DOI: 10.31038/IMROJ.2017221

Abstract

Background: Molecular tools for detection of low-density asymptomatic Plasmodium infections are needed in malaria elimination efforts. This study reports results from the hitherto largest implementation of loop-mediated isothermal amplification (LAMP) for centralized mass screening of asymptomatic malaria in Zanzibar.

Methods: Healthy individuals present and willing to participate in randomly selected households in 60 villages throughout Zanzibar were screened for malaria by rapid diagnostic tests (RDT). In 50 % of the study households, participants were asked to provide 60 μL of finger-prick blood for additional LAMP screening. LAMP was conducted in two centralized laboratories in Zanzibar, by trained technicians with limited or no previous experience of molecular methods. The LAMP assay was performed with LoopampTM MALARIA Pan/Pf Detection Kit (Eiken Chemical Company, Japan). Samples positive for Plasmodium genus (Pan)-LAMP were re-tested using Plasmodium falciparum-specific LAMP kits.

Results: Paired RDT and LAMP samples were available from 3983 individuals. The prevalence of asymptomatic malaria was 0.5 % (CI 95 % 0.1-0.8) and 1.6 % (CI 95 % 1.1-2.2) by RDT and Pan-LAMP, respectively. LAMP detected 3.4 (CI 95 % 2.2-5.2) times more Plasmodium positive samples than RDT. DNA contamination was experienced, but solved by repetitive decontamination of all equipment and reagents.

Conclusions: LAMP is a simple and sensitive molecular tool, and has potential in active surveillance and mass-screening programmes for detection of low-density asymptomatic malaria in pre-elimination settings. However, in order to deploy LAMP more effectively in field settings, protocols may need to be adapted for processing larger numbers of samples. A higher throughput, affordable closed system would be ideal to avoid contamination.

Keywords

Plasmodium, Malaria, Low-density, Asymptomatic, Loop-mediated isothermal amplification, Mass screening, DNA contamination

Background

Asymptomatic Plasmodium infections are an important reservoir for continued malaria transmission that needs to be addressed in the context of malaria elimination [1]. Detection of asymptomatic infections, which are often sub-patent, i.e., fall beneath the threshold of detection of both microscopy and rapid diagnostic tests (RDT), requires highly sensitive molecular tools. The use of polymerase chain reaction (PCR)-based assays in field settings is, however, limited due to the need for a cold chain, specialized equipment and know-how [2]. Loopmediated
isothermal amplification (LAMP) offers several advantages over PCR in field settings. LAMP requires minimal equipment, has short time-to-result (30 min-1 h), with an analytical sensitivity similar to PCR, and results that can be read by eye using UV fluorescence [3–5].

The Loopamp™ MALARIA Pan/Pf Detection Kit (Eiken Chemical Company, Japan) has been developed as a
field-friendly kit, comprising strips of reaction tubes containing vacuum-dried and temperature-stable reaction
components for either Plasmodium genus (Pan)-specific or Plasmodium falciparum-specific malaria detection. The
kit has been evaluated both in laboratory and field settings [6–8], and was piloted on a small scale in Zanzibar as a health facility-based, point-of-care, diagnostic tool for mass screening and treatment in 2013 [9].

This study reports results from the hitherto largest implementation of LAMP in the field, for scaled-up,
centralized mass screening of asymptomatic malaria in Zanzibar, a pre-elimination setting.

Methods

Study sites and study design

Zanzibar, located 35 km off the coast of mainland Tanzania, consists of two main islands, Unguja and Pemba, with respective populations of approximately 900,000 and 400,000. This study was performed as part of a larger knowledge, attitude, practice, and behavior (KAPB) malaria survey, conducted in Zanzibar April-May 2014. Household visits were carried out in 60 villages in ten districts (six in Unguja and four in Pemba) covering
the whole of Zanzibar. A proportional number of households were sampled from each village to reach a sample
size of 2162 households, powered for the KAPB study. Healthy individuals present and willing to participate in
the randomly selected households were screened for malaria by RDT. In 50 % of study households (in even
house numbers), participants were asked to provide 60 μL of finger-prick blood for additional LAMP screening.
Nexus seven tablet computers were used to conduct questionnaires as part of the KAPB survey. All participants or
guardians provided written informed consent prior to blood sampling. Ethical approvals were obtained from the ethical committees in Zanzibar (ZAMREC/0002/FEBRUARY/014) and the Regional Ethics Committee in Stockholm (2009/387-31).

Training of field enumerators and sample collection

Household visits were conducted by 40 field enumerators in teams of two, together with four field supervisors with prior experience of similar studies. All enumerators attended five days of training for RDT performance, blood sample collection for LAMP, and use of tablet computers. There were 14 teams in Unguja and six teams in Pemba, and each team visited six or seven households per day. RDT screening was conducted with either SD-Bioline Malaria Ag P.f/PanW (Standard Diagnostic, Inc, USA) (used for >90 % of screening) or First ResponseW Malaria Ag Combo (pLDH/HRP2) (Premier Medical Corporation Limited India). Results were recorded on the tablet computer during household visits, and RDT positive indi-viduals were referred to the closest health facility for treat-ment and registration in the Zanzibar malaria surveillance system. In 50 % of study households, 60 μL of finger-prick blood was collected using a plastic capillary tube (Dropstir, Medical Precision Plastics, USA), dispensed into a 1.5-ml pre-labelled sample collection tube containing 60 μL of pre-aliquoted DNA extraction buffer (400 nM NaCl, 40 mM Tris pH 6.5, 0.45 SDS), and mixed by flicking. Blood samples were collected in microtube storage racks with lids and transported at the end of each day to two centralized laboratories, one on each island, where they were stored at 4 °C overnight.

Training of laboratory technicians

Four technicians, two for each laboratory, with limited or no experience of LAMP were trained over three-and-a-half days. Training included a theoretical introduction to LAMP and the LAMP protocol, hands-on practical sessions with malaria positive blood samples diluted to different known concentrations, how to record results on tablet computers, and a half-day field trial with sam-ples collected the same day by the field enumerators.

Screening by LAMP in centralized laboratories

LAMP procedures were similar to the pilot study [9], with some modifications for scale-up of sample sizes. One cen-trifuge, three heat-blocks (1.5-ml block at 95 °C, 0.2-ml block at 65 °C and a 0.2-ml block at 95 °C) and a UV lamp were required in each laboratory. All samples collected in Pemba and half of the samples collected in Unguja (see below) were processed within 24 h of sampling. To reduce the risk of mix-up of samples and contamination, sets of pre-labelled sample collection tubes (containing 60 μL of aliquoted DNA extraction buffer) and pre-labelled DNA dilution tubes (containing 300 μL of aliquoted sterile water) were prepared prior to the start of the study. DNA extraction and the LAMP assays were performed in separ-ate areas to avoid contamination. DNA was extracted by the boil and spin method [10] and 26 μL of the super-natant was transferred to the DNA dilution tubes. The LAMP assay was performed with Loopamp™ MALARIA Pan/Pf Detection Kit (Eiken Chemical Company) as per protocol [10]. Samples positive for Pan-LAMP were retested using P. falciparum-LAMP specific kits. LAMP positive individuals (who were not positive by RDT) were visited by malaria surveillance officers and provided treat-ment within 48 h of sampling where possible.

Freezing of samples

Due to a delay in the shipment of LAMP kits, half of the LAMP samples collected in Unguja (N = 1414) were stored at −20 °C after DNA extraction and dilution, until the remaining reaction tubes arrived five weeks later. Dilution tubes from LAMP-positive samples in Unguja were also stored at −20 °C, for quality control of frozen DNA.

Statistical

Results are reported from individuals for which both RDT and LAMP were conducted (i.e., where paired data are available). Statistical analyses were conducted using Stata/SE 12.1 (StataCorp LP, Texas, USA). The survey de-sign was taken into consideration when calculating 95 % confidence intervals (CI 95 %) for prevalence estimations, using the survey [svy] command in Stata accounting for household and village sampling/stratification. The sensi-tivity and specificity of RDT was calculated using LAMP as the gold standard. McNemar’s test was used to compare the methods. Statistical significance was determined as p < 0.05.

