disease spectrum in patients attending the male infertility clinic
 

Table 3. Common pathologies of azoospermic patients
 
Most patients (66.1%) sought ART. Of these patients, 94 azoospermic patients (56 patients with non-obstructive azoospermia, 37 with obstructive azoospermia, and one with both components) required sperm retrieval procedures. Besides, 12.4% patients chose surgical treatments for reversible causes of male infertility. The procedures included varicocelectomy, vas reconnection, and vasoepididymostomy. Four patients with varicoceles and severe oligospermia or azoospermia proceeded to varicocelectomy and employed ART as backup treatment. Also, 19.6% patients elected to have no further treatment of infertility (Table 4).
 

Table 4. Treatment patterns of the male infertility clinic
 
Of 81 patients who had clinically significant varicoceles and abnormal semen parameters, 23 proceeded to surgery and 38 chose ART. Of 67 patients who had obstructive azoospermia, 37 proceeded to ART; 28 of these patients had congenital absence of vas deferens that was irreversible, requiring sperm retrieval and ART. For the other patients with reversible causes of obstructive azoospermia, nine preferred sperm retrieval and ART, while 25 elected to have surgical treatments (Table 5).
 

Table 5. Common pathologies and treatment patterns
 
Discussion
Infertility has remained a worldwide problem in the past two decades.5 Traditionally, the female partner has shouldered the major burden of infertility assessment and treatment. With recent advances in male infertility treatment6 and increasing public awareness, there is a growing demand for assessment and treatment of men with fertility issues.
 
When the infertility clinic at Queen Mary Hospital was first established, it consisted of a joint clinic assessment both by urologists specialising in male infertility treatment and by gynaecologists specialising in ART. Due to the long waiting list at the conjoint clinic, the male infertility clinic has since separated out. All infertile couples with clinically suspected male infertility factors—such as gross abnormalities in semen parameters, or erectile or ejaculatory dysfunction—are referred to the male infertility clinic for prompt assessment.
 
The median duration of infertility in this study was 3 years before the infertile couples attended for assessment. Upon referral, a large proportion (36.2%) of patients had azoospermia. This figure was much higher than the commonly quoted figures in the current literature, where azoospermia was found in 1% of all men and 10% to 15% of infertile men.7 8 9 The much higher figure in the present study was probably related to referral bias. Male partners with milder forms of abnormalities in semen parameters might not have been referred for assessment. These couples with an azoospermic male partner would have benefited from earlier intervention instead of wasting precious time attempting natural conception. The present study illustrates the importance of a premarital, or at least a pre-pregnancy, checkup. Simple semen analysis would have identified male partners with azoospermia or severe deficits of semen parameters for early assessment, fertility treatment, counselling, and potential intervention.
 
Besides, 11.4% of patients had normal semen parameters and fell into the category of unexplained infertility.10 After common female factors have been ruled out, there are still many possible causes of infertility, ranging from the couple’s miscomprehension of the female fertility window and coital behaviours to abnormal sperm function.11
 
Clinically significant varicocele was the commonest identifiable cause of male infertility in the present study. This was concurrent with the contemporary literature.12 Controversies over the best treatment of varicoceles in infertile couples have been met with a meta-analysis13 and randomised controlled trials14 15 favouring surgery in terms of pregnancy outcomes. Varicocelectomy is offered to patients according to the criteria of the American Society for Reproductive Medicine,12 namely, documented history of infertility, grade 2 or above varicocele, abnormalities in semen parameters, and reversible female factors. In our institution, the microsurgical subinguinal approach is used for its lower risks of recurrence and hydrocele.16 In the present study, 38 patients with varicoceles chose ART, while 23 patients chose surgery. The decision to proceed to ART versus varicocelectomy was made after thorough counselling of the involved couples. Factors considered included the female partner’s age, semen quality, risks of surgery versus ART, expertise of the surgeons and ART centre staff, and the respective treatment outcome audits. Both male and female partners were strongly encouraged to attend counselling together and arrive at the decision that is most agreeable to both parties.
 
A significant proportion of patients in the study had azoospermia, of which 47.9% had obstructive causes. Congenital absence of vas deferens was the commonest cause of obstructive azoospermia, which constituted 8.0% of the study population. This was higher than the 1% to 2% of infertile men reported in the literature.7 9 The incidence of congenital absence of vas deferens is not well reported in Chinese men with infertility. One of the reasons for the high incidence in this study could be referral bias, which led to a very high incidence of azoospermia in our study population. Hence, the proportional percentage of congenital absence of vas deferens was much higher than is usually quoted. Sperm retrieval and ART was offered as the only solutions for childbearing. In Caucasians, congenital absence of vas deferens is associated with cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations of cystic fibrosis,17 and routine genetic study is offered to patients and their female partners. Recent data in Chinese patients with congenital absence of vas deferens showed different CFTR gene mutations,18 which might lead to the development of a mild genital form of cystic fibrosis. Cystic fibrosis is very rare in Asian populations, but genetic counselling for patients with congenital absence of vas deferens is still advised by most authorities. Unfortunately, genetic study is not available at Queen Mary Hospital, and the huge number of possible CFTR gene mutations (>1500) makes targeted examination in Chinese patients a big challenge.
 
Of 256 patients who proceeded to ART, 94 with azoospermia needed some sort of sperm retrieval procedures. For patients with congenital absence of vas deferens and markedly distended epididymal tubules, percutaneous epididymal sperm aspiration provided a simple and reliable method of sperm retrieval. For patients with obstructive azoospermia secondary to infection or idiopathic causes, microsurgical epididymal sperm aspiration was employed to retrieve the maximum number of sperms with the least blood contamination. Sometimes extensive adhesiolysis needed to be performed to expose distended epididymal tubules. Non-obstructive azoospermia was the most difficult condition to treat. Conventional testicular sperm extraction (TESE) involves multiple random testis biopsies and can fail to find focal seminiferous tubules harbouring active spermatogenesis. This method involves excision of more testicular tissues and is associated with more postoperative intra-testicular haematoma and scarring.19 Microdissection TESE (MicroTESE) involves identifying the spermatogenically active regions of the testes by direct examination of larger seminiferous tubules under high magnification.20 This method is targeted and involves retrieval of the maximum number of sperms with the least testicular tissue loss. However, MicroTESE is time-consuming and involves a steep learning curve.21 Even in the hands of experts, the procedure takes an average of 1.8 and 2.7 hours for successful and unsuccessful cases, respectively.
 
Of 36 patients with reversible causes of obstructive azoospermia (Table 5), 25 (69.4%) chose surgical treatment, nine proceeded to ART, and two preferred conservative treatment. In the era of ART, surgical treatment remains a valuable armamentarium in the management of reversible obstructive azoospermia.1 At Queen Mary Hospital, microsurgical intussusception vasoepididymostomy was offered to patients with epididymal obstruction secondary to infection or idiopathic causes.22 The choice between surgical treatment and ART was made after thorough consideration of the female partner’s age, surgical expertise and ART success rates, and the infertile couple’s wishes.
 
Within this study population, 142 (36.7%) patients needed either surgical sperm retrieval and ART or surgical correction of reversible male infertility conditions.
 
Conclusions
The present study describes the disease spectrum of a local male infertility clinic. The incidence of azoospermia and congenital absence of vas deferens was much higher than that described in the current literature. There was high demand for sperm retrieval or surgical correction services in this group of patients.
 
References
1. Lee R, Li PS, Schlegel PN, Goldstein M. Reassessing reconstruction in the management of obstructive azoospermia: reconstruction or sperm acquisition? Urol Clin North Am 2008;35:289-301. CrossRef
2. Practice Committee of American Society for Reproductive Medicine in collaboration with Society for Male Reproduction and Urology. The management of infertility due to obstructive azoospermia. Fertil Steril 2008;90(5 Suppl):S121-4. CrossRef
3. Infertility diagnosis by age of patients receiving RT procedures (other than DI and AIH) in 2012. Council on Human Reproductive Technology. Available from: http://www.chrt.org.hk/english/publications/files/table17_2012.pdf. Accessed Aug 2014.
4. Cooper TG, Noonan E, von Eckardstein S, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update 2010;16:231-45. CrossRef
5. Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med 2012;9:e1001356. CrossRef
6. Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Report on optimal evaluation of the infertile male. Fertil Steril 2006;86(5 Suppl 1):S202-9. CrossRef
7. Wosnitzer M, Goldstein M, Hardy MP. Review of azoospermia. Spermatogenesis 2014;4:e28218. CrossRef
8. Berookhim BM, Schlegel PN. Azoospermia due to spermatogenic failure. Urol Clin North Am 2014;41:97-113. CrossRef
9. Wosnitzer MS, Goldstein M. Obstructive azoospermia. Urol Clin North Am 2014;41:83-95. CrossRef
10. Hamada A, Esteves SC, Agarwal A. Unexplained male infertility—looking beyond routine semen analysis. Eur Urol Rev 2012;7:90-6.
11. Agarwal A, Bragais FM, Sabanegh E. Assessing sperm function. Urol Clin North Am 2008;35:157-71, vii. CrossRef
12. Practice Committee of American Society for Reproductive Medicine. Report on varicocele and infertility. Fertil Steril 2008;90(5 Suppl):S247-9. CrossRef
13. Marmar JL, Agarwal A, Prabakaran S, et al. Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. Fertil Steril 2007;88:639-48. CrossRef
14. Abdel-Meguid TA, Al-Sayyad A, Tayib A, Farsi HM. Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial. Eur Urol 2011;59:455-61. CrossRef
15. Mansour Ghanaie M, Asgari SA, Dadrass N, Allahkhah A, Iran-Pour E, Safarinejad MR. Effects of varicocele repair on spontaneous first trimester miscarriage: a randomized clinical trial. Urol J 2012;9:505-13.
16. Leung L, Ho KL, Tam PC, Yiu MK. Subinguinal microsurgical varicocelectomy for male factor subfertility: ten-year experience. Hong Kong Med J 2013;19:334-40. CrossRef
17. Esteves SC, Miyaoka R, Agarwal A. Sperm retrieval techniques for assisted reproduction. Int Braz J Urol 2011;37:570-83. CrossRef
18. Lu S, Yang X, Cui Y, et al. Different cystic fibrosis transmembrane conductance regulator mutations in Chinese men with congenital bilateral absence of vas deferens and other acquired obstructive azoospermia. Urology 2013;82:824-8.  CrossRef
19. Okada H, Dobashi M, Yamazaki T, et al. Conventional versus microdissection testicular sperm extraction for nonobstructive azoospermia. J Urol 2002;168:1063-7. CrossRef
20. Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum Reprod 1999;14:131-5. CrossRef
21. Dabaja AA, Schlegel PN. Microdissection testicular sperm extraction: an update. Asian J Androl 2013;15:35-9. CrossRef
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A validation study of the Hong Kong version of Montreal Cognitive Assessment (HK-MoCA) in Chinese older adults in Hong Kong

Hong Kong Med J 2014;20(6):504–10 | Epub 15 Aug 2014
DOI: 10.12809/hkmj144219
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
ORIGINAL ARTICLE
A validation study of the Hong Kong version of Montreal Cognitive Assessment (HK-MoCA) in Chinese older adults in Hong Kong
PY Yeung, MB, ChB, MRCP (UK)1; LL Wong, FHKCPsych, FHKAM (Psychiatry)2; CC Chan, MRCP (UK), FHKCP3; Jess LM Leung, MRCPsych, FHKCPsych2; CY Yung, FHKCP, FHKAM (Medicine)3
1 Department of Rehabilitation, Kowloon Hospital, 147A Argyle Street, Hong Kong
2 Department of Psychiatry, United Christian Hospital, Kwun Tong, Hong Kong
3 Department of Medicine and Geriatrics, United Christian Hospital, Kwun Tong, Hong Kong
 
Corresponding author: Dr PY Yeung (yeunpy3@ha.org.hk)
 Full paper in PDF
Abstract
Objective: To validate the Hong Kong version of Montreal Cognitive Assessment (HK-MoCA) in identification of mild cognitive impairment and dementia in Chinese older adults.
 
