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Wangge.Editorial

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Behind and beyond the gatekeepers’ transformation

Grace Wangge1,2

1 Editor of Medical Journal of Indonesia2 Departement of Community Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia

Editorial

Medical Journal of Indonesia

Since 2014, Indonesia implements the universal health coverage (UHC) as part of the country health care reform. Despite of the political reasoning behind it, the UHC itself is a long due realization from the 2004 social insurance law that aim to improve health access of the country’s 200 million citizen. UHC is also a part of the United Nations Sustainable Development Goals that all UN Member States, including Indonesia, have agreed to achieve by 2030.

One of the key World Health Organization (WHO) recommendation for a successful implementation of UHC is strengthening of the primary health care.1 This recommendation appears to contradict the major direction of medical science development towards Nano and genomic technology. However, real world evidence clearly indicates that the strengthening of primary care, especially in middle and low income countries, succeeds in reducing morbidity and mortality rates. In a 2003 study, data from 42 countries worldwide showed that six million infant mortalities could be prevented yearly due to effective primary care service.2 The number is equated to 100 football stadiums of full of children.3 More success stories of primary care strengthening in developing countries were widely described in reports and publications.3,4

The terms primary health care, primary care, general practice and family medicine are often used interchangeably. It usually defines as initial contact of patient with health care professionals, hence the term “gatekeeper”. Despite of its noble meaning, the term itself have been connoted differently among medical practitioners. In the analogy of a football match as a health system, a gatekeeper considered as someone who has a role to assure that only certain people can enter the arena. The gatekeeper has no particular authority in determining who can stay in the arena, nor has the opportunity to watch the whole match fully. The notion of the

role of gate keeper is widely embraced not only by other specialists, but also by primary care doctors themselves. This misconception has decreased the gatekeepers’ self-confidence and discourage them to develop their primary care skill.

In the 1978 declaration of Alma-Ata, instead of the traditional approach of medical service, the primary care should embrace the principles of social justice, equity, self-reliance, appropriate technology, decentralization, community involvement, intersectoral collaboration, and affordable cost.5 The declaration clearly demands primary care doctors to attain role beyond a bouncer in their country health system.

In this issue of Medical Journal of Indonesia, Werdhani6 highlights the important role of primary care doctors as a manager of patient’s case management. The author described in her article, the ideas how such leadership capability can be developed within the primary care workplace. In the same nuance, Taher describes how primary care have a long standing history not just as the provider of quality and equitable services for the community, but has established themselves in the root of genomic medicine. Tahir highlights the opportunity of primary health care doctors to contribute better to medical world as both public health specialist and basic-science scientists.

The high expectations for the primary care emphasize the need for improvement in the primary care doctors’ capabilities. In their systematic review of postgraduate training for primary care physicians, Widyahening et al7 describe the postgraduate education for primary care physicians exists in 62 (86%) in UHC-attaining countries worldwide. These postgraduate training was established as part of implementation of UHC in 11 (18%) countries. These facts are not surprising, as investment in primary health care workforce is

82 Med J Indones, Vol. 26, No. 2June 2017

recommended by WHO as a cost-effective measure in improving health care services, provided it is supported by good governance, comprehensive facilities, sufficient supply of medicine and information technology systems.8

Those evidence exclaim that despite of the long ongoing debates on whether or not Indonesia need a formal postgraduate education for primary care doctors, strengthening of primary care is currently inevitable. These efforts will surely, not only focus in transformation of the gatekeepers, but more importantly requires a reverse way of thinking from the traditional approach of top-down health service. The latest could be the hardest challenge for health care reformists in Indonesia. All stakeholders in the end must remember that the goal of the health care system is to ensure the health for all citizens, thus any effort taken in the reformation are merely a means, not an end.

REFERENCES 1. WHO | Universal health coverage (UHC) [Internet].

WHO. World Health Organization; 2016 [cited 2017 Jun

29]. Available from: http://www.who.int/mediacentre/factsheets/fs395/en/.

2. Jones G, Steketee RW, Black RE, Bhutta ZA, Morris SS, Bellagio Child Survival Study Group L. How many child deaths can we prevent this year? Lancet (London, England) [Internet]. [update Jul 2003; cited 2017 Jun];362(9377):65–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12853204.

3. Mossman K, Bhattacharyya O, McGahan A, Mitchell W. Expanding the Reach of Primary Care in Developing Countries.pdf. Harvard business review [Internet]. 2017 Jun; Available from: https://hbr.org/2017/06/expanding-the-reach-of-primary-care-in-developing-countries.

4. Atun R. What are the advantages and disadvantages of restructuring a health care system to be more focused on primary care services ? World Heal Organ Off Eur [Internet]. 2004; (January):18. Available from: http://www.euro.who.int/__data/assets/pdf_file/0004/74704/E82997.pdf.

5. Beard TC, Redmond S. Declaration of Alma-Ata. Lancet. 1979;313(8109):217–8.

6. Werdhani RA. Leadership in doctor-patient relationship: Implementation on patient’s case management in primary care. Med J Indones. 2017;6:158–66.

7. Widyahening IS, Tanoto R, Rinawan F, Setiawati EP, Leopando ZE. Does the establishment of universal health coverage drive the foundation of postgraduate education for primary care physicians?. Med J Indones. 2017;6:141–51.

8. WHO. The world health report: health systems financing: the path to universal coverage. 2010.

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.2130 • Med J Indones. 2017;26:81–2

Corresponding author: Grace Wangge, [email protected]

Copyright @ 2017 Authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original author and source are properly cited.

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https://doi.org/10.13181/mji.v26i2.2130

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International collaboration for implementation of equal access to family-based primary healthcare in Indonesia

Jörg Haier,1–4 Jürgen Schäfers,2 Hans-Joachim Freisleben1,4

1 German-Indonesian Medical Association (GIMA, DIGM e.V.) 2 German-Indonesian Healthcare Development Group (GIHDG) 3 Nordakademie – University of Applied Sciences, Hamburg-Elmshorn, Germany4 Editor of Medical Journal of Indonesia

Editorial


Recently, Indonesian Minister of Health (MoH), Prof. Dr. dr. Nila F. Moeloek, provided a detailed overview about the Indonesian national health policy in the transition of disease burden and health insurance coverage.1 Based on an analysis of main current disease patterns and promotive-preventive approaches her editorial described the key features of the ambitious governmental program for development of healthcare delivery. The GERMAS program and its supporting activities as well as the Sustainable Development Goals (SDG) formulated by the World Health Organization (WHO) are challenging scopes, especially to guarantee the equal access for the entire population in Indonesia.

International collaborations have been implemented during the last years to support this development in Indonesian healthcare. For example, the European Union agreed in Art. 31 of the its bilateral contract2 to cooperate in the health sector in areas of mutual interest, with a view to strengthening activities in the fields of research, health system management, nutrition, pharmaceuticals, preventive medicine, major communicable and non-communicable diseases. Similarly, the bilateral Indonesian-German governmental contract (Jakarta Declaration, 2012)3 included in Chapter III Health (Art. 22, etc.) “Strengthening cooperation in the health sector particularly in the areas of medical equipment technology and industry, hospital management, healthcare providers, the development of traditional medicine, capacity building, as well as the insurance and standardization of health and food… Welcoming the German sponsored initiative on Healthcare Partnership to improve the healthcare infrastructure…”. Many of these activities have been followed up recently during the second meeting of Indonesia-Germany Bilateral

Steering Committee (BSC).4 Their joint report includes a review on the implementation of the Jakarta Declaration, and gives recommendation about the cooperation fields and activities in the future with special considerations on Healthcare and educational issues.

Soon after the Jakarta Declaration, the German-Indonesian Healthcare Development Group (GIHDG) consisting of academic, political, business and financial partners in both countries started activities to implement the healthcare-related topics of the contract. Academic bilateral co-operations supported by the German-Indonesian Medical Association (DIGM) as a binational society with longstanding focus on (bio) medical education and development of healthcare in Indonesia have been intensified. In addition to the established biomedical and clinical education and training programs supported by the German Academic Exchange Service (DAAD) and DIGM, a know-how transfer concept mainly requesting a healthcare train-the-trainer approach was worked out and numerous educational events have taken place at different Indonesian institutions for professional groups, e.g. doctors and nurses. The German Embassy in Jakarta and DAAD as well as the Indonesian MoH were guests in these events and supported the collaborations.

Joint healthcare research projects were performed as cooperation between universities in both countries (e.g. maternal mortality)5 and are currently continued with specific focus in public health issues. Based on these results the GIHDG provided a bilateral concept for the improvement of healthcare in Indonesia, especially for the equal access to family-based and primary care throughout the country. This concept considers


existing structures within the different Indonesian regions and suggests a nationwide eHealth-based solution that was presented at and discussed with the MoH in both countries.

Key issues of the concept target the poorly developed selection and referral system of patients between the healthcare providers at various levels of service (e.g. between primary care and hospitals or among different hospitals) and the limited availability of qualified medical staff, esp. in rural and remote areas. Cultural and regional characteristics, existing infrastructure and healthcare services as well as anticipated knowledge transfer are considered for an Indonesian model instead of exporting Western solutions. Therefore, the proposal for the management of primary healthcare also includes an educational concept that combines different joint approaches between Indonesian and German universities, such as Joint Master Course of Healthcare Management.

eHealth opportunities for GERMASGERMAS and other associated activities for health development in Indonesia currently face some major barriers: • shortage of qualified medical personnel • restricted distribution of primary healthcare

facilities• inefficient patient selection and referral

systemAll factors affect the availability esp. for primary healthcare and can be found mainly in (but not limited to) rural and remote areas. Although grown on historical circumstances and influenced by national and cultural background, such problems are known not only in Indonesia with its specific geographical challenges, but also in other countries around the world. Improved distribution of healthcare access points may be solved in collaboration with investment partners and might even include novel ways of healthcare delivery, such as mobile stations, boats and container-based facilities. Improved patient selection and referral processes can be also achieved in short terms, if modern technologies are combined with community empowerment. International experience demonstrates that more effective and efficient usage of available healthcare resources by reorganizing referral and selection processes appear necessary to strengthen the health system within the given

financial framework, such as by national health insurances. In contrast, shortage of qualified medical personnel cannot be solved within short periods of time. Therefore, innovative approaches to provide medical expertise esp. to rural and remote areas may be necessary and combined with preventive and early detection action plans handled by healthcare workers.

Internationally, eHealth-based solutions have been started to overcome the above-mentioned limitations at varying understanding and extent, but not restricted to exchange of diagnostic images for teleradiology or telepathology. Several eHealth initiatives were already piloted in Indonesia.

In a comprehensive approach, eHealth can provide better opportunities for integrated healthcare delivery processes and improved patient referral structures. Modern technologies enable combinations of electronic, web-based health records, medical data exchange, (semi)automatic basic diagnostic procedures, videoconferencing, assisted patient guidance and healthcare reporting. By adjusting medical processes and selecting suitable tools within such systems eHealth can integrate disease prevention, early detection of risk factors, family-based approaches and community health education, and at the same time significantly contribute to equal access to primary healthcare throughout the country.

Furthermore, eHealth medical records can provide a very valuable source for healthcare and public health research, analysis and reporting of health-related issues, quality assurance within the medical delivery chains, if used as regional or even national platforms.

Medical education and trainingOne major conclusion of the analysis of the GERMAS targets and supporting programs is the requirement to overcome the limited availability of qualified staff and to newly implement educational opportunities and knowledge transfer for healthcare management. Joint venture structures can provide a solid basis to resolve various barriers for education, such as licensing, international accreditation, organizational aspects, selection of participants and start-up financing. In addition, ensured continuation and sustainability of training and education programs

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need to be guaranteed. As an initial realization, the German system-accredited Nordakademie Hamburg-Elmshorn, which is specialized in academic management education will provide an internationally accredited licensing and development process for the implementation of specific master programs: a joint Master Course for Healthcare Management shall be implemented as pilot project for bilateral collaboration with Indonesian governmental educational institutions (e.g. Universitas Indonesia – Faculty of Public Health). This Master program is planned to become available for Indonesian participants by a specific organizational format, lecturing in English and offering broad accessibility.

Political support will be necessary to ensure the adaptation of the program as much as possible according to legal frameworks, the regional achievements and requirements in Indonesia but also for international recognition and accreditation of participants’ graduation. Furthermore, governmental support is needed to overcome potential barriers towards assuring broad accessibility for applicants, financing and fast spreading of the program throughout the country.

Current tasks for bilateral collaborationGIHDG and DIGM currently aim towards the following topics as continuous and intensified implementation of the Indonesian-German Jakarta Declaration in health and education:- Providing a detailed medical concept and

implementation roadmap for eHealth-based healthcare delivery grounded on reimbursement structure of the national healthcare insurance BPJS and Indonesian legal framework;

- Starting step-by-step roll-out of this eHealth concept in initial implementation regions in collaboration with Indonesian MoH and other stakeholders;

- Implementing joint educational programs to train and provide the necessary personnel (academic cooperation; acceptance of achieved degrees must be guaranteed);

- Integrating associated joint research projects and academic knowledge transfer.

In this context, GIHDG has identified a high-potential German investment group willing to fully finance nationwide roll-out of the primary care concept. Furthermore, the Asian Development Bank (ADB) confirmed their willingness to participate in this project, which was discussed during the Annual ADB Conference in Frankfurt/Main, Germany, in 2016 where Indonesia was one of the key countries.

The Medical Journal of Indonesia – in the frame of its cooperation with DIGM - would continue to accompany these activities and developments as the scientific platform for related analyses and research topics and as an important partner to spread information about international healthcare collaboration and knowledge exchange.

REFERENCES

1. Moeloek NF. Indonesia national health policy in the transition of disease burden and health insurance coverage. Med J Indones. 2017;26(1):3–6.

2. FRAMEWORK AGREEMENT on comprehensive partnership and cooperation between the European Community and its Member States, of the one part, and the Republic of Indonesia, of the other part. Official Journal of the European Union. 2014 Apr 26;L125:17–43. Available from: http://trade.ec.europa.eu/doclib/docs/2016/july/tradoc_154810.pdf (access June 26th, 2017).

3. “JAKARTA DECLARATION” Indonesia-Germany Joint Declaration for a Comprehensive Partnership: Shaping Globalisation and Sharing Responsibility. Available from: http://www.ag-friedensforschung.de/regionen/Indonesien/jakarta-declaration.pdf (access June 26th, 2017).

4. Indonesia - Germany Raised Various Cooperation in Comprehensive Partnership Scheme. [Source: Dit. Eropa II. 2017 Apr 19, about 1 p.] Available from: http://www.kemlu.go.id/en/berita/Pages/Indonesia---Germany-Raised-Various-Cooperation-in-Comprehensive-Partnership-Scheme.aspx (access June 26th, 2017).

5. Reinke E, Supriyatiningsih, Haier J. Maternal mortality as a Millennium Development Goal of the United Nations: A systematic assessment and analysis of available data in threshold countries using Indonesia as example. J Glob Health. 2017 Jun;7(1):010406. doi: 10.7189/jogh.07.010406.


Corresponding author: Hans-Joachim Freisleben, [email protected]



http://trade.ec.europa.eu/doclib/docs/2016/july/tradoc_154810.pdf

http://trade.ec.europa.eu/doclib/docs/2016/july/tradoc_154810.pdf

http://www.ag-friedensforschung.de/regionen/Indonesien/jakarta-declaration.pdf

http://www.ag-friedensforschung.de/regionen/Indonesien/jakarta-declaration.pdf

http://www.kemlu.go.id/en/berita/Pages/Indonesia---Germany-Raised-Various-Cooperation-in-Comprehensive-Partnership-Scheme.aspx






Science, research and technology in primary health care: Covering from neglected tropical diseases to personalized medicine

Akmal TaherCommission Member of Medical Sciences, Indonesian Academy of Sciences, Indonesia

Invited Editorial


Health is a prerequisite, an indicator, and a purpose of a sustainable development. In order to achieve equitable health, global concensus has been held and agreed, such as Alma Ata in 1987, Millennium Development Goals (MDGs) in 2000, and Sustainable Development Goals (SDGs) in 2015, which are intended to fulfill the right to healthy living for all. Although the MDGs have completed in 2015, Indonesia still has many unresolved issues, such as the number of child and maternal mortality, communicable diseases, neglected tropical diseases, and access to sexual and reproductive health services. In addition, Indonesia has to face a new agenda of SDGs, such as mortality due to non-communicable diseases and diseases caused by cigarettes, negative effects of drugs and alcohol consumption, traffic accidents deaths, Universal Health Coverage, air, soil, and water pollution, and international health regulations.

Primary health care To be able to achieve health for all, we need a health system which is able to solve current problems and to respond to the future challenges and the increasing expectations of the society. Therefore, based on evidences gained in many countries, in 2008 WHO has pointed out the importance of undertaking four mandatory reformations in the health service system: 1. The implementation of universal health

coverage1 to give social and financial protection for patients, so that they will not fall into poverty or become poorer. This reformation has been implemented through a national health insurance (JKN) which is organized by the Social Security Insurance Agency (BPJS).

2. The changes in public policy.1 It becomes urgent considering that disease prevention is not solely determined by health institutions, but also by institutions outside health institutions, such as the procurement of

clean water, adequate housing, limitation of salt, fat, and sugar consumption, and smoking behavior. Related to the second reformation, the government has launched and soon will launch Gerakan Masyarakat Hidup Sehat. This movement is an attempt to mobilize all ministries to engage in disease prevention or at least make health impacts as a consideration in making public policy. Along with this, a massive health promotion is done to enable the public to behave clean and healthy.

3. The reformation in the field of leadership and governance.1 The harmony between the policies directed by the central government and its implementation in the region in the era of decentralization/ regional autonomy becomes absolute; on the other hand, community participation remains an important determinant. Local government law No. 23 of 2014 is helpful because it provides clarity on the role and the function of central, provincial, and district/ city governments. In addition, the existence of Minimum Service Standards in the health sector that becomes the benchmark of the performance of regents/ mayors will be a compressive strenght for local governments to create programs that are align with national planning.

4. The reformation in health services is commonly referred to as primary care in order to respond to the needs and the expectations of the community and to succeed.1 It is absolutely necessary that disease preventions, treatments, and most public health problems are addressed in this service stratum. The challenges faced by primary care will be increasingly complex given the unfinished reproduction health and nutrition problems, as well as infectious diseases, such as AIDS, tuberculosis, and

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malaria. In addition, it is exacerbated by the increasing prevalence of non-communicable diseases and the proportion of elderly patients.

Furthermore, countries with limited resources often interpret the primary service as simple as those of our experienced and thought for so long. This simple interpretation can be seen in the right column.

Therefore, creating a good primary service takes political policy and government budget, accompanied by consistent implementation. Experience in many countries demonstrates that strengthening primary services took a long period of time because it demands a change of mindset and perspective from all parties, both local governments, doctors, and other health professionals, also society as the most crucial stakeholders.

The primary services should be provided by a team of various medical workers. It cannot be denied that the role of medical workers’ competency is one of the determinant success factors in primary care, including the doctors’ competency. WHO has been reported that a lot of studies showed that the success of primary care cannot be separated from the empowerment of doctors with additional post-graduate education, such as family physicians or general practitioners.1 In Indonesia, this has been facilitated by the presence of primary care physicians who have the basic competence of family medical, supported by community medical science and public health. This profession has the same level of Indonesian National Qualification Framework as specialist doctors.

A lot of evidence also showed positive contributions of a strong primary service to a country’s health indicators. One of the study, aimed at assessing the contribution of primary health care to health parameters in 18 countries, incorporated with the Organization for Economic Co-operation and Development (OECD), showed that the strength of the primary service system of a country is inversely related to: all-cause mortality, all-cause premature mortality, early mortality due to asthma and bronchitis, emphysema and pneumonia, and heart disease. This inverse relationship is significant although it has controlled determinant factors on the

health of a population at the macro level (gross domestic product per capita, number of doctors per 1,000 of population, and percentage of the elderly population) and at the micro level (average number of outpatient visits, income per capita, alcohol consumption, and smoking).2 This evidence is not only shown in developed countries, but also in low- and middle-income countries. Based on a systematic review encompassing the implementation of primary service initiation in low- and middle-income countries in the past 30 years and on 16 national primary service programs, the initiation of primary service in low- and middle-income countries has increased access to health care, including the poor, at a relatively low cost. In addition, the primary care program is able to decrease the mortality rate in children and able to effectively strengthen the health system.3

Based on the description above, it is clear that primary care plays an important role in providing quality and equitable services to the wider community. Furthermore, it should be observed how the role of primary services in the field of medical science development and innovation.

Although there are less numbers than secondary or specialist medical research, a lot of primary care research from college has a good quality. It appears that the existence of primary care department in hospitals, not just in the Faculty of Medicine, can be a first step to increase research in the scope of primary care. In this way, collaboration and resource sharing with specialists are easier to happen. This can be realized by the Government Regulation which enables the existence of primary care carried out as one of the main education hospital.