Results

Study population

Participation was high; informed consent was given by 96.9 % of those present at the time of the survey (Fig. 1). Both RDT and LAMP results were available for 3983/4085 (97.5 %) of the individuals willing to participate. The remaining 102 (2.5 %) were excluded from further ana-lysis. The study population consisted of all ages (median: 18 years, range 0–98), with a higher proportion of females (59.0 %). Sample collection was conducted during a total of 19 days with an average of 220 samples processed per day in the two laboratories combined.

Prevalence of malaria by RDT and LAMP

The prevalence of asymptomatic malaria was 0.5 % (CI 95 % 0.1-0.8) and 1.6 % (CI 95 % 1.1-2.2) by RDT and Pan-LAMP, respectively (Table 1). Pan-LAMP detected 3.4 (CI 95 % 2.2-5.2) times more Plasmodium positive samples than RDT. Out of the Pan-LAMP positive sam-ples 64.6 % (42/65) were also positive by P. falciparum-LAMP. RDT had a sensitivity of 24.6 % (14.7-36.9) and specificity of 99.9 % (99.7-100.0) when compared to Pan-LAMP. Comparison by McNemar’s test showed a signifi-cant difference between the two methods (p <0.001).

Table 1. Prevalence of malaria detected by RDT and LAMP

	RDT	LAMP
Overall prevalence (%; CI 95 %a)	0.5; 0.1-0.8 19/3983	1.6; 1.1-2.2 65/3983
Relative proportion positive in:
Only Panb (%; CI 95 %)	5.3; 0.0-16.4 1/19	35.4; 23.4-47.4 23/65
Pan + P. falciparumc (%; CI 95 %)	31.6; 8.5-54.6 6/19	64.6; 52.6-76.6 42/65
Only P. falciparumd (%; CI 95 %)	63.2; 39.2-87.1 12/19	NDe

Both RDT brands used for malaria screening are two-band RDTs detecting P. falciparum HRP2 and Pan-Plasmodium LDH simultaneously, although with different detection limits (50–100 parasites/μL for P. falciparum HRP2 and 200–500 parasites/μL for Pan-Plasmodium LDH). In contrast, only the Pan-LAMP positive samples were assessed for P. falciparum during the LAMP screening, with a detection limit of 2–5 parasites/μL for both Pan-Plasmodium
and P. falciparum

^aConfidence intervals for prevalences were calculated using the survey [svy] command in Stata, accounting for household and village sampling/stratification
^bPositive for Plasmodium genus only
^cPositive for Plasmodium and P. falciparum
^dPositive for P. falciparum only
^eND = not determined

Discrepancies in LAMP after freezing of samples

DNA extracted from half of the samples (N = 1414) in Unguja was stored at −20 °C prior to LAMP testing due to a delay in the shipment of LAMP kits. Among these samples, 32 (2.3 %) were positive by Pan-LAMP, out of which 12 was also positive by RDT. However, amongst the frozen samples there were also three RDT positive samples that were found negative by Pan-LAMP. These three samples were positive for P. falciparum HRP2 only, Pan-Plasmodium LDH only, and both P. falcip-arum HRP2 and Pan-Plasmodium LDH, respectively. Among the samples from Unguja that were screened be-fore freezing (N = 1370), 11 (0.8 %) were positive by Pan-LAMP, out of which one was also positive by RDT. The 11 Pan-LAMP positive samples were stored at −20 °C, as a quality control of freezing DNA, however only 7/11 (63.6 %) were positive when re-tested after thawing.

LAMP-amplified DNA contamination

During the study DNA contamination of LAMP arose in the central laboratory in Pemba [see Additional file 1 for flow chart of events]. The contamination resulted from using a heat block with a heated pressurized lid during the 95 °C enzyme inactivation stage, and not allowing the samples to cool to room temperature before removing the strips for recording of results. ‘Fizzing’ was observed around the lid of the LAMP strips resulting in leakage of LAMP-amplified DNA. All equipment and reagents were subjected to repetitive decontamination with 5 % sodium hypochlorite over three days, and moved away from the epicentre of the contamination to a laboratory space avail-able in another building. The final enzyme inactivation step of the protocol [10] was removed as this was thought to be the source of contamination; instead results were read and recorded immediately after the amplification re-action. A negative control was included in each strip of eight reaction tubes, and any Pan-LAMP positive samples were repeated and only recorded as positive if positive in both runs. During the first few days following the contam-ination there were some samples that were considered false positive, but the numbers declined and reached zero within one week after the contamination.

Discussion

This is the hitherto largest reported implementation of LAMP for detection of asymptomatic malaria in a field setting. In order to scale-up the breadth of sampling, LAMP testing was centralized in two laboratories, meaning samples could be collected from all over the islands with fewer resources. The time-to-result was ap-proximately 24 h, compared with three hours in the pilot study where LAMP was used as a health facility-based, point-of-care, diagnostic tool for mass screening and treatment [9].

The results confirm the improved sensitivity of LAMP over RDT, as has been shown previously [3, 9]. The MALARIA Pan/Pf Detection Kit has a detection limit of 2–5 parasites/μL [3, 6], for both Pan-Plasmodium and P. falciparum. This is comparable to PCR, and substantially lower than the detection limits of P. falciparum-specific HRP2 (50–100 parasites/μL) and Pan-Plasmodium LDH (200–500 parasites/μL) in combo RDTs. The proportion of samples detected only by Pan-LAMP (35.4 %) sug-gests the presence of species other than P. falciparum. Similarly, other studies in Zanzibar have shown that up to 40 % of PCR-detectable malaria infections contained non-falciparum species [11, 12]. Non-falciparum infec-tions tend to be of lower parasite densities than P. falcip-arum infections [13], emphasizing the need for more sensitive species-specific methods for non-falciparum Plasmodium detection. The sensitivity (83.8 %) and speci-ficity (99.7 %) of Pan-LAMP, calculated using PCR as the reference standard, was high in the pilot study conducted in Zanzibar [9]. This is similar to previously reported sen-sitivities and specificities [6–8, 14, 15] and, together with the results of this study, suggests malaria LAMP is a use-ful molecular tool sensitive enough for detection of low-density asymptomatic malaria infections in field settings.

Importantly, some discrepancies were shown amongst samples screened following freezing of diluted DNA. RDT false positivity due to recently cleared infections has been well documented when detecting P. falciparum HRP2 [16], although none of the three study participants who were RDT positive/LAMP negative reported receiv-ing malaria treatment within the previous two weeks, and two of the RDTs were positive for Pan-Plasmodium LDH suggesting ongoing infections. The lack of repro-ducibility of results following freezing of samples sug-gests that DNA extracted by simple methods such as boil and spin may not be suitable for long-term storage and should be amplified by LAMP within a short period of time [17]. Alternatively, low reproducibility of PCR for detection of low-density infections has been reported [18] and parasite densities close to the LAMP detection limit could also explain the lack of reproducibility.

The potential risk of contamination with LAMP is large, due to the high efficiency of the reaction, although the risk is reduced when using a closed system [3, 19]. The MAL-ARIA Pan/Pf Detection Kit is manufactured with tubes that cannot be re-opened once closed, in order to avoid contamination with amplified DNA. However, as demon-strated in this study, the exposure of such tubes to high temperatures, as during enzyme inactivation, results in softening of the plastic and leakage of the contents. While removing the inactivation step solved this problem in this case, contaminations have been experienced in other research settings [8, 20] and these issues are important to report. Although MALARIA Pan/Pf Detection Kit is a field-friendly option, three days’ training is not sufficient for dealing with such events. Successful decontamination requires a larger understanding of molecular techniques and rigorous repetitive methods to ensure that the area is free of contamination.