Design: Cross-sectional study.
 
Setting: Cognition clinic and memory clinic of a public hospital in Hong Kong.
 
Participants: A total of 272 participants (dementia, n=130; mild cognitive impairment, n=93; normal controls, n=49) aged 60 years or above were assessed using HK-MoCA. The HK-MoCA scores were validated against expert diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed) criteria for dementia and Petersen’s criteria for mild cognitive impairment. Statistical analysis was performed using receiver operating characteristic curve and regression analyses. Additionally, comparison was made with the Cantonese version of Mini-Mental State Examination and Global Deterioration Scale.
 
Results: The optimal cutoff score for the HK-MoCA to differentiate cognitive impaired persons (mild cognitive impairment and dementia) from normal controls was 21/22 after adjustment of education level, giving a sensitivity of 0.928, specificity of 0.735, and area under the curve of 0.920. Moreover, the cutoff to detect mild cognitive impairment was 21/22 with a sensitivity of 0.828, specificity of 0.735, and area under the curve of 0.847. Score of the Cantonese version of the Mini-Mental State Examination to detect mild cognitive impairment was 26/27 with a sensitivity of 0.785, specificity of 0.816, and area under the curve of 0.857. At the optimal cutoff of 18/19, HK-MoCA identified dementia from controls with a sensitivity of 0.923, specificity of 0.918, and area under the curve of 0.971.
 
Conclusion: The HK-MoCA is a useful cognitive screening instrument for use in Chinese older adults in Hong Kong. A score of less than 22 should prompt further diagnostic assessment. It has comparable sensitivity with the Cantonese version of Mini-Mental State Examination for detection of mild cognitive impairment. It is brief and feasible to conduct in the clinical setting, and can be completed in less than 15 minutes. Thus, HK-MoCA provides an attractive alternative screening instrument to Mini-Mental State Examination which has ceiling effect (ie may fail to detect mild/moderate cognitive impairment in people with high education level or premorbid intelligence) and needs to be purchased due to copyright issues.
 
 
New knowledge added by this study
  •  This study verified that the Hong Kong version of Montreal Cognitive Assessment (HK-MoCA) has high diagnostic accuracy for detection of dementia (sensitivity, 92.3%; specificity, 91.8%).
  •  It is a reasonably good screening tool for mild cognitive impairment with comparable efficacy with the Cantonese version of Mini-Mental State Examination (MMSE).
Implications for clinical practice or policy
  •  HK-MoCA is brief and feasible to conduct in the clinical setting, and can be completed in less than 15 minutes.
  •  HK-MoCA provides an attractive screening instrument in place of MMSE which has ceiling effect and needs to be purchased due to copyright issues.
 
 
Introduction
Dementia implies decline in cognitive function interfering with an individual’s life. Mild cognitive impairment (MCI) is a clinical transitional state in which a person is cognitively impaired, typically in the memory domain, which is greater than that expected for a person at the given age and education level. A longitudinal study revealed that MCI patients proceeded to overt dementia at a rate of 10% to 15% per year, compared with a rate of 1% to 2% in control subjects.1 This implies that MCI patients have high risk of progressing to dementia. Prevalence of MCI varies widely, depending on the diagnostic criteria used and population studied. Its prevalence ranges from 3% to 13% in people above 65 years of age.2 Hence, identification of MCI patients is important for successful implementation of preventive strategies and early interventions. In practice, cognitive screening tools are used to detect persons with cognitive impairment who then undergo a detailed assessment process to ascertain the subtype, severity, caregiver status, and the presence of behavioural and psychological symptoms of dementia.
 
The Mini-Mental State Examination (MMSE) is the most widely used screening tool introduced by Folstein et al in 1975.3 It was originally designed for screening Alzheimer’s disease and does not encompass all cognitive deficits. It has several well-known drawbacks, including low level of task difficulty, likelihood of ceiling effects (ie may fail to detect mild/moderate cognitive impairment in people with high education level or premorbid intelligence), and narrow range of cognitive domains assessed. Consequently, it has low sensitivity for MCI patient detection. The Cantonese version of Mini-Mental State Examination (CMMSE) was translated and validated by Chiu et al in 19944 with good sensitivity (97.5%) and specificity (97.3%) to discriminate subjects with moderate-to-severe dementia from normal subjects.
 
The Montreal Cognitive Assessment (MoCA) is a brief and potentially useful screening tool developed and validated by Nasreddine et al.5 It was conceptualised in MCI patients performing within a normal range on the MMSE. The MoCA is a one-page test with a maximum score of 30. One point is added if the person has 12 years of education or less. A score of 23 to 26 represents MCI, 17 to 22 represents moderate impairment, and 16 or below represents severe impairment suggesting dementia.6 The original validation study of MoCA reported a sensitivity of 100% and specificity of 87% in detecting mild Alzheimer’s disease using a cutoff score of 26. It reported a sensitivity of 90% in detecting MCI.6 It was validated to detect cognitive impairment in different clinical populations including those with Parkinson’s disease, brain metastases and stroke, and had established cross-cultural performance in detecting MCI and dementia.7 8 9 10 11 12 However, educational adjustment and cutoffs varied. In a Korean study, a cutoff score of 22/23 yielded a sensitivity of 89% and specificity of 84% for screening MCI.7 A study in mainland China suggested 20/21 as cutoff score (Xie He Hospital version) with 84.6% sensitivity and 76% specificity.8 It was the same as the Hong Kong version: 73% sensitivity and 75% specificity for patients with small vessel disease (SVD).13 Furthermore, the original MoCA has high level of internal consistency (Cronbach’s alpha of 0.83) and test-retest reliability (correlation coefficient=0.92, P<0.001).5
 
This study employed the Hong Kong version of MoCA (HK-MoCA) which has been validated in Chinese patients with cerebral SVD by Wong et al.13 The primary objective was to evaluate the HK-MoCA as a screening tool in identification of MCI and dementia in Chinese older adults, and to determine the corresponding optimal cutoff points. In addition, the ability of HK-MoCA in discriminating dementia subtypes was examined.
 
Methods
Participants
This was a cross-sectional validation study performed from August 2011 to June 2013 to validate HK-MoCA as a cognitive screening instrument. It was conducted at the Cognition Clinic of Department of Medicine and Geriatrics and the Memory Clinic of Department of Psychiatry in a general hospital (United Christian Hospital) of Hong Kong. Cantonese-speaking Chinese adults aged 60 years or above, who were seen for suspected cognitive impairment and gave consent, were recruited. They were divided into three groups: subjects with dementia, subjects who met the criteria for MCI, and cognitively normal controls (NC). Besides, NC were recruited from those who attended clinics of other subspecialties or elderly vaccination programmes under Department of Medicine and Geriatrics.
 
Patients were excluded if they had a history, as documented in medical records, of neurodegenerative disorders, central nervous system infection, brain tumour, significant head trauma, subdural haematoma, epilepsy, significant psychiatric disorders (such as major depression or schizophrenia), substance abuse, or alcoholism. Besides, persons with inability to use a pen or with communication barriers such as deafness or significant language or speech problem were also excluded. Last of all, advanced dementia patients with Global Deterioration Scale (GDS) stage 6 or above were not recruited. The flowchart of participant recruitment is shown in the Figure. Ethical approval was obtained from the Kowloon Central/Kowloon East Cluster Clinical Research Ethics Committee of the Hospital Authority.
 

Figure. Flowchart of participant recruitment
 
Measurements
Clinical assessment
Basic demographic information (age, gender, and education level), cardiovascular risk factors (diabetes mellitus, hypertension, hyperlipidaemia, coronary heart disease, and stroke) as well as clinical information about drinking and smoking habits was collected. Besides, a semi-structured mental status examination and a comprehensive neuropsychological battery (including biochemical screening and cerebral imaging tests) were performed for making a final cognitive diagnosis by experienced geriatricians and psychogeriatricians according to the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria14 for dementia and Petersen et al’s criteria for MCI.6 The HK-MoCA scores were validated against expert diagnoses.
 
Cognitive assessment
The CMMSE and HK-MoCA were administered to each subject at the same consultation. The administration was standardised and was done in turn by two investigators. The HK-MoCA had more questions and was harder than CMMSE. To avoid frustration, CMMSE was administered before HK-MoCA. Fatigue may reduce attention span and increase the likelihood of error. Hence, there was a 5-to-10-minute break to minimise the fatigue effect.
 
Functional decline of demented subjects was determined using the GDS. It predicted a patient’s ability to function, as reflected in activities of daily living (ADL) and instrumental ADL as well as psychiatric morbidity on the basis of progressive cognitive delcine.9 It is composed of seven stages defined by a set of clinical characteristics. Stages 1 to 3 are pre-dementia stages. Stages 4 to 7 are dementia stages. Beginning in stage 5, an individual can no longer survive without assistance.
 
Sample size calculation
Statistical software, MedCalc V12.3.0.0, was used for sample size calculation. Based on a previous study,15 the estimated prevalence rates of MCI and dementia were 8.5% and 12.5%, respectively. The overall sample size was determined to be 138 (NC:MCI:dementia=1:1:1) with a power of 0.8 and a type I error of 0.05. In the receiver operating characteristic (ROC) curve analyses of normal versus cognitive impaired groups, a sample of 90 from the positive group would achieve 90% power to detect a difference of 0.12 between the area under the curve (AUC) of alternative hypothesis and an AUC under the null hypothesis of 0.9000 (for MoCA) using a two-sided z-test at a significance level of 0.05.
 
Statistical analyses
All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 17.0 and a difference with a P value of <0.05 was regarded as statistically significant (two-tailed test). Group differences in demographic characteristics and various medical diseases were examined using one-way analysis of variance or Chi squared test for categorical data. Pairwise comparisons were performed afterwards with the significance level adjusted by the Bonferroni method. For differences attaining statistical significance, multivariate linear regression was performed to examine the influence upon performance of the HK-MoCA total score.
 
Inter-rater reliability was reflected by intraclass correlation coefficients with a sub-sample of 20 participants (persons with cognitive impairment and NC) being tested 2 to 4 weeks apart. Convenience sampling was employed with 10 participants by each investigator. According to the optimal cutoff points suggested in this study, five of them were NC, four were persons with MCI, and 11 were demented persons. Internal consistency was measured using Cronbach’s alpha which measured pairwise correlations between tested items. Criterion validity was assessed using ROC analysis which gave the sensitivity and specificity of HK-MoCA at different cutoff points. With that, optimal cutoff scores were chosen using highest Youden index (sensitivity – [1 – specificity]). In case the indexes were very close between the two scores, the one with higher sensitivity would be chosen. The CMMSE and GDS scores were used to test the concurrent validity. The relationships between the performance of HK-MoCA, CMMSE, and GDS were evaluated using Pearson and Spearman’s rho correlation coefficients. Finally, the discriminatory power of individual cognitive domains was explored by examining any significant difference in scores among the three groups.
 