The development of cutting edge medical science and technology in primary health careSince the early stages of the Human Genome Project, progress in sequencing has led to the genome revolution. This revolution leads to the advances in computing power and database storage, developing and cost reduction in overall genome and exome sequencing have made genome-based treatment a clinical setting reality within the next couple of years.4

David et al. lays out an interesting thought of the Institute of Medicine about genomic medicine and

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primary care. Philosophically, genomic medicine is rooted in primary care, which strongly supports the importance of long-term relationships and a thorough patient’s knowledge. In addition, personalized medicine will have the greatest impact when integrated with primary care where most services occur. In Indonesia, 80% of services in the social security system occurs in primary care.5

The description of the primary care characteristics (focus on patient, comprehensive, coordinative) is a picture of the complexity of challenges in personalized medicine practice. Personalized medicine includes a wide range of applications, from pre- and neonatal examinations to germ line checks and tumor diagnosis, pharmacogenomics, as well as results interpretation guidelines that include family history and subspecialty collaboration.

Every attempt to redesign a comprehensive primary service should include a strategy to integrate personal medicine with primary care for both primary and non-primary education services. In addition, it requires the involvement of personal medicine experts in developing a clinical implementation strategy.

Implementation of personalized medicine is close to the clinical setting. Many studies have been conducted, such as a study by Bottinger et al. about genomic medicine to guide the health care of African-American race for hypertensive patients through genomic information.6 In addition, University of Oxford through the Nuffield Department of Primary Care Health Science has used big data to formulate a new outlook in primary services, such as through an open prescribing project where raw data from the National Health Service (NHS) on medicines prescribed by general practitioners is converted into an easy-to-read data that can help patients or health service decision makers to provide more efficient prescriptions.7

Some of the examples above show how primary care can play a role in cutting-edge medical research even in the need for large amounts of clinical, family and environmental data. Over a long term, the role of physicians working in primary care becomes very strategic. It suggests that primary care physicians can contribute

much in the development of basic medical science. The amount of contributions depends on the motivation and desire of the doctors to get involved; whether just participate in data collection or involve in the research from the beginning until the end.

In conclusion, the government should open the widest possible opportunity for interested doctors, so that primary care becomes more attractive and head-to-head with secondary and tertiary services. For instance by providing the necessary facilities and rewards that are appropriate for them.

This can be started from a primary service incorporated in the Academic Health System that forms a unified system of primary until tertiary services affiliated to a university. Traffic data that occurs in one AHS can be arranged in a way that it can be the beginning of the availability of big data which can then be analyzed for various research purposes. Since 2014, the Ministerial Regulation as a legal basis for some AHS is already available. The keywords are motivation, collaboration and consistency.

Finally, the government is expected to accommodate the need of developing primary services, so that in the future the primary services will no longer be a work place of the forced or temporary health worker.

REFERENCES

1. Gauld R, Blank R, Burgers J, Cohen AB, Dobrow MK, Ikegami NKI, et al. The World Health report 2008 - Primary healthcare: How wide is the gap between its agenda and implementation in 12 high-income health systems? Healthc Policy. 2012;7(3):38–58.

2. Macinko J, Starfield B, Shi L. The contribution of primary care systems to health outcomes within Organization for Economic Cooperation and Development (OECD) countries, 1970-1998. Health Serv Res. 2003;38(3):831–65.

3. Kruk ME, Porignon D, Rockers PC, Lerberghe W Van. The contribution of primary care to health and health systems in low-and middle-income countries: A critical review of major primary care initiatives. Soc Sci Med [Internet]. 2010;70(6):904–11. Available from: http://dx.doi.org/10.1016/j.socscimed.2009.11.025.

4. Rahimzadeh V, Bartlett G. Genetics and primary care: where are we headed? J Transl Med [Internet]. 2014;12(1):238. Available from: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&i


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d=25164605&retmode=ref&cmd=prlinks%5Cnpapers2://publication/doi/10.1186/s12967-014-0238-6.

5. David SP, Johnson SG, Berger AC, Feero WG, Terry SF, Green LA, et al. Making personalized health care even more personalized: Insights from activities of the IOM genomics roundtable. Ann Fam Med. 2015;13(4):373–80.

6. Bottinger EP, Horowitz CR. Genomic medicine pilot for hypertension and kidney disease in primary care [Internet]. [cited 2017 Mar 1]. Available from: http://grantome.com/grant/NIH/U01-HG007278-01.

7. Science ND of PCH. Big Data [Internet]. [cited 2017 Mar 1]. Available from: https://www.phc.ox.ac.uk/research/big-data.


Corresponding author: Akmal Taher, [email protected]


http://mji.ui.ac.id

https://www.phc.ox.ac.uk/research/big-data

https://www.phc.ox.ac.uk/research/big-data



Detection and identification of azithromycin resistance mutations on Treponema pallidum 23S rRNA gene by nested multiplex polymerase chain reaction

Keywords: PCR, syphilis, Treponema pallidum resistance

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.1543 • Med J Indones. 2017;26:90–6• Received 26 Aug 2016 • Accepted 23 May 2017

Corresponding author: Yeva Rosana, [email protected]


Desy A. Gultom,1 Yeva Rosana,1 Ida Efendi,1 Wresti Indriatmi,2 Andi Yasmon1

1 Department of Microbiology, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia2 Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital,

Jakarta, Indonesia

Basic Medical Research


ABSTRAK

Latar belakang: Saat ini telah terjadi peningkatan kasus T. pallidum resisten azitromisin akibat mutasi gen 23S ribosome-ribonucleic acid (rRNA). Hingga kini belum ada kit pengujian laboratorium untuk mengidentifikasi mutasi yang terkait resistensi T. pallidum. Oleh karena itu, pada penelitian ini dikembangkan sistem uji nested multiplex polymerase chain reaction (PCR) untuk mendeteksi dan mengidentifikasi mutasi titik A2058G dan A2059G gen 23S rRNA.

Metode: Tiga pasang primer digunakan pada reaksi nested PCR. Untuk mendapatkan kondisi uji yang optimal, dilakukan optimasi parameter yang penting pada proses PCR. Uji spesifisitas dilakukan terhadap beberapa mikroorganisme yang dapat menyebabkan reaksi silang. Selain itu, dilakukan uji sensitivitas untuk mendapatkan deteksi deoxyribonucleic acid (DNA) minimal. Metode PCR yang sudah dioptimasi diujikan pada 45 sampel klinis darah yang hasilnya dikonfirmasi dengan DNA sekuensing.

Hasil: Uji nested multiplex PCR dapat mendeteksi 4.400 jumlah copy DNA dan tidak bereaksi silang terhadap mikroorganisme yang potensial menyebabkan hasil positif palsu. Melalui uji pada 45 sampel klinis darah ditemukan 13 sampel positif T. pallidum dan tidak ditemukan mutasi baik A2058G maupun A2059G. Dua sampel positif dikonfirmasi dengan DNA sekuensing dan menunjukkan tidak ada mutasi.

Kesimpulan: Uji nested multiplex PCR yang dikembangkan pada penelitian ini menunjukkan uji yang spesifik dan sensitif untuk mendeteksi T. pallidum dan mengidentifikasi mutasi A2058G dan A2059G gen 23S rRNA.

ABSTRACT

Background: Azithromycin-resistant strains of Treponema pallidum is associated with the mutation of 23S rRNA gene of T. pallidum. Although these strains are now prevalent in many countries, there is no laboratory test kit to detect and identify these mutations. Thus, in this study we developed a nested multiplex polymerase chain reaction (PCR) to detect and identify A2058G and A2059G mutations in 23S rRNA gene.

Methods: Three primer sets were designed for nested PCR reactions. To obtain maximum PCR reaction, all parameters were optimized. The specificity of the primer sets was evaluated towards some microorganisms. A sensitivity test was conducted to get detection limit of deoxyribonucleic acid (DNA). Forty-five whole blood specimens were tested by PCR, and positive results were confirmed by the DNA sequencing.

Results: The assay could detect at least 4,400 DNA copy number and showed no cross reaction with other microorganisms used in the specificity test. A total 13 of 45 whole blood specimens were PCR positive for T. pallidum, and no single mutations (either A2058G or A2059G) were detected. Two positive specimens were confirmed by the DNA sequencing and showed no mutation.

Conclusion: Nested multiplex PCR developed in this study showed a specific and sensitive test for the detection and identification of A2058G and/or A2059G mutations of 23S rRNA T. pallidum gene.


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Following decades of low prevalence, syphilis is now resurgent in many developed countries.1 Although penicillin remains the preferred treatment for syphilis, the convenience of single-dose oral administration of azithromycin, its long half-life in tissue, and its efficacy, which is equivalent to penicillin, have led to the frequent use of this antibiotic for the treatment of syphilis.1–4

Widespread use of azithromycin for the treatment of syphilis has resulted in the emergence of resistant strains to the antibiotic. Some research also showed that recent macrolide used for unrelated infections (e.g., oral, skin, respiratory, and genital infections) contributed to the increased prevalence of macrolide-resistant Treponema pallidum by providing a selective pressure.1,5,6

Azithromycin resistance is often associated with alteration of the target site (i.e., the peptidyl transferase region in domain V of 23S ribosome-ribonucleic acid (rRNA)) via mutation an adenine (A)-to-guanine (G) transition at position A2058G or A2059G in the 23S rRNA gene, that alters the active site of antibiotic on ribosomes.1–3,6–8 Studies have shown the increased prevalence of azithromycin-resistant T. pallidum in many developed countries over the years.9 The use of macrolide especially azithromycin is increasing in developing countries, and therefore it is likely that azithromycin-resistant T. pallidum will eventually emerge or will be introduced via travel and/or tourism.1

Antibiotic resistance indicates the need to determine the sensitivity of T. pallidum using molecular method because this bacterium cannot be cultured on artificial medium.10,11 Although resistant strains are now prevalent in many countries, no laboratory test kit is available to detect and identify these mutations. Thus, in this study we developed a nested multiplex PCR to detect and identify A2058G and A2059G mutations of T. pallidum 23S rRNA gene. Several methods could be used to detect mutation such as the polymerase chain reaction–restriction fragment length polymorphism (PCR RFLP), real time polymerase chain reaction (PCR), and deoxyribonucleic acid (DNA) sequencing.12–14 However, real time PCR and DNA sequencing are highly expensive (reagents and instruments) and time consuming, as well as needs special skills especially for the DNA sequencing.15,16 PCR-RLFP and nested PCR are not expensive methods, in which PCR-RFLP is less sensitive than nested

PCR.17 Therefore, nested multiplex PCR was developed as an alternative assay for the detection of A2058G and A2059G mutations of T. pallidum.

METHODS

Clinical specimenForty-five whole blood specimens were obtained from patients with secondary syphilis from the sexually transmitted diseases (STD) clinic of Cipto Mangunkusumo Hospital, the STD clinic of Puskesmas Pasar Rebo, the STD clinic of Tambora, and Perkumpulan Keluarga Berencana Indonesia (PKBI) Jatinegara. All patients agreed to enroll in this study by signing informed consent forms. This study was approved by Fakultas Kedokteran Universitas Indonesia (FKUI) research ethical committee no. 158/UN2.F1/ETIK/2015.

Primer designThree sets of primers were designed using primer designer (please kindly contact corresponding author to get the primer sequences). One set of the primer was used to detect T. pallidum 23S rRNA gene while the other two primer sets were used to detect the mutations (A2058G and A2059G) of T. pallidum 23S rRNA gene; thus, the nested multiplex PCR produced three DNA segments (187 bp, 130 bp and 100 bp).

Positive control A synthetic positive control was purchased from gBlocks® gene fragments (194 bp length) having the sequences of T. pallidum 23S rRNA gene with mutations A2058G and A2059G.

DNA extractionThe DNA of T. pallidum from 200 μl whole blood specimens were extracted using high pure PCR template preparation kit (Roche) according to the manufacturer’s instructions with final elution of 70 μL.

Nested multiplex PCRThe reaction mixture of PCR 1 (20 μL): 1x PCR buffer, 1.75 mM MgCl2, 0.2 μM dNTP mix, 1x Q-solution, 0.2 μM of each primer (PCR1-F and PCR1-R), 0.5 U enzyme Taq DNA polymerase (HotStarTaq® Qiagen), and 5 μl of DNA template. The thermal cycles of PCR I: 95°C for 15 min (initial activation); 25 cycles of 95°C for 30 sec 58°C for 30 sec, and 72°C for 30 sec; and 72°C for 10 min (final


Figure 1. Scheme illustrating primer positions and products (DNA segments) produced by first and second round of nest-ed multiplex PCR. 130-bp and 100-bp DNA segments will be amplified if there is mutation A2058G and/or A2059G re-spectively. The 3’ end of primer forward (2058 F) and reverse (2059 R) have been designed that they can only hybrid with A2058G and A2059G mutations of 23S rRNA respectively. A 187-bp DNA segment will be amplified only from T. pallidum 23S rRNA gene (internal control for bacterial detection)

extension). The reaction mixture of PCR 2 (20 μL): 1x PCR buffer, 1.13 mM MgCl2, 0.35 μM dNTPmix, 1x Q-solution, 0.45, 0.25, 0.15, 0.4 μM of 2058F, 2058R, 2059F, and 2059R primers, respectively; 1.5 U enzyme Taq DNA polymerase, and 1 μL of PCRI product. The thermal cycles of PCR II: 95°C for 15 min (initial activation); 35 cycles of 95°C for 30 sec 61°C for 30 sec, and 72°C for 1 min; and 72°C for 10 min (final extension). DNA amplification was done using the PCR machine (BioRad) according to the manufacturer’s instructions. All parameters in the PCR reactions, including annealing temperature, primer concentration, enzyme concentration, annealing time, magnesium concentration, extension time, and cycle number of PCR, have been optimized before applying for clinical samples. Nested multiplex PCR products were analyzed by electrophoresis using gel agarose 2% and colorized by GelRedTM. Nucleotide bands visualized by the UV trans-illumination of Gel Doc machine BioRad®. GeneRuler 50 bp DNA ladder (Thermo Scientific) used as marker size molecules.

Specificity and sensitivity of PCRNested multiplex PCR specificity was tested against DNA of some various pathogens potential causing false positive results including: Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, Pseudomonas aeruginosa, Enterococcus faecalis, Candida albicans, Epstein Barr virus, cytomegalovirus, herpes simplex virus, and varicella zoster virus. The sensitivity of nested multiplex PCR was performed using distilled water solutions containing serial dilation (1/104-1/1012) of purified T. pallidum DNA. This test was used to find the detection limit of DNA in the PCR-reactions.

DNA sequencingIn order to verify nested multiplex PCR assays, the A2058G and A2059G mutations were confirmed by DNA sequencing.

RESULTS

Primer designIn this study, we designed three sets of primers (one set of primer for PCR 1 and two sets of primers for PCR 2). The second PCR will produce three DNA fragments with different length (Figure 1). One DNA segment (187 bp) indicates T. pallidum 23S rRNA gene. The other two of DNA segments (130 bp and 100 bp) indicated A2058G and A2059G mutations respectively.

Optimization of nested multiplex PCROptimization of nested multiplex PCR reaction was conducted in order to obtain optimum PCR result. From optimization of the annealing temperature, the results showed that the optimum annealing temperature for the amplification (both PCR 1 and PCR 2) was 60.9°C (61°C). Optimization of primer concentration showed that concentration of 0.13 μM, 0.3 μM, 0.4 μM, and 0.47 μM for each primer, gave the optimum result (at total volume reaction of 20 μL). Optimization of enzyme concentration showed that 1.5 units of Taq DNA polymerase at a total reaction volume of 20 μl gave the optimum result. From optimization of the annealing time, the results showed that the optimum annealing time for the amplification was 30 seconds. Optimization of magnesium ion concentration showed that concentration 0.33 mM magnesium

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ion at a total reaction volume of 20 μL gave the optimum result. From the optimization of the number of cycles, the results showed that the optimum one was 35 cycles.

Specificity and sensitivity of nested multiplex PCRTo determine the specificity of nested multiplex PCR, we tested a panel of microorganisms including Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, Pseudomonas aeruginosa, Enterococcus faecalis, Candida albicans, Epstein Barr virus, cytomegalovirus, herpes simplex virus, and varicella zoster virus. The results showed no cross reacting with those microorganisms. Specificity

Figure 2. Examples of polymerase chain reaction (PCR) positive and negative results from whole blood samples. K- and K+: negative and positive controls. Positive control consisted of three DNA segments (187 bp, 130 bp and 100 bp). 187 bp: a DNA band indicating T. pallidum 23S rRNA gene (bacterial detection). 130 bp and 100 bp: DNA bands indicating A2058G and A2059G mutations respectively

Figure 3. An example of deoxyribonucleic acid (DNA) sequencing result from positive sample. Red circle shows adenine (A) in position 2058 and 2059 of T. pallidum 23S rRNA gene, indicating azithromycin-sensitive T. pallidum

of the primers was also analyzed by primer basic local alignment search tool (BLAST) program and showed no cross reacting with the DNA fragment from other microorganisms except T. pallidum. The detection limit of DNA of nested multiplex PCR was 4,400 DNA copy number.

Detection of T. pallidum in clinical specimensPCR results showed that 13 of 45 whole blood specimens were positive T. pallidum 23S rRNA gene with no mutations (A2058G and/or A2059G)

Confirmation of PCR results by DNA sequencingTwo positive samples with no mutations were confirmed by DNA sequencing. The DNA sequencing results clarified that there were no mutations in 2058 and 2059 position of 23S rRNA gene and in accordance with PCR results.

DISCUSSION

The inability to cultivate T. pallidum on artificial medium and the limitations of conventional methods for direct detection of pathogenic treponemes in clinical specimens, have made clinical decision-making of syphilis is often based upon serological tests despite the fact that their results may not correlate with disease activity.18

The increased prevalence of azithromycin-resistant T. pallidum indicates the importance of determining the sensitivity of T. pallidum to antibiotic. The sensitivity test using conventional method cannot be conducted because the inability to cultivate T. pallidum on artificial medium. As a result, molecular method would enable rapid detection to detect and identify mutations of T. pallidum.

187 bp130 bp100 bp


In this research, we developed a nested multiplex PCR using three primer sets to detect T. pallidum and to identify mutations (A2058G and A2059G) of T. pallidum 23S rRNA gene that caused azithromycin and macrolide resistant T. pallidum. The 3’end of primers (2058F and 2059R) were designed to hybrid only at A2058G and 2059 positions of 23S rRNA gene resistant T. pallidum. Besides the mutation identifications, the assay also could detect the T. pallidum that was indicated by a 187-bp DNA segment (Figure 1). The PCR method to detect the mutations of 23S rRNA has also been developed by other researchers with different approaches. Lukehart et al.7 developed a conventional method for the detection of A2058G mutation used a nested PCR followed by MboII restriction enzyme digestion and agarose gel electrophoresis. An additional restriction enzyme (BsaI) is needed to detect the A2059G mutation as developed by Matejkova et al6 and Chen et al19 developed a real-time multiplex PCR to simultaneously detect both mutations without two separate enzymatic digestions.

All parameters in the PCR reactions including annealing temperature, primer concentration, enzyme concentration, annealing time, magnesium ion concentration, extension time, and cycle number of PCR were optimized to obtain ideal results. There is no single protocol or single set of conditions that is optimal for all PCR.20,21 Therefore, each new PCR application is likely to require specific optimization to overcome problems, such as no detectable or low yield of PCR product, the presence of nonspecific bands or smeary background; the formation of “primer-dimers” that compete with the chosen template/primer set for amplification; or mutations caused by errors in nucleotide incorporation.20,21 Furthermore, syphilis specimens, such as blood, may contain extremely low concentrations of treponemes.18 It was, therefore, essential to improve an assay’s sensitivity with optimization of some parameters such as annealing temperature, primer concentration, enzyme concentration, annealing time, magnesium ion concentration, extension time, and cycle number of PCR.20–22

To determine the specificity of nested multiplex PCR, we tested a panel of microorganisms including Staphylococcus aureus, Streptococcus pneumonia, Escherichia coli, Klebsiella pneumonia, Salmonella typhi, Pseudomonas aeruginosa, Enterococcus faecali, Candida albicans, Epstein

Barr virus, cytomegalovirus, herpes simplex virus, and varicella zoster virus. The results showed no cross reacting with those microorganisms. Chen et al19 determined the specificity of the triplex PCR assay with DNA extracted from an in-house specificity panel comprising closely related T. pallidum subsp. endemicum and T. pallidum subsp. pertenue, nonpathogenic treponemes (T. denticola, T. refringens, and T. phagedenis), and pathogenic and commensal genital tract microorganisms, as well as normal skin flora. The number microorganisms for specificity study were limited. However, the specificity of the primers were also analyzed by primer-BLAST program and showed no cross reacting with DNA fragment from other microorganisms beside T. pallidum. We recommend that it is important to perform the specificity test against larger representative microorganisms in the future.