Standard malaria diagnostic tools including microscopy and RDT are not sensitive enough to detect low-density asymptomatic infections [12]. Nucleic acid amplification-based methods provide the, to date, most sensitive and ac-curate tools to detect and identify pathogens [21]. Recently published, highly sensitive quantitative PCR methods state detection limits as low as 0.02 and 0.03 parasites/μL blood [22, 23]. However, these methods lack the field applicability that LAMP offers. Furthermore, the cost of LAMP is estimated to be a tenth of that of conven-tional PCR [15], although the cost of the field friendly kit is still at 5.3 US$ per reaction i.e., considerably more expensive than RDTs [3].

The high cost and risk of contamination may yet limit the implementation LAMP at a point-of-care level, but LAMP will be valuable for research purposes and for evaluating malaria elimination efforts. LAMP may, for ex-ample, be useful in mass/focal screening and treatment (MSAT/FSAT) programmes, for which the deployment of RDTs, perhaps due to their low sensitivity, has had varying results [11, 24]. In any case it will be important to evaluate the impact and cost effectiveness of deploying LAMP, in comparison to the deployment of standard diagnostic tools as well as in comparison to alternative molecular methods.

Conclusions

LAMP is a simple and sensitive molecular tool, and has potential in active surveillance and mass-screening pro-grammes for detection of low-density asymptomatic mal-aria in pre-elimination settings. However, in order to deploy LAMP more effectively in field settings, protocols may need to be adapted for processing larger numbers of samples. A higher throughput, affordable closed system would be ideal to avoid contamination.

Competing interests

IG is an employee of the Foundation for Innovative New Diagnostics (FIND), a co-developer of the Loopamp™ MALARIA Pan/Pf Detection Kit. All other authors declare no competing interest.

Authors’ contributions

MIM, IJG, AM, ASA, AB, and JC conceived and designed the study. UM, MK, BAS, AKA, and JC carried out the training and were responsible for the fieldwork in Zanzibar. UM, BAS and MHN were responsible for the training and conducting of LAMP. UM and JC analysed the data, and drafted the manuscript. All authors read and approved the final manuscript.

Acknowledgments

We would like to thank all participants, staff members, and ZAMEP employees involved in the KAPB survey for their dedicated participation. We would also like to acknowledge Colin Sutherland, Spencer Polly, Michelle Hsiang and Alanna Schwartz for their intellectual input regarding experience of dealing with DNA contamination. This work was supported by Global Fund [Grant number ZAN-809-G07–M, work plan GFRD 8 phase 2 2013]; President’s Malaria Initiative (PMI) [Implementation letter # 45, work plan for FY 2013]; the Swedish Medical Research Council (VR) [grant numbers 2009–3785 and 2013–6594]; the Foundation for Innovative New Diagnostics (FIND) with funds from the German Federal Ministry of Education and Research (BMBF) through the KfW Entwicklungsbank; and the Einhorn foundation. In memoriam of Ali K Abass, a much missed friend and colleague.

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DOI: 10.31038/IMROJ.2016126

Abstract

Background: Helicobacter pyelori is endemic in Egypt and present a main cause of gastrointestinal bleeding.

Aim: Aim of this study is to evaluate the prevalence of Hpylori infection in hemophilic patients, and to assess its impact on gastrointestinal bleeding associated with this infection in such patients.

Methods: We prospectively investigated the prevalence of H. pylori infection in 40 Egyptian patients with hemophilia A, B and von Willebrand syndrome and 20 normal male subjects were included. Every patient and control subject in the study were tested one time for H. pylori stool antigen by ELISA. All patients and control subjects were tested for occult blood using Guaiac-based fecal occult blood test.

Results: Twenty eight out of 40 patients (70%) are H. pylori positive ; and 12 out of 20 control (60%) are H. pylori positive. The odds ratio is ‎‎1.55, 95% CI (0.6162 to 3.9269), ‎Significance level P = 0.3497. Among 28 H.pylori positive patients, 5 patients (17.9 %) tested positive for occult blood. Among the 12 H.pylori positive subjects ‎ in the‎ control group, only one tested positive for occult blood (8.3%). Odds ratio for Occult bleeding in H pylori positive patients and control was 2.39: P= 0.4504. None of the H. pylori negative patients or control subjects had a positive occult blood disease.

Conclusion: Patients with hemophilia, H. pylori should not be considered as an important cause of GI bleeding. The recurrence of the infection and GI bleeding could be prevented with eradication of H. pylori. Screening tests for H. pylori would not be needed in patients with hemophilia in endemic areas.

Keywords

Haemophilia, Hpyelori

Introduction

In Egypt, it is estimated that 5050 people with haemophilia and , 499 with vWD are registered within the six hemophilia treatment centers (www.wfh.org annual report 2013)

More than 50% of the world’s population harbor Helicobacter pylori in their upper gastrointestinal tract. Infection is more prevalent in developing countries, and incidence is decreasing in Western countries. [1]

According to world gastroenterology organization report in 2010, H.pylori incidence in adult Egyptians was 90% (www.worldgastroenterology.org)

It has been hypothesized that the host immunologic response against H. pylori plays a main role in determining gastric mucosal injury, through the release of cytokines and the action of autoantibodies against H1/K1-adenosine triphosphatase of gastric epithelial cells. [2]

Infection with H pylori is the main etiological factor for erosive gastritis and duodenal or gastric peptic ulcers that often complicat with life-threatening bleeding in patients with coagulation disorders. [3]

The Egyptian government provides approximately 38% of healthcare costs of treating haemophilic patients (www.wfh.org annual report 2013). Most hemophilia patients are treated with plasma or cryoprecipitate, resulting in a high risk of transfusing blood-borne diseases like HIV and hepatitis B and C. Factor concentrate is available only in limited quantities, and patients must travel long distances to get it.

There is a contradictory in the previous studies between prevalence of H pyelori and risk of GIT of bleeding, we prospectively investigated the prevalence of H. pylori infection in patients with hemophilia A or B or von Willebrand syndrome and it is impact on risk of bleeding in those patients and compare our results with others’.

Patients and methods

This is a case control study. All participants are adult patients ‎visiting the hematology clinic of kasr Al Aini hospital and ‎the Egyptian society of Hemophilia. The study received research ethical committee approval from Kasr Al Aini ‎medical school and all participants gave written consents. Forty patients with bleeding disorders (mean age 24); categorized as: 30 patients with Hemophilia A, 6 patients with Hemophilia B and 4 patients with VWD. Patients who received triple therapy before or Patients with liver cirrhosis, thrombocytopenia, any platelet or vascular defects or patients with peptic ulcer were excluded. Control group included 20 subjects (mean age 27) of the same socioeconomic level and the same exclusion criteria of the patients included in the study. Each Patient and control subject in the study were tested for H. pylori stool antigen by ELISA, This technique is non-invasive, rapid, easy-to-use, and shows good performance characteristics for diagnosis of H. pylori infections, with sensitivity, specificity, Positive predictive value (PPV),negative predictive value (NPV), and efficiency were 100%, 90.0%, 96.9%, 100%, and 97.6% respectively).[4] All Patients and control subjects were tested for occult blood using guaiac-based fecal occult blood test. [5] All diet and drug precautions were applied before obtaining samples to prevent false positive results as dietary restriction of both hemoglobin and vegetable peroxidase containing substances is essential for valid screening for occult blood.[6]

Statistics

Using SPSS V.16.0 for calculation of the means and z test for comparison between the prevalence of H. pylori infection among ‎Hemophilia A, Hemophilia B and von Willibrand patients and the prevalence of H. pylori infection among the control group to investigate whether there is a ‎difference in prevalence between both groups or not.

Comparison between the odds ratio (OR) of developing occult GI bleeding (indicted by positive guaiac test) among Hemophilia A, Hemophilia B and von Willibrand patients who test positive for H. pylori and the odds ratio of developing occult GI bleeding ‎ among the control group who test positive for H. pylori to investigate whether there is a relation between the possible risk and the outcome.

Results

The patients’ group included 40 male patients (‎30‏‎ patients with Hemophilia A (75%), ‎‏6 patients with Hemophilia B (15%), and 4 patients with VWD (10%)) with age ranged from 12 to 52 years (mean age 24 years).