Results
A total of 272 eligible subjects completed the HK-MoCA screening in which 49 were NC, 93 were MCI subjects, and 130 were demented subjects (99 with mild and 31 with moderate severity of dementia). Of all the subjects with dementia, 49.2% had Alzheimer’s disease, 16.2% had vascular dementia, and 34.6% had dementia of mixed aetiology. The administration time depended on the education level and severity of cognitive impairment, and was around 10 to 15 minutes.
 
Demographic and clinical characteristics
Sample characteristics are summarised in Table 1. Overall, 60% of recruited subjects were females with a mean (± standard deviation) age of 77.41 ± 7.53 years. The level of education was primary and below in 76% of the participants, with a mean of 4.21 ± 4.43 years of education. Significant differences among the three groups (NC, MCI, and dementia) were found in the variables of age (F [2,269]=13.230, P<0.001), years of education (F [2,269]=6.502, P=0.002), HK-MoCA score (F [2,269]=126.892, P<0.001), CMMSE score (F [2,269]=152.868, P<0.001), and GDS score (F [2,269]=933.751, P<0.001). There was no significant difference among the three cognition groups by gender (Chi squared test=3.653, P=0.161). Subjects in the dementia group were significantly older (79.53 ± 6.84 years; P<0.001) and had less years of education (3.26 ± 4.03 years; P=0.002) than those in the other two groups. In contrast, no significant differences were demonstrated among the three subgroups of dementia (Alzheimer’s disease, vascular dementia, and mixed dementia) in terms of age (F [2,127]=2.873, P=0.060), years of education (F [2,127]=0.630, P=0.534), HK-MoCA score (F [2,127]=0.428, P=0.653), CMMSE score (F [2,127]=0.322, P=0.725), and GDS score (F [2,127]=0.161, P=0.851).
 

Table 1. Demographic characteristics by cognition group
 
There was no significant difference between those with dementia and NC in terms of drinking and smoking habits, and various medical conditions, except for stroke (P=0.031). The result was reasonable as stroke is a known cause of dementia.
 
Score distribution of Hong Kong version of Montreal Cognitive Assessment
From the original MoCA study, differences across cognition groups were more pronounced using MoCA than MMSE.5 This study did not reproduce the wide dispersion of MoCA scores and, indeed, mean scores of HK-MoCA of various groups were lower in general. The results were justified by the generally low education level of local Chinese older adults.
 
The effect of age and education level
The appropriateness of original education adjustment of MoCA total score was uncertain in local Chinese older adults. This study examined the effect of age and education level upon the performance of HK-MoCA by regressing the unadjusted raw score of HK-MoCA on age, years of education, and clinical diagnosis using multivariate linear models. The results are summarised in Table 2. There was a positive relationship between years of education and performance on HK-MoCA (β, 0.318; P<0.001) independent of age and clinical diagnosis. The effect of age was not significant (P=0.530).

Table 2. Effect of age, education, and diagnostic groups (NC, MCI, and dementia) on HK-MoCA total scores (multivariate linear regression)
 
The original MoCA recommendation of adding one point to subjects with 12 years of education or less was probably unsuitable here. In this study, the level of education in 76% of subjects was primary and below. Only 11 (4%) subjects had more than 12 years of education. For this reason, we adopted a lower level of education adjustment to 6 years of education which had been employed by studies in China,8 10 Korea,7 and Hong Kong.13 Using this adjustment for education level, regression R2 coefficient was 0.587. Thus, more than half of the variation in HK-MoCA was explained by the model.
 
Psychometric properties of Hong Kong version of Montreal Cognitive Assessment
Intraclass correlation coefficient for the inter-rater reliability was 0.987 (P≤0.001). Besides, the Cronbach’s alpha score was 0.767, indicating a high level of internal consistency. Comparison of GDS, CMMSE, and HK-MoCA scores between NC, MCI, and dementia groups showed that the severity level of cognitive impairment graded by GDS score was significantly correlated with HK-MoCA score with Spearman’s rho correlation coefficient of -0.739 (P≤0.001). Similarly, Pearson correlation coefficient of CMMSE with HK-MoCA scores was 0.894 (P≤0.001). Together, it supported high concurrent validity of HK-MoCA.
 
Criterion validity of the adjusted HK-MoCA score was examined using ROC analysis. Various optimal cutoff scores are listed in Table 3. The optimal cutoff score for HK-MoCA to differentiate persons with cognitive impairment (MCI and dementia) from NC was 21/22, giving a sensitivity of 0.928, specificity of 0.735, and AUC of 0.920 (95% confidence interval [CI], 0.881-0.959). Moreover, the cutoff to detect MCI was also 21/22 with a sensitivity of 0.828, specificity of 0.735, and AUC of 0.847 (95% CI, 0.778-0.902). For comparison, CMMSE score to detect MCI was 26/27 with a sensitivity of 0.785, specificity of 0.816, and AUC of 0.857. The optimal cutoff score for HK-MoCA to detect dementia was 18/19 with a sensitivity of 0.923, specificity of 0.918, and AUC of 0.971 (95% CI, 0.935-0.991).
 

Table 3. Optimal cutoff scores and psychometric properties of HK-MoCA and CMMSE for identifying MCI and dementia
 
Discriminatory ability
The HK-MoCA total score and seven cognitive domain scores discriminated NC, MCI, and dementia groups in a stepwise fashion. In general, demented participants performed most poorly, followed by the MCI participants. Like the original study, delayed recall task was the first and most impaired domain in MCI participants. Besides, sample participants with GDS score equal to 4 were used to examine the discriminatory ability in differentiating subtypes of dementia; no significant difference was demonstrated (P values ranged from 0.243 to 0.672). The generally low education level and small dementia subgroup sample size might have compromised the results.
 
Discussion
Validity and clinical utility of the Hong Kong version of Montreal Cognitive Assessment
This study verified that HK-MoCA has high diagnostic accuracy for detecting dementia subjects (92.3% sensitivity, 91.8% specificity). It is reasonably good and comparable with CMMSE in screening for MCI. The original MoCA by Nasreddine et al5 in 2005 and other validation studies of MoCA in different languages established the superiority to MMSE. Explanations are that MMSE did not test complex cognitive impairments in domains such as visuospatial/executive function and abstract reasoning. In addition, the attention and delayed recall tasks are not as challenging as that in MoCA. In practice, MoCA picks up more deficits in executive function, attention, and delayed recall.16 This study did not reproduce the superiority to MMSE and this may be related to the low education level of Chinese older adults. Due to the Chinese Civil War from 1927 to 1950, the majority of elderly Chinese individuals did not receive much education and many were illiterate. According to published data,17 the average number of years of education for elderly Chinese individuals is about 5 years, which is significantly less than that of their western counterparts.
 
The validity of HK-MoCA is based on its non-inferiority to CMMSE. This study compared HK-MoCA with CMMSE using a new cutoff point derived from the same study and found comparable sensitivity and specificity in detection of MCI. If the CMMSE cutoff as suggested by Chiu et al4 was utilised, HK-MoCA is definitely more sensitive. As such, HK-MoCA is relatively easy to use (both required less than 15 minutes to administer) and incorporates important domains missed in CMMSE. It is a clinically efficient and effective screening instrument and can be generalised for use in Chinese older adults with MCI or dementia. Customarily, many memory clinics utilise MMSE as a screening tool as it is convenient to use and available free of charge. Considering the ceiling effect of MMSE due to the low level of task difficulty and the copyright fees introduced recently, validated HK-MoCA provides an attractive alternative.
 
Psychometric properties of the Hong Kong version of Montreal Cognitive Assessment
Montreal Cognitive Assessment is one of the common cognition screening instruments used locally and worldwide. It is commonly used to discriminate cognitive impairment due to various causes. In Hong Kong, there was only one validation study conducted by Wong et al13 involving use of HK-MoCA in patients with cerebral SVD. They demonstrated that HK-MoCA differentiated SVD patients from controls (AUC=0.81) with an optimal cutoff at 21/22. This cutoff point was valid to predict SVD patients with cognitive impairment only, although in clinical practice, it was commonly used to discriminate cognitive impairment of various causes. This study successfully generalised the validity of HK-MoCA for identifying MCI and dementia in Chinese older adults, and determined the optimal cutoff points of these conditions. The optimal cutoff points yielded were similar to those in previous studies in China8 10 and Korea7 using the same descended educational adjustment. The HK-MoCA is useful for detecting persons with cognitive impairment in Chinese older adult population and a score of below 22 should prompt detailed diagnostic investigations. The results demonstrated good intra-rater and inter-rater reliability and internal consistency. It showed good convergent validity with CMMSE and GDS scores as well. Besides, the study investigated the effect of education on this cognitive screening instrument with respect to the low education level of Chinese older adults and employed a descended education adjustment from 12 to 6 years of education. This descended education adjustment is supported by studies conducted in China8 and Korea.7
 
Limitations
There were several limitations to the HK-MoCA. This instrument required the participants to follow verbal and written commands, hence the performance of elderly with hearing or visual impairment would be affected. Illiterate or poorly educated persons might have difficulty in comprehending the instructions and the cube and clock drawing tasks were too difficult. Furthermore, stroke patients whose dominant hand has been affected might not be able to perform the drawing test.
 
In this study, subjects were recruited from a local general hospital situated in a lower social class residential area. Three quarters of the participants received primary education or less. The descended education adjustment from 12 to 6 years of education should be subject to review with respect to the trend of education received by older adults. Besides, short break between CMMSE and HK-MoCA administration might not totally relieve the fatigue error. One might argue that geriatricians and psychogeriatricians in this study were not blinded from the HK-MoCA, CMMSE and GDS scores, which might have introduced bias when they made the final cognitive diagnosis. Furthermore, inter-rater reliability established using convenience sampling of 20 participants being tested 2 to 4 weeks apart was not an optimal way to determine the concordance between the two co-investigators. Last but not the least, the predictive values could not be ascertained in this study as the patient groups and NC were not recruited consecutively from a designated population, leaving the true prevalence unknown. Further study can explore the ability of HK-MoCA to grade the severity of cognitive impairment and predict long-term cognitive decline.
 
Conclusion
This study validated that HK-MoCA is a sensitive screening instrument for use in Chinese older adults in Hong Kong with MCI or dementia, irrespective of the underlying aetiology. This validated HK-MoCA is brief and feasible to conduct in the clinical setting, and can be completed in less than 15 minutes. It is an attractive alternative screening instrument to MMSE which has ceiling effect and needs to be purchased due to copyright issues. A score of less than 22 should prompt further diagnostic assessment.
 
Acknowledgement
The authors thank Dr Ziad S Nasreddine for his permission to use the Hong Kong version of Montreal Cognitive Assessment test.
 
Declaration
No conflicts of interest were declared by authors.
 
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Nurse-led orthopaedic clinic in total joint replacement

Hong Kong Med J 2014;20(6):511–8 | Epub 29 Aug 2014
DOI: 10.12809/hkmj134150
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
ORIGINAL ARTICLE
Nurse-led orthopaedic clinic in total joint replacement
Jason CH Fan, FHKAM (Orthopaedic Surgery); Carmen KM Lo, MN; Carson KB Kwok, FHKAM (Orthopaedic Surgery); KY Fung, FHKAM (Orthopaedic Surgery)
Department of Orthopaedics and Traumatology, Alice Ho Miu Ling Nethersole Hospital, Tai Po, Hong Kong
 
This study was presented at the 33rd Annual Congress of the Hong Kong Orthopaedic Association on 23 November 2013.
 