From the sensitivity test, we found that the detection limit of DNA of the assay was 4,400 DNA copy numbers. This result was different from Liu et al23 and Orle et al24 which had a sensitivity of 10 organisms. These differences might occur as a result of using different gene target, set primers or specimen in each study. Liu et al23 and Orle et al24 using polA as gene target and swab from genital ulcer as sample. Many studies showed that swab from genital ulcer specimens or from skin active lesions have better sensitivity than blood specimens.10,25,26 However, in this study we could not obtain the skin specimens because not all of patients showed wet skin lesion; thus, we only obtained the whole blood samples. Although the sensitivity of T. pallidum bacteremia detection is lower, it varies according to stage.10 Moreover, we also used more than one primer pair (three sets of primers) that might affect the sensitivity assay.27

A total 13 of 45 whole blood specimens were PCR positive for T. Pallidum, and no single point mutation (either A2058G or A2059G) were detected. Nested multiplex PCR could only detect mutations from positive control that always ran parallel with PCR reactions from samples. This result was different from other studies of mutations A2058G and A2059Gof 23S rRNA gene that caused azithromycin and macrolide resistant T. pallidum. Studies from many countries showed the increase of resistant T. pallidum strain.2,3,9,10 It is not enough evidence to conclude that resistance strains of T. pallidum do not emerge in Indonesia

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because of the samples we tested only taken from one city that is Jakarta. We suggest to conduct further studies by using clinical specimens from other provinces in Indonesia to obtain national data of azithromycin-resistant T. pallidum.

In conclusion, we have developed nested multiplex PCR for simultaneous detection and identification of A2058G and A2059G mutations 23S rRNA T. pallidum gene by using three sets of primers. This assay has been optimized to obtain the optimal condition of PCR with high specificity and sensitivity. Optimized PCR have been tested for clinical specimens and showed the same results as confirmatory DNA sequencing. Based on this study, the PCR developed is potential to apply for clinical specimen.

Conflicts of InterestThe authors declare that they have no conflict of interests.

AcknowledgmentThis research was funded by PUPT DIKTI 2015-2016. We thank the team of Microbiology and Dermatology-Venereology Department for cooperation and technical assistance. We also thank the STD clinic of Cipto Mangunkusumo Hospital, the STD clinic of Puskesmas Pasar Rebo, the STD clinic of Tambora, and PKBI Jatinegara for their contribution and cooperation.

REFERENCES

1. Stamm LV. Global challenge of antibiotic-resistant Treponema pallidum. Antimicrob Agents Chemother. 2010;54(2):583–9.

2. Stamm LV. Syphilis: antibiotic treatment and resistance. Epidemiol In fect. 2015; 143(8):1567–74.

3. Katz KA, Klausner JD. Azithromycin resistance in Treponema pallidum. Curr Opin Infect Dis. 2008(1);21:83–91.

4. Mitchell SJ, Engelman J, Kent CK, Lukehart SA, Godorne C, Klausner JD. Azithromycin-resistant syphilis infection: San Francisco, California, 2000–2004. Clin Infect Dis. 2006;42(3):337–45.

5. Marra CM, Colina AP, Godornes C, Tantalo LC, Puray M, Centurion-Lara A, et al. Antibiotic selection may contribute to increases in macrolide-resistant Treponema pallidum. J Infect Dis. 2006;194(2):1771–3.

6. Matejkova P, Flasarova M, Zakoucka H, Borek M, Kremenova S, Arenberger P, et al. Macrolide treatment failure in a case of secondary syphilis: a novel A2059G mutation in the 23S rRNA gene of Treponema pallidum subsp. Pallidum. J Med Microbiol. 2009; 58(Pt 6):832–6.

7. Lukehart SA, Godornes C, Molini BJ, Sonnett P, Hopkins S, Mulcahy F, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med. 2004;351:154–8.

8. Vester B, Douthwaite S. Macrolide resistance conferred by base substitution in 23S rRNA. Antimicrob Agents Chemother. 2001;45:1–12.

9. Tipple C, Taylor GP. Syphilis testing, typing, and treatment follow-up: a new era for an old disease. Curr Opin Infect Dis. 2015;28(1):53–60.

10. Tipple C. Molecular studies of Treponema pallidum [thesis]. Imperial College London; 2013.

11. LaFond RE, Lukehart SA. Biological basis for syphilis. Clin Microbiol Rev. 2006; 19(1):29–49.

12. Grimes M, Sahi SK, Godornes BC, Tantalo LC, Roberts N, Bostick D, et al. Two Mutations associated with Macrolide Resistance in Treponema pallidum: Increasing Prevalence and Correlation with Molecular Strain Type in Seattle, Washington. Sex Transm Dis. 2012;39(12):954–8.

13. Zhu B, Bu J, Li W, Zhang J, Huang G, Cao J, et al. High resistance to azithromycin in clinical samples from patients with sexually transmitted diseases in Guangxi Zhuang Autonomous Region, China. PloS ONE. 2016;11(7):e0159787.

14. Molini B, Tantalo LC, Sahi SK, Rodriguez V, Brandt SL, Fernandez MC. et al. Macrolide resistance in Treponema pallidum correlates with 23S rDNA mutations in recently isolated clinical strains. Sex Transm Dis. 2016;43(9):579–83.

15. Harishankar A, Chandy M, Bhattacharya S. How to develop an in-house real-time quantitative cytomegalovirus polymerase chain reaction: Insights from a cancer centre in Eastern India. Indian J Med Microbiol. 2015;33(4):482–90.

16. Sboner A, Mu XJ, Greenbaum D, Auerbach RK, Gerstein MB. The real cost of sequencing: higher than you think! Genome Biol. 2011;12:125.

17. Oh BH, Song YC, Lee YW, Choe YB, Ahn KJ. Comparison of nested PCR and RFLP for identification and classification of malassezia yeasts from healthy human skin. Ann Dermatol. 2009;21(4):352–7.

18. Burstain JM, Grimprel E, Lukehart SA, Norgard MV, Radolf JD. Sensitive detection of Treponema pallidum by using the polymerase chain reaction. J Clin Microbiol. 1991;29(1):62–9.

19. Chen CY, Chi KH, Pillay A, Nachamkin E, Su JR, Ballard RC. Detection of the A2058G and A2059G 23S rRNA gene point mutations associated with azithromycin resistance in Treponema pallidum by use of a TaqMan real-time multiplex PCR assay. J. Clin. Microbiol. 2013;51(3):908–13.

20. Grunenwald H. Optimization of polymerase chain reaction. Dalam: Bartlett JMS, Stirling D, editor. Methods in molecular biology. Vol. 226: PCR protocols. 2nd Ed. Totowa, NJ: Humana Press Inc.; 2003. p. 89–100.

21. Innis MA, Gelfand DH. Optimization of PCRs. Dalam: Innis MA, Gelfand DH, Sninsky JJ, White TJ, editor. PCR protocols: a guide to methods and applications. San Diego, CA: Academic Press, Inc.; 1990. p. 3–12.

22. Rylichlik W, Spencer WJ, Rhoads RE. Optimization of the annealing temperature for DNA amplification in vitro. Nucleic Acids Res. 1990;18(21):6409–12.


23. Liu H, Rodes B, Chien CY, Steiner B. New test for syphilis: rational design of a PCR method for detection of Treponema pallidum in clinical specimens using uniqe regions of the DNA plimerase I gene. J. Clin. Microbiol. 2001;39(5):1941–6.

24. Orle, K. A., C. A. Gates, D. H. Martin, B. A. Body, and J. B. Weiss. 1996. Simultaneous PCR detection of Haemophilus ducreyi, Treponema pallidum, and herpes simplex virus types 1 and 2 from genital ulcers. J. Clin. Microbiol. 1996;34(1):49–54.

25. Martin IE, Tsang RSW, Sutherland K, Tilley P, Read R, Anderson B, et al. Molecular characterization of syphilis

in patients in Canada: azithromycin resistance and detection of Treponema pallidum DNA in whole-blood samples versus ulcerative swab. J. Clin. Microbiol. 2009;47(6):1668–73.

26. Grange PA, Gressier L, Dion PL, Farhl D, Benhaddou N, Gerhardt P, et al. Evaluation of a PCR test for detection of Treponema pallidum in swab and blood. J. Clin. Microbiol. 2011;50(3):546–52.

27. Elnifro EM, Ashshi AM, Cooper RJ, Klapper PE. Multiplex PCR: optimization and application in diagnostic virology. Clin. Microbiol. Rev. 2000;13(4):559–70.

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Afandi, et al.Domestic violence in emergency setting

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Prevalence and pattern of domestic violence at the Center for Forensic Medical Services in Pekanbaru, Indonesia

Keywords: domestic violence, forensic examination finding, prevalence, women, wound

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.1865 • Med J Indones. 2017;26:97–101• Received 13 Feb 2017 • Accepted 03 May 2017

Corresponding author: Dedi Afandi, [email protected]


Dedi Afandi,1 Mohammad T. Indrayana,1 Iriandanu Nugraha,2 Dinda Danisha2

1 Department of Forensic and Legal Medicine, Faculty Medicine, University of Riau, Riau, Indonesia2 Faculty Medicine, University of Riau, Riau, Indonesia

Clinical Research


ABSTRAK

Latar belakang: Kekerasan dalam rumah tangga masih merupakan masalah kesehatan global yang signifikan, terutama pada perempuan. Penelitian tentang insiden dan prevalensi kekerasan dalam rumah tangga di Indonesia masih terbatas. Penelitian ini bertujuan mendapatkan prevalensi, jenis kekerasan, dan temuan pemeriksaan forensik mengenai kekerasan dalam rumah tangga di unit gawat darurat.

Metode: Penelitian ini adalah penelitian retrospektif dari korban kekerasan dalam rumah tangga yang diperiksa di Unit Gawat Darurat Rumah Sakit Bhayangkara, Pekanbaru, Indonesia, antara tahun 2010 dan 2014. Kasus kekerasan dalam rumah tangga ditentukan berdasarkan visum et repertum dan surat permintaan visum et repertum dari polisi.

Hasil: Didapatkan 6.876 kasus kekerasan pada korban hidup dan 755 (10,9%) di antaranya adalah kasus kekerasan dalam rumah tangga. Perempuan adalah korban terbanyak (93,8%) dengan frekuensi tertinggi pada rentang usia subur (77,9%). Sebagian besar korban kekerasan dalam rumah tangga adalah ibu rumah tangga (67,0%). Kekerasan fisik merupakan jenis kekerasan yang paling sering terjadi (98,7%). Memar adalah jenis luka paling dominan pada korban kekerasan dalam rumah tangga (76,2%), dan luka lecet ditemukan pada hampir setengah dari korban (48,1%). Kepala dan anggota gerak adalah lokasi yang paling sering ditemukan luka. Kekerasan tumpul dialami oleh lebih dari tiga perempat korban (88,5%).

Kesimpulan: Prevalensi kasus kekerasan dalam rumah tangga cukup tinggi pada korban hidup di unit gawat darurat, dan mayoritas korban adalah perempuan.

ABSTRACT

Background: Domestic violence (DV) is still a significant public health problem, especially in women’s health. Few studies have reported the prevalence and domestic violence in Indonesia. The aim of this study was to identify the prevalence, type of violence, and forensic examination on domestic violence victims in emergency departments.

Methods: This study was a retrospective analysis of domestic violence victims observed in the Emergency Department at the Bhayangkara Hospital, Pekanbaru, Indonesia, between 2010 and 2014. The determinations of DV cases are based on the medico-legal reports (visum et repertum) and the police’s official inquiry letters.

Results: Out of 6,876 medico-legal injury reports of living victims were reviewed, and 755 (10,9%) cases were DV. The majority of victims in DV were women (93.8%) with childbearing age group as the highest frequency (77.9%). Most of the DV victims were housewives (67.0%). Moreover, physical assault was the most common DV types (98.7%). Bruise was the predominant type of wound among the DV victims (76.2%), and almost half of the victims had abrasions (48.1%). Head and limbs were the predominant sites of wound. Blunt injury was found in more than three-quarters of the victims (88.5%).

Conclusion: The prevalence of domestic violence was high among living victims in the emergency department, with women as the majority of victims.



Domestic violence (DV) is a type of violence in the household. DV is defined by the World Health Organization (WHO) as any behavior within an intimate relationship that causes physical, psychological, or sexual harm.1 The perpetrator belongs to the victim’s “domestic environment”: an intimate partner, husband, former intimate partner, family member, friend or acquaintance in a domestic setting.2

Women are more likely to be victims. DV is more likely to be a form of violence against women due to the number of women as victims. A WHO study concluded that the proportion of women who had ever suffered physical violence ranged from 13% to 61%, and sexual violence ranged from 6% to 59% was done by a male partner.1 The WHO reported that the global prevalence of physical and sexual intimate partner violence is 30%, with the highest prevalence in the South-East Asia. DV is associated with physical, mental, sexual and reproductive health.1,3,4 Data showed that 42% of victims received physical injury from their partner. Effects on mental health include depression and alcohol use disorder. Mortality is caused by homicide by partner and suicide by themselves.3

Generally, Indonesia lacks of national data on DV. Few studies have reported on the prevalence of DV in Indonesia. Hayati et al5 reported that the prevalence of lifetime exposure to sexual and physical violence was 22% and 11% was among women in rural areas.

There is no data regarding the prevalence of DV in urban areas. Pekanbaru is the capital city of the Riau Province, one of the 34 provinces in Indonesia. This city is the third largest (inland) urban area on the Sumatra Island with a population of approximately 1.2 million people. The aim of this study was to identify the prevalence, type of violence, and forensic examination finding in domestic violence victims in Emergency Department of Bhayangkara Hospital Pekanbaru (BHP). This hospital is a teaching hospital of the Faculty of Medicine, University of Riau and the hospital center for forensic medical services in Pekanbaru. All DV cases reported to the police will be referred to the Bhayangkara Hospital Pekanbaru.

METHODS

A retrospective descriptive study was conducted at the BHP. All medico-legal injury reports of living victims from January 1st 2010 to December 31st 2014 were studied for the prevalence of DV by using basic data, such as sex, age, profession, type of domestic violence and basic forensic parameters (type, number, site of wound and type of injury). The determinations of DV cases are based on the medicolegal report (visum et repertum) and the police’s official inquiry letter. The completeness of the data obtained by collecting and recording the necessary data that contained in the visum et repertum of DV cases. The research protocol was

2010 2011 2012 2013 2014living victim cases 1014 1429 1548 1489 1396Domestic Violence 64 256 122 136 177 % 6.3 17.9 7.9 9.1 12.7

02468101214161820

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Figure 1. The number of living victim cases, domestic violence victims, and percentage by year

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Variable n (%)*

SexFemale 708 (93.8)Male 47 (6.2)

Age category (years), median 31 (19–77)19–20 43 (5.7)21–30 308 (40.8)31–40 280 (37.1)41–50 93 (12.3)51–60 23 (3.0)>60 8 (1.1)

ProfessionUnemployed, housewife 506 (67.0)Irregular limited, income work 180 (23.8)Regular limited, income work 35 (4.6)Student 27 (3.6)Housemaid 7 (0.9)

Type of domestic violencePhysical injury 745 (98.7)Sexual assault 10 (1.3)

Presence of woundBruise 575 (76.2)Abrasion 363 (48.1)Vulnus laceratum 57 (7.5)Vulnus scissum 9 (1.2)Burn 1 (0.1)

Number of woundNo wound finding 61 (8.1)1 wound finding 394 (52.2)- Bruise 290 (38.4)- Abrasion 86 (11.4)- Vulnus laceratum 14 (1.9)- Vulnus scissum 3 (0.4)- Burn 1 (0.1)

2 wounds finding 277 (36.7)>2 wounds finding 23 (3.0)

Site of woundHead 471 (62.4)Neck 94 (12.5)Trunk 147 (19.5)Limbs 466 (61.7)

Type of injuryBlunt injury 668 (88.5)Sharp injury 4 (0.5)Blunt and sharp injury 22 (2.9)No injury 61 (8.1)

Table 1. Distribution of demographic, type of violence and injury pattern of domestic violence victims (n=755)

*Data presented in absolute number (%) except stated otherwise

approved by the institutional research committee of the Faculty of Medicine, University of Riau (No. 52/UN19.1.28/UEPKK/2015).

RESULTS

A total of 755 cases were identified for inclusion in this study. Overall, the total number of medico-legal injury reports of living victims in the BHP over the study period was 6,876. The domestic violence percentage of all cases of living victims was 10.9% and varied from 6.3% to 17.9% per year (Figure 1).

Almost all of the DV victims were women (93.8 %). The ages of victims ranged from 19 to 77 years old, with a median of 31 years old. The largest age-groups were between 21–30 years and 31–40 years. The age-group of 21–40 years comprised 77.9% of DV victims. Most of the DV victims were housewives (67.0%), in which seven DV victims (0.9%) were housemaids (Table 1).

Physical assault was the most common DV types (98.7%). Bruising was the predominant type of wound that presented among DV victims (76.2%), and almost half of the victims had abrasions (48.1%). One number of wound was found in more than half of victim (52.2%). Head was the most common location of wounds (62.4%) followed by limbs (61.7%). More than three-quarters of victims (88.5%) reported that the type of injury was a blunt injury (Table 1).

DISCUSSION

A study regarding the prevalence of DV among living victims who attended the emergency department in Western countries reported a prevalence of DV cases: 1.1% in the United Kingdom (UK)6 and 4–6.6% in Northern Ireland.7 The prevalence of DV in eastern countries has been largely restricted to reports and estimates. The prevalence of DV in this study was higher than the previous study in the UK and Northern Ireland. These differences might be related to methodological differences and the socio-demographics of the victims, such as gender norms, culture, marital status, ethnicity and education gap.2,5,8



Our study showed the prevalence at the emergency department was lower compared to prevalence in population based study. Several population-based studies reported that the prevalence of DV was 56% in Eastern India,9 and 26.4% of women and 15.9% of men in the United States (US).10 Globally, the WHO estimates a prevalence of lifetime physical and or sexual violence for women ranging between 24.6% in the Western Pacific to 37.7% in South-East Asia.3 This difference could be explain because in initial studies, most women refrain to report their physical assault and or sexual violence due to traditional gender norms, subordination from their spouse, education, taboo, fear of not being believed, not being asked if they had been affected by domestic violence, especially by health professionals, fears of reprisal, and feelings of love, shame, and guilt.2,3,5,7,9

Our study revealed that almost all DV victims were women (93.8%). This result is similar to many studies about violence against women. This is reasonable because DV is a different form of violence again women related to gender-based violence.1–3,11 The results of this study indicated that the phenomenon of violence against women in rural areas5 also occurred in urban areas. This study further reinforced that woman’s position is still subordinated from man in Indonesia. Forty-seven (6.2%) men were victims of DV in our study. Another study showed a higher number of men as DV victims, 11.5% in Portugal12 and 22% in Greece.13 This can be explained due to greater gender equality in Western compared to Eastern countries. The findings in this study indicated that both men and women could be victims of DV. However, given the smaller number of male victims in this study, more attention should be given to female victims of DV in Indonesia.

The peak incidence of DV occurred in the childbearing age groups (77.9%), the age group 21–40 years (40.8%) and the age group 31–40 years (37.1%). Another study reported 65% in Hong Kong,14 while the WHO estimated 31.1%–36.6% for five years for each group in the age group 20–39 years.3 The profession of most of the DV victims in our study was housewife (67%), which was higher than the study in Greece (32.2%).13 Meanwhile, a population-based study in Eastern India reported is 80%.9 From our study, we found seven housemaids that were DV victims. Murty15 reported two cases of maid abuse in Malaysia.

According to the Indonesian’s Elimination of Domestic Violence Act,16 a housemaid who receives violence from their employer or member of their house could be a DV victim.

Almost all of the DV victims in our study had physical injuries (98.7%) compared to sexual assault (1.3%). The prevalence of sexual assault in this study was lower than the prevalence of DV from other studies, in Indonesian rural areas (22%)5 and Eastern India (19.7–32.4%).9 Only a few women who were sexually assaulted would report it to the authorities due to taboo and religious reasons. Based on the Indonesian Penal Code, sexual assault is defined as a sexual violence occurs outside marriage. In the Indonesian’s Elimination of Domestic Violence Act,16 sexual assault is categorized as one type of DV. However, the Indonesian Council of Ulama declared that sexual assault in marriage can be considered as DV if the husband coerces sexual intercourse in conditions that are prohibited syar’i: if the wife is in a state of menstruation and childbirth or during Ramadhan fasting, religious pilgrimage, anal sex, and if the wife is ill.