Twenty eight out of 40 patients (70%) are H. pylori positive; and 12 out of 20 controls (60%) are H. pylori positive. Odds ratio: 1.55 ‎) 95% Confidence Interval: ‎0.6162 to 3.9269‎; P = ‎0.3497)

Among 28 H. pylori positive patients, 5 patients tested positive for occult blood (17.9 %). all patients positive for occult blood were also positive for H. pylori stool antigen. Among the 12 subjects positive for H. pylori in the control group subjects, only one tested positive for occult blood (8.3 %), and he was also H. pylori positive. Odds ratio was 2.3913 (95% Confidence Interval: 0.2485 to 23.0104; P = 0.4504). None of the H. pylori negative patients or control subjects had a positive occult blood disease.

Table 1 and Figure 1 & Figure 2 demonstrate the prevalence of H.pylori and occult bleeding in patients and control.

Table 1. Prevalence of H.pylori and occult bleeding in patients and control

Diagnosis	Occult Blood Positive		Occult blood negative
	H. pylori Positive	H. pylori Negative	H. pylori Positive	H. pylori Negative
Hemophilia A	5	0	15	10
Hemophilia B	0	0	4	2
VWD	0	0	4	0
Total	5	0	23	12

Discussion

The prevalence of H. pylori infection in patients with hemophilia A or B or von ‎Willebrand syndrome was investigated and compared to the prevalence of H. pylori infection in normal control subjects in many studies with variable results. In our study, we didn’t find significant difference between prevalence of H. pylori among hemophilia and VWD patients (70 %) n=40 and its prevalence among normal control subjects (60 %) n=20, the odds ratio is ‎‎1.55, 95% CI (0.6162 to 3.9269), z statistic 0.935, ‎Significance level P = 0.3497).The Prevalence of H. pylori revealed by this study doesn’t differ from the reported prevalence in ‎general population: 72.38% .[7] While the odd ratio of H. pylori infection is about 1.5; It is insignificantly higher for occult ‎bleeding detected by FOBT in absence of history of frank ‎bleeding; Odd ratio is 2.39, 95% Confidence Interval: 0.2485 to ‎‎23.0104, , P= 0.4504. Our case and control were matched for geographic distribution, age, socio economic status and educational level to avoid misleading results as described previously by wang.[8] Our results are also concomitant with Braden et al who found similar prevalence of Helicobacter pylori Infection in seventy patients with haemophilia and WVD and 100 age-related volunteers P value were statistically insignificant.[9] Also Eleftheriadis studied thirty-seven patients with hereditary haemorrahgic diseases and 26 control. ELISA was used to detect IgG, anti-CagA, and IgA antibodies to H. pylori in the serum and saliva. Result of this study revealed that 64.8% of the patients and 65.4% of the controls had H. pylori IgG antibodies in serum (P= 0.1 (. [10] Szczepanik also found that the prevalence of H. pylori infection in hemophilic patients in Poland was comparable to that in patients without coagulation disorders (49.3% vs 39% respectively P = 0.11).[3]

However our results were inconsistent with the study of upper gastrointestinal bleedings in patients with hereditary coagulation disorders in Northwest of Iran. The prevalence of H. pylori infection was investigated by stool antigen test, and serum serologic tests including immunoglobulin G and anti-CagA. Results Among 90 patients (81 men, nine women, mean age 31.30 ±10.72 years), 66 patients with hemophilia A, 10 patients with hemophilia B, six patients with Von Willebrand disease, five patients with platelet function disorders, and three patients with other factor deficiencies were evaluated. About 46.7% of patients in group A, and 23.3% of patients in group B were anti-CagA–positive (P = 0.02), whereas 76.7% of patients in group A and 51.7% of patients in group B had H. pylori immunoglobulin G antibodies (P= 0.02). H. pylori antigen in stool was positive in 76.7% in group A and 55% in group B (P = 0.03). [11]

Our study also found statistically insignificant increased risk of fecal occult ‎bleeding in absence of history of frank ‎bleeding in patients with hemophilia A; Odds ratio was ‎‎2.39, 95% (Confidence Interval: 0.2485 to ‎‎23.0104, z statistic: 0.755, Significance level: ‎P= 0.4504).‎

Though the prevalence of H pylori in Szczepanik et al. study were statistically insignificant however the gastrointestinal bleeding was reported in 46 patients (31.5%) with hemophilia and in two control group patients (2.0%) (P < 0.0001). Gastrointestinal bleeding was significantly more frequent in patients with hemophilia infected with H. pylori (33/46; 71.7%) than in patients with no H. pylori infection (13/46; 28.3%; P = 0.0002). Concluding that Helicobacter pylori infection is a risk factor for duodenal and gastric ulcer bleeding in hemophilia patients. [3]

Eyster et al detected antibodies against H. pylori in 14 (35%) of 40 subjects who had upper gastrointestinal bleeding event compared with 7 (17%) of 41 controls who were closely matched for age and other factors. Bleeding was substantially but not significantly increased (OR: 4.6; 95% CI: 0.3-83.9) with H. pylori seropositivity. [12]

Though Choe studied a group of haemophilic children but his results concluded significant role of H pylori in inducing GIT bleeding. Helicobacter pylori infection was found in four of six (66.7%) patients with GI bleeding (3, duodenal ulcer; 1, H. pylori associated chronic gastritis). The patients with H. pylori infection had an eradication treatment of triple therapy and no recurrence happened. [13]

According to our results screening for H. pylori should be routine work-up for all patients with hemophilia A, and all patients with positive stool antigen test should be treated immediately to prevent gastrointestinal bleeding, and to repeat testing to ensure eradication of the bacteria which may definitely lower the costs as was described by Schulman.[14]

Conclusion

Patients with hemophilia, H. pylori should not be considered as an important cause of GI bleeding. The recurrence of the infection and GI bleeding could be prevented with eradication of H. pylori. Screening tests for H. pylori would not be needed in patients with hemophilia in endemic areas.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent was obtained from all individual participants included in the study.

Authors declare no conflict of interest. Authors declare that the results have not been published previously and are not under submission elsewhere.

References

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• Braden B, Wenke A, Karich HJ, Dietrich CF, Scharrer I, et al. (1998) Risk of gastrointestinal bleeding associated with Helicobacter pylori infection in patients with hemophilia or von Willebrand’s syndrome.Helicobacter 3: 184-187. [crossref]
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• Dolatkhah R, Khoshbaten M, Asvadi Kermani I, Reza Bonyadi M, Ghojazadeh M, et al. (2011) Upper gastrointestinal bleedings in patients with hereditary coagulation disorders in Northwest of Iran: prevalence of Helicobacter pylori infection. Eur J Gastroenterol Hepatol 23:1172-7.
• Eyster ME, Asaad SM, Gold BD, Cohn SE, Goedert JJ (2007) Upper gastrointestinal bleeding in haemophiliacs: incidence and relation to use of non-steroidal anti-inflammatory drugs. Haemophilia 13:279-86.
• Choe BH, Kim JY, Lee JH, Kim JM, Chu MA, Cho SM (2010) Upper gastrointestinal bleeding in children with haemophilia: a clinical significance of Helicobacter pylori infection. Haemophilia 16:277-80
• Schulman S, Rehnberg AS, Hein M, Hegedus O, Lindmarker P, Hellström PM (2003) Helicobacter pylori causes gastrointestinal hemorrhage in patients with congenital bleeding disorders. Thromb Haemost 89:741-6.

DOI: 10.31038/IMROJ.2016125

Abstract

Background

Obesity results in both health and financial tolls for individuals and society. Despite the great efforts to increase awareness, the obesity epidemic continues at an alarming rate. Subcutaneous fat represents 85% of the fat mass in obese patients, while intra-abdominal fat, including both visceral and retroperitoneal adipose, represent about 15%. Both subcutaneous and visceral fat have a negative effect on individual health and promote metabolic diseases. Logic would thus suggest that adipose tissue removal by liposuction and/or visceral tissue removal could effect an improvement in metabolic diseases such as Type 2 diabetes?