Corresponding author: Dr Jason CH Fan (fchjason@netvigator.com)
 Full paper in PDF
Abstract
Objectives: To introduce the practice of a nurse-led orthopaedic clinic for managing stable patients after total hip or knee replacement and to evaluate its efficacy.
 
Design: Case series.
 
Setting: A public hospital in Hong Kong.
 
Patients: Patients who had stable primary total knee replacement or total hip replacement done for longer than 2 years were managed in a nurse-led total joint replacement pilot clinic.
 
Results: From July 2012 to March 2014, 431 patients (including 317 with total knee replacement and 114 with total hip replacement) were handled, and 408 (94.7%) nurse assessments were independently performed. Six cases of prosthesis-related complications were diagnosed. One patient was hospitalised for prosthetic complications within 3 months after follow-up. The satisfaction rate was 100%. From November 2012 to April 2013, an advanced practice nurse, one resident specialist, and one associate consultant independently charted Knee Society Knee Score or Harris Hip Score for the patients attending preoperative assessment clinic to check the inter-observer reliability. Overall, 23 patients with 37 knees and 11 patients with 17 hips were examined. The mean correlation coefficient between assessments by the associate consultant and advanced practice nurse was 0.912 for Knee Society Knee Score, and 0.761 for Harris Hip Score. The advanced practice nurse could achieve better or equally good correlation with associate consultant when compared with the correlation between resident specialist and associate consultant (0.866 and 0.521 for Knee Society Knee Score and Harris Hip Score, respectively) and with international standard.
 
Conclusion: Nurse-led total joint replacement clinic was safe, reliable, and well accepted by patients.
 
 
New knowledge added by this study
  •  Management of stable postoperative total joint replacement patients by well-trained nurses is safe, reliable, and well accepted by patients.
Implications for clinical practice or policy
  •  Nurse-led clinics should be established for managing patients with total joint replacement to handle the escalating workload in Hong Kong.
  •  Well-structured nurse training should be organised for managing stable patients with total joint replacement in orthopaedic clinics.
 
 
Introduction
Nursing practice is moving towards both proletarianisation and professionalisation.1 The former means the transfer of some basic routine care to less-skilled assistants. The latter means advanced nursing practice with nurses handling complex health problems using advanced health assessment and intervention measures. Nurse-led clinic is one of the forms of professionalisation and has been adopted in Hong Kong since 1990s. Diabetes clinic, wound clinic, and continence clinic are the three most common nurse-led clinics in Hong Kong2 and they have demonstrated significant impact on patient outcomes.3 Orthopaedic nurses in total joint replacement (TJR) have been focusing on patient education in preoperative assessment clinics.
 
In order to enhance the role of orthopaedic nurses and ensure the continuity of patient care before and after TJR, a new advanced nursing practice was introduced, namely, the Ambulatory Comprehensive Arthroplasty Clinic (ACAC), a nurse-led orthopaedic postoperative clinic in TJR. An advanced practice nurse (APN) with 17 years of post-registration experience and 5 years of advanced nursing practice was interviewed and showed dedication and enthusiasm towards the orthopaedic work in TJR. She received some basic training from November 2011 and the ACAC started in January 2012. She ran the clinic one session each week under the supervision of an associate consultant (AC) till June 2012, and then independently. She was supported by a multidisciplinary team and could refer patients to physiotherapy, occupational therapy, and prosthetics and orthotics as indicated. She also participated in a multidisciplinary meeting for day-patient rehabilitation after TJR.
 
The APN continued with her one-on-one training by an AC specialised in TJR. Each week, she observed about 15 cases in the specialist TJR clinic and two cases in the preoperative assessment clinic. She was exposed to and was taught the basic knowledge on total knee replacement (TKR) and total hip replacement (THR), the proper way to chart Knee Society Knee Score (KSKS) and Harris Hip Score (HHS), and about physical findings and radiographic features of stable prosthesis, infection, and aseptic loosening. Reading material and tutorials were also provided to teach her about various complications of TJR. Until March 2014, she completed about 110 weeks of continuous training.
 
As we have been using KSKS and HHS since 1998 for assessing the progress of patients after TJR, these were retained as part of the assessment tools in ACAC for continuity of care. In part of the KSKS and HHS, physical examination is necessary. It was a difficult area for the APN and could lead to potential error and discrepancy. Therefore, part of the APN training was concentrated in this area and a separate study was launched to test her reliability.
 
This article aimed to introduce the practice of a nurse-led orthopaedic clinic for managing stable postoperative patients with TKR and THR and describe the outcomes in a series of cases. This also presents the result of the reliability of the APN in charting various scores.
 
Methods
From August 1997 to December 2013, 895 primary TKRs and 268 primary THRs were performed in Alice Ho Miu Ling Nethersole Hospital. Until 31 December 2013, 801 TKRs and 232 THRs were performed for more than 2 years and were followed up yearly in the specialist out-patient clinic. During each follow-up, the assessment included history taking and physical examination, charting KSKS or HHS, and checking radiographs. Patients who had undergone primary TKR or THR more than 2 years ago and who were assessed as being stable and minimally symptomatic by specialists were recruited in the ACAC for yearly follow-up. One day before follow-up, the AC analysed the radiographs taken in the earlier year and the finding was discussed with the APN for teaching purpose. During ACAC, the APN assessed the patients by TKR (Fig 1) or THR (Fig 2) questionnaire, charted KSKS or HHS, interpreted follow-up radiographs, and then educated the patients on care of and precautions with the prosthesis. The findings were recorded in consultation notes in the computer medical system (CMS). Patients were managed according to the workflow (Fig 3). When the TJR specialist was consulted on-site for any problem related to the prosthesis, minor procedures like knee aspiration could be done by the specialist at the same consultation. After the clinic, the questionnaires and the radiographs were screened by the specialist for any significant problems.
 

Figure 1. Questionnaire for total knee replacement follow-up
 

Figure 2. Questionnaire for total hip replacement follow-up
 

Figure 3. Workflow of patient arrangement
 
The questionnaires were collected and the consultation notes in CMS were studied. The relevant data were then summarised and described in an Excel file, including the number of cases of TKRs and THRs, the number of on-site specialist consultations, the number of prosthesis-related complications diagnosed by the APN, the number of patients referred to orthopaedic clinic and other health care professionals, the number of medication prescriptions, patients’ satisfaction, and patients’ acceptance of consultation without medication. Patients’ waiting time for the clinic was also obtained by calculating the difference between the consultation time and the allocated time slot. The CMS was also checked for any hospital admission or clinic attendance for any problems related to TJR after ACAC follow-up.
 
From November 2012 to April 2013, an APN, one resident with specialist qualification (RS), and one AC independently charted KSKS or HHS for patients attending the preoperative assessment clinic. Knee Society Knee Score is composed of function score (FS) and knee score (KS)—FS is made up of three components and KS is made up of seven components. Harris Hip Score is composed of 17 components. Overall, 23 patients with 37 knees and 11 patients with 17 hips were examined. In order to analyse the inter-rater reliability between the AC and APN (comparison A), between AC and RS (comparison B), and between RS and APN (comparison C), each component of the KSKS and HHS was analysed for single-measure intraclass correlation coefficient (ICC) and statistical significance using the Statistical Package for the Social Sciences (Windows version 15.0; SPSS Inc, Chicago [IL], US). To see any statistically significant difference between ICCs among the three groups and between comparison A and international standards,4 5 Fisher’s z-transformation was performed by online calculator (www.vassarstats.net/rdiff.html).
 
Results
In the initial period from January to June 2012, on-site specialist consultation was necessary in 21 (22.8%) cases out of the 92 cases (68 TKRs and 24 THRs). From July 2012 to March 2014, a total of 431 patients (including 317 TKRs and 114 THRs) were managed and 408 (94.7%) nurse assessments were independently performed. Six cases of prosthesis-related complication were diagnosed including two cases of patellar clunk in TKR, two cases of TKR loosening, and two cases of THR loosening. Number of referrals to other orthopaedic clinics and health care professionals is shown in the Table. Among the 523 patients on ACAC follow-up, 131 (25.0%) requested medications. Average patient waiting time improved over the study period (26 minutes in December 2012, 18 minutes in April 2013, and 14 minutes in March 2014). Of these 523 patients, 485 patients were interviewed; 354 were extremely satisfied and 131 were satisfied with ACAC follow-up by the nurse, and 373 (76.9%) patients accepted follow-up without drug prescription.
 

Table. Number of patients referred to other clinics and treatment centres
 
One patient who had undergone right TKR 12 years ago was hospitalised at 3 months after nurse clinic follow-up because of sudden onset of right knee effusion. X-ray showed no sign of prosthesis loosening. Surgical exploration of the right knee showed catastrophic wear of the polyethylene insert while the prosthesis was stable. Two patients at 6 months after nurse assessment attended general out-patient clinic for getting analgesics.
 
Study of reliability of the advanced practice nurse in charting Knee Society Knee Score and Harris Hip Score
The result for KSKS is shown in Figure 4. The mean ICCs were 0.912 (range, 0.660-0.987), 0.866 (range, 0.735-0.974), and 0.851 (range, 0.599-0.996) for comparisons A, B and C, respectively. The lowest ICC among all the components in KSKS was that of mediolateral stability (0.599-0.797). When comparing with those of Bach et al,4 the ICCs of FS and all its components for comparison A were significantly better. This was also the case for ICCs of three of the five computable components of KS and that of KS.
 

Figure 4. Results for Knee Society Knee Score
The ICCs for comparison among A, B, and C in AP and Ext lag could not be computed because one of the variables was constant. All the available ICCs for comparison between A and C were statistically significant (P<0.05)
 
The result for HHS is shown in Figure 5. The mean ICCs were 0.761 (range, 0.211-1) for comparison A, 0.521 (range, 0.101-0.940) for comparison B, and 0.481 (range, -0.231 to 0.940) for comparison C. The ICCs for charting total HHS were 0.964, 0.747, and 0.722 for comparisons A, B and C, respectively. When the ICC of comparison A (0.964) was compared with that in the study by Kirmit et al5 (0.91), the difference was found to be statistically insignificant (P=0.124).
 

Figure 5. Results for Harris Hip Score
 
Discussion
In the current study, the well-trained APN could independently handle 94.7% of the stable postoperative cases in TJR after the initial learning phase. She could successfully diagnose six cases of prosthesis-related complications out of all the 523 patients she handled. One patient who was asymptomatic at the ACAC follow-up presented with sudden onset of right knee effusion, and showed catastrophic wear of polyethylene. Nurse-led clinic in TJR was, therefore, safe. It was well accepted by patients with a 100% satisfaction rate. As the APN grew more confident and gained more experience, she also became more efficient. This, together with improvement in workflow in taking radiographs, led to progressive shortening of patient waiting time from 26 minutes in the initial phase (December 2012) to 14 minutes in March 2014. It could greatly relieve the burden of the specialist clinic. Within 2 years, 523 patient attendances were handled by the APN. About five to seven cases were seen in each session of this clinic. Moreover, more detailed patient education, which is not possible in the busy specialist clinic, can be provided to patients who may have forgotten the details given several years ago before the operation.
 