Our study reported that 76.2% of victims had bruises, followed by abrasions (48.1%). The combination of wounds was found in less than half of the victims. This result is similar to another study in Turkey17 that reported that most DV victims had soft tissue lesions. More than 60% of wounds were on the head and limbs, in conjunction with the study in Greece (75% in limbs, and 50% in head).13 The most common type of injury was blunt force injury (88.5 %), and only 0.5% was caused by a sharp injury. This finding is similar to a study in Turkey (0.7%).17 The findings of this study indicated that DV could lead to morbidity for the victims.

The limitation of this study is that the prevalence of DV is not indicative of the real magnitude of the number of cases of DV. However, the results of this study could add to our knowledge regarding the magnitude of the DV problems, as well as the importance of medicolegal aspects of DV. This study may also add to our overall understanding of the problem and may help to identify patterns or trends in DV, especially among urban areas and the childbearing age population group and may assist in implementing effective preventative measures.

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In conclusion, the prevalence of domestic violence is high among living victims in the emergency department, with women as majority of victims. Almost all victims experienced physical assault. Bruises and abrasions were the most types of wound with head as the common site. Blunt injuries were also mostly found in domestic violence victims.

Conflicts of interestThe authors affirm no conflict of interest in this study.

AcknowledgmentWe thank the Director of Bhayangkara Hospital Pekanbaru, administrative staff of Medicine and Health Department Riau Regional Police for their assistance in collecting medico-legal report.

REFERENCES

1. García-Moreno C, Jansen HA, Ellsberg M, Heise L, Watts C. WHO Multi-country Study on Women’s Health and Domestic Violence against Women Initial results on prevalence, health outcomes and women’s responses Full Report. World Health. 2005. p. 13–40.

2. Flury M, Nyberg E, Riecher-Rössler A. Domestic violence against women: Definitions, epidemiology, risk factors and consequences. Swiss Med Wkly. 2010;140(w13099):2–7.

3. www.who.int [Internet]. Global and regional estimates of violence against women: prevalence and health effects of intimate partner violence and non-partner sexual violence. [update 2013; cited 2017 Feb]. Available from: http://www.who.int/reproductivehealth/publications/violence/9789241564625/en/

4. Hegarty K. Domestic violence: the hidden epidemic associated with mental illness. Br J Psychiatry. 2011;198(3):169–70.

5. Hayati EN, Högberg U, Hakimi M, Ellsberg MC, Emmelin M. Behind the silence of harmony : risk factors for

physical and sexual violence among women in rural Indonesia. BMC Women’s Health. 2011;11:52.

6. Boyle A, Todd C. Incidence and prevalence of domestic violence in a UK emergency department. Emerg Med J. 2003;20(5):438–43.

7. Stevenson TR, Goodall EA, Moore CB. A retrospective audit of the extent and nature of domestic violence cases identified over a three year period in the two district command units of the police service of Northern Ireland. J Forensic Leg Med. 2008;15(7):430–6.

8. Bazargan-Hejazi S, Kim E, Lin J, Ahmadi A, Khamesi MT, Teruya S. Risk factors associated with different types of intimate partner violence (IPV): an Emergency Department Study. J Emerg Med. 2014;47(6):710–20.

9. Babu BV, Kar SK. Domestic violence against women in eastern India: a population-based study on prevalence and related issues. BMC Public Health. 2009;9(1):129.

10. Breiding MJ, Black MC, Ryan GW. Prevalence and risk factors of intimate partner violence in eighteen U.S. States/Territories, 2005. Am J Prev Med. 2008;34(2):112–8.

11. Watts C, Zimmerman C. Violence against women: global scope and magnitude. Lancet. 2002;359(9313):1232–7.

12. Carmo R, Grams A, Magalhães T. Men as victims of intimate partner violence. J Forensic Leg Med. 2011;18(8):355–9.

13. Kosmidis G, Vlachomiditropoulos D, Goutas N, Spiliopoulou C. Medico-legal aspects of family violence cases in Athens, Greece. Int. J. Caring Sci. 2014;7(2):488–96.

14. Chan KL, Choi WM, Fong DY, Chow CB, Leung M, Ip P. Characteristics of family violence victims presenting to Emergency Departments in Hong Kong. J Emerg Med. 2013;44(1):249–58.

15. Murty OP. Maid abuse. J Forensic Leg Med. 2009;16(5):290–6.

16. www.ditjenpp.kemenkumham.go.id [Internet]. Undang-Undang Nomor 23 Tahun 2004 tentang penghapusan kekerasan dalam rumah tangga. [update 2017; cited 2017 Feb]. Available from: http://ditjenpp.kemenkumham.go.id/hukum-pidana/653-undang-undang-no-23-tahun-2004-tentang-penghapusan-kekerasan-dalam-rumah-tangga-uu-pkdrt.html

17. Balci YG, Ayranci U. Physical violence against women: Evaluation of women assaulted by spouses. J Clin Forensic Med. 2005;12(5):258–63.


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Can glycated hemoglobin act as a reliable glycemic indicator in patients with diabetic chronic kidney disease? evidence from the Northeast of Thailand

Keywords: Diabetic CKD, eGFR, Glycated hemoglobin, Thailand

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.1995 • Med J Indones. 2017;26:102–8• Received 10 May 2017 • Accepted 12 Jun 2017

Corresponding author: Sojib Bin Zaman, [email protected]


Sojib Bin Zaman,1,2,3 Naznin Hossain,4 Ahmed E. Rahman,3 Sheikh M.S. Islam5,6

1 Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand2 Institute of Tropical Medicine and International Health, Charité – University Medicine Berlin, Berlin, Germany3 Maternal and Child Health Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh4 Department of Pharmacology, Dhaka Medical College, Dhaka, Bangladesh5 Faculty of Medicine, University of Sydney, Sydney, Australia6 Cardiovascular Division, The George Institute for Global Health, Sydney, Australia

Clinical Research


ABSTRAK

Latar belakang: Penyakit ginjal kronis (PGK) adalah komplikasi yang sering terjadi pada penyandang diabetes melitus (DM) yang membutuhkan kontrol kadar gula darah (glikemik) yang adekuat. Glycated hemoglobin (HbA1c) adalah penanda biologis konvensional untuk memperkirakan status glikemik, namun perannya pada pasien PGK akibat DM masih belum jelas. Oleh karena itu, penelitian ini bertujuan untuk mengetahui apakah pasien dengan HbA1c tinggi berhubungan dengan timbulnya PGK.

Metode: Data diperoleh dari registri klinis pasien diabetes yang dirawat di sebuah rumah sakit di sebelah timur laut Thailand. CKD ditentukan berdasarkan perkiraan laju filtrasi glomerulus yaitu LFG<60mL/menit/1.73m2. Pengukuran antropometri dan biokimia pasien diambil dari rekam medis. Analisis regresi logistik multipel digunakan untuk mengetahui kemungkinan hubungan antara HbA1c dan PGK.

Hasil: Dari 4.050 pasien DM, terdapat 1.027 (25,3%) pasien yang memiliki PJK akibat DM. Usia yang lebih tua (adjusted odds ratio (AOR): 4,88, (95% CI: 3,71–6,42) p<0,05), perempuan (AOR: 1,38, 95% CI: 1,05–1,73, p<0,05), dan hipertensi (AOR: 1,52, 95% CI: 1,21–1,91, p<0,05) merupakan faktor risiko terjadinya PGK akibat DM. Akan tetapi, pasien dengan HbA1c tinggi (>6,5%) berhubungan terbalik dengan PGK akibat DM (AOR: 0,66, 95% CI: 0,51–0,86, p<0,05).

Kesimpulan: Penelitian ini menemukan pasien dengan HbA1c lebih tinggi tidak berkaitan dengan kejadian PGK akibat DM. Oleh karena itu, penggunaan nilai batas ambang HbA1c pada konvensional penderita PGK akibat DM tidak dapat digunakan di klinis. Peningkatan upaya deteksi status glikemik pada pasien dengan PGK akibat DM perlu diperketat untuk meningkatkan luaran.

ABSTRACT

Background: Chronic kidney diseases (CKD) is a common microvascular complication in patients with diabetes mellitus (DM) which requires adequate glycemic control. Glycated hemoglobin (HbA1c) is a conventional biomarker to estimate glycemic status, but its role in diabetic CKD patients is unclear. Therefore, this study aimed to determine whether patients with high HbA1c are associated to develop diabetic CKD.

Methods: Data were obtained from a clinical registry of diabetic patients who were treated in a district hospital in the Northeast of Thailand. CKD was defined according to the estimated glomerular filtration rate (eGFR<60mL/min/1.73m2). Anthropometric and biochemical measurements of the patient were taken by review of medical records. Multiple logistic regression analysis was used to determine the likelihood of the association between HbA1c and CKD.

Results: Among 4,050 participants, 1,027 (25.3%) developed diabetic CKD. Older age (adjusted odds ratio (AOR): 4.88, 95% confidence interval (CI): 3.71–6.42, p<0.05), female (AOR: 1.38, 95% CI: 1.05–1.73, p<0.05), and hypertension (AOR: 1.52, 95% CI: 1.21–1.91, p<0.05) were found as the risk factors of diabetic CKD. However, patients with high HbA1c (>6.5%) were negatively associated with diabetic CKD (AOR: 0.66, 95% CI: 0.51–0.86, p<0.05).

Conclusion: This study found patients with higher HbA1c level were not associated with diabetic CKD. Therefore, using the conventional cut-off values of HbA1c in diabetic CKD patients may be problematic in the clinical settings. Enhanced detection of glycemic status in patients with diabetic CKD is warranted to improve the outcome.


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Chronic kidney disease (CKD) is a frequent microvascular complication among patients with diabetes mellitus (DM). CKD is considered to be the leading cause of renal failure1 with its high prevalence in South-East Asia.2 Thailand has experienced the epidemiological transition for the recent years, and non-communicable diseases have come into the limelight to cause significant morbidities and mortalities.3 Thailand is also connected to the ‘stone belt’ zone which normally extends from Central Asia to South Asia.4 Therefore, the rate of kidney disease is high in the North-eastern Thailand.5 Although all diabetic patients are not at risk to develop CKD, minimal damage to the kidney is frequent.6 Age, sex, race, positive family history, and high blood pressure are the known risk factors of diabetic CKD. Chronic hyperglycemia due to uncontrolled DM plays the key role to initiate renal vascular complications.7 However, a previous study reported that diabetic kidney disease could develop with a relatively short duration of diabetes.8 Adequate diabetic management and glycemic control are essential to prevent diabetic kidney disease and other complications.9

Glycated hemoglobin (HbA1c) is one of the essential elements of human red blood cells which acts like the conventional biomarker to estimate glycemia.10 HbA1c is usually developed by the reduction of glucose with the amino contents of beta chains in hemoglobin A. Thus, HbA1c can reflect glucose status of a person as far as the viability of erythrocyte remains active in the blood. One-time determination of high HbA1c means that glycemic status of a particular patient was not under control for the last three to four months.

The prime target of diabetic care is to control patient’s high glycemic which reiterates the demands of using a valid test to detect accurate glycemia in patients with diabetic CKD.11 Traditionally, clinicians use HbA1c to measure the glycemic status of a diabetic patient, assess the efficacy of treatment, and recommend the appropriate adjustments to lifestyle. Some studies have found that HbA1c might not predict the exact glycemia in CKD patients under the pathophysiological evidence.12–14 However, these theoretical arguments have created some controversies which need to be justified and proved in real life setting as well.15 Most of

the developing countries use HbA1c as a valid glycemic indicator, and contemporary guidelines advocate the same cut-off point of HbA1c to detect glycemic status in CKD and non-CKD patients.16 Therefore, it demands an attention to know whether HbA1c can detect the accurate glycemic status in patients with diabetic kidney disease. This study aimed to determine whether patients with high HbA1c are more associated to develop diabetic kidney disease in compared to patients with low HbA1c.

METHODS

Data sources A hospital-based retrospective data analysis was performed between May 2016 and October 2016. The data were collected from the clinical registry of diabetic patients which was obtained from a district hospital in the northeast of Thailand. This hospital is the secondary referral facility with a catchment population of about 114,588. The study data represented one-year sample involving the yearly check-up investigation records of the patients.

Data collection This study has used the clinical registry to collect the records of 4,050 patients who were enrolled between 1 January 2015 and 31 December 2015. Among the diabetic patients, the number of CKD and non-CKD patients were 1,027 (25.3%) and 3,023 (74.7%) respectively. Demographic information, biochemical reports, and anthropometric measurements were extracted from the medical records. Age was categorized into two sub-groups according to the Thai retirement age.21 Occupation was classified as ‘farmer,’ ‘unemployment’ and ‘different jobs’ among the participants. We collected the last recording of HbA1c, LDL-cholesterol, and blood pressure from laboratory investigation reports. Fasting blood samples were used to assess HbA1c and lipid profile levels. Physical measurements and blood pressure were recorded twice to minimize the observer error. The data entry was done by a group of skilled data operator under the active supervision of a data management officer.

Ethical approval The Ethical Committee of Khon Kaen University (KKU) approved this study (approval no.


HE2247). The Director of the district hospital allowed the researchers to use the hospital data. Retrospective anonymous data were taken from the hospital clinical records, and all participant provided consent to be included in the registry. Hence, the Institutional Review Board of KKU exempted us from obtaining written consents from patients.

Definition of variables and measurementsDiabetes mellitus was defined according to the measurement of fasting blood sugar (FBS >126 mg/dL). For the detection of poor glycemic control among the patients with diabetic kidney disease, this study used the recommended World Health Organization (WHO) cut-off point for HbA1c >6.5%.17 Body mass index (BMI) was classified into four categories according to the WHO guideline: Underweight (<18.5 kg/m2), normal (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2) and obese (≥30 kg/m2). Hypertension was defined according to increase systolic (≥140 mmHg) and/or increase diastolic blood pressure (≥90 mmHg) and/or history of anti-hypertensive medication. High LDL-cholesterol was categorized as LDL ≥130mg/dL according to the guideline of American Association of Clinical Endocrinologists (AACE). Diabetic CKD has been defined based on estimated glomerular filtration rate (eGFR) value (if eGFR <60mL/min/1.73 m2) according to the clinical guidelines of the National Kidney Disease Outcomes Quality Initiative (NKF KDOQI).18 Modification of diet in renal disease-four variable (MDRD-4) equation was used to calculate eGFR in the clinical setting.19

Statistical analysisFrequency and proportions were used to present categorical variables. Mean and standard deviation (SD) were used for continuous variables. Differences in variables between the CKD and the non-CKD group were examined by Student t-test for the continuous variables and by chi-squared test for the categorical values. Binary logistic regression analysis was carried to find the association of HbA1c and other risk factors with CKD. Moreover, multiple logistic regression was conducted to determine the likelihood of the association after adjusting for risk factors. Stata version 13 special edition (College Station, Texas, USA) was used for the data analysis. A conventional cut-off value of 0.05 was taken as a statistical significance.

RESULTS

Among the 4,050 patients with diabetes, 1,027 (25.3%) patients developed CKD. The characteristics of the patients are summarized in Table 1 based on presence or absence of CKD. Most of the CKD patients were above 60 years (83%), female (68%), and farmer (67%). Around 30% of participants were overweight, and nobody was categorized as underweight in this study.

Characteristics of diabetic patients with or without CKDAbout 79% of CKD patients were presented with high HbA1c values, and 25% were possessed above average LDL-cholesterol level. The mean age (58.78 versus 69.00 years), serum creatinine (0.76 versus 1.52 mg/dL), and LDL-Cholesterol (111.0 versus 109.93 mg/dL) were higher among the CKD group compared to the non-CKD group. However, the mean BMI (25.3 versus 24.3 kg/m2) and HbA1c (8.6% versus 8.3%) were slightly higher in the non-CKD group.

Association of HbA1c and different risk factors of CKD From the bi-variable analysis, we found that older age, female sex, occupation, high HbA1c, high blood pressure, and high BMI were associated with CKD. Moreover, these associations were statistically significant. Increased LDL-cholesterol, smoking, and alcohol drinking were not associated with CKD in this study (Table 2). In multivariable analysis, this study found that age more than 60 years, female sex, and hypertension were positively associated with diabetic CKD. After adjusting all the risk factors: age, sex, occupation, LDL, BMI, smoking, and alcohol drinking, this study found that patients with high HbA1c were negatively associated with diabetic CKD (AOR=0.66, 95% CI: 0.51–0.86, P<0.05).

DISCUSSION

This study showed that patients with high HbA1c were not positively associated with diabetic CKD. Our findings support a previous study where HbA1c were not positively associated with the advanced stage of kidney disease.20 Some studies have suggested that HbA1c might not a good

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estimator for the end stage of kidney disease patients.12–14 Based on the pathophysiological evidence, HbA1c can lose its credibility to measure exact glycemia in diabetic CKD patients.12–14 There are strong possibilities that CKD creates renal uremia that modifies the longevity of erythrocytes resulting in alteration of HbA1c component.21 Moreover, normal erythroid precursor cells fail to stimulate erythropoiesis due to the limited response of bone marrow activity with a raised

CharacteristicsNon-CKD (n=3023) CKD (n= 1027)

p value*

Number (%) Number (%)Age, in years

<60 years 1,730 (57.23) 1781 (7.33) -≥60 years 1,293 (42.77) 849 (82.67) 0.001Mean (SD), years 58.78 (10.30) 69.00 (9.33) 0.01

GenderMale 1,114 (36.85) 332 (32.33) -Female 1,909 (63.15) 695 (67.67) 0.001

OccupationUnemployment 265 (8.77) 191 (18.60) -Farmer 1,745 (57.72) 686 (66.80) 0.001Different jobs 1,013 (33.51) 150 (14.61) 0.001

BMI (n=3934) Normal 1,552 (52.63) 635 (63.56) -Overweight 1,043 (35.37) 295 (29.53) 0.005Obese 354 (12.00) 69 (6.91) 0.002

Blood pressureNormotensive 1,443 (47.73) 288 (28.04) -Hypertensive 1,580 (52.27) 739 (71.96) 0.001

LDL-C (n=3734)Normal 2,130 (75.88) 695 (74.97) -High 677 (24.12) 232 (25.03) 0.48Mean (SD) 111.0 (34.51) 109.93 (34.49) 0.89

HbA1c (n=3504)Optimal control 390 (14.90) 182 (20.52) -Poor control 2,227 (85.10) 705 (79.48) 0.002Mean (SD) 8.61 (2.18) 8.32 (2.35) 0.04

SmokingNon-smoker 2,911 (96.30) 994 (96.7) -Current-smoker 112 (3.70) 33 (3.21) 0.37

Alcohol drinkingNon-drinker 2,984 (98.71) 1,012 (98.5) -Current-drinker 39 (1.29) 15 (1.46) 0.49

*p value with χ2 test (categorical) or student t-test (continuous). SD= standard deviation; HbA1c= glycated hemmoglobin; BMI= body mass index; LDL-C= low density lipoprotein cholesterol

Table 1. Characteristics of study participants with or without CKD

level of parathyroid hormone. On the contrary, activities of hypersplenism can induce the process of red blood cell destruction. Therefore, patients with an advanced stage of CKD develops anemia which causes the shorter lifespan of erythrocyte. Consequently, normal hemoglobin might fail to indicate the exact glycemia. Moreover, CKD patients receive iron, vitamin B12, blood transfusion, and other medications for the purpose of anemia correction. This sort


Characteristics COR (95% CI)

AOR †(95% CI)

Age≤60 years ref ref

>60 years 6.38(5.28–7.70)*

4.88(3.71–6.42)*

SexMale ref ref

Female 1.22(1.05–1.42)*

1.38(1.05–1.73)*

OccupationUnemployed ref ref

Farmer 0.54(0.44–0.67)*

0.90(0.65–1.23)

Different jobs 0.24(0.15–0.26)*

0.74(0.49–1.11)

HbA1cOptimal control ref ref

Poor control 0.67(0.55–0.82)*

0.66(0.51–0.86)*

Blood pressureNormotensive ref ref

Hypertensive 2.34(2.00–2.74)*

1.52(1.21–1.91)*

LDL- cholesterolNormal ref ref

High 1.05(0.88–1.24)

1.14(0.88–1.47)

BMINormal ref ref

Overweight 0.69(0.58–0.81)*

0.73(0.58–0.93)

Obese 0.49(0.37–0.65)*

0.53(0.35–0.81)

SmokingNon-smoker ref ref

Current-smoker 0.86(0.58–1.28)

0.50(0.20–1.24)

Alcohol Drinking Non-drinker ref ref

Current-drinker 1.13(0.63–1.13)

2.15(0.77–5.97)

Table 2. Association of different risk factors with diabetic CKD (n=1,027)

*p value <0.05; †= Adjusted for age, sex, occupation, LDL, BMI, smoking, and alcohol drinking; COR= crude odds ratio; AOR= adjusted odds ratio; HbA1c= glycated hemoglobin; BMI= body mass index

of treatment frequently increases the production of immature red cells which subsequently alter the original hemoglobin structure.22 The above mentioned multifaceted physiological changes within the hemoglobin structure can compromise the accuracy to measure glycemia.20

Blood glucose level can fall in a patient with end-stage renal disease due to malnutrition along with decrease glucose production using the gluconeogenesis pathway. Therefore, physiological changes of insulin secretion occur for these CKD patients. Such insulin usually might get extended half-life and destroy relatively more blood glucose in comparison to regular insulin. Moreover, alterations in insulin metabolism can shorten the lifetime of erythrocytes by changing the characteristics of the hemoglobin content of red blood cells.22 A few studies also found that the survival of RBC usually decreases in patients who were on dialysis. Thus, increased destruction of erythrocyte might result in producing low HbA1c values.22 Traditionally, most of the patients suffering from advanced stages of CKD are prescribed with erythropoietin stimulating agents (ESA) by the clinicians. There might be an inverse association of HbA1c with the introduction of erythropoietin medication.14 Application of these external ESA is responsible for increasing the production of RBC. These RBC get insufficient exposure time to go under the glycosylation process which consequently might lower the HbA1c concentration. Thus, the lower HbA1c level can give a false impression regarding the overall glycemic control.21

The risk factors of diabetic CKD vary according to geographical aspect, ethnicity, and racial consideration.23 In our study, diabetic CKD was more prevalent in older ages (above 60 years) which was similar to a previous communication.24 This study found that increased age could be a risk factor of renal insufficiency which might result due to degenerative changes in the glomerular tissue. According to this study, hypertensive diabetic patients were 1.5 times more likely to develop CKD which supports a previous communication. Diabetic patients who were farmer or employed showed decrease risk of CKD compared to those who were unemployed. Therefore, patients with high HbA1c level were not associated with diabetic CKD in this study even after adjusted to the risk factors.