Methods

The scientific literature was searched to illustrate and describe the effect of adipose tissue on metabolism and the effect of its removal on inflammatory and metabolic markers.

Results

Adipose tissue is an endocrine organ and in obesity serves as a source of systemic proinflammatory signals arising from stressed adipocytes and/or infiltrating macrophages. These signals are associated with insulin resistance, dyslipidemia and hypertension (metabolic syndrome). The benefits of fat removal on metabolic syndrome remain controversial.

Conclusion

Visceral and subcutaneous fat is associated with high risk of coronary heart disease, insulin resistance, and other metabolic risk factors. Abdominal lipectomy is a well-known cosmetic procedure and used widely for its benefits on improving body image. However, its benefit on the metabolic disorder remains inconclusive. On the other hand, current evidence would suggest that omentectomy offers no benefit in relation to improvements in systemic inflammation and metabolic control. Removal of visceral adipose tissue in and of itself would thus appear to have limited efficacy as an approach to the treatment of the obesity-related metabolic syndrome.

Key words

Visceral and subcutaneous fat, Liposuction, Omentectomy, Metabolic Syndrome

Introduction

Obesity is defined as a systemic disease that shows excessive and abnormal accumulation of body fat leading to adverse health effects. Obesity has negative effects on health and exerts significant financial tolls on individuals and society. Despite significant efforts to increase awareness, the obesity epidemic continues at an alarming rate [1]. More than 50% of the European population is overweight and up to 30% is obese with prevalence worldwide doubling since 1980 [World Health Organization 2011] [2].

Abdominal obesity is defined as increased visceral fat and trunk subcutaneous fat which leads to increased waist circumference [3]. The contribution of abdominal subcutaneous fat mass and the visceral fat mass to the pathogenesis of metabolic disease is controversial, but it is associated with high risk of coronary heart disease, insulin resistance, and other metabolic risk factors[3, 4].

Subcutaneous fat represents 85% of the fat mass in obese patients, while intra-abdominal fat, including both visceral and retroperitoneal adipose, represent about 15%[5]. Visceral obesity is presumed to predispose individuals to hepatic insulin resistance based on its anatomical site and venous drainage to the liver through the passage of adipocytes products into the portal vein[6-8].

Waist circumference [WC] and waist to hip circumference ratio [WHR] are used to measure abdominal obesity [9, 10], Body mass index [BMI] which equals the ratio of weight in kilograms divided by height in meters squared [kg/m2] is used to measure general obesity [11]. Each of these three parameters can be used to measure the association of obesity and metabolic risk factors, but the combination of the three [BMI, WC, and WHC] appears more useful than the use of BMI alone [12, 13].

Theoretically, WC cut-off results are >88 cm in women and >102 cm in men but actually, it is difficult to apply in all populations due to the marked difference in the average levels of measurement. Asians are characterized by higher morbidity at lower cut-off for WC than other populations [14].

The metabolic effects of visceral and subcutaneous adipose tissue

Although body fat mass distribution is characterized by marked individual variations it can generally be classified into the following four types, a]Abdominal subcutaneous: most of the fat stored subcutaneously around the stomach and chest, b]Lower body: fat storage around the thighs, hip, and buttocks, c] Overall coverage: fat accumulation in the arms, breast, thighs, buttocks, lower back and breast, d] Visceral: fat deposition within visceral cavity surrounding the viscera including stomach, intestine, liver and pancreas [Figure 1] [15].

More specifically, upper body fat distribution and increased visceral fat is more associated with metabolic dysregulation[16-18] than lower body and abdominal subcutaneous fat accumulation [19, 20]. Metabolic disorders associated with subcutaneous and visceral obesity include insulin resistance, type 2 diabetes [21, 22], dyslipidemia [23], and hypertension [24, 25].

Adipose tissue is an endocrine organ producing proinflammatory molecules from adipocytes and/or infiltrating macrophages in patients with high BMI, WC, and WHC [26]. These include tumor necrosis factor-alpha [TNF-α], C-reactive protein [CRP],interleukin-18 [IL-18], and interleukin-6 [IL-6] [27-30]. These cytokines have been linked to impairments in insulin action in liver, muscle, and adipose tissue [31-33].

TNF-α in obesity is increased in both systemic and portal circulation [32], which affects insulin sensitivity within adipocytes and stimulates secretion of IL-6 [34] Also, IL-6 concentration is 50% higher in the portal vein than in the peripheral circulation for patients with high visceral obesity [32].

Leptin and adiponectin expression is higher in subcutaneous fat compared with visceral adipose tissue [35, 36], but cytokine expression such as IL-6, IL-8 appears to be higher in visceral adipose tissue compared with subcutaneous fat [37].

Excess visceral and subcutaneous fat mass are associated with an elevation in postprandial [38] and post-absorptive fatty acid concentration in portal vein and systemic circulations [39]. Chronic exposure of the liver to the high concentration of free fatty acids promotes liver gluconeogenesis facilitating hepatic glucose production, thus providing a continuous source of energy and substrate that tends to raise fasting glycaemia [8, 40]. Increased insulin resistance and reduced fatty acid oxidation increase fat storage and synthesis in the liver [41-43].

Adipose tissue removal surgeries

Liposuction

Liposuction is one of the most common plastic surgeries and aims to remove subcutaneous adipose tissue from different body areas so as to improve body image and create more physical balance [44]. Since its introduction by Illouz 30 years ago, its popularity has rapidly increased, making it the second most common cosmetic surgical procedure in 2012 [313,011 patients] [45]. nearly 400,000 procedures are performed annually in USA [45].

The removal of subcutaneous fat with a blunt cannula attached to a suction generating device was first popularized in Europe in the late 1970s. The procedure of liposuction has undergone many refinements and evolved with improvement in techniques and technology since its introduction by Illouz in 1982 [46-48].

a) Traditional liposuction

Liposuction was first practiced without any preparation of the fat before suctioning it from the subcutaneous tissue and this was called ‘Dry liposuction’ which was associated with a high incidence of hemorrhage and hematoma. Then Illouz developed the wet technique by injecting normal saline, water, and hyaluronidase to create a weak hypotonic solution to destroy the fat cell wall [49]. Hetter added lidocaine and dilute epinephrine to the injected solution [50], then the super wet and tumescent techniques were developed by injecting the standard wetting solution [1 ml of epinephrine and 50ml of 1% xylocaine for each 1 liter of lactated Ringer solution] [51].

The ratio of the volume of wetting solution infused to the volume of fat aspirate is 1:1 in wet technique but 2 or 3:1 in the tumescent. Although, wetting and tumescent techniques are different in this ratio, they both involve infusion of the wetting solution to the point of tissue turgor or a “peau d’orange” of the overlying skin followed by suction of the subcutaneous tissue [51].

b) Ultrasound-assisted liposuction[UAL]

Zocchi is credited for the application of ultrasonic energy in liposuction to allow more selective tissue targeting [52]. It works by having expansion and compression parts of the cycle as a sound wave,which exerting a negative pressure that overcomes molecular forces results in cellular fragmentation with the intracellular content release, which leading to interstitial cavities hence termed as cavitation.Subsequently, a low-power suction can be performed [52, 53]. In this technique, sufficient amount of wetting solution must be used to limit the effect of heat generated by Us probe. Cellular disruption has been confirmed by the homogenous, macroscopically-acellular aspirated fat which contains a high level of adipocyte-specific intracellular glycerol 3-phosphate dehydrogenase isozyme [54]. UAL is highly efficient in removal of fat in fibrous areas such as the upper back, the hypogastrium, and the breast. UAL has been shown to cause less disruption of vasculature than SAL and hence less bruising [55].

c) Power assisted liposuction[PAL]

In the late 1990s, PAL was developed to subside some of UAL side effects. Actually,it is traditional liposuction with a special reciprocating cannula [Figure 2]. It is useful for fibrous rich areas liposuction and easy for the surgeon to use. No heat generation considers its main advantage over PAL [56].

d) Laser-assisted liposuction [LAL]

LAL is defined as, the simultaneous use of a bare laser fiber as a free beam or a confined beam to lyse, liquefy the fat while simultaneously coagulating small blood vessels at the cannula fat interface. Harness in 1990 described the use of 1064 nm Nd-YAG laser for liposuction with promising results such as minimal incision and skin contraction produced by its photothermal effect [47]. Recently, the use of 1,320-, 1,440- and 2,100-nm wavelengths also have been proposed, with claims of less bleeding, faster healing, and better tissue tightening using laser lipolysis [57-60].

e) Radiofrequency-assisted liposuction [RFAL]

Radiofrequency-assisted liposuction [RFAL] means usage of bipolar radiofrequency energy [similar to that of diathermy] to disrupt the fat cell membrane and facilitate lipolysis with a lesser requirement for suction power [61, 62]. A controlled subdermal thermal injury produced by this energy leads to healing by contraction which produces a secondary effect on skin contraction such as LAL [61].