Bach et al4 studied the inter-observer correlation of four commonly used TKR outcome scores—Hungerford score, Hospital for Special Surgery score, Knee Society score, and Bristol score. Two experienced orthopaedic surgeons independently assessed 118 TKRs in 92 patients. The correlation coefficient for mediolateral knee stability was the lowest among all the components of all scoring systems (0-0.38). This was due to the difficulty in physical examination and proper measurement with goniometer at the same time. For all the comparisons in this study, we encountered the same difficulty and found the same finding of lowest correlation coefficient for mediolateral stability (0.599-0.797) among all the components in KSKS. Kirmit et al5 evaluated the inter-observer reliability of five different hip scores including HHS. Three physiotherapists assessed 48 hips with osteoarthritis in 35 patients. The correlation coefficients ranged from 0.82 to 0.91 for HHS, which was comparable to the result in our study (0.722-0.964). With proper training of the APN by the AC in this hospital, she could achieve better or equally good correlation with the AC as compared with an orthopaedic specialist and international standard for charting KSKS and HHS.
 
In order to match the evolution of the health care environments and patient care needs, the roles and responsibilities of APNs have been reshaping.6 They have active and important places in taking care of patients from various specialties. Their contribution by running nurse-led clinics has been shown to be tremendous in and outside Hong Kong. They add value to patient care and complement specialist clinics.3 7 8 9 Over 80% of their work are independent of or interdependent with physicians and involve skills such as adjusting medications, and initiating therapies and diagnostic tests according to protocols.3 10 To further advance professionalisation of nursing practice, Newey et al11 reported the training of nurse practitioners to provide initial assessment in clinics, perform carpal tunnel release, and manage these patients in postoperative follow-up.
 
Shiu et al12 pointed out four boundaries and six hindering factors for expanding advanced nursing practice in nurse-led clinics. The former included community-hospital, wellness-illness, public-private, and professional-practice boundaries. The latter included stakeholder and public awareness of advanced nursing practice role in nurse-led clinics, provision of advanced specialty education programmes, organisational support, multidisciplinary collaboration, and changing health care context and provision. When ACAC was commenced, professional-practice boundary was the first and the most important hurdle. The APN was directly coached by an AC about various aspects in TJR. The TKR and THR questionnaires and workflow protocol were devised to facilitate the patient care process. She was authorised to order standard radiographs according to the region of interest, and make referral to physiotherapy, occupational therapy, prosthetics and orthotics, and the general orthopaedic clinic. However, nurse prescription was not possible and doctor prescription was necessary in 25% of the cases. Getting help from doctors was also required in a few cases for writing referral letters to medical departments, applying for car park permits for the disabled, applying for public housing, and signing disability allowance forms. In order to solve these remaining problems, there should be appropriate legislation to redefine the professional code of nursing practice, and organisational support to offer a clear policy for nurse prescribing.12 Stakeholder and public awareness should be aroused to allow inter-departmental referral and granting public certification.
 
The second hurdle was the provision of advanced specialty education programmes. Currently, there is no programme or course in universities and Hospital Authority teaching nurses about TJR. Direct coaching was chosen as the training method, and continuous education was provided to broaden her exposure. This may be less than ideal and a complete curriculum was not present. If the nurse-led clinic were to be promoted and accepted as the method to deal with the escalating workload from various joint replacement centres, the Co-ordinating Committee (COC), which is one of the Hospital Authority Head Office committees for clinical service, in orthopaedics and traumatology has to collaborate with COC in nursing to formulate a good training programme for nurses with special interest in TJR. Knowledge of pharmacology is also necessary for nurse prescription. The nursing schools in various universities should revise the curriculum to make nurse-led orthopaedic clinics feasible and safe.
 
Conclusion
The success of nurse-led postoperative clinic in TJR is multifactorial including the experience and dedication of the APN, support of the trainer specialist and department, a good working guideline and protocol, and support of other health care professionals. Its running is not perfect yet because the specialty nurse cannot prescribe medications and she is not community-recognised to sign legal documents. However, such a clinic should be established in Hong Kong to align with the development of joint replacement centres in Hospital Authority. Apart from the preoperative assessment clinic and postoperative follow-up clinic, the trained specialist nurse can also play important roles in other stages of patient care. This requires further exploration and collaboration with other health care professionals.
 
Acknowledgements
We thank Ms Amy MY Cheng and Winnie YC Lam for valuable inputs when setting up the nurse-led clinic.
 
References
1. Wong FK. Health care reform and the transformation of nursing in Hong Kong. J Adv Nurs 1998;28:473-82. CrossRef
2. Hospital Authority Annual Plan 2008-2009. Available from: http://www.ha.org.hk/visitor/ha_visitor_index.asp?Parent_ID=100&Content_ID=300&Dimension=100&Lang=ENG. Accessed Aug 2010.
3. Wong FK, Chung LC. Establishing a definition for a nurse-led clinic: structure, process, and outcome. J Adv Nurs 2006;53:358-69. CrossRef
4. Bach CM, Nogler M, Steingruber IE, et al. Scoring systems in total knee arthroplasty. Clin Orthop Relat Res 2002;399:184-96. CrossRef
5. Kirmit L, Karatosun V, Unver B, Bakirhan S, Sen A, Gocen Z. The reliability of hip scoring systems for total hip arthroplasty candidates: assessment by physical therapists. Clin Rehabil 2005;19:659-61. CrossRef
6. Bonsall K, Cheater FM. What is the impact of advanced primary care nursing roles on patients, nurses and their colleagues? A literature review. Int J Nurs Stud 2008;45:1090-102. CrossRef
7. Larsson I, Bergman S, Fridlund B, Arvidsson B. Patients’ experiences of nurse-led rheumatology clinic in Sweden: a qualitative study. Nurs Health Sci 2012;14:501-7. CrossRef
8. Slight C, Marsden J, Raynel S. The impact of a glaucoma nurse specialist role on glaucoma waiting lists. Nurs Prax N Z 2009;25:38-47.
9. Kirkwood BJ, Pesudovs K, Latimer P, Coster DJ. The efficacy of a nurse-led preoperative cataract assessment and postoperative care clinic. Med J Aust 2006;184:278-81.
10. Ng SL, Tse YB, Ho KL, Yiu MK. Efficacy of a Urology Nurse-led Clinic in Queen Mary Hospital of Hong Kong. Proceedings of the 11th Asian Congress of Urology of the Urological Association of Asia; 2012 Aug 22-26; Pattaya, Thailand. Int J Urol 2012;19(Suppl 1):432 abstract no. OP2512-07.
11. Newey M, Clarke M, Green T, Kershaw C, Pathak P. Nurse-led management of carpal tunnel syndrome: an audit of outcomes and impact on waiting times. Ann R Coll Surg Engl 2006;88:399-401. CrossRef
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Dermoscopy for common skin problems in Chinese children using a novel Hong Kong–made dermoscope

Hong Kong Med J 2014 Dec;20(6):495–503 | Epub 12 Sep 2014
DOI: 10.12809/hkmj144245
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
ORIGINAL ARTICLE
Dermoscopy for common skin problems in Chinese children using a novel Hong Kong–made dermoscope
David CK Luk, MSc, FHKAM (Paediatrics); Sam YY Lam, MB, ChB, MRCPCH; Patrick CH Cheung, FRCPCH, FHKAM (Paediatrics); Bill HB Chan, FRCPCH, FHKAM (Paediatrics)
Department of Paediatrics and Adolescent Medicine, United Christian Hospital, Kwun Tong, Hong Kong
 
Corresponding author: Dr David CK Luk (davidluk98@hotmail.com)
 Full paper in PDF
Abstract
Objective: To evaluate the dermoscopic features of common skin problems in Chinese children.
 
Design: A case series with retrospective qualitative analysis of dermoscopic features of common skin problems in Chinese children.
 
Setting: A regional hospital in Hong Kong.
 
Participants: Dermoscopic image database, from 1 May 2013 to 31 October 2013, of 185 Chinese children (aged 0 to 18 years).
 
Results: Dermoscopic features of common paediatric skin problems in Chinese children were identified. These features corresponded with the known dermoscopic features reported in the western medical literature. New dermoscopic features were identified in café-au-lait macules.
 
Conclusion: Dermoscopic features of common skin problems in Chinese children were consistent with those reported in western medical literature. Dermoscopy has a role in managing children with skin problems.
 
 
New knowledge added by this study
  •  This is the first research on dermoscopy in Chinese children.
  •  Dermoscopic features reported in western medical literature could be identified in Chinese children.
Implications for clinical practice or policy
  •  Routine use of dermoscopy has a role in managing paediatric skin problems.
 
 
Introduction
Skin complaints are common in both community-based and hospital paediatric practices. The range of skin problems is diverse, including categories like inflammatory conditions (eg eczema, psoriasis), birthmarks (eg haemangiomas, port-wine stains, melanocytic naevi), infectious skin diseases, and hair and nail problems.
 
In many situations, the clinical diagnosis of paediatric skin problems is straightforward but masquerading conditions also exist.1 2 Although histopathological examination can confirm the clinical diagnosis, skin biopsy in young children may require special arrangements such as sedation. In recent years, the gap between clinical and histopathological examination of skin lesions has been filled by various skin imaging modalities.3 4 As a simple, quick,5 non-invasive clinical technique, dermoscopy has gained popularity in the examination of skin in western countries.6 7 Dermoscopy refers to the examination of skin with a handheld device to reveal surface and subsurface skin structures. This is achieved by an optical system to magnify, illuminate, and remove light flare and reflection from the skin surface. It provides the link between eyeball clinical inspection and histopathological examination. With more than 1500 articles published after its introduction in 1980s, dermoscopy has been established as a routine skin examination technique in many western countries.8 As dermoscopy is extremely useful in the diagnosis of malignant melanoma9 and is able to reduce the need for skin biopsy,10 11 it is most widely used in the management of pigmented skin lesions. Recently, dermoscopic features of a wide range of non-pigmented skin problems have also been reported.12 13 With the uncovering of more dermoscopic features, dermoscopy has gained importance in the diagnosis of skin lesions, and its benefits in educating medical students and use in family practice have also been published recently.14 15 16
 
Medical researches on dermoscopy in Chinese populations, however, have rarely been published.17 18 19 With the understanding that ethnicity may affect dermoscopic findings,20 the aim of this study was to identify dermoscopic features in Chinese children and assess if those are in line with internationally published features.
 
The clinical use and research on dermoscopy in children worldwide had been limited by both patient factors and equipment factors. Camera-mounted dermoscope required lengthy setup and was not user-friendly in busy clinics. In addition, babies and young children might not stay still during the examination. To ensure an efficient dermoscopic examination and a good-quality dermoscopy image capture, a novel device developed by the biomedical engineering team of the Hong Kong Productivity Council was applied. This study evaluated the dermoscopic features of common skin problems in Chinese children using the dermoscopy image database established with the dermoscope.
 
Methods
A retrospective analysis of the dermoscopic features of skin lesions of Chinese children (aged 0-18 years) was performed. The study was approved by the local Research Ethics Committee and conducted at the Department of Paediatrics and Adolescent Medicine, United Christian Hospital, Hong Kong, using the dermoscopic image database from 1 May 2013 to 31 October 2013, which contained only cases with symptoms and signs classical for their respective clinical diagnoses. These images were examined by a paediatrician trained in dermoscopy. A two-step algorithm was used to assess dermoscopy images with the first step aiming at differentiating melanocytic from non-melanocytic lesions and the second step on specific pattern analysis. The results of the analysis were categorised according to the clinical diagnoses.
 