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It appears that biochemical parameters of the diabetic CKD patients are different from that of the non-CKD patients. HbA1c might not be a reliable indicator to give the correct measurement of glycemic control in diabetic CKD patients. However, setting HbA1c target in patients with CKD needs to be individualized based on the patient’s age, lifestyle factors, and clinical assessment.25 Several studies have suggested that one-time measurement of glycated albumin may be a better alternative to HbA1c test for the CKD patients.12,13

This study has certain limitations. It was a single-center study, and we could not collect relevant information regarding the first time diagnosis of DM. Patients were exposed to medications, and it was not possible to obtain the details of medication use, food, and behavior related information. As this was a retrospective secondary data analysis, it is hard to explore the possibility of reverse causality. However, the data were derived from a large clinical registry with an adequate quality control.

In conclusions, to the best of our knowledge, this study was the first to assess the relationship of HbA1c and diabetic kidney disease in Thailand. HbA1c did not appear to estimate the actual glycemia in diabetic patients with CKD. Therefore, using conventional cut-off values of HbA1c in diabetic CKD patients may be problematic in the clinical settings. Future investigations are expected to infer the clinical stage at which HbA1c values get unpredictable and identify methods for better detection of glycemic status in diabetic CKD patients.

Conflict of Interests The authors affirm no conflict of interests in this study.

Acknowledgment This research study was partially supported by the German Academic Exchange Service (DAAD). The authors would like to thank Professor Frank P. Schelp and Prof. Pattara Sanchaisuriya, Wilaiphorn Thinkhamrop, and Ina Hammesfahr for their guidance and advices. The authors are also grateful to all the staff from Faculty of Public Health, KKU of Thailand and Institute of Tropical Medicine and International Health Berlin, Germany.

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3. Islam SM, Purnat TD, Phuong NT, Mwingira U, Schacht K, Fröschl G. Non-communicable diseases (NCDs) in developing countries: a symposium report. Global Health. 2014;10(1):81.

4. Jha V. End-stage renal care in developing countries: the India experience. Ren Fail. 2004;26(3):201–8.

5. Zaman SB. Detection of Chronic Kidney Disease by Using Different Equations of Glomerular Filtration Rate in Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Analysis. Cureus. 2017;9(6):e1352.

6. Rossing K, Christensen PK, Hovind P, Tarnow L, Rossing P, Parving H-H. Progression of nephropathy in type 2 diabetic patients. Kidney Int. 2004;66(4):1596–605.

7. Bhutani J, Bhutani S. Worldwide burden of diabetes. Indian J Endocrinol Metab. 2014;18(6):868–70.

8. Islam SM, Rawal LB, Mainuddin A, Wahiduzzaman M, Niessen LW. Clinical profile of patients with diabetic nephropathy in a tertiary level hospital in Dhaka, Bangladesh. Arch Med Health Sci. 2015;3(2):191.

9. Nitiyanant W, Chetthakul T, Sang-A-kad P, Therakiatkumjorn C, Kunsuikmengrai K, Yeo JP. A survey study on diabetes management and complication status in primary care setting in Thailand. J Med Assoc of Thai. 2007;90(1):65–71.

10. Koenig RJ, Peterson CM, Kilo C, Cerami A, Williamson JR. Hemoglobin AIc as an indicator of the degree of glucose intolerance in diabetes. Diabetes. 1976;25(3):230–2.

11. Zaman SB, Hossain N. Universal Health Coverage: A burning need for developing countries. J Med Res & Innov. 2017;1(1):18–20.

12. Chujo K, Shima K, Tada H, Oohashi T, Minakuchi J, Kawashima S. Indicators for blood glucose control in diabetics with end-stage chronic renal disease: GHb vs. glycated albumin (GA). J Med Invest. 2006;53(3–4):223–8.

13. Freedman BI, Shenoy RN, Planer JA, Clay KD, Shihabi ZK, Burkart JM, et al. Comparison of glycated albumin and hemoglobin A1c concentrations in diabetic subjects on peritoneal and hemodialysis. Perit Dial Int. 2010;30(1):72–9.

14. Inaba M, Okuno S, Kumeda Y, Yamada S, Imanishi Y, Tabata T, et al. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J Am Soc Nephrol. 2007;18(3):896–903.

15. Zaman SB, Hossain N, Ahammed S, Ahmed Z. Contexts and Opportunities of e-Health Technology in Medical Care. J Med Res & Innov. 2017;1(2):AV1–AV4.

16. Muktabhant B, Sanchaisuriya P, Sarakarn P, Tawityanon W, Trakulwong M, Worawat S, et al. Use of glucometer and fasting blood glucose as screening tools for


diabetes mellitus type 2 and glycated haemoglobin as clinical reference in rural community primary care settings of a middle income country. BMC Public Health. 2012;12:349.

17. www.who.int [Internet]. Use of glycated haemoglobin (HbA1c) in diagnosis of diabetes mellitus: abbreviated report of a WHO consultation. [update 2011; cited May 2017]. Available form: http://www.who.int/cardiovascular_diseases/report-hba1c_2011_edited.pdf

18. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Inter Med. 2003;139(2):137–47.

19. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Inter Med. 2009;150(9):604–12.

20. Vos FE, Schollum JB, Coulter CV, Manning PJ, Duffull SB,

Walker RJ. Assessment of markers of glycaemic control in diabetic patients with chronic kidney disease using continuous glucose monitoring. Nephrology (Carlton). 2012;17(2):182–8.

21. Agarwal R, Light RP. Relationship between glycosylated hemoglobin and blood glucose during progression of chronic kidney disease. Am J Nephrol. 2011;34(1):32–41.

22. Ly J, Marticorena R, Donnelly S. Red blood cell survival in chronic renal failure. Am J Kidney Dis. 2004;44(4):715–9.

23. Zaman SB. Importance of learning the public health leadership. Public Health Indones. 2017;3(1):1–3.

24. Srivanichakorn S, Sukpordee N, Yana T, Sachchaisuriya P, Schelp FP. Health status of diabetes type 2 patients in Thailand contradicts their perception and admitted compliance. Prim Care Diabetes. 2011;5(3):195–201.

25. Islam S, Rawal L. Setting HbA1c targets for patients with type 2 diabetes. J Diabetol. 2015;2:5.

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Assessment of the nutrient intake and micronutrient status in the first trimester of pregnant women in Jakarta

Keywords: first trimester, nutrient intake, nutritional status, pregnancy

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.1617 • Med J Indones. 2017;26:109–15• Received 20 Oct 2017 • Accepted 22 Apr 2017

Corresponding author: Rima Irwinda, [email protected]


Noroyono Wibowo,1 Saptawati Bardosono,2 Rima Irwinda,3 Inayah Syafitri,3 Atikah S. Putri,3 Natasya Prameswari3

1 Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia

2 Department of Nutrition, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia3 Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia

Clinical Research


ABSTRAK

Latar belakang: Nutrisi maternal sebelum dan saat hamil penting untuk luaran kehamilan yang sehat. Berdasarkan Riset Kesehatan Dasar (Riskesdas) 2013, sebesar 24,2% ibu hamil memiliki risiko kurang energi kronis (KEK), dan 37,1% menderita anemia. Tujuan dari penelitian ini adalah untuk mengetahui asupan nutrisi dan status mikronutrien dalam serum wanita hamil di Jakarta pada trimester pertama.

Metode: Studi deskriptif dilakukan pada 234 wanita hamil pada trimester pertama (<14 minggu). Asupan nutrisi didapat dari konversi frequency food questionnaire (FFQ) semi kuantitatif menggunakan Nutrisurvey. Serum maternal diperiksa untuk menilai kadar nutrisi.

Hasil: Rerata asupan energi maternal harian adalah 1.256,1 kkal. Sebagian besar subjek memiliki asupan nutrisi di bawah rekomendasi Institute of Medicine (IOM) dan angka kecukupan gizi (AKG) 2013 yaitu energi (88,9%), protein (80,8%), besi (85%), asam folat (74,8%), kalsium (90,6%), and seng (94,9%). Sebaliknya, 70,5% subjek memiliki asupan tinggi vitamin A. Pemeriksaan serum maternal menunjukkan sebagian besar subjek mengalami defisiensi vitamin A (69,7%), vitamin D (99,6%), and seng (81,2%). Tidak ditemukan korelasi antara asupan nutrisi maternal dengan status nutrisi maternal.

Kesimpulan: Pada trimester pertama, sebagian besar ibu hamil di Jakarta memiliki asupan energi dan nutrisi maternal yang rendah, kecuali vitamin A. Selain itu, sebagian besar ibu juga memiliki kadar serum vitamin A, vitamin D, dan seng maternal yang rendah.

ABSTRACT

Background: Maternal nutrition before and during pregnancy is important for a healthy pregnancy outcome. According to National Basic Health Research (Riskesdas) 2013, 24.2% of pregnant women are at risk of chronic malnutrition and 37.1% of them suffer from anemia. The aim of this study was to obtain information about the nutrient intake and serum micronutrient status in the first trimester of pregnant women in Jakarta.

Methods: A descriptive study was conducted towards 234 pregnant women with gestational age no more than 14 weeks. The nutrient intake data was obtained from the conversion of frequency food questionnaire (FFQ) which was semi quantitative data using a Nutrisurvey application. The maternal serum was examined to obtain data about nutrient level.

Results: The mean of daily maternal energy intake was 1,256.1 kcal. Most subjects had nutrient intake below the recommendations of Institute of Medicine (IOM) and recommended dietary allowances (RDA), i.e. energy (88.9%), protein (80.8%), iron (85%), folic acid (74.8%), calcium (90.6%), and zinc (94.9%). However, they showed a high intake level of vitamin A (70.5%). Most subjects had deficiency in vitamin A (69.7%), vitamin D (99.6%), and zinc (81.2). No correlation was found between the maternal nutrient intake and nutritional status.

Conclusion: Most of the first-trimester-pregnant-women in Jakarta had low maternal energy and nutrient intake, except for vitamin A, as well as low serum vitamin A, vitamin D, and zinc level.



Maternal nutrition before and during pregnancy is important for a healthy pregnancy outcome. The first trimester is the most critical period because during this first 13 weeks, conception, implantation, and organogenesis take place. Deficiencies of macro and micronutrient potentially give negative effects to health of the mother and the fetus. Suboptimal nutrient status has been found to lead to miscarriage, intrauterine growth restriction, preeclampsia, infection, preterm delivery, low birth weight, and anemia. Furthermore, it increases the risk of maternal and neonatal mortality.1,2

Maternal nutrition has also major effects on the long term health of the children including ‘programming’ of non-communicable disorders. Many studies have proven that the first 1,000 days of life (during pregnancy and the first two years of life) is a crucial period for optimizing the growth and the development of children. Good nutrition and healthy growth at this period would give lasting benefits throughout life.3,4

Dietary energy and nutrient requirements during pregnancy are generally increased to support the growing fetus, placenta, and maternal tissues. However, according to a systematic review,5,6 macronutrient and micronutrient intakes of pregnant women in developing countries were generally below recommendations. Deficiencies of micronutrients such as iron, vitamin A, folate, and iodine are common during pregnancy.1 Globally maternal undernutrition, including chronic energy and micronutrient deficiencies, is prevalent in many regions. Maternal undernutrition (body mass index <18.5 kg/m²) varied from 10–19% in most countries.7 Based on the 2011 estimates, the prevalence of anemia in pregnant women worldwide was 38%.7 In Indonesia, 37.1% of pregnant women were anemic and 24.2% were at risk of chronic energy deficiency.8

The aim of this study was to assess nutrient intake and serum micronutrient status in the first trimester of pregnant women in Jakarta.

METHODS

The data obtained in this study was secondary data from two previous interventional studies

conducted in Cipto Mangunkusumo Hospital and Budi Kemuliaan Hospital, Jakarta, during February 2012 to April 2015. The collection of data was approved by the Ethical Committee for Research in Human from the Faculty of Medicine, Universitas Indonesia (No. 480/PT02.FK/ETIK/2012 and No. 71/H2.F1/ETIK/2013). After written consent was obtained, 234 subjects were included in this study, with the inclusion criteria were women with no more than 14 weeks of gestational age without congenital anomaly (confirmed by ultrasound examination), agreed to participate, did not take any pregnancy milk nor supplementation, and was not enrolled in any other interventional study. The exclusion criteria were subjects with hyperemesis gravidarum, women with intrauterine fetal death, and abortion.

The data presented were nutrient intake from subjects’ recall using semiquantitative frequency food questionnaire (FFQ) for a month and blood test results of blood count and nutrient level. FFQ was assessed by two trained nutritionists using food model, and it was converted into certain nutrient intake using the Nutrisurvey version 2007 program with food database from Indonesia. The maternal serum was assessed in Prodia laboratory. The iron serum was assessed by (National Institute of Occupational Safety and Health (NIOSH)), serum zinc by inductively coupled plasma mass spectroscopy (ICP-MS) (Inductively Coupled Plasma Mass Spectroscopy), serum vitamin A by high performance liquid chromatography (HPLC) (High Performance Liquid Chromatography), serum vitamin diasorin (D) by clinical laboratory improvement amendments (CLIA) (Clinical Laboratory Improvement Amendments), serum vitamin B12 by HPLC, and serum folic acid by HPLC. The data was then analyzed by statistical package for the social sciences (SPSS) (Statistical Package for the Social Sciences) statistics data editor version 20. The normality of variables was tested using a Kolmogorov-Smirnov test. Data with normal distribution was then summarized by means and standard deviations and by medians and minimum-maximum values for data with abnormal distribution. Classification, and correlation between variables were analyzed using a Spearman or Pearson test. The classification of nutrient intake and serum

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level was based on the criteria of Institute of Medicine9 and recommended dietary allowances (RDA).9,10

RESULTS

The data of 234 subjects were analyzed. The characteristics of the subjects are shown in Table 1. 40.6% of the subjects were in the age group of 26–30 years old, 57.7% had jobs, 90.6% had graduated from high schools i.e. were considered high educated, and 42.3% had normal body mass index (BMI).

The maternal nutrient intake is shown in Table 2. The median of daily energy intake is 1,256.1 Kcal. 208 subjects (88.9%) had energy intake below RDA 2013 recommendation. Most subjects also had low intake of other nutrients, i.e. protein (80.8% of the subjects), iron (85%),

Characteristic N %Mother’s age

16–20 3 1.321–25 47 20.126–30 95 40.631–35 62 26.536–40 25 10.741–45 2 0.9

Mother’s jobHousewife 99 42.3Working 135 57.7

Mother’s last educationElementary school not graduated 1 0.4Elementary school graduated 5 2.1Junior high school 16 6.8Senior high school 113 48.3Non degree graduated 51 21.8Degree graduated 48 20.5

Mother’s BMI at screeningUnderweight 20 8.5Normal 99 42.3Overweight 38 16.2Obese grade I 61 26.1Obese grade II 16 6.8

TOTAL 234 100

Table 1. Characteristics of the subjects

BMI= body mass index

folic acid (74.8%), calcium (90.6%), and zinc (94.9%). Most of them had high daily intake of vitamin A (70.5 %).

Maternal blood and nutrient status are shown in Table 3. Most of the subjects had deficiency in vitamin A (69.7%), vitamin D (99.6%), and zinc (81.2%), while folic acid level was distributed evenly (normal 49.6%, high 50.4%). Significant correlation was found between albumin and hemoglobin level (r=0.34, p<0.001). Using a comparative test, a significant difference was found between BMI with hemoglobin level (p=0.023), hematocrit level (p=0.005), and leukocyte level (p=0.004). However, no significant correlation was found between maternal nutrient intake and its blood nutrient status, such as protein, folic acid, iron, zinc, and vitamin A, as shown in Table 4.

As determined by one-way ANOVA, there was statistically significant difference in the mean of iron intake between different ages of mothers. The Tukey post hoc revealed that iron intake was lower in mothers of 26–30 years old (16.7±21.8 mg/day, p=0.042) compared to the group of 31–35 years old (27.3±29.7 mg/day).

Using independent samples T-test, this study found that junior and senior high school graduates had higher blood 25-hydroxy vitamin D (25(OH)D) and ferritin level compared to non-degree graduates. Working mothers, compared to housewives, also had significantly lower level of blood vitamin D 25 OH and blood ferritin level. Meanwhile there are no correlation between mother's education and job to other variable, e.g. albumin, folic acid, vitamin A, vitamin B12, vitamin E, zinc, haemoglobin, hematocrit and leucocyte (p<0.05).

DISCUSSION

Data from FFQ showed mostly low intake of energy, protein, iron, folic acid, calcium, and zinc. This result was consistent with researches conducted in other developing countries. The average calories intake of developing countries according to Food and Agriculture Organization (FAO) (Food and Agriculture Organization)are 2850 kcal/day, 2940 kcal/day in the world, and



Maternal nutrient intake / blood status Range Mean±SD /Median (min-max) %

Daily maternal intakeEnergy 1,256.1 (411.4–3,863.9)

Low <1,700 kcal 88.9Normal 1,700–2,000 kcal 7.7High >2,000 kcal 3.4

Protein 44.7 (10.9–145.6)Low <56 g 80.8Normal 56–71 g 11.5High >71 g 7.7

Fe 11.4 (2.8–186.4)Low >30 mg 85.0Normal 30–60 mg 11.1High <60 mg 3.8

Folic acid 104.9 (0–1,088.8)Low <400 μg 74.8Normal 400–1,000 μg 24.4High >1,000 μg 9.0

Calcium 437.5 (20.5–3,457.5)Low <1,000 mg 90.6Normal 1,000–1,300 mg 4.7High >1,300 mg 4.7

Zinc 3.2 (0.3–54.3)Low <11 mg 94.9Normal 11–20 mg 2.1High >20 mg 3.0

Vitamin A 1,470.6 (12.9–1,0623)Low <770 μg 28.6Normal 770–800 μg 0.9High >800 μg 70.5

Maternal blood and nutrient statusAlbumin 4.1 (3.3–4.9)

Low <3.4 g/dL 0.4Normal 3.4–4.8 g/dL 99.1High >4.8 g/dL 0.4

Folic acid 19.5 (10.7–40)Low <7 ng/dL 0.0Normal 7–19.4 ng/dL 49.6High >19.4 ng/dL 50.4

Vitamin A 470 (160–7,260)Low <550 μg/L 69.7Normal 550–3,000 μg/L 29.9High >3,000 μg/L 0.4

Vitamin B12 414.5 (145–997)Low <211 pg/mL 2.6Normal 211–911 pg/mL 97.0High >911 pg/mL 0.4

Vitamin D 11.3 (4.3–30.4)Low <30 ng/mL 99.6Normal 30–200 ng/mL 0.4High >200 ng/mL 0.0

Vitamin E 12.9 (5.1–24.4)Low <12 mg/L 40.2Normal 12–1,000 mg/L 59.8High >1,000 mg/L 0.0

Zinc 61 (28.3–1,641.4)Low <660 μg/L 81.2Normal 660–1,000 μg/L 1.3High >1,000 μg/L 11.5

Hemoglobin 12.3 (9.2–15.7)Low <11 g/dL 9.8Normal 11–15.5 g/dL 89.7High >15.5 g/dL 0.4

Hematocrit 36.3±2.87Low <38 % 70.5Normal 38–52 % 29.5High >52 % 0.0

Ferritin 65.2 (4–483.7)Low <20 ng/mL 13.2Normal 20–150 ng/mL 74.4High >150 ng/mL 12.4

Leukocyte 8.6 (4.3–15.1)Low <3.6 x 103 /μL 0.0Normal (3.6–11) x103 /μL 84.6High >11 x 103 /μL 15.4

Table 2. Maternal nutrient intake, blood and nutrient status

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Nutrient intake Blood nutrient status p

Protein Albumin 0.182Folic acid Folic acid 0.999Iron hemoglobin 0.260Iron Ferritin 0.111Zinc Zinc 0.924Vitamin A Vitamin A 0.097

Table 3. Correlation between maternal intake and blood nutrient status

Table 4. Correlation between mother’s education and job to clinical variable

3440 kcal/day in industrialized countries.11 But with the vast range of calories intake (411.4–3,863.9) and 32.9% of the subjects were classified obese. These data showed the double burden of developing countries; undernutrition along with increasing rates of obesity. The shift of food system also influences the food selection, with easier access to “empty calorie” foods and beverages. Thus, it explains the low intake of micronutrients.12 Choosing micronutrient-dense foods can be challenging due to the access and expensive prices.13

Despite the low nutrition intake, no correlation was found between nutrition intake and serum level. This might be caused by several factors. FFQ was used to measure subjects’ intake with its validity limitation. FFQ is a subject-dependent tool with various strength (correlation coefficient) for each nutrient measured.14,15 Several nutrients from FFQ were measured without taking fortified nutrients into account. Fortification program in Indonesia consists of fortified salt with iodine;

flour with iron, zinc, folic acid, vitamin B1 and B2; cooking oil with vitamin A; and rice with iron.16

The food database had included vitamin A, i.e. fortificant in palm oil, and no other fortificant was found in food vehicles such as flour and rice. The palm oil consumption was measured by estimating how much fried-food was consumed. It was assumed that this was not an objective measurement. Therefore, the high intake of vitamin A of most subjects was questioned, and no correlation was found between vitamin A intake and serum level.