Omentectomy

Omentectomy [OM] defined as, surgical removal of the whole greater omentum which is a thin fold of abdominal tissue that encases the stomach, large intestine, and other abdominal organs. There are two main types of omentectomy: completely removing the omentum which is called total or supra colic omentectomy and removing a portion of the omentum which refers to partial omentectomy.

The procedure may be performed traditionally or laparoscopically, the traditional approach involves mini-laparotomy with a median supraumbilical incision of 8 to 10 cm to release the omentum from the large gastric curvature while preserving the gastroepiploic artery [63].

Laparoscopic omentectomy technique: Four trocars are used to reach the abdominal cavity at the following positions, under the umbilicus, right lower quadrant, and two at left lower quadrant [63]. After inflation of the abdominal cavity, body and fundus of the stomach are released from the greater omentum and short gastric vessels by harmonic scalpel with remaining of gastroepiploic vessels intact. After detaching the omentum from the transverse colon pulled out through the infra-umbilical incision [64].

Effect of adipose tissue removal on metabolic disease

Liposuction

A study by Giugliano et al, examined the effect of subcutaneous fat suction on insulin resistance and vascular inflammatory markers in 30 obese women by comparing the pre and postoperative [6 months] HOMA [fasting plasma glucose [mmol/l] x fasting serum insulin [mU/ml] divided by 25] as an index of peripheral insulin resistance., High HOMA scores denote low insulin sensitivity. Levels of IL-6, IL-8, TNF-α, CRP and adiponectin were also assessed. Results demonstrated that liposuction was associated with significant decrease in all parameters, except adiponectin, which significantly increased [Table 1] [65]. The risk of cardiovascular death and the incidence of insulin resistance was reduced at follow-up in association with improvements in metabolic and inflammatory markers.

Table 1. Results of Giugliano et al, study [65].

	Baseline	Six months postoperative	P-value
Weight	88	85	<0.001
HOMA	4.1	3.08	<0.05
IL-6 pg/ml	4.1	3.2	<0.05
IL-18 pg/ml	246	219	<0.05
TNF-a pg/ml	5.1	4.1	<0.02
CRP ml/l	2.9	2.4	<0.02
Adiponectin ug/ml	5.1	6.4	<0.02

In a study by Ramos et al, patients underwent abdominoplasty from October 2010 to September 2011. Total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], very low-density lipoprotein [VLDL], triglycerides, glucose, insulin, and HOMA index were measured preoperatively and 3 months post-operative. The results showed a significant reduction in triglyceride and LDL and a non-significant trend for improvements in HOMA, cholesterol,glucose, insulin and HDL[Table 2] [66]. The findings of this study were more or less similar to the Swanson study, which included 322 patients and demonstrated a significant reduction in triglycerides only [67].

Table 2. Results of Ramos et al., study [66].

	Baseline	Three months postoperative	P-value
Weight kg	69.1	68.6	0.79
Glucose mg/dl	91.45	90.71	0.81
Insulin Ul/ml	17.11	11.79	0.28
HOMA	3.96	2.58	0.22
Cholesterol mg/dl	224	220	0.84
Triglyceride mg/dl	193	133	0.03
HDL mg/dl	44	49	0.18
VLDL mg/dl	43	39.1	0.55
LDL mg/dl	137	79.61	0.04

In the cohort study of Marfella et al, 20 patients underwent abdominoplasty and 28 patients were exposed to diet, exercise, and behavioral counseling. Authors compared preoperative and 2-month postoperative measurements of triglycerides, insulin, insulin sensitivity, IL-6, TNF-α, and HDL-cholesterol. A significant reduction in triglycerides and insulin and improved insulin sensitivity was observed in both groups, with significant decreases in IL-6 and TNF-α occurring only in abdominoplasty group. There were no changes in HDL-cholesterol during the study period [68]. In a prospective cohort study, 12 obese patients that underwent abdominoplasty were followed up and plasma triglycerides, HDL, cholesterol, and insulin sensitivity measured during the preoperative period and at 50 days postoperative [69]. In difference to other studies in the field, no improvements were observed in any of the parameters studied.

An overall survey of the literature suggests that on balance, besides the cosmetic results of liposuction, a positive impact on lipid profile and other metabolic markers can arise as a secondary benefit of the procedure. However diet, lifestyle, and exercise modification subsequent to liposuction are likely to significantly enhance the magnitude and duration of beneficial effects by preventing new fat deposition [66]. Whether liposuction can be advocated primarily for its metabolic effects remains however rather controversial and there is still an insufficient evidence base to support its use in this context.

Omentectomy

Fabbrini et al, conducted a randomized controlled trial to test the hypothesis of the effect of visceral fat removal on metabolic diseases. Eleven patients underwent laparoscopic combined Roux-en-y [RYGB] with omentectomy, but RYGB alone was performed to the same number. Leptin, blood glucose, HbA1c, insulin, CRP, cholesterol, LDL, HDL, and triglyceride were measured preoperatively, 6 months and 12 months postoperative. Results of comparing pre and postoperative investigations demonstrated that hepatic insulin sensitivity increased 4-fold and skeletal muscle insulin sensitivity approximately doubled at 12 months after surgery in both groups, Critically no significant augmentation of improvements in these parameters was observed in patients undergoing omentectomy. So, metabolic variables improved after RYGB surgery but visceral fat removal has no additive effect on these variables . [70]. However, these data did not preclude the possibility that stand-alone omentectomy could be of metabolic benefit. To examine this, the same trial incorporated a treatment arim in which 10 patients underwent laparoscopic omentectomy alone. Results demonstrated that metabolic variables and minimal model-derived indices of insulin sensitivity, glucose effectiveness, and Beta-cell function did not change significantly 3 months after omentectomy compared with baseline [70].

Lima et al, and Herrera et al, are two prospective randomized trials looking at omentectomy[71, 72]. Both studies randomized patients equally into two groups, patients of the first group underwent RYGB with omentectomy but RYGB alone was performed to patients of the other group. Both studies used blood samples to measure metabolic and inflammatory markers for patients as in the study of Fabbrini and drew the same conclusions, i.e. omentectomy did not confer any additional benefit on top of RYGB.

From the previous studies and trials, it is thus clear that omentectomy does not induce any improvement in the components of metabolic syndrome and inflammatory mediators. Given the constitutive protective function of the omentum in the abdomen, there appears to be no basis for pursuing omentectomy as a viable intervention for metabolic disease.

Conclusion

Theoretically, increased visceral and subcutaneous adiposity are major risk factors for insulin resistance, dyslipidemia, and other metabolic disorders. Abdominal lipectomy is a well-known cosmetic procedure and used widely for its benefits on improving body image. However, its benefit on the metabolic disorder remains controversial. On the other hand, Omentectomy also does not induce any improvement in the components of inflammatory mediators but its effect on metabolic diseases considered an arguable issue. The currently available literature on visceral fat removal and liposuction are characterized by a small number of patients, we need more powerful randomly controlled trials to provide additional evidence. Intriguingly the fact that removal of subcutaneous rather than visceral fat, [at least the omentum] confers metabolic benefits, challenges current orthodoxy regarding the involvement of the two major fat depots in metabolic syndrome.