Literature search of the MEDLINE database was performed to identify specific dermoscopic features for each clinical diagnosis. The key words used in the literature search were “dermoscopy, dermatoscopy, dermoscope, dermatoscope”. Key words specific to individual clinical diagnosis were used to facilitate the search. It was then assessed if the dermoscopic features of this study corresponded with those from published medical literature.
 
During the study period, all dermoscopy images were captured by the novel Hong Kong–made dermoscope. It was an all-in-one pocket-size autofocusing polarised digital dermoscope with Wi-Fi and USB connectivity capable of capturing dermoscopy image of all ages including young infants within 5 seconds (Fig). An extensible optic barrel was hinged on the body of the dermoscope so that both gross photos and 10-times magnified dermoscopy photos could be taken. The images were then uploaded to a computerised dermoscopy image database.
 

Figure. A novel Hong Kong–made dermoscope
 
Results
Dermoscopic images of 185 Chinese children (86 boys and 99 girls) suffering from 22 skin conditions were retrieved. The mean age of these children was 5.2 years (range, 2 days to 17 years). The top 12 diagnoses reported (in descending order of frequency) were port-wine stain (n=42), melanocytic naevus (n=41), haemangioma (n=30), café-au-lait macule (CALM; n=15), sebaceous naevus (n=8), viral wart (n=7), atopic dermatitis (n=6), alopecia areata (n=5), cutis aplasia (n=5), psoriasis (n=4), scabies (n=3), and molluscum contagiosum (n=3).
 
The dermoscopic features of these 12 diagnoses were further analysed. They were grouped into four main disease categories: birthmarks (pigmentary and vascular), infections, hair problems, and inflammatory dermatoses. Forty-two dermoscopic features were identified (Table 1).
 

Table 1. Dermoscopic features of the four main disease categories identified in the current study
 
In the pigmentary birthmark category, there were 41 children with 51 melanocytic naevi (mean age, 7.3 years). The most common dermoscopic pattern of melanocytic naevus was mixed, followed by globular, homogeneous, and reticular. In the mixed pattern naevi, globular-homogeneous was the commonest (n=13), followed by globular-reticular-homogeneous (n=6), reticular-homogeneous (n=4), and globular-reticular (n=3). There were 15 children with CALM (mean age, 3.5 years). All 10 children with facial CALM showed a homogeneous brown patch with perifollicular hypopigmentation. The five children with CALM on neck showed a reticular pattern.
 
In the vascular birthmark category, there were 42 children with port-wine stains (mean age, 6.5 years) and 30 infants with infantile haemangiomas (mean age, 6 months). For those with port-wine stains, both globular (n=4) and reticular (n=9) vascular patterns were identified but the most common dermoscopic pattern was mixed pattern (n=29) with both globular and reticular components. Among the 30 infantile haemangiomas, 25 had vessels of various morphologies, and red lacunae were noted in 24. None of the haemangiomas had melanocytic pattern.
 
In the infectious diseases category, there were seven children with viral warts on hands or feet (mean age, 10.5 years). Thrombosed capillaries presented as black-to-red dots, and papilliform surfaces and interrupted skin lines were identified in all cases. All three children with molluscum contagiosum (mean age, 5 years) showed orifices but vessels and specific vascular patterns could be found in only one case. In the three cases of scabies (mean age, 12.5 years), triangular head, transparent body, and burrows were present.
 
Patients with patchy alopecia were identified in the hair category. Eight patients had sebaceous naevus (mean age, 8.4 years), with four having yellow dots not associated with hair follicles, three having yellow lobules displacing blood vessels, and one having sebaceous hyperplasia. In the five patients with alopecia areata (mean age, 12 years), dermoscopic features including yellow dots (n=2), black dots (n=2), short vellus hair (n=4), broken hair (n=4), and micro-exclamation mark hair (n=3) were noted. Five patients with cutis aplasia (mean age, 3 years) were featured by a complete lack of skin appendages (n=5) and translucent appearance (n=4).
 
There were six patients with atopic dermatitis (mean age, 6.5 years) and four patients with psoriasis (mean age, 11 years) in the inflammatory dermatoses category. Atopic eczema was featured by structureless erythema (n=6), scales (n=6), and patchy dotted vessels (n=4) while the psoriasis patients had light red background (n=4), diffuse white scales (n=3), regular dotted vessels (n=4), and glomerular vessels (n=2).
 
Discussion
Our study documented the dermoscopic findings of common paediatric skin conditions in Chinese children. In the analysis of the dermoscopy images using a two-step algorithm, the first step was differentiation between melanocytic and non-melanocytic lesions. This study identified typical melanocytic patterns (globular and reticular pattern21) in melanocytic naevi, and absence of melanocytic patterns in all haemangiomas. This two-step algorithm analysis of skin lesions confirmed the findings on clinical inspection and provided a standard approach to dermoscopic examination even in difficult cases.
 
Birthmarks are very common in children. Salmon patches occur in half of the neonates22 23 and infantile haemangiomas in one tenth of premature babies, while the prevalence of capillary malformations (port-wine stain) has been reported to be 0.3% to 2.1%.24 25 Within the vascular birthmark category, both port-wine stains and haemangiomas could present as neonatal erythematous patches. As lacunae pattern was commonly identified in haemangiomas but not in port-wine stains, it may serve to differentiate haemangiomas from port-wine stains. An early diagnosis of haemangiomas facilitates timely management as some may rapidly proliferate or develop complications in the first few months of life. In our series, the majority of the port-wine stain lesions showed a mixed pattern with both globular and reticular components (n=29/42) while reticular (n=9/42) and globular (n=4/42) patterns were less common. The ectatic capillary plexus was situated deeper in the dermis in those with a reticular pattern than those with a globular pattern; this difference may have treatment and prognostic implications on response to laser treatment.13 As such, laser treatment strategy aiming at the deeper dermal layer would be required to improve treatment results.
 
In the pigmentary birthmark category, both congenital and acquired melanocytic naevi were included. The common dermoscopic patterns of globular, reticular, homogeneous, and mixed reported in our series were in line with those reported in the western medical literature.26 27 28 29 As dermoscopy improves the detection of melanomas,30 its use was suggested in the monitoring of congenital melanocytic naevi (CMN), especially the smaller CMN.31 32 33 Sequential digital dermoscopy imaging can also reduce the unnecessary excision of suspicious pigmented skin lesions.34 This has been emphasised in children with epidermolysis bullosa who are at risk of developing skin cancers, and in whom overtreatment of the fragile skin should be avoided.35
 
This is the first report of dermoscopic features of CALM in medical literature. It was noted that the dermoscopic patterns of CALM might vary according to the location on the body. All the 10 cases of facial CALM showed homogeneous brown patches with perifollicular hypopigmentation while the five cases of CALM on the neck had a faint brown reticular pattern. As it may be difficult to differentiate CALM from CMN in infancy by inspection,36 dermoscopy provides a quick and non-invasive diagnostic tool to guide subsequent management.
 
In the infectious disease category, all viral warts were on the hands or feet, and all of them showed the classical features of thrombosed capillaries present as black-to-red dots and globules on papilliform surfaces with interrupted skin lines. These findings were consistent with features reported in the medical literature.37 The confirmation of the diagnosis of viral wart before initiating treatment is important because acral melanoma, which is more common in Chinese, has been reported to be misdiagnosed as viral wart with disastrous consequences.38 39 40 Moreover, dermoscopy could help guide treatment by identifying residual warty structures or confirming complete resolution of warts.37
 
In our series, there were three children with scabies who had either the classical dermoscopic sign of ‘triangular structure’41 or the round bodies42 43 of the scabies mite. The “z”- or “s”-shaped burrows were also well depicted on dermoscopy in two of them. Dermoscopy is a simple, accurate, and rapid44 technique for diagnosing scabies even in inexperienced hands.45 In a study involving 756 patients, dermoscopic examination for scabies was found to be 91% sensitive and 86% specific.45 It greatly enhances treatment decisions45 and allows fast introduction of proper treatment.42 Diagnosing scabies in children by dermoscopy is child-friendly as it requires no skin scrappings, thus, causing no fear or pain.42 In addition, demonstration of scabies mite to patient may foster treatment adherence in both patients and asymptomatic family members.44
 
Molluscum contagiosum is a common skin infection in children46 and is highly contagious47 with outbreaks reported.48 In our three children with molluscum contagiosum, the reported dermoscopic features included orifices with amorphous white centre and polylobular appearance surrounded by vessels.49 50 When the typical clinical features of molluscum contagiosum are not apparent, dermoscopy can be helpful for diagnosis.51
 
Three common causes of patchy alopecia in children were reported in this study. For neonates or infants with congenital patchy alopecia, the differentiation between sebaceous naevus and cutis aplasia may be difficult.52 In our study, the dermoscopic features of sebaceous naevi with yellow dots unassociated with hair follicles, sebaceous hyperplasia, and yellow lobules displacing blood vessels53 were demonstrated. On the other hand, cutis aplasia showed a complete lack of skin appendages and skin translucency.52 While no specific treatment is usually needed for cutis aplasia, surgical excision of sebaceous naevi is often advised with its potential for developing into basal cell carcinoma.54
 
The lifetime risk of alopecia areata in the general population is approximately 1.7% and as many as 60% of patients with alopecia areata have disease onset before 20 years of age.55 The clinical features of hair loss vary with clinical subtypes.56 In our series of five children with alopecia areata, black dots, yellow dots, short vellus hair, broken hair, and micro-exclamation mark hairs were noted. These dermoscopic features may be useful clinical indicators in alopecia areata which have both diagnostic and prognostic values.57 58
 
Concerning the inflammatory dermatoses category, clinical similarities exist between atopic dermatitis and psoriasis as both are chronic pruritic scaly erythematous skin conditions. It is known that characteristic dermoscopic vascular patterns facilitate differentiation of psoriasis from atopic dermatitis.59 In our study, the patchy dotted vessels60 and linear vessels of atopic dermatitis could be differentiated from the red globular rings61 and glomerular vessels62 of psoriasis.
 
The clinical significance of dermoscopy in children’s skin conditions is summarised in Table 2.
 

Table 2. Clinical significance of dermoscopic examination in children with skin lesions
 
Although various dermoscopic features of skin problems could be identified in this study, it had several limitations. First, the dermoscopy database only contained images captured during routine clinical service when the clinical features were classical of their respective diagnosis. As such, the database was not representative of all common skin problems in children. In addition, with the small case numbers for some of the diseases such as atopic dermatitis and psoriasis, further research is required to confirm our preliminary findings. Moreover, features of skin diseases in children are age-dependent and phase-dependent but these factors were not evaluated in the present study.
 
Conclusion
Dermoscopy is a well-established skin examination tool with known dermoscopic features for many diagnoses. Our study confirmed that the dermoscopic features reported in the medical literature could be identified in Chinese children. While the value of dermoscopy in diagnostic, prognostic, and disease monitoring is being unveiled, further studies are required to understand its role in various paediatric skin diseases.
 
Acknowledgements
We would like to thank Ms Carol YB Liu and Mr Bryan MK So of Hong Kong Productivity Council and Hong Kong Innovation and Technology Fund for the support on the dermoscopy device for this study.
 