The result showed that from 234 subjects, 70.5% subjects had low level of vitamin A. Vitamin A deficiency has been recognized as a health issue in developing countries. Another study reported that among 107.4 million of pregnant women in regions of the world, 7.2 million (6.7%) have deficient vitamin A status (serum or breast-milk retinol concentrations <0.70 μmol/L) and 13.5 million (12.5%) have low vitamin A status (0.70–1.05 μmol/L). The risk factors for vitamin A deficiency are poor nutritional status, a low dietary intake in sources of vitamin A (eggs, dairy products, fruits and vegetables), and a high rate of infections, particularly measles, diarrhea and respiratory tract infections.17, 18

The study found that almost all the subjects had low vitamin D level (99.6%). Only one subjects had normal vitamin D level. The deficiency of vitamin D is quite prevalent worldwide, particularly in Asia countries. The prevalence of vitamin D deficiency was over 70% in South Asia and ranged from 6% to 70% in Southeast Asia. The important determinants for the vitamin D levels are dietary intake and skin synthesis that is dependent on the sunlight exposure, latitude, skin pigmentation, skin coverage, and use of sunscreen. Although South and Southeast Asia countries get sunshine throughout the year, the prevalence vitamin D deficiency in these countries that is closer to the equator is higher. This can be caused by skin pigmentation. Populations in closer area to the equator (warmer climates) tend to have greater skin pigmentation which can decrease the ability of the skin to synthesis vitamin D. It is because in dark pigmentation, ultraviolet (UV) light cannot reach the appropriate layer of the skin for the synthesis of vitamin D. Skin contains 7-dehydrocholesterol which on exposure to UV light in sunshine gets converted to cholecalciferol (Vitamin D3).19–21


Category Vitamin D 25 OH (ng/mL)

Ferritin (ng/mL)

Last educationJunior high school 15.5±7.6* 119.2±112.6*Senior high school 12.4±4.4† 91.0±74.1†

Non degree graduated 10.2±3.6 56.2±34.4Job

Working 10.7±4.0** 69.7±56.2**Housewife 13.6±5.1 100.6±83.5

*p<0.01; †p<0.05


In this study, no subject had low level of folic acid. All the subjects had normal or high folic acid level despite the low level of folic acid intake. It might be caused by the fortification of flour with folic acid that has not been included into FFQ data base. The fortification of flour with folic acid has been done in many countries around the world, including Indonesia (200 µg/100 g flour), which is regulated by the Ministry of Health. This mandatory fortification is expected to reduce the prevalence of neural tube defect births.16,17

Our finding showed significant correlation between albumin and hemoglobin. It supported the theory of protein as requirements of hemoglobin synthesis.22 The significant difference of BMI status with hemoglobin and hematocrit level showed that the underweight group was more anemic than other BMI groups. This might be caused by lower intake of food and iron.23 A significant difference was found between different BMI status with leukocyte level, showing an increasing trend of leukocyte counts in higher BMI. This could be due to the high release of proinflammatory factor such as tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) found in obese patient, causing increased production of leukocytes.24

We acknowledged several limitations in this study. Firstly, the population scope was limited in Central Jakarta that did not represent thoroughly the population of Jakarta. Secondly, the economic factor such as family’s income level was not evaluated in this study. And thirdly, the FFQ method was performed in reliance with subjects’ memory, rendering it was less objective although food model was used to reduce bias.

Further study involving broader scope of population is needed to obtain more representative data. For the first-trimester-pregnant-women, we recommend to take multi-micronutrient supplementation to improve nutrient intake and status.

In conclusion, most of the first-trimester-pregnant-women in Jakarta had low maternal energy and nutrient intake, except for vitamin A, and most of them had low vitamin A, vitamin D, and zinc level.

Conflict of interestThe authors confirm no conflict of interest in this study.

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Cardiovascular response and backward, upward, right push maneuver during laryngoscopy: comparison between CMAC® video laryngoscopy and conventional Macintosh

Keywords: BURP maneuver, cardiovascular response, CMAC®, conventional Macintosh, laringoscopy

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.1505 • Med J Indones. 2017;26:116–21• Received 20 Jul 2016 • Accepted 21 May 2017

Corresponding author: Arif H.M. Marsaban, [email protected]


Arif H.M. Marsaban, Aldy Heriwardito, I G.N.A.D. YundhaDepartment of Anesthesiology and Intensive Therapy, Faculty of Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia

Cl inical Research


ABSTRAK

Latar belakang: Peningkatan tekanan darah dan laju nadi merupakan komplikasi yang paling sering terjadi saat laringoskopi dan dapat mengakibatkan komplikasi yang berat. Perbaikan teknik dan alat laringoskopi mengurangi stimulasi nosiseptif dan dapat mencegah tanggapan kardiovaskular. Manuver backward, upward, right push (BURP) lazim digunakan untuk menurunkan nilai Cormack-Lehane, tetapi manuver ini memberikan rangsang nyeri saat laringoskopi. Penelitian ini bertujuan untuk membandingkan tanggapan kardiovaskular dan kebutuhan manuver BURP saat laringoskopi antara CMAC® dan Macintosh konvensional.

Metode: Dilakukan uji klinis acak tersamar tunggal pada 139 pasien. Para pasien akan menjalani anestesia umum dengan intubasi endotrakea, yang dibagi ke dalam kelompok kontrol (Macintosh konvensional) dan kelompok perlakuan (CMAC®). Parameter kardiovaskular (sistolik, diastolik, Tekanan arteri rerata, dan laju nadi) diukur sebelum induksi (T1). Midazolam 0,05 mg/kgBB dan Fentanyl 2 mikrogram/kgBB diberikan 2 menit sebelum induksi. Propofol 1 mg/kgBB dan dilanjutkan infus Propofol 10 mg/kg/jam. Atrakurium 0,8–1 mg/kgBB. Parameter kardiovaskular (T2) diukur setelah nilai train-of-four (TOF-0), lalu dilakukan laringoskopi. Setelah nilai Cormack-Lehane 1 atau 2 (dengan atau tanpa manuver BURP) parameter kardiovaskular (T3) diukur.

Hasil: Uji-T tidak berpasangan menunjukkan tanggapan kardiovaskular lebih rendah secara bermakna pada kelompok perlakuan dibandingkan pada kelompok kontrol (p<0,05). Kebutuhan Manuver BURP lebih sedikit secara bermakna pada kelompok perlakuan dibandingkan kelompok kontrol (13,9% vs 40,3%; p<0,05) dengan uji K-kuadrat.

Kesimpulan: Tanggapan kardiovaskular dan kebutuhan manuver BURP saat laringoskopi lebih rendah secara bermakna pada penggunaan CMAC® dibandingkan dengan Macintosh Konvensional.

ABSTRACT

Background: Increased blood pressure and heart rate are the most frequent response to laryngoscopy which sometimes causes serious complications. Laryngoscopy technique and tools modification lessen the nociceptive stimulation, thus preventing hemodynamic response. BURP maneuver is used to lower Cormack-Lehane level, but it can cause additional pain stimulation during laryngoscopy. The aim of this study was to compare the cardiovascular response and the need of BURP maneuver during laryngoscopy between CMAC® and conventional Macintosh.

Methods: A randomized, single blinded, control trial was performed to 139 subjects who underwent general anesthesia with endotracheal tube. Subjects were randomised into a control group (conventional Macintosh) and an intervention group (CMAC®). The cardiovascular parameters (systolic, dyastolic, mean arterial pressure, and heart rate) were measured prior to induction (T1). Midazolam 0.05 mg/kg and Fentanyl 2 micrograms/kg were given 2 minutes before the induction. Moreover, they were given propofol 1 mg/kg followed by propofol infusion of 10 mg/kg/hour and Atracurium 0.8–1 mg/kg. After TOF-0 cardiovascular parameters (T2) were remeasured, it was proceeded to laryngoscopy. When Cormack-Lehane 1–2 was reached (with or without BURP maneuver), cardiovascular parameters were measured again (T3).

Results: Unpaired T-test showed that cardiovascular response during laryngoscopy were significantly lower in the intervention group compared to the control group (p<0.05). The need of BURP maneuver was significantly lower in the CMAC® group compared to the Convensional Macintosh group (13.9% vs 40.3%; p<0.05).

Conclusion: Cardiovascular response and BURP maneuver during laryngoscopy with CMAC® were significantly lower compared to conventional Macintosh.


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Laryngoscopy creates painful stimuli, resulting in cardiovascular response in the form of increased blood pressure and heart rate. Although these responses are transient, they could be problematic for patients with cardiac diseases and intracranial lesion.1 Higher dose intravenous opioid and intravenous lidocaine cannot repress cardiovascular response totally.2 Inhalation agents used to deepen anesthesia cause blood pressure drop, resulting in poor coronary and brain perfusion. Neural blockage in airway needs special skills and experiences due to the difficulty level and high risk of local anesthesia injection into the vessels. Topical anesthesia use in the airway is still in research.3 Cardiovascular blocker drugs such as bisoprolol or esmolol can be given, but sympathetic activity would be repressed leading to decreased coronary perfusion.4 Laryngoscopy technique and tools modification lessen the nociceptive stimulation, thus preventing hemodynamic response.5,6

Backward, upward, right push (BURP) maneuver is a maneuver to push larynx from outside, to get a better larynx visualization during laryngoscopy. Laryngoscopy will push larynx downward (caudal), upward (anterior) and to the left. BURP maneuver positioned larynx to its original position, and the epiglottis is still lifted, creating an optimal visualization of larynx and glottis.7–9

Laryngoscopy video’s role is increasing in the last 10 years, especially for difficult airway management. The larynx was visualized better, decreasing failed intubation.10–12 The advantages of CMAC® such as increased successful first attempt of intubation, shorter laryngoscopy duration, and decreasing Cormack-Lehane grade interest the researchers to compare the cardiovascular responses and BURP maneuver necessity during laryngoscopy between video laryngoscopy CMAC® and the conventional Macintosh.

METHODS

After getting approval from the ethics committee, the Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital and consents from patients (No. 878/UN2.F1/ETIK/2015), a randomised, single blinded, control trial was conducted in Cipto Mangunkusumo Hospital,

Jakarta from October to December 2015. Population was surgery patients who underwent general anesthesia with endotracheal intubation in Cipto Mangunkusumo Hospital.

The inclusion criteria were adult (18–65) years old, body mass index (BMI) 18.5–30 kg/m2, physical status American Society of Anesthesiology (ASA) 1–2, and have consented to participate in this study. The exclusion criteria were pregnancy, history of cardiac diseases, cerebrovascular disease history, hypertension, hypotension, tachycardia, bradycardia, patients consuming cardiovascular drugs, difficult airway suspicion, increased intracranial pressure, and converted general anesthesia patients from regional anesthesia. Furthermore, the drop-out criteria were patients who moved during laryngoscopy, patients with desaturation or other emergencies, train-of-four (TOF) score did not reach 0 with induction and relaxation dose according to study protocol, Cormack-Lehane level other than 1 or 2 at the first laryngoscopy attempt with BURP maneuver (60 seconds maximum).

Samples were obtained through non probability sampling with consecutive sampling. Randomization for subjects was done with block randomization using tables. The sample size was calculated using analytic categorical sample size formula for unpaired two groups. Proportion was obtained from previous research. The subjects were divided into two groups of laryngoscopy; the Macintosh blade group and the video laryngoscopy CMAC® group.

The recorded data were name, age, sex, medical record, height, weight, and ASA status. A vital signs monitor was put on patients on the operating table. Systolic and diastolic blood pressure, mean arterial pressure, and heart rate were recorded/ time-1 (T1). Both groups received midazolam 0.05 mg/kgBW and fentanyl 2 mcg/kgBW intravenous, oxygen 80 via face mask, tidal volume 6–8 mL/kgBW, and respiratory rate 12–14 x/minute. Two minutes after midazolam and fentanyl administration, induction with propofol 10 mg/kgBW was done, followed by continued infusion of propofol 10mg/kg/hour. Atracurium 0.8–1 mg/kgBW was given after eyelashes reflect was lost. After TOF score was 0, systolic and diastolic blood


pressure, mean arterial pressure, and heart rate were recorded/ time-2 (T2). Laryngoscopy was performed until Cormack-Lehane grade 1 or 2 for larynx visualization achieved, maximum 60 minutes according to the designated laryngoscopy group. Systolic and diastolic blood pressure, mean arterial pressure, heart rate and BURP maneuver were recorded/ time-3 (T3).

Patients were given face mask, excluded, and treated with the ASA algorithm if laryngeal visualization was failed. In cases of emergency, the advance life support (ALS) and basic life support (BLS) algorithms were done, and patients were excluded.

T1-T2 was analyzed with unpaired T-test, and the result was p>0.05 (not significant difference) in every cardiovascular parameter. This result showed that two groups met the same effect of induction, and there was no confounding factor between two groups.

Data were analysed using statistical product and service solutions (SPSS) Cardiovascular response and unpaired T-test and Mann-Whitney-U test as alternative test methods. BURP maneuver was analyzed with a Chi-squared and a fisher test as alternative test methods.

RESULTS

The research flowchart was presented in figure 1. Table 1 shows subjects’ characteristic.

Accessible population (n=207)

Randomization (n=139)

Conventional Macintosh (n=70)

Exclusion criteria (n=51) Inclusion Criteria not met (n=17)

CMAC (n=69)

Drop-out criteria (n=3)

Analyzed sample (n=67)

Drop-out criteria (n=2)

Analyzed sample (n=67)

Figure 1. Consolidated standards of reporting trials (CON-SORT) flow-chart

Characteristics Macintosh (n=67) CMAC (n=67)Age (years) 38.8±13.3 38.6±13.2Sex (n %)

Male 23 (34.3) 24 (35.8)Female 44 (65.7) 43 (64.2)

ASA (n %)I 20 (29.8) 18 (26.8)II 47 (70.2) 49 (73.2)

Body weight (kg) 58±10.6 59.1±7.6Body height (m) 1.58±0.7 1.61±0.7BMI (kg/m2) 22.9±3.1 22.5±2.2

Table 1. Subjects’ characteristics

Data were presented in mean ± SD and n (%). ASA= American Society of Anesthesiology; BMI= body mass index

BURP maneuver p*

Yes No

Conventional Macintosh (n=67)

27 (40.3) 40 (59.7) 0.014

CMAC® (n=67) 13 (19.4) 54 (80.6)

Table 2. BURP naneuver necessity

*p is significant if p<0.05. Data were presented in frequency (n) (%). BRUP= backward, upward, right push

Cardiovascular responses were shown in Figure 2. It showed the difference between T1-T2 and T2-T3. T1-T2 difference showed a decreasing trend, which means the cardiovascular parameters declined after induction. T2-T3 difference showed an increasing trend.

Figure 3 showed statistical tests done to investigate differences in the variables between Macintosh intubation and CMAC® intubation. Systolic blood pressure (CI 95%=5.58-14.44), diastolic blood pressure (CI 95%=2.93-9.54), and heart rate (CI 95%=2.26-8.66) showed a significant T2-T3 difference.

Table 2 showed BURP maneuver necessity between Macintosh and CMAC®. Figure 4 showed illustration between conventional Macintosh and CMAC equipment and the effects in larynx.

DISCUSSION

This study evaluated cardiovascular parameters

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Figure 3. Statistical test for cardiovascular parameter differ-ence between T2-T3 represented cardiovascular response due to laryngoscopy. T1-T2 (not shown) was analyzed with un-paired t-test, and the result was p>0.05 (not significant differ-ence) in every cardiovascular parameter. This result showed that two groups met the same effect of induction, and there was no confounding factor between two groups. *p<0.001

Figure 4. Illustration between conventional Macintosh and CMAC® equipment and the effect in larynx

such as systolic and diastolic blood pressure, mean arterial pressure, heart rate, and BURP maneuver necessity during laryngoscopy to achieve Cormack-Lehane grade 1 or 2. Cardiovascular parameter of T1 of each group were not different (Table 1), means confounding factors of cardiovascular parameters before induction and during induction were eliminated through inclusion and exclusion criteria. Biometric factors (age, height, weight, BMI) could affect the airway anatomy and airway management difficulty; thus, the inclusion criteria included age and BMI. ASA physical status was limited to 1 and 2 in order for methods to be applied to all subjects and to lessen pre-operative confounding factors (e.g. hypovolemia, cardiovascular drugs, arrhythmia, etc.).

Both groups were given similar drug types and doses to eliminate confounding factors. To avoid hypercarbia as a confounding factor of

cardiovascular response, laryngoscopy duration was limited to 60 seconds.13

The Macintosh group showed a significant larger change of the parameters in T2-T3 compared to the CMAC® group. This change was induced by pain during the procedure. Laryngoscopy using Macintosh blade required a laryngeal lift maneuver, so the larynx axis was in line with the operator’s eye axis.8,14 Mechanical pain stimulation due to the blade was sensed by the nociceptors in the tongue base mucosa, valecula, and anterior epiglottis surface. Neural stimulus traveled to suprarenal gland, inducing catecholamine release, and thus, it increased sympathic activities such as blood pressure and heart rate.15,16 The difference between Macintosh and CMAC® showed different pain stimuli produced by each method. CMAC® has a camera at the end of its blade. The camera would be in front of the larynx in laryngoscopy. Cormack-Lehane grade 1 or 2 can be achieved by slightly lifting larynx up, which is in accordance with Noppens’ study17 that stated CMAC® showed better laryngeal visualization; therefore, pain stimulus and catecholamine release were decreased.17 CMAC® has wider visualization than Macintosh (60° vs 15°),18 aid to achieve better visualization of larynx and minimize pain stimulus, time for intubation, and BURP maneuver needs.19

Heart rate showed the smallest change compared to other parameters. T3 heart rate in Macintosh was 10.29±10.41 bpm and in CMAC® was 10.29±10.41 bpm. This might be the result of fentanyl administration 5–6 minutes before laryngoscopy. After 5–6 minutes, fentanyl reached its peak plasma concentration. Fentanyl 2 mcg/kgBW and propofol induction can decreased sinoatrial node frequency.20 Study showed that heart rate during induction was 11–27% lower than pre-induction state, while it decreased 7–15% as laryngoscopy response.

BURP maneuver was less needed in the CMAC®

group compared to the Macintosh group since the camera in CMAC® blade was almost directly in front of the larynx, facilitating Cormack-Lehane I or II visualization.17,21 Facilitation from CMAC® video laryngoscopy in larynx visualization had lesser painful stimulus during laryngoscopy procedure compared with the

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Macintosh visualization, which resulted in lower cardiovascular responses in the CMAC® group compared to the Macintosh group significantly. BURP maneuver, in other hand, could create additional painful stimulus. BURP maneuver exerted pressure to larynx from the outside at the same time when the blade pressed tongue-base, valecula, and anterior epiglottis surface, resulting in simultaneous painful stimuli.