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DOI: 10.31038/IMROJ.2016124

Abstract

There is widespread use of physical restraints among the elderly with dementia in residential setting and acute hospitals. Physical restraints are means to limit a person’s freedom of movement. The commonest indications for restraining an elderly are to manage agitated and aggressive elderly at risk of harming themselves or others, reduce falls risk and avoid dislodgement of medical devices. Physical restraints have not been proven to benefit the patients and have been reported to be associated with injuries, falls and deaths. The ethical dilemma associated with restraint use is often conflicting. There are active moves to reduce/ remove physical restraints use in institutions among the elderly with dementia and challenging behaviours. The use of restraints should be considered a last resort when there is imminent danger and where other means of management have failed and patients being restrained should be reviewed regularly to have the restraint removed at the earliest opportunity.

Key words

physical restraints, behavioral and psychological symptoms, dementia, elderly with dementia

Introduction

With the rapid aging population in the world, there is an increasing trend of people living with dementia. Reports have estimated that there will be about 131.5 million people with dementia by 2050. Dementia has a huge economic impact, costing US $818 billion in total worldwide, and it will become a trillion dollar disease by 2018. In many parts of the world, there is a growing awareness of dementia, but a diagnosis of dementia can bring with it stigma and social isolation. Today, it is estimated that 94% of people living with dementia residing in low and middle income countries are cared for at home. These are regions where health and care systems often provide limited or no support to people living with dementia or to their families. [1]

In an acute hospital setting, people with dementia have more than three times hospital stays per year compared to the elderly without dementia. Utilisation of healthcare resources for chronic medical conditions, such as stroke, cancers, diabetes, coronary heart disease is increased among the elderly with dementia. [2]

The elderly patients with dementia in an acute hospital are at high risk of being restrained, especially if they require assistance with their activities of daily living (ADLs) and the most frequently cited reasons for restraint use are for the protection of the patients themselves, and to prevent interference with medical therapies. Physical restraint usage is between 33-68% among the elderly in hospitals. [3]

The elderly with dementia and behavioural symptoms

Dementia is a group of prolonged, debilitating neuropsychiatric disorders which affect the patients and their family for years after diagnosis. The presence of behavioural and psychological symptoms of dementia occurs among 98% of individuals with dementia at some point during their disease progression. Behavioral and Psychological Symptoms of Dementia (BPSD) has been associated with more rapid decline in cognition, greater impairment of ADLs, caregiver burden leading to caregiver burnout, diminished quality of life for caregivers and patients and early institutionalisation. [4-7] The caregiver for a person with dementia has been described as living a 36 hour day by Mace and Rabins, resulting in physical, emotional and mental fatigue. [8]

The spectrum of behavioural abnormalities in BPSD can be divided into behavioural or psychological abnormalities, as shown in (Table 1). Currently, there is no recommended single treatment for BPSD. Clinicians use a combination of drugs such as Cholinesterase inhibitors, anti-depressants, anti-convulsants with mood stabilising properties, antipsychotics, benzodiazepines and N-Methyl-D-aspartate receptor antagonist with varying degree of success. The elderly are more susceptible to side effects of these medications, including anticholinergic side effects with agitation and sedation, extrapyramidal side effects and orthostatic hypotension contributing to fall risk. [9] The non-pharmacological treatment of BPSD with an aim to reduce medication side effects have been studied with music therapy, art therapy, aromatherapy, touch therapy, orientation therapy, physical exercises and tailored activities have been tried with variable success rate due to heterogeneity of the study designs and further research is required. [10]

Table 1. Spectrum of BPSD

Behavioural	Psychological
Agitation-e.g. restless, pacing, disrobing inappropriately.	Mood disorders- anxiety, depression
Aggression-hitting, biting, scratching, pushing, throwing objects, destroying property, tearing items.	Changes in personality
Verbal aggression- cursing, swearing, shouting, screaming	Psychosis- delusions, hallucination
Wandering	Pathological crying
Repetition	Apathy
Sexual disinhibition	Irritability
Urination/ defecation-at inappropriate time and place	Mood lability
Hoarding	Elation

Behavioural symptoms in dementia suggest the presence of underlying unmet needs and must therefore be looked at as means of communication as cognitive abilities decline. The unmet needs include physical causes like medical illness and pain or psycho social and emotional needs. Agitation signifies progression of dementia. At the middle stages of dementia where verbal communication is diminishing, verbally agitated behaviours such as repetitions, cursing or screaming, are common. In severe stages of dementia, physically agitated behaviours predominate because they have lost the abilities to communicate verbally. [11] Agitated behaviours may be a reflection of others’ behaviour where the elderly with dementia does not comprehend or does not want. Agitation is associated with poor outcome for health and general wellbeing. Agitated behaviour places an elderly at risk of harm on themselves, caregivers and often leads to early institutionalisation. Nurses often see an agitated elderly as a challenge and feel helpless to intervene. [12]

Causes of BPSD- Theoretical models

Cohen-Mansfield applied theoretical models to analyse the causes of BPSD. The problematic behaviours in dementia may arise from various causes such as 1.) unmet needs, 2.) behavioural/ learning models and 3.) environmental factors.

Unmet needs among the person with dementia are frequently not obvious to the caregivers. Among some of these include inadequately treated pain, toileting needs, thirst, hunger, sensory deprivation, boredom and loneliness. Use of restraints causes restriction in independence, social isolation and may worsen behaviour. Assisting the person with dementia with proper eye wear and hearing aids, regular toilet rounds, assistance for physical exercise, meaningful activities and meals, providing sensory stimulation like pet therapy, music therapy, social interactions may reduce agitation.

The ABC model of behaviours consists of antecedent events which are the stimuli leading to the behaviour and consequences of the behaviours. The consequences reinforce certain behaviours in response to the antecedents. Many problem behaviours are learned through reinforcements by staff who paid attention when problem behaviours are displayed. To modify the behaviours requires new learning experiences which change the antecedent and behaviour.

The environmental theory suggests that persons with dementia are more vulnerable to environmental stimuli and they have a lower threshold at which their behaviour changes in response. The persons with dementia lose their coping abilities progressively and find the environmental changes increasingly more stressful. The threshold for stress also lowers progressively. When environmental stimuli exceed the stress threshold, they are more likely to show anxiety and inappropriate behaviours. [13]

Cohen-Mansfield suggested that the different models may interact and complement each other. For example, an environmental stimulus (unfamiliar surrounding) may cause an unmet need to surface (getting lost looking for toilets, bedroom) which may account for different behaviours (resulting in pacing, agitation, incontinence, etc) among different people. The different models provide the basis for intervention and the effectiveness of interventions indicates the usefulness of these models.

Indications for Physical restraints

The commonest reasons for restraints use are prevention of falls, protection of medical devices, means to control behaviour like aggression and wandering and to stabilise patient’s position. The traditional management for an agitated elderly is to restrain them either physically or chemically or ignored. [12] A physical restraint is any physical or mechanical method attached or adjacent to the body which restricts one’s freedom or movement or normal access to one’s body. [14] There are various types of physical restraints available, among the commoner ones used in the hospitals and nursing homes include body vest, pelvic vest, limb ties, mittens, lap belts, bed rails and tray tables. The most commonly used restraints are bed rails and belts. The predictors for restraints usage are, poor mobility, cognitive impairment, high physical dependency, organisational characteristics and high fall risk. [15]

Fall prevention and restraints- is there a role?