Declaration
David CK Luk acted as advisor to Hong Kong Productivity Council on the development of dermoscope prototype. No conflicts of interests were declared by authors.
 
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The benefit of prothrombin complex concentrate in decreasing neurological deterioration in patients with warfarin-associated intracerebral haemorrhage

Hong Kong Med J 2014 Dec;20(6):486–94 | Epub 7 Nov 2014
DOI: 10.12809/hkmj144246
© Hong Kong Academy of Medicine. CC BY-NC-ND 4.0
 
ORIGINAL ARTICLE
The benefit of prothrombin complex concentrate in decreasing neurological deterioration in patients with warfarin-associated intracerebral haemorrhage
WC Fong, FRCP, FHKAM (Medicine)1; WT Lo, MRCP, FHKAM (Medicine)1; YW Ng, MRCP, FHKAM (Medicine)1; YF Cheung, MPH, FHKAM (Medicine)1; Gordon CK Wong, MRCP, FHKAM (Emergency Medicine)2; HF Ho, FRCS, FHKAM (Emergency Medicine)2; John HM Chan, FRCP, FHKAM (Medicine)1; Patrick CK Li, FRCP, FHKAM (Medicine)1
1 Division of Neurology, Department of Medicine, Queen Elizabeth Hospital, Jordan, Hong Kong
2 Department of Accident and Emergency, Queen Elizabeth Hospital, Jordan, Hong Kong
 
Corresponding author: Dr WC Fong (fwcz01@ha.org.hk)
 Full paper in PDF
Abstract
Objective: To compare the outcomes of patients with warfarin-associated intracerebral haemorrhage given different treatments to reverse the effect of anticoagulation.
 
Design: Historical cohort study.
 
Setting: A regional hospital in Hong Kong.
 
Patients: Patients on warfarin who developed intracerebral haemorrhage.
 
Interventions: Prothrombin complex concentrate versus fresh frozen plasma treatment.
 
Main outcome measures: The primary outcome measures included the international normalised ratio before and after prothrombin complex concentrate treatment and the neurological deterioration in patients with Glasgow Coma Scale score of more than 8/not intubated/not planned for immediate surgery (target group). Secondary outcome measures were haematoma expansion, 7-day and 30-day mortality rates, and 3-month functional outcome. Safety outcome was the occurrence of a thrombotic event after prothrombin complex concentrate treatment within the index admission.
 
Results: Among 33 patients with clearly documented time of infusion of prothrombin complex concentrate, and whose international normalised ratio was checked before and after prothrombin complex concentrate treatment, the mean international normalised ratio was reduced from 2.81 to 1.21 within 24 hours. Within the target group of patients, there was a significantly lower rate of neurological deterioration in the prothrombin complex concentrate group (17.4% of 23 patients) versus fresh frozen plasma group (45.5% of 33 patients) [P=0.027]. In terms of the 7-day mortality, 30-day mortality, and 3-month functional outcome, prothrombin complex concentrate–treated group showed a favourable trend although the difference did not reach a statistical significance. No patient developed thrombotic complications after prothrombin complex concentrate treatment.
 
Conclusions: Prothrombin complex concentrates can reverse the warfarin effect of prolonged international normalised ratio in a timely manner. It might better improve the outcome of warfarin-associated intracerebral haemorrhage compared with fresh frozen plasma treatment by reduction in neurological deterioration.
 
 
New knowledge added by this study
  •  Outcome of warfarin-associated intracerebral haemorrhage might be improved by prothrombin complex concentrate treatment.
Implications for clinical practice or policy
  •  Prothrombin complex concentrate should be considered the first-line reversal agent for patients with warfarin-associated intracerebral haemorrhage unless contra-indicated.
 
 
Introduction
Warfarin-associated intracerebral haemorrhage (ICH) is associated with high mortality of 40% to 60%. Compared with spontaneous ICH, it has a higher mortality rate and poorer functional outcome.1 2 Up to 50% of patients will have haematoma expansion within 24 hours, and the haematoma expansion time interval is more prolonged versus those with spontaneous ICH.3 Predictors of poor outcome include age, Glasgow Coma Scale score (GCS) on admission, baseline haematoma volume, and haematoma expansion2 4; of these, haematoma expansion is the only predictor that can be modified upon admission. Controlling/limiting haematoma expansion, thus, serves as the target for improving the outcome.
 
Prompt reversal of anticoagulation has been found to decrease haematoma expansion, especially if it can be reversed within 2 hours of admission.5 6 The available agents for this include vitamin K, fresh frozen plasma (FFP), prothrombin complex concentrates (PCC), and recombinant factor VII (rFVIIa). Vitamin K should be given to all patients for sustained international normalised ratio (INR) reversal; however, given by itself, it is associated with a slow onset of action. Prothrombin complex concentrate contains factor II, IX, X (3-factor), and some preparations also have factor VII (4-factor). If only 3-factor PCC are available, as in the case of hospitals in Hong Kong, it has been recommended to give additional FFP to replenish factor VII levels.7 8 Prothrombin complex concentrates are preferred over FFP alone for warfarin reversal as these can be given quickly without any need for cross-matching of blood or thawing, and have a much smaller volume of infusion, decreasing the risk of volume overload. The onset of action is much faster than FFP and the INR can be reversed in as early as 15 minutes after infusion; in contrast, FFP may take hours for INR reversal. Prothrombin complex concentrates are readily available, are less expensive than rFVIIa, and have a longer half-life than rFVIIa.1 Many international societies recommend PCC as the first-line agents for warfarin reversal in emergency situations.9 10 11 12 Those recommendations are, however, mainly based on rapid reversal of INR by PCC. Currently, there is no prospective, randomised study comparing PCC versus FFP in terms of the long-term functional outcomes. In Hong Kong, PCC are not commonly used for warfarin reversal, probably because these have not been proven to be superior to FFP in large-scale studies, and are associated with a low but definite risk of thrombosis.
 
Our hospital started formal implementation of PCC protocol for warfarin-associated ICH in 2011, initially in the Department of Medicine, and subsequently in the Accident and Emergency Department and Department of Neurosurgery (Fig 1) [while PCC were used in 2010, a formal protocol was not implemented until 2011]. The PCC preparation in our hospital was Prothrombinex-HT, and was later supplied as Prothrombinex-VF (3-factor; CSL Behring, Broadmeadows, Australia). Our protocol recommends the prompt use of the 3-factor PCC with dosage based on INR level, together with intravenous injection of 10 mg vitamin K and 2 units of FFP upon diagnosis, and rechecking INR 30 minutes after administration of PCC; additional warfarin reversal agents are given provided the INR remains high.
 

Figure 1. Dose protocol for administering prothrombin complex concentrates in QEH, Hong Kong
Upon diagnosis of warfarin-associated ICH, the management would be stratified based on the availability of INR values. If INR values were not available, an empirical PCC dose would be given first depending on whether the patient had an underlying mechanical heart valve. The PCC dose would be adjusted after the INR result was available
 
The objectives of this study were to review the use of PCC in our hospital (including the use, dosage, complications) and to compare the clinical outcomes with patients given FFP treatment, with the ultimate aim of looking for indirect evidence of benefit of PCC over FFP treatment.
 
Methods
This was a retrospective review of patients admitted to Queen Elizabeth Hospital, a tertiary hospital in Hong Kong. Data on patients with ICH and use of warfarin prior to admission were retrieved from the Clinical Data Analysis and Reporting System. Data of patients who were treated with PCC from February 2011 (start of implementation of PCC protocol) to September 2013 were analysed. This was the PCC group. Similarly, data from January 2007 to September 2013 were reviewed and data of patients given treatment other than PCC were analysed. Only patients given FFP were included in the comparison arm. This was the FFP group.
 
Patients given no reversal agents or solely given vitamin K were not included in this study. One patient given rFVIIa was excluded. Patients with known or suspected secondary causes of bleeding such as tumour bleeding, underlying subacute bacterial endocarditis, and vasculitis were excluded. Patients with haemorrhagic transformation of infarct, subdural haemorrhage, and subarachnoid haemorrhage were excluded. One patient who was started on warfarin reversal agent in another hospital and later transferred to our hospital after a few days was also excluded.
 
From the case records, all data including demographics (age, sex, indications for anticoagulation, concomitant use of antiplatelet agent, co-morbidities such as diabetes, hypertension, ischaemic heart disease, prior stroke), clinical state at the time of admission (GCS, limb power), management including reversal agents used (vitamin K, FFP, PCC), intubation, and whether surgery had been performed were reviewed. Laboratory data (INR on admission and after PCC use) and radiological data (baseline haematoma volume and follow-up computed tomography [CT] brain scans) were reviewed from the Electronic Patient Record system. The CT scans were reviewed by two authors who were not blinded to the treatment information, while the intracerebral haematoma volume was calculated based on the ABC/2 score.13 Haematoma volume within the ventricular extension was estimated by using the intraventricular haemorrhage score.14
 
The primary outcome measure was neurological deterioration, defined as ≥2-point decrease in GCS or limb power. This was selectively studied in patients with an initial GCS of more than 8, who were not intubated and who were not initially considered for surgery upon diagnosis of ICH, ie those who were initially selected for medical treatment (target group). The rationale for this was that the patients who have the maximum benefit from rapid reversal agents are those with initial good GCS, for whom the agents can prevent further deterioration. Patients with poor GCS due to large ICH upon presentation probably do not benefit much from rapid reversal. The secondary clinical outcome measures were haematoma expansion (defined as >33% increase in haematoma volume),15 7-day and 30-day mortality rates, and modified Rankin scale (mRS) on 3 months of follow-up.
 
Statistical analysis was performed using the Statistical Package for the Social Sciences (Windows version 20; SPSS Inc, Chicago [IL], US). Proportion between groups was compared using the Fisher’s exact test, and continuous variables were compared using the Wilcoxon rank sum test. P value was considered significant if it was less than 0.05.
 
Results
Figure 2 shows the recruitment of patients with warfarin-associated ICH identified before and after protocol implementation and the subsequent formation of cohorts for analysis.
 

Figure 2. Recruitment of patients with warfarin-associated intracerebral haemorrhage before and after prothrombin complex concentrates protocol implementation and formation of cohorts for analysis
 
Analysis of use of prothrombin complex concentrates (from February 2011 to September 2013 after implementation of protocol)
Of 70 patients who had warfarin-associated ICH, 61 were given PCC, and nine patients were not given PCC for the following reasons: too ill for undergoing CT brain when stroke was suspected, and stroke confirmed only afterwards (n=1); nearly moribund state on admission (n=6; one of these had concomitant allergy to FFP and two had recent pulmonary embolism/deep vein thrombosis); and small ICH size (0.07 cm3) and symptom onset more than 1 week ago with a mechanical heart valve and carotid stent (n=1). No reason was documented for one patient.
 
Only 41 out of the 61 patients given PCC from February 2011 to September 2013 were included in the PCC group for INR analysis and for comparison with the FFP group. Twenty patients were excluded because the reversal treatment regimen had been modified by the treating clinicians and was different from our protocol (n=17), and patient records were kept by other parties and we failed to confirm the dose given (n=3).
 
Their mean age was 74 years and their mean GCS on presentation was 11. A total of 18 patients had GCS of ≤8/were immediately intubated/planned for operation; 16 patients had GCS of >13 on presentation.
 