Blood pressure and mean arterial pressure were measured by a non-invasive blood pressure monitor, requiring 20–40 seconds to measure. This method is a standard observation procedure from ASA. Intra-arterial observation is more invasive and more expensive. Confounding factors of cardiovascular parameters were posed by BURP maneuver’s association with the parameters and required time to achieve Cormack-Lehan 1 or 2 (from the start of laryngoscopy). Since these are not the aim of the studies, data regarding these were not analyzed.

We suggest further studies measuring blood catecholamine level during laryngoscopy and BURP maneuver in association with cardiovascular parameters needs to be done. Blood catecholamine level increases with pain stimuli, in order that, we can compare the response of pain stimuli better due to Macintosh and CMAC®. Limitation of this study included catecholamine level that was not measured as a response to laryngoscopy due to high cost of this laboratory examination. Cardiovascular changes were assumed due to painful stimuli of laryngoscopy.

In conclusion, cardiovascular response and BURP maneuver during laryngoscopy with CMAC® video laryngoscopy were significantly lower compared to conventional Macintosh.

Conflict of interestThe authors affirm no conflict of interest in this study.

AcknowledgmentThere is no conflict of interest including any financial interests or financial conflicts to declare relating to the past 5 years or the foreseeable future. The study was supported by Department of Anesthesiology and Intensive Care, Faculty of Medicine, Universitas Indonesia.

REFERENCES

1. Hagberg CA, Artime CA. Airway management in adult. In: Miller RD, Weiner-Kronish JP, Young WL, editors. Miller’s anesthesia. 8th ed. Philadelphia. Elsevier Saunders; 2015. p. 1647–83.

2. Hassani V, Movassaghi G, Goodarzi V, Safari S. Comparison of fentanyl and fentanyl plus lidocaine on attenuation of hemodynamic responses to tracheal intubation in controlled hypertensive patients undergoing general anesthesia. Anesth Pain Med. 2013;2(3):115–8.

3. Chaundary B, Shah SM, Sarvaiya VU. Comparative study of two different doses of fentanyl citrate 2 microgram/kg and 4 microgram/kg intravenous in attenuation of hemodynamic responses during intubation. NHL Journal of Medical Science. 2013;2(2):41–3.

4. Deem SA, Bishop MJ, Bedford RF. Physiologic and patophysiologic responses to intubation. In: Hagberg CA, editor. Benumof’s airway management. 2nd ed. Philadelphia. Mosby Inc; 2007. p. 193–214.

5. Kapuangan C, Soenarto RF, Marsaban AHM. Respons kardiovaskular pada laringoskopi intubasi: Perbandingan antara esmolol 100 mg dengan lidokain 1.5 mg [thesis]. Jakarta: Universitas Indonesia; 2008. p. 1–5. Indonesian.

6. Kanchi M, Nair HC, Banakal S, Murthy K, Murugesan C. Haemodynamic response to endotracheal intubation in coronary artery disease: direct versus video laryngoscope. Indian J Anesth. 2011;55(3):260–5.

7. Rosenblatt, WH. Airway Management In: Barash PG, Cullen BF, Stoelting RK, editors. Clinical Anesthesia. 5th Ed. Lippincot & Wilkins. Philadelphia;2006. p. 595–643.

8. Thomas EBM, Moss S. Tracheal intubation. Anesth and Intens Care Med.2014;15(1):5–7.

9. Butterworth IV JF, Mackey DC, Wasnic JD, editors. Airway management. In: Morgan and Mikhail’s clinical anesthesiology. 5th Ed. New York: Lange; 2013. p. 308–41.

10. Aziz M. The role of video laryngoscopy. Adv in Anesth. 2013;31:87–98.

11. Niforopulou P, Pantazopoulos I, Demestiha T, Koudouna E, Xanthos T. Video-laryngoscopes in adult: A topical review of the literature. Acta Anesthesiol Scand. 2010;54(9):1050–61.

12. Charters S, Charters P. Alternative techniques for tracheal intubation. Anesth Intens.2014;15(5):209–14.

13. Dominguez-Roldan JM, Barrera-Chacon JM, Murillo-Cabezas F, Santamaria-Mifsut JL, Rivera-Fernandez V. Clinical factors influencing the increment of blood carbon dioxide during the apnea test for the diagnosis of brain death. Transplantation Proceeding. 1999;31:2599–600.

14. Murphy MF, Barker TD, Schneider RE. Endotracheal intubation in: Wals RM, Murphy MF, editors. Manual of emergency airway management. 3rd ed. Lippincot Williams & Wilkins. Philadelphia; 2008. p. 63–75.

15. Rosenquist RW, Vrooman BM. Chronic pain management. In: Butterworth IV JF, Mackey DC, Wasnic JD, editors. Morgan and Mikhail’s clinical anesthesiology. 5th Ed. New York. Lange; 2013. p. 1023–85.

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16. Lubenow TM, Ivankovich AD, Barkin R. Management of acute postoperative pain. In: Barash PG, Cullen BF, Stoelting RK, editors. Clinical Anesthesia. 5th Ed. Lippincot & Wilkins. Philadelphia; 2006. p. 1405–40.

17. Noppens RR, Geimer S, Eisel N, David M, Piepho T. Endotracheal intubation using the C-MAC® video laryngoscope or the macintosh laryngoscope: A prospective, comparative study in the ICU. Crit Care. 2012;16(3):1–8.

18. Anonymous. Video intubation systems in storz the world of endoscopy. 5th ed. Tuttlingen: Karl Storz Corp; 2012. p. 61–3.

19. McElwain J, Malik MA, Harte BH, Flyn NM, Laffey JG. Comparison of the CMAC® video laryngoscope with the macintosh, glidescope®, and airtraq® laryngoscope in easy and difficult laryngoscopy scenarios in manikins. Anaesthesia. 2010;65(5):483–9.

20. Kovac AL. Controlling the hemodynamic response to laryngoscopy and endotracheal intubation. J Clin Anaesth. 1996;8(1):63–79.

21. Kautto UM. Attenuation of the circulatory response to laryngoscopy and intubation by fentanyl. Acta Anaesthesiol Scand. 1982;26(3):217–21.


Additional diagnostic value of digital radiology in plantar fasciitis diagnosis

Keywords: calcaneus bone, digital radiography, plantar fasciitis, plantar aponeurosis, ultrasonography

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.1514 • Med J Indones. 2017;26:122–7• Received 03 Aug 2016 • Accepted 16 Apr 2017

Corresponding author: Marcel Prasetyo, [email protected]


Marcel Prasetyo, Thariqah Salamah, Trifonia P. SiregarDepartment of Radiology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National Hospital, Jakarta, Indonesia

Clinical Research


ABSTRAK

Latar belakang: Ultrasonografi (USG) adalah pemeriksaan standar baku emas untuk membedakan fascia plantaris yang normal dengan yang mengalami plantar fasciitis. Radiografi konvensional atau foto polos umumnya hanya digunakan untuk menyingkirkan diagnosis banding. Akhir-akhir ini, radiografi konvensional sudah banyak mengalami digitalisasi, sehingga pencitraan jaringan lunak oleh foto polos menjadi lebih baik. Namun, tidak diketahui apakah hasil evaluasi radiografi digital daerah kalkaneus, baik kualitatif maupun kuantitatif, memiliki nilai diagnostik serupa dengan temuan USG. Penelitian ini bertujuan untuk mengetahui nilai diagnostik temuan radiografi digital dan USG dalam mendiagnosis plantar fasciitis.

Metode: Studi ini menggunakan desain potong-lintang, dengan subjek pasien dewasa (>18 tahun) yang memiliki keluhan nyeri tumit bawah. Ketebalan plantar aponeurosis diukur dengan radiografi digital dan ultrasonografi. Masing-masing pengukuran dilakukan sebanyak tiga kali dan diambil nilai rerata. Fat stranding, entesofit kalkaneus dan mikrofraktur entesofit kalkaneus juga dievaluasi dalam radiografi digital. Hasil ketebalan plantar aponeurosis selanjutnya diklasifikasikan menjadi diagnosis plantar fasciitis.

Hasil: Tidak terdapat korelasi yang bermakna antara ketebalan plantar aponeurosis yang diukur menggunakan radiografi digital dan ultrasonografi (r=0,069, p=0,688). Tidak terdapat hubungan yang signifikan antara diagnosis plantar fasciitis dengan radiografi digital dan ultrasonografi menggunakan Fisher’s exact test (p=0,162). Namun, radiografi digital memiliki sensitivitas yang tinggi dalam mendeteksi plantar fasciitis.

Kesimpulan: Radiografi digital berpotensi untuk digunakan sebagai modalitas diagnosis definitif untuk plantar fasciitis.

ABSTRACT

Background: Ultrasonography (USG) is regarded as the gold standard to differentiate normal plantar fascia and plantar fasciitis. Conventional radiography or plain X-ray is typically used to exclude differential diagnosis. Lately, conventional radiography has been digitalized and leads to better visualization of the soft tissue. However, it is not known whether digital radiography evaluation for calcaneus area, both qualitative and quantitative, has a similar diagnostic value as USG findings. Therefore, this study aimed to evaluate whether there is a strong correlation between digital radiographic and USG findings for diagnosing plantar fasciitis.

Methods: This is a cross sectional study examining adult patients (>18 years old) presenting with inferior heel pain. Plantar aponeurosis thickness was measured by digital radiography and ultrasonography; measurement was performed three times in each modality, and the average value was recorded. Fat stranding, presence of calcaneal enthesophyte, and microfracture were also evaluated in digital radiography. Measurement results were classified into plantar fasciitis diagnosis using the cut-off value 4 mm.

Results: There was no significant correlation between plantar aponeurosis thickness measured by digital radiography and by ultrasonography (r=0.069, p=0.688). There was no significant association between plantar fasciitis diagnosis by digital radiography and ultrasonography (p=0.162). However, digital radiography showed good sensitivity to detect plantar fasciitis using a cut-off value of >4 mm plantar fascia thickness.

Conclusion: Digital radiography might be used to aid definitive diagnosis for plantar fasciitis.


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Plantar fasciitis is a common cause of inferior heel pain due to edema or inflammation in the plantar aponeurosis. Although the etiology has not been clearly identified, several things has been identified as risk factors, such as increasing age, obesity, biomechanic abnormality of the feet, and heavy physical activity.1 Radiology plays an important role in diagnosing plantar fasciitis and in providing evaluation after treatment.2 Conventional radiography is typically used to exclude differential diagnosis. Radiographic findings in plantar fasciitis include osteophyte formation in calcaneus bone although it is not specific. Ultrasonography (USG) is an effective tool, regarded as the gold standard, for differentiating normal plantar fascia and plantar fasciitis. High-frequency USG is used to evaluate edema or thickening of plantar fascia; thickness of more than 4 mm is a diagnostic feature for plantar fasciitis.3,4

In the Department of Radiology of Cipto Mangunkusumo General Hospital, conventional radiography or plain X-ray has been digitalized to increase its image quality; it can visualize the soft tissue in a better quality.5 However, it is not known whether digital radiography evaluation for calcaneus area, both qualitative and quantitative, has a similar diagnostic value as USG findings. Therefore, this study aimed to evaluate whether digital radiographic correlates with ultrasonography (USG) findings in diagnosing plantar fasciitis.

METHODS

This is a cross-sectional study conducted at the Radiology Department of Cipto Mangunkusumo General Hospital from December 2014 to February 2015. This study has been approved by the Ethics Committee of the Faculty of Medicine, University of Indonesia (No. 80/UN2.F1/ETIK/2015). Subjects were recruited in consecutive sampling from plantar fasciitis patients who were referred to the Radiology Department of Cipto Mangunkusumo General Hospital. We included adult patients (>18 years old) presenting with inferior heel pain. Patients with open wound, mass, or infection in plantar surface of foot were excluded. Patients with history of surgery in plantar surface of foot, history of trauma, or fracture in the foot or ankle were also excluded.

Sample was plantar aponeurosis on the plantar side of the foot; since both feet were examined in this study, one patient could give 2 samples. Plantar fascia thickness was measured by two radiologists (MP, TS) for ultrasonography because the examination was very operator-dependent. The two operators were blinded; they did not know the digital radiography results and other operator’s ultrasonography result. Digital radiography data were interpreted by other radiologist (TP.S).

Patients underwent both digital radiography and USG examination on the same day; both feet were examined. Digital radiography used Siemens Multix Compact K/1175640X2187 machine, with exposure 40–50 kV and 4 mAs. Lateral projection was taken with subject lying on the lateral side of the examined foot, e.g. if the right foot was examined, the patient was asked to lie on his/her right side. The ankle was dorsiflexed, and digital radiography plate sized 18x24 cm was placed under the lateral malleolus. The fifth finger must be touching the radiography plate, and the ankle was on the centre of the plate. The other feet was placed in front of the plate and not be included in the film. The X-ray beam was centered on the calcaneus bone, which was about 2-3 cm below the medial malleolus. Lateral projection of both feet was taken to evaluate the calcaneus bone and the soft tissue surrounding it. A radiologist then evaluated the bone structure (normal/subluxation/dislocation), bone density (normal/porotic/sclerotic), osteophyte or enthesophyte formation particularly the enthesophyte in plantar side of calcaneus bone, fragmentation of osteophyte of enthesophyte, and edema or fat stranding in fat tissue surrounding the plantar fascia. In digital radiography, plantar fascia thickness was measured exactly on the inferior border of calcaneus bone where plantar aponeurosis inserted into calcaneus bone. Measurement was conducted three times, and then the average value was recorded.

USG was conducted using the Medison Accuvix V20 Prestige machine using linear transducer with 9–15 MHz frequency. Subject was lying in prone position, ankle dorsiflexed in 90 degrees. The operator examined from patient’s right-hand side, and the plantar aponeurosis was visualized in sagittal projection to evaluate the echogenicity (hypoechoic/ hyperechoic), linearity or plantar aponeurosis fibers (parallel/not parallel), enthesophyte formation, musculoaponeurosis,


and rupture. Plantar aponeurosis thickness was measured in the anterior side of calcaneus bone’s inferior border, where plantar aponeurosis was inserted into calcaneus bone (Figure 1). Measurement was performed three times by each examiner, and the average value was recorded.

Data were analyzed using SPSS version 20.0 to evaluate whether there was a correlation between plantar fascia thickness measured with digital radiography and USG as the gold standard. Sensitivity and specificity of digital radiography findings to diagnose plantar fasciitis were also tested.

Figure 1. Plantar aponeurosis thickness measurement in USG, (a) longitudinal projection of calcaneus bone’s inferior border, showing normal plantar aponeurosis fibers (short arrow), (b) diagram showing transducer position for plantar aponeurosis thickness measurement. (C= calcaneus bone, FP= fat pad, P= probe/ ultrasound transducer, PF= plantar fascia)

RESULTS

PatientsThere were 18 subjects enrolled in this study. Basic charasteristic of subjects can be seen in table 1.

Radiographic and ultrasonographic findingsThirty six feet was examined, two from each patient. Mean plantar aponeurosis (PA) thickness in digital radiography was 6 mm, (3.5–9.8). PA >4 mm was found in 33 samples in digital radiography. Mean PA thickness in ultrasonography was 6 mm, (3.5–9.8). PA >4 mm was found in 34 samples in ultrasonography.

In digital radiography, fat stranding was found in 33 samples (91.6%), calcaneal enthesophyte in 32 samples (88.8%), and microfracture of calcaneal enthesophyte in 22 samples (61.1%) (Figure 2).

Correlation between digital radiographic and ultrasonographic measurementThere was no significant correlation between measurement using digital radiography and using ultrasonography with Pearson correlation test (p=0.688) (Figure 3). The measurement results was then classified using the cut-off 4 mm thickness, positive if the thickness was more than 4 mm and negative if less than 4 mm. There was no significant association between plantar fasciitis diagnosis using digital radiography and using ultrasonography (p=0.162)(Table 2).

There was no significant association between fat stranding found in digital radiography and plantar

Characteristics n %Gender

Male 1 5%Female 17 95%

Age40–45 years old 1 5%45–50 years old 2 10%>50 years old 15 85%

Heel painRight heel 2 11%Left heel 5 27%Right and left heel 11 62%

Table 1. Patients’ characteristics

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fasciitis found in ultrasonography (p=0.162). Fat stranding was present in all plantar fasciitis cases diagnosed by digital radiography. There was no significant association between calcaneal enthesophyte, as well as microfracture, found in digital radiography and plantar fasciitis found in ultrasonography (p=1.000) (Table 3).

DISCUSSION

Plantar fasciitis is an inflammation process, which can be diagnosed accurately using ultrasonography, with plantar fascia thickness cut-off value 4 mm. Other ultrasonography findings can also support the diagnosis, such as

Plantar fasciitis based on ultrasonography TotalPositive Negative

Plantar fasciitis based on digital radiography

Positive 32 (97%) 1 (3%) 33Negative 2 (66.7%) 1 (33.3%) 3 p=0.162Total 34 2 36

Table 2. Plantar fasciitis diagnosis using plantar fascia thick-ness (>4 mm) criteria by digital radiography measurement and ultrasonography measurement

Plantar fasciitis based on ultrasonography Total

Positive Negative

Fat strandingPositive 32 (97%) 1 (3%) 33Negative 2 (66.7%) 1 (33.3%) 3 p=0.162Total 34 2 36

EntesophytePositive 30 (93.8%) 2 (6.2%) 32Negative 4 (100%) 0 (0%) 4 p=1.000Total 34 2 36

MicrofracturePositive 21 (95.5%) 1 (4.5%) 22Negative 13 (92.9%) 1 (7.1%) 14 p=1.000Total 34 2 36

Table 3. Fat stranding, calcaneal entesophyte, and micro-fracture found in digital radiography and plantar fasciitis found in ultrasonography

hypoechoic plantar aponeurosis, fluid collection in the surrounding fat tissue, and pain elicited by compression maneuver. Lateral projection radiography of calcaneus bone is also widely used in plantar fasciitis, but its utilization is focused on calcaneal enthesophyte or spur detection and excluding differential diagnoses. Levy et al6 proved that radiography was not beneficial in diagnosing plantar fasciitis. Osborne et al7 showed that plantar fascia thickness and fat pad abnormality found in calcaneus bone radiography (lateral projection) had 85% sensitivity and 95% specificity to diagnose plantar fasciitis.

Digital radiography of calcaneus bone using lateral projection could visualize plantar aponeurosis clearly, and its thickness could be measured. In this study, plantar aponeurosis measurement has been done three times, and the mean value was used for data analysis. However, this study did not find significant correlation between plantar aponeurosis measurement using digital radiography and using ultrasonography. Acutely inflamed plantar aponeurosis is often accompanied with surrounding fat tissue edema, which was also looked radio-opaque, known as “fat stranding”. The presence of fat stranding actually made plantar aponeurosis measurement more difficult; this was probably due to the inconsistency in radiographic measurement. Therefore, measurement of plantar aponeurosis thickness by digital radiography was inferior to ultrasonography.

When the plantar aponeurosis thickness was classified into less than 4 mm and more than 4 mm, digital radiography findings had no significant association with ultrasonography (p=0.162). However, statistical analysis showed good sensitivity and positive predictive value, both >80%, for plantar fasciitis diagnosis by digital radiography. The surrounding fat tissue edema (fat-stranding) could make plantar fascia thicker than it actually was when measured by digital radiography. As a result, normal plantar fascia thickness (<4 mm) appeared abnormal, and false positive could happen more frequently (lower specificity) in digital radiography. Conversely, a true abnormal plantar thickness (>4 mm) would be more highlighted by the surrounding edema, and therefore, false negative could rarely happen (higher sensitivity). In this study, all patients who actually had plantar fasciitis (diagnosed by ultrasonography) also had fat-stranding in digital radiography. This finding


Figure 2. Digital radiography of patient with A) fat stranding (arrow); B) calcaneal enthesophyte; C) calcaneal microfracture

A B C

Figure 3. Scatter plot of plantar aponeurosis thickness mea-surement using digital radiography (X-axis) and using ultra-sonography (Y-axis)

was consistent with the pathophysiology of plantar fasciitis, in which acutely inflamed plantar fascia was often accompanied by edema of the surrounding fat tissue. Thus, the presence of fat-stranding had good sensitivity in detecting an actual plantar fasciitis, as showed by Osborne et al7 This initial result and previous studies showed potential utilization for digital radiography to provide definitive diagnosis of plantar fasciitis. However, further study with larger sample size would be needed before we could recommend the use of digital radiography alone, without ultrasonography, to diagnose plantar fasciitis.