The elderly with dementia are more likely to be put on physical restraints because of poor memory for recent events, behavioural symptoms, delirium, language dysfunction with impaired abilities to communicate needs. Falls risk increases in dementia due to unsteady gait, poor safety awareness and poor judgement. [16] In a hospital setting, inpatient falls are considered a risk management issue and carries with it guilt, self-blame and possible litigations. There are measures in place in hospitals to reduce falls such as early fall risk assessment with policies for fall precautions and provision of a safe environment. Among some of the data published on nurses’ attitude towards restraint usage among the elderly, most nurses feel negatively towards restraining the elderly. However, they do believe there is a need for restraints mainly to reduce falls. This causes moral conflicts. Generally, when in doubt, most nurses were in favour of restraints. [17]

Staffs frequently have a sense of false security when they put an elderly on restraints to protect them from falls. Physical restraints have not been shown to reduce falls. In fact, restraints like body vests have been associated with higher fall risk and fractures. Tinetti showed that usage of physical restraints resulted in three fold increase likelihood of serious fall-related injures compared to the unrestrained elderly, after adjusting for other factors. [18, 19] Patients being restrained often struggle to get out and in doing so, they often become more agitated with reports of patients getting trapped between mattress and bed rail, some of the patients become more restless and attempt to climb over bed rails resulting in falls from greater height. The struggling also causes fatigue and prolonged restraints imposed immobility causes significant muscular atrophy which is accelerated compared to the younger patients, leading to falls, functional decline and needing longer periods of rehabilitation to restore. Muscle strength reduces by up to 5% a day. Repeated episodes of atrophy and recovery may lead to permanent loss of skeletal muscle mass and strength with disability. [20, 21]

Once a physical restraint has been deemed unnecessary, removal of physical restraints has not been shown to increase falls among nursing home residents. In fact, restraint removal has positive effects on the welfare and independence of the elderly, with changes in behaviour and reductions in the number of antipsychotic prescriptions. [22, 23]

Harm associated with physical restraints

Despite the widespread use of physical restraints in Nursing homes and hospitals, the safety and efficacy have not been well studied. Currently, there is no evidence that restraint prevent falls or secondary injuries. The types of restraint related injuries reported include direct injuries where the physical restraint causes direct physical damage to skin, with skin tear and haematomas being the commonest. Other reported direct injuries include nerve injuries, asphyxiation and sudden death. Sudden deaths occurred among elderly patients with cardiac conditions who struggled to be free of physical restraints. Vests have been associated with asphyxiation leading to death, the mechanisms included patients hanging by vest over bed rails, with vest caught against the neck. Retrospective reviews of death certificates identified deaths associated with restraints use among people in beds or chairs. Bed rails have been associated with getting heads trapped between mattress and bed rails. [24]

Indirect injuries associated with restraint use include increased mortality, falls, longer hospital length of stay, physical deconditioning, contractures, nutritional impairment, pressure ulcers, bowel and urinary incontinence. Patients put on restraints for more than 4 days were at higher risks of developing pressure sores and nosocomial infections. [24]

Apart from physical injuries, restraining the elderly with no or moderate cognitive impairment in a residential setting has been associated with greater decline in cognition. The elderly with severe cognitive impairment seemed to be unaffected. [25] Physical restraints have also been reported to be associated with more unsociable behaviours, depression, fear and regression. [26]

The ethics of using physical restraints

There will be occasions where the patient may be of danger to himself or others around them, and there is a need of using physical restraints to limit harm by restricting patient’s movement. However, sometimes physical restraints are misused in circumstances for staff’s convenience or punishing patient for their bad behaviour.

Autonomy

Respect for autonomy is the belief in individual freedom. The individual has a right to make his/her own decisions and intentionally act upon them, without being coerced or manipulated. The individual also has a right to liberty or self-determination, without controlling influence or interference from others. In people with dementia, there is progressive loss in the decision making capacity. For making a decision on medical treatment, we as healthcare providers need to ensure that the medical information provided is clear and understood. There is capacity to make a decision without coercion or deception. In the cases where the patient has limited decision making capacity, principles of beneficence and non-maleficence outweighs autonomy. [27]

In the situation of treating elderly with behavioural issues and dementia, there is often coercion or deception involved in the behavioural management, like hiding medications in food, putting up seat belts or bed rails when the elderly with dementia are not complying with treatment and yet failed to understand the risk to their own safety if they fail to comply with instructions. The paternalistic view that healthcare professionals are specialists who know best and the patients under their care, in their sick roles are expected to comply. Compliance itself suggests a requirement to yield in the context of cure. The patients are expected to believe their caregivers have the best knowledge, determine the best outcome and act in the patient’s best interest, and often, the interventions are beyond question. Nursing staffs are often faced with the dilemma of weighing the patient’s autonomy and their safety especially when there is a shortage of staff to provide better supervision. In nursing and medical practice, when the expectation is for patient to comply, there may be coercion or deception involved and autonomy is often compromised. [28]

Beneficence and nonmaleficence

In health care, healthcare workers are to act for the patients’ benefits, maximising utility and taking into account risks and cost incurred in doing a procedure or action. Among patients who may have difficulties making decisions, autonomy may be constrained by beneficence. Beneficence is a continuum from preventing or removing harm to doing good or promoting a person’s welfare.

Nonmaleficence in medical ethics means do no harm, remove harm and facilitate good. In the case of physical restraint use among the elderly, there is evidence to show that restraints cause more harm than benefits. [24-26] Since there is no evidence for effectiveness, it is questionable to classify restraint as therapeutic. It is therefore important to ask if restraint use violate the principle of nonmaleficence.

The principle of beneficence to an agitated elderly is rarely absolute where safety is concerned. It is unclear whether restraint actually confers safety to the patients. Instances where immediate safety of patient/ staff is threatened, beneficence is in conflict with autonomy. Other than in those instances where safety is really a legitimate concern, we need to consider the principles of beneficence and nonmaleficence carefully. [29]

The ethical struggle- clinicians left with “dirty hands”

In situations where the patient is at risk of imminent danger to himself or staff, restraining them may be the unavoidable and right thing to do. This may give rise to conflict in professional practice. The argument goes that patient may benefit from restraint and this justifies the risk of harm. This paradox constitutes the philosophical dilemma of dirty hands which essentially means to commit a moral wrong in order to do what is right. Healthcare workers often have to use coercive methods to treat patients with dementia, or getting them to comply with treatment, leaving them with a complex moral stain in order to do “right” for the patients. [30]

Is it possible to have a restraint free environment?

The Federal Drug Authority put forth warnings of safety and alert on vests, limb restraints and bedrails in 1992 and 1995. The legal standard has changed their stand from liability from failure to restrain to one that presumes appropriate care relying on interventions other than restraints.

In the United States, moves to care for the elderly without using restraints include, better tolerance of behavioural symptoms, complete ban of restraints in homes, nurses’ low acceptance for restraint use, improving staff knowledge about restraint hazards, minimising falls risk, understanding and responding to behaviours. Education and leadership of a gerontological trained nurse was helpful in reducing not only restraint use, there was no increase in staff number, psychoactive drug prescription or serious falls-related injuries. [31]

Individualised care plans with psychosocial interventions like anticipation of needs, physiological needs like pain management, planned activities and environmental interventions such as low beds, contoured chairs, based on the individual patient’s needs were also effective in reducing restraint use. The individual’s needs to assist with activities of daily living with walking aids, sensory aids are helpful to determine the changes in functional abilities from baseline. Premorbid toileting habits were adhered to minimise agitation from discomfort. Medical interventions like oxygen tubes or feeding tubes are minimised or disguised to reduce discomfort and distract the patient. Behavioural patterns and psychosocial needs were explored with the family to provide an idea of changes from baseline and to reduces the stresses of environmental changes in causing agitation and restlessness. [32] Environmental modifications like contoured chairs, low beds are safer and more comfortable for the elderly. Bedside alarms and commodes are recommended to reduce injuries and reduce restraint use. [33]

Summary

Physical restraints should be eliminated for the care of elderly with dementia. The risks of harm for physical restraints far outweigh the benefits. Careful, individualised assessment and individualised care plans addresses needs which are often unmet among the elderly with dementia. Education and guidance from a specialist trained nurse has been shown to be successful. A restraint free care environment is possible only if there is support from the organisation.

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