Dosage of prothrombin complex concentrates and reversal of warfarin effect
Among the 41 patients, time of infusion of PCC was clearly documented and INR was checked before and within 24 hours after PCC infusion in 33 patients. The mean pre-PCC INR was 2.81 (interquartile range [IQR], 1.95-2.92) and the mean post-PCC INR was 1.21 (IQR, 1.09-1.39). In 29/33 (87.9%) patients, INR was reversed to ≤1.4 in the post-PCC INR test. The mean time of checking the INR post-PCC was 4 hours and 15 minutes. In 11 patients, INR was checked within 2 hours after PCC had been given. Nine (81.8%) out of these 11 patients achieved INR of ≤1.4 within 2 hours, with mean pre-PCC INR being 2.43 (IQR, 2.05-2.73) and mean post-PCC INR being 1.27 (IQR, 1.17-1.40).
 
Haematoma expansion
One patient underwent brain imaging in a private hospital and, thus, the baseline haematoma volume could not be traced. Of the 41 patients, 32 underwent follow-up CT brain within 7 days (within 48 hours in 27 patients, within 2 to 3 days in two patients, and between 3 and 7 days in three patients). Of these 32 patients, seven (21.9%) had haematoma expansion. In three out of these seven patients, INR was checked within 2 hours and corrected to ≤1.4. The INR was not rechecked promptly in the remaining four patients.
 
Thromboembolic complications
One patient had an ischaemic infarct 19 days after ICH. This patient had underlying atrial fibrillation and warfarin was withheld after admission. There were, otherwise, no patients with recorded thromboembolic events within the index admission in the whole group of 61 patients given PCC.
 
Comparison between two groups receiving either prothrombin complex concentrates or fresh frozen plasma
Fifty-seven patients identified from January 2007 to September 2013 had warfarin-associated ICH which was not treated with PCC. Of these, only 44 patients were finally included in our analysis for comparison with the PCC group. Ten patients had not been given any warfarin reversal agents. Three other patients were excluded—one had started warfarin reversal agents in another hospital and was later transferred to our hospital days (for geographical reasons); one was given rFVIIa; and in one patient the diagnosis of ICH was made retrospectively, after cardiac arrest.
 
Mortality and functional outcome in the whole group
The outcomes of both groups were similar in terms of 7-day and 30-day mortality rates and 3-month mRS (Table 1). However, there were differences in terms of proportion of target group patients. In the PCC group, 43.9% had GCS of ≤8/intubated/already planned for operation on admission; in contrast, only 25% from the FFP group were in this group (Table 2). Since patients with poor GCS were associated with poor outcomes, such baseline differences probably abolished the treatment effect of PCC over FFP.
 

Table 1. Outcomes of the two groups
 

Table 2. Comparison of baseline data between the two groups
 
Outcome analysis in the target group
As more than 40% of our patients had a GCS of ≤8 on presentation, and were destined to have a poor functional outcome, we selectively compared the outcome in patients of the target group (GCS >8, not intubated, not initially considered for surgery upon diagnosis of ICH) as planned. Their baseline characteristics were similar, apart from age which was higher in the PCC group (Table 3). The neurological deterioration rate was significantly lower in those given PCC (n=4/23; 17.4%) versus those given FFP (n=15/33; 45.5%; P=0.027). After adjustment for age by logistic regression, PCC treatment was independently associated with lower risk of neurological deterioration (odds ratio=0.256; 95% confidence interval, 0.069-0.956; P=0.043).
 

Table 3. Baseline and outcome comparison between different treatments in the target group
 
Among patients who underwent follow-up CT scan, haematoma expansion was lower in patients given PCC for warfarin reversal (n=3/19; 15.8%) versus those given FFP (n=10/25; 40.0%; P=0.078). Within the target group, the 7-day and 30-day mortality rates were lower in PCC-treated patients (with PCC: 8.7% and 17.4%; with FFP: 12.1% and 30.3%, respectively) but the differences were not significant (Table 3). More patients were able to walk without assistance on follow-up at 3 months in the PCC group versus the FFP group, without any significant increase in dependency.
 
Additional analysis of all patients treated with prothrombin complex concentrates
Of 61 patients given PCC, 20 were excluded from target group analysis because they had not been given PCC according to the protocol (in the form of PCC dose variation or without concomitant FFP). Since there might be a potential possibility of selection bias with one third of the patients excluded from analysis, we repeated the analysis by including all the 61 patients. Among the 20 additional patients, 12 patients fulfilled the criteria of target group (GCS >8, not intubated, not initially considered for surgery upon diagnosis of ICH). Hence, the number of PCC patients in the target group was increased from 23 to 35. On comparison between all patients given PCC, irrespective of whether it was given according to the protocol (n=35) and patients given FFP (n=33), the neurological deterioration rate remained significantly less in the PCC group (n=7/35; 20% vs n=15/33; 45.5%; P=0.023). The haematoma expansion rate was 21.9% (n=7/32) in the PCC group, and 40% (n=10/25) in the FFP group (P=0.117). There were no significant differences in the 7-day, 30-day mortality rates, and 30-day functional outcome.
 
Discussion
Warfarin-associated ICH is associated with a poor outcome and high mortality, and different studies have demonstrated that haematoma expansion is a causative factor. Prompt reversal of anticoagulation has been demonstrated to decrease haematoma expansion, and improve outcome.16 In Huttner et al’s study,5 reversal of INR within 2 hours was associated with less haematoma expansion, and more patients could achieve this with PCC than with FFP. Our study similarly showed that PCC given according to our protocol could adequately reverse INR in a timely manner.
 
However, a significant improvement in long-term outcomes and decrease in mortality compared to FFP treatment were not well demonstrated in our study; these findings are also not observed in data from published studies. This is partly due to the difficulty in recruiting large number of patients to demonstrate a meaningful difference in outcome.17 Furthermore, we postulate that not all patients will benefit from rapid reversal of INR by PCC as compared with FFP treatment. Patients with low level of consciousness are associated with poor outcome,4 which might not be improved no matter what kind of reversal treatment is implemented. In order to demonstrate improvement in clinical outcome, studies should stratify patients according to the neurological state on admission or depending on whether surgery has been performed, both of which will affect interpretation of the outcome.
 
On analysis of the whole PCC group irrespective of GCS, the 30-day mortality rate was 41.5% in our study. The 30-day mortality rate among those with GCS of ≤8, intubated or planned for surgery on presentation was 72.2% (n=13/18 patients), whereas it was 17.4% (n=4/23 patients) in those in the target group. As the mortality rate and functional outcome are confounded by the baseline GCS level and also by whether surgery has been done and the outcome of the surgical procedure, we targeted our study on the incidence of neurological deterioration for patients with a fair-to-good admission GCS and who had initially decided to receive conservative medical treatment. This was the target group of patients who was likely to benefit the most from timely treatment in terms of decreased chances of haematoma expansion and neurological deterioration and subsequent poor functional outcome and death. Our study showed that PCC treatment did decrease the risk of deterioration significantly. And to the best of our knowledge, it is the first study to demonstrate that the potential benefit of PCC over FFP is derived from patients with GCS of >8 when treatment is started. Such benefit in the reduction of neurological deterioration probably accounted for the trend towards a lower mortality rate and better functional outcome (mRS, 0-3) in the PCC group compared with the FFP group, even though the result was not statistically significant (which might be related to the small sample size). Equally important is the finding that PCC use was not associated with a significant increase in dependency on follow-up at 3 months. This is an important finding as it suggests that decreased mortality with PCC treatment is not associated with an increase in the number of patients in severely dependent state.
 
It is important to recognise that haematoma expansion and deterioration can occur even in patients with small haematomas, with the chances of neurological deterioration being higher and the duration more prolonged compared with those with spontaneous ICH.3 We postulated that patients with small haematomas or stable GCS are the ones who would benefit most from PCC treatment as it can reduce the chances of subsequent deterioration due to haematoma expansion if the bleeding tendency is not rapidly reversed. Treatment should be initiated as soon as possible before any haematoma expansion develops. Initiation of PCC treatment at accident and emergency level, even before INR result is available (as in our protocol), is probably an important factor for improving the outcome of our patients.
 
The main concern in the use of PCC instead of FFP is the associated risk of thrombosis. In our study, one patient developed an acute ischaemic stroke 19 days after the ICH episode. The elimination half-lives of factor II, factor IX, and factor X within the Prothrombinex-VF are 60 hours, 20 hours, and 30 hours, respectively.18 Hence, the ischaemic stroke was likely related to the underlying atrial fibrillation rather than to PCC treatment as the time interval between its use and the ischaemic stroke was more than five half-lives of PCC. However, in view of the small sample size of our study, the safety of PCC treatment with our protocol cannot be definitely demonstrated. From other reviews, the incidence of thrombotic events was about 1%, including deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischaemic stroke but this risk of thrombosis was also related to the underlying indication of anticoagulation in the first place.11 18 19 Also, the risk may be lower with newer preparations of PCC.18 In view of this low thrombotic risk and high risk of haematoma expansion, the benefit of PCC for rapid reversal of anticoagulation effect probably overweighs the risk from its thrombogenicity, except in the presence of contra-indications for PCC treatment, namely evidence of active thrombosis or disseminated intravascular coagulation. Patients treated with PCC should be observed closely for symptoms or signs of thrombosis, embolism, myocardial infarction, ischaemic stroke, and disseminated intravascular coagulation.
 
Limitations
The most important limitation is that it is a retrospective comparative study of two cohorts, instead of a randomised study. Although FFP was the only treatment available for patients before the introduction of PCC protocol, and PCC was given to most patients after the protocol was implemented; potential bias in the selection of treatment might still occur. Some patients might be excluded from PCC or any treatment because of their moribund status. Also, for this study of two sequential cohorts, there might be potential bias in that the standard of acute care of ICH might have improved over this 7-year period, leading to better outcomes in the PCC treatment group.
 
The other limitation is that the data collected were neither complete nor standardised due to the retrospective nature of study design. International normalised ratios were not checked regularly at fixed time intervals post-PCC; similarly, follow-up CT brain scans were not performed in all patients. Thus, the number of patients available for analysing the adequacy of prompt INR reversal and haematoma expansion was not large. Although the PCC protocol recommended measuring the INR 30 minutes after PCC administration, it was not always performed in a busy clinical setting. Patients who were regarded stable or too unstable might not have undertaken follow-up CT brain to look for haematoma expansion. Bias might also have occurred while measuring haematoma volumes since the raters were not blinded to the treatment given and volumetric analysis of haematoma size was not available. As a result, the validity in assessment of INR reversal and haematoma expansion was diminished. In view of the potential selection and measurement bias inherited from the study design, the favourable trend of the PCC treatment should be interpreted with great caution. Similarly, the retrospective design of the study did not allow pre-specified investigations to reveal the potential thrombotic complications of PCC. It was unreliable to diagnose those complications based on review of case notes alone, especially in such a group of ICH patients with impaired conscious level. As a result, the safety of PCC treatment remained unconfirmed in this study.
 
Conclusions
The current study suggests that the use of PCC in the management of warfarin-associated ICH can promptly normalise the INR. It showed a trend of outcome improvement in terms of reduction in the risk of subsequent neurological deterioration, without an increase in dependency. Whilst we await results from an ongoing randomised study20 to provide us with high-level evidence, PCC should be considered the first-line reversal agent for patients with warfarin-associated ICH after its potential benefit has been weighed against its small but definite risk of thromboembolism.
 
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