The presence of calcaneal enthesophyte or microfracture in digital radiography and plantar

fasciitis diagnosis in ultrasonography both showed insignificant association. There was a wide difference in significance value between association of enthesophyte in radiography – plantar fasciitis in ultrasonography, and fat stranding in radiography – plantar fasciitis in ultrasonography, suggesting that the presence of calcaneal enthesophyte or microfracture in digital radiography was truly not associated with plantar fasciitis, and conducting further study with larger sample size would not bring any difference in its statistical significance. This finding was also supported by Abreu et al8 which showed only 3% of calcaneal enthesophyte was located inside the plantar aponeurosis, while more than 90% was found outside plantar aponeurosis region. Therefore, plantar fasciitis was most likely not influenced by calcaneal enthesophyte.

Digital radiography could be potentially used to provide definitive diagnosis of plantar fasciitis, using plantar aponeurosis thickness cut-off value of 4 mm. However, this study had limitation: the small sample size. If further studies with larger sample size could confirm it, the plantar fasciitis diagnosis could be more efficient and cost-effective. By using digital radiography alone, examination time could be much shortened. It would also be more comfortable for patients because in ultrasonography examination, patients had to be lying in prone position, which was uncomfortable especially for obese patients. Additionally, digital radiography could also evaluate bony structure of the heel, which could not be evaluated in ultrasonography. Therefore, not only digital radiography could diagnose plantar fasciitis, but it could also evaluate or exclude other causes of heel pain, such as microfracture and heel spur.

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thickness in digital radiography (mm)

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In conclusion, digital radiography might be used to provide definitive diagnosis in plantar fasciitis cases, using plantar fascia thickness cut-off value 4 mm.

Conflicts of interestThe authors affirm no conflicts of interest in this study.

AcknowledgmentThe authors acknowledge dr. Benedicta Mutiara Suwita for her contribution in editing the manuscript. This study received fundings from National General Hospital Cipto Mangunkusumo operational research grant.

REFERENCES

1. Nuran S, Semra D, Baki Y, Nevzat K, Sibel C. Clinical Utility of Sonography in Diagnosing Plantar Fasciitis. J Ultrasound Med. 2005; 24(8):1041–8.

2. Potter VAJ. Investigating Plantar Fasciitis. The Foot and Ankle Online Journal. 2009;2(11):4.

3. Ahn JM, El-Khoury GY. Radiologic Evaluation of Chronic Foot Pain. Am Fam Physician. 2007;76(7):975–983.

4. Wearing SC, Smeathers JE, Sullivan PM, Yates B, Urry SR, Dubois P. Plantar Fasciitis: Are Pain and Fascial Thickness Associated With Arch Shape and Loading?. Phys Ther. 2007;87(8):1002–8.

5. www.idexx.com [Internet]. Computed Radiography in Perspective. [updated 2014 July 11; cited 2016 Feb 09]. Available from: https://www.idexx.com/.

6. Levy JC, Mizel MS, Clifford PD, Temple HT. Value of Radiographs in the Initial Evaluation of Nontraumatic Adult Heel Pain. Foot Ankle Int. 2006;27(6):427–30.

7. Osborne HR, Breidhl WH, Allison GT. Critical differences in lateral X-rays with and without a diagnosis of plantar fasciitis. J Sci Med Sport. 2006;9(3):231–7.

8. Abreu MR, Chung CB, Mendes L, Mohana BA, Trudell D, Resnick D. Plantar calcaneal enthesophytes: new observation regarding sites of origin based on radiographic, MR imaging, anatomic, and paleopathologic analysis. Skeletal Radiol. 2003;32(1):13–21.

http://www.idexx.com


Management of bladder stones: the move towards non-invasive treatment

Keywords: Bladder stone, cystholithotripsy, ESWL, sectio alta

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.1602 • Med J Indones. 2017;26:128–33• Received 06 Oct 2016 • Accepted 04 Mar 2017

Corresponding author: Ponco Birowo, [email protected]


Isaac A. Deswanto,1 Ari Basukarno,1 Ponco Birowo,1,2 Nur Rasyid1,2

1 Department of Surgery, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia 2 Department of Urology, Cipto Mangunkusumo Hospital, Jakarta, Indonesia

Clinical Research


ABSTRAK

Latar belakang: Batu buli merepresentasikan sekitar 5% dari semua kasus batu saluran kemih. Penanganan batu buli terus berkembang dari operasi terbuka, intracorporeal lithotripsy dan extracorporeal shock wave lithotripsy (ESWL). ESWL adalah sebuah modalitas yang menjanjikan dalam penanganan batu buli karena dapat ditoleransi dengan baik dan lebih sederhana. Penelitian ini dilakukan untuk mengumpulkan data yang dapat menggambarkan keamanan dan efektifitas dari ESWL dalam penanganan batu buli.

Metode: Studi ini merupakan sebuah studi retrospektif yang mengambil data dari rekam medis 92 pasien yang didiagnosa batu buli di Rumah Sakit Cipto Mangunkusumo (RSCM) dari Januari 2011 sampai April 2015. Data yang dikumpulkan meliputi usia pasien, jenis kelamin, jenis batu, prosedur yang dilakukan dan status disintegrasi batu, lama rawat dan komplikasi yang mungkin terjadi. Semua data dianalisis secara statistik menggunakan SPSS versi 20.

Hasil: Mayoritas pasien menjalani prosedur ESWL (49 dari 92, 53,3%). Angka bebas batu untuk tindakan ESWL, intracorporeal lithotripsy, dan sectio alta adalah 93,9%, 97,0% dan 100% secara berurutan. Salah satu pasien harus mengulang prosedur ESWL. Rerata ukuran batu ditemukan paling kecil pada kelompok ESWL bila dibandingkan dengan kelompok intracorporeal lithotripsy dan sectio alta (2,5 cm±2,0 cm vs 4,8 cm±3,7 cm vs 7,4 cm±5,4 cm secara berurutan). Prosedur ESWL dilakukan pada klinik rawat jalan.

Kesimpulan: ESWL dapat direkomendaasikan sebagai modalitas terapi yang efektif dan non-invasif dalam penanganan batu buli dengan angka bebas batu yang cukup baik (93,9%) Tindakan ESWL bisa dilakukan di poliklinik rawat jalan dengan komplikasi yang minimal.

ABSTRACT

Background: Bladder stone accounts for 5% of all cases of urolithiasis. Bladder stones management has evolved over the last decades from open bladder surgery (sectio alta) to intracorporeal cystholithotripsy as well as extracorporeal shock wave lithotripsy (ESWL). ESWL presents to be a promising modality in the management of bladder calculi due to its simplicity and well tolerability. This study is thus conducted to present data on the safety and effectiveness of ESWL in the management of bladder stone patients.

Methods: This is a retrospective study evaluating the medical records of 92 bladder calculi patients admitted to Cipto Mangunkusumo General Hospital (RSCM) from January 2011 to April 2015. Patient’s age, gender, type of stone and procedure being done, status of stone disintegration, length of hospital stay, and any complications that may occur are noted down and statistically analyzed using SPSS v. 20.

Results: Majority of the patients underwent ESWL (49 out of 92, 53.3%). The stone free rates for ESWL, intracorporeal lithotripsy, and sectio alta are 93.9%, 97.0% and 100% respectively. One patient had to repeat ESWL. The ESWL group had the smallest stone size average compared to the intracorporeal lithotripsy and section alta group (2.5 cm±2.0 cm vs 4.8 cm±3.7 cm vs 7.4 cm±5.4 cm respectively). The ESWL sessions were conducted in the outpatient clinic, and thus no hospital stay was required.

Conclusion: ESWL can be suggested as an effective non-invasive approach in the disintegration of bladder stone of ≤25 mm with a promisingly high stone-free rate (93.9%) Furthermore, ESWL can be performed on an outpatient basis with minimal complications.


Deswanto, et al.ESWL and bladder stone

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The advent of antimicrobial treatment and improvement in nutritional intake has played a significant role in reducing the incidence of bladder stones in the last couple of decades. Nowadays, bladder stones or calculi represent approximately 5% of all cases of urolithiasis.1 Formations of bladder calculi are usually facilitated by the presence of bladder outlet obstruction, neurogenic voiding dysfunction, infection, as well as foreign objects.2 Some other additives, for example in melamine-containing milk, had also been reported to cause formation of melamine-uric acid vesical stone in a child.3

Management options for bladder calculi are varied, and novel approaches have been developed in the last decades. Nevertheless, an ideal single approach to achieve stone clearance remained debatable due to the variations in stone burden and patient characteristics.2 In general, sectio alta is usually reserved for pediatric bladder stone and evacuation of large calculi(stone size >4 cm).2 This approach may also be indicated in hard stones that are refractory to endoscopic procedures. On the other hand, transurethral approach for bladder stone clearance provides an attractive alternative because it requires no incision (as it uses normal orifice) and permits the use of diverse tools for stone fragmentation. These include mechanical stone crusher, ultrasound, pneumatic and electrohydraulic lithotriptors, and combined ultrasonic/pneumatic lithotripsy device and laser energy sources, each of them with its own advantages and disadvantages.2,4–6 Alternatively, extracorporeal shock wave lithotripsy (ESWL) also presents a promising management for bladder stones due to its simplicity and tolerability. It is especially indicated in high-risk patients who are poorly tolerant to operative procedures.2 Additionally, ESWL is usually performed on an outpatient basis, does not require anesthesia and avoids prolonged urethral instrumentation.7,8 Many previous studies presented promising data on its efficacy as a monotherapy in bladder stone.9–11 Therefore, this retrospective study is conducted to explore the safety and effectiveness ofbladder stone management in the Cipto Mangunkusumo General Hospital (RSCM) who underwent ESWL.

METHODS

This is a retrospective study evaluating the medical records of patients who were admitted at the Cipto Mangunkusumo General Hospital with the diagnosis of bladder stones from January 2011 to April 2015. The confidentiality of the subjects identities was guaranteed. Case of bladder stones were diagnosed radiographically either by plain radiography or ultrasonography. Data regarding patient’s age, gender, type of stone, type of procedure being done, status of stone disintegration, days of hospital stay, and any complications that may occur are noted down. The Ethics Committee of the Faculty of Medicine, University of Indonesia, with regards of the protection of human rights and welfare in medical research, has carefully reviewed and approved this study with Ethical Clearance (No. 446/UN2.F1/ETIK/2016).

Patients who underwent ESWL were treated on supine position using PiezoLith 3,000 Plus –Richard Wolf. The number of shocks delivered in each session ranges from 4,000 to 6,000 shocks. After undergoing ESWL, the patients were re-evaluated by ultrasonography or plain abdominal radiograph at two weeks interval. Second ESWL session was indicated or conducted in the presence of significant stone fragment (>5 mm). Patients not undergoing ESWL underwent either intracorporeal lithotripsy procedure using electro-pneumatic lithotriptor (ELMED VIBROLITH) or cystolithotomy/sectio alta.

The data gathered in this study are analyzed using SPSS Statistics 20. The average age, stone size, and hospital stays in between different treatment groups (ESWL, intracorporeal lithotripsy, and sectio alta group) will be statistically analyzed using one way Anova to test whether there are statistically significant difference in various treatment groups in terms of average age, stone size, and duration of hospital stays. Post Hoc test will then be conducted to show the difference between treatment groups.

RESULTS

From January 2011 to April 2015, 92 patients had been admitted to the Cipto Mangunkusumo


General hospital with diagnosis of bladder stone. They were mostly male patients (83 patients out of 92, 90.2%) with the average age around 51.3 (±14.4) years old. 78.3% (n=72) underwent plain abdominal imaging whereas only 8.7% (n=8) of them underwent ultrasonography (USG) examination. The rest of the patients underwent both radiographic examinations before being treated. The stones found from these patients are predominantly radiopaque (88 out of 92, 95.7%) and solitary in nature (84 out of 92, 91.3%) as shown in Table 1.

Majority of the patients admitted with bladder stone were managed by ESWL (49 out of 92, 53.3%) followed by intracorporeal lithotripsy (33 out of 92, 35.9%). Sectio alta was only performed in 10 out of 92 patients (10.9%). The stone free rate for ESWL, intracorporeal lithotripsy, and sectio alta are 93.9%, 97.0%, and 100% respectively (Table 2). Following the procedure, surgical site infection accompanied with fever was noted in one patient (1 out of 10, 10%) in sectio alta group (Table 3).

Demographic characteristics (n = 92)Patient’s age (years) 51.3±14.4Gender

Male 83 (90.2%)Female 9 (9.8%)

Radiologic examination Plain radiograph 72 (78.3%)USG 8 (8.7%)Plain radiograph + USG 12 (13.0%)

Type of stoneRadioopaque 88 (95.7%)Radioluscent 4 (4.3%)

Number of stonesSingle 84 (91.3%)Multiple 8 (8.7%)

Status of stone fragmentationStone free 88 (95.7%)Stone fragments present 4 (4.3%)

Table 1. Demographic characteristics

Overall, 49 patients out of 92 were treated with ESWL. One of these patients underwent ESWL

Figure 1. (A) Plain X-ray of patient with bladder stone (as indicated by black arrow); (B) Plain X-ray two weeks after last extra-corporeal shockwave lithotripsy (ESWL) session

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for more than one session due to the presence of residual stone fragments two weeks post ESWL. The remaining patients underwent either intracorporeal lithotripsy or cystolithotomy. In general the average age of patients in ESWL and intracorporeal lithotripsy treatment group are similar (53.4±10.8 and 53.2±2.6 years old, respectively) and older than patients undergoing sectio alta (36.9±22.9 years old). One way Anova test shows that the mean age in between these three treatment groups are significantly different (p=0.004). However, Post Hoc test results have been inconclusive.

The average stone size was found to be the largest in patients undergoing sectio alta and the smallest in the ESWL group (7.4±5.4 and 2.5±2.0

ESWL Intracorporeal lithotripsy Cystolithotomy/ sectio alta pPatients (n) 49 32 10 -Age of patients (year) 53.4±10.3 53.2±12.5 33.5±22.8 0.004Stone size (cm) 2.5±2.0 4.2±2.8 7.4±5.4 <0.001Hospital stay (days) 0 4.8±3.3 10.9±8.2 -

Table 4. Comparison between ESWL patients and patients from other treatment groups

ESWL=extracorporeal shockwave lithotripsy

respectively). Similarly, there was also significant difference in the average stone size (cm) in between the three groups. Tamhane Post Hoc test shows that this significant difference lies between ESWL and Intracorporeal lithotripsy group (2.5±2.0 vs 4.2±2.8 respectively, p=0.014). ESWL was conducted in an outpatient setting therefore no hospital stay was required. On the contrary, the average days of hospitalization were 4.8±3.3 and 10.9±8.2 days for Intracorporeal lithotripsy and sectio alta group respectively. On the other hand, however, Post Hoc test did not show significant difference in the duration of hospital stay between intracorporeal lithotripsy and sectio alta group. In general, patients who underwent sectio alta had longer duration of hospital stay (Table 4).

DISCUSSION

Bladder calculi represents approximately 5% of all cases of urolithiasis1 with unique predisposing factors in different age groups and gender.2,3,12–14 In the early days, bladder calculi was first evacuated by open bladder surgery/sectio alta.15 Further development of endourology technique had also contributed greatly in the transurethral management of bladder stones (intracorporeal lithotripsy). Intracorporeal lithotripsy had also been commonly performed simultaneously with trans-urethral resection of prostate (TURP) in male patients of older population with history of bladder outlet obstruction caused by benign enlargement of prostate glands.5 Nevertheless, it is still being questioned whether performing TURP simultaneously with transurethral cystolitholapaxy is superior to medical therapy for benign prostate hyperplasia (BPH) alone.16

Both sectio alta and transurethral approach of stone evacuation are more advantageous than ESWL in the fragmentation of larger bladder stones. Nevertheless, both procedures have

Type of procedure (n=92) Stone-free rateESWL 49 (53.2%) 93.9% (46/49)Intracorporeal lithotripsy 33 (35.8%) 97.0% (32/33)Cystolithotomy/ sectio alta 10 (10.8%) 100.0% (10/10)

Table 2. Stone-free rate of each procedure

ESWL=extracorporeal shockwave lithotripsy

Complications ESWL(n=49)

Sectio alta(n=10)

Intracorporeal lithotripsy

(n=33)

Fever 0(0.0%) 1(10.0%) 0(0.0%)UTI 0(0.0%) 0(0.0%) 0(0.0%)Urethral injury - 0(0.0%) 0(0.0%)Stone fragment impaction

0(0.0%) 0(0.0%) 0(0.0%)

Uncontrolled bleeding - 0(0.0%) 0(0.0%)Surgical site infection - 1(10.0%) -Bladder perforation - 0(0.0%) 0(0.0%)

Table 3. Procedural complications

ESWL=extracorporeal shockwave lithotripsy; UTI=urinary tract infection


also a number of disadvantages since they must be performed under anesthesia, and long tedious postoperative hospital stay is inevitable. Additionally, transurethral approach also has several additional disadvantages such as longer operating time, hematuria, risk of bladder perforation, and potential urethral injury as their disadvantages.7,17 ESWL, on the contrary, is a non-invasive modality that utilizes high energy acoustic pulses generated outside the body.18 The effective applications of ESWL in disintegrating both radiopaque and radiolucent renal stones (e.g. uric acid stones) have been well described.19 Kostakopoulos et al,11 Al-ansari et al,20 and Telha et al21 have also mentioned ESWL’s role as a monotherapy in bladder stones fragmentation. The use of ESWL as a monotherapy in bladder stones, however, still has some controversial issues to address. The first is the fact that the recurrence rate of bladder stone after ESWL monotherapy is not well determined yet. This raises some debates on how long a patient needs to be followed up after an ESWL session.9 Secondly, there has also been some controversies regarding the proper patient positioning during the ESWL session. Some authors suggested a prone position17 while others recommended conducting the session in a supine position.10 Some authors prefered supine position because they assumed that in prone position, the sacrum might hinder stone fragmentation to some extent.21

In this study, 49 out of 92 patients underwent ESWL with stone-free rate of 93.9%. The stone-free rate observed in this study is comparable to the results gathered by El-Halwagy et al8 and Telha et al21 with stone-free rate of 96.6% and 95.5%.8,21 One case series of twenty patients with bladder stone with concurrent paraplegia have demonstrated 100% stone-free rate after ESWL session.22 The stone free rate of ESWL compared favorably to patients who underwent either intracorporeal lithotripsy or sectio alta (stone-free-rate of 97% and 100% respectively). Both these studies mentioned above, included patients in which ESWL is the first procedure performed for bladder stone management. This provides some suggestions that ESWL may be recommended to patient as the first line therapy before looking at other more invasive approaches. In this study, the success of ESWL in bladder stone treatment may be affected by the stone diameter. Apparently, the stone diameter of patients who underwent

ESWL are significantly smaller than the patients undergoing intracorporeal lithotripsy and sectio alta (2.5±2.0 vs 4.2±2.8 vs 7.4±5.4 respectively, p=0.004). This finding in mean stone diameter in patients undergoing ESWL was similar to the study conducted by El-Halwagy et al8 (2.6±1.0 cm) and Kilciler et al22 (2.9±0.6). The smaller diameter of bladder stone in patients undergoing ESWL may be one of the determinants in the success rate. Other possible factors that may play a role in successful stone fragmentation in ESWL include the presence of bladder outlet obstruction and stone composition.2 Nevertheless, bladder outlet obstruction has been proven to have limited effect in ESWL’s success rate of stone fragmentation.8 Additionally, in this study, patients underwent ESWL on the outpatient basis, and thus no hospital stay was required. Moreover, after each ESWL session, clearance of stone fragments did not require any placement of urinary catheters.

This study, however, has a number of limitations. Firstly because this study is retrospective by nature. Confounding factors that may affect treatment’s success rate could not be minimized. Therefore, the impact of stone composition, urinary tract infection (UTI), stone burden, and presence of bladder outlet obstruction (BOO) on the treatment outcome could not be addressed. Secondly, this study also has a limitation in presenting the data of the recurrence rate of bladder stone after ESWL monotherapy. Additionally, this study also has limited data on the comorbidities in patients indicated to undergo ESWL treatment. These limitations can be tackled effectively if future studies in regards to ESWL monotherapy in bladder stone cases are conducted prospectively.

In summary, ESWL is a promising modality in the fragmentation of bladder stones. It provides a relatively high stone-free-rate (93.9%), can be done on an outpatient basis, and at the same time minimizes the need for anesthesia and urethral instrumentation with minimal complications. Therefore, ESWL can be suggested as a definitive treatment in patients with bladder stone of ≤25 mm in size especially in those with high anesthetic complications.

Conflicts of interestThe authors affirm no conflict of interest in this study.

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AcknowledgmentMuch gratitude to all staffs of the Department of Urology, Cipto Mangunkusumo General Hospital in helping to make the construction of bladder stone patient’s database possible.

REFERENCES

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2. Papatsoris AG, Varkarakis I, Dellis A, Deliveliotis C. Bladder lithiasis: from open surgery to lithotripsy. Urol Res. 2006;34(3):163–7.

3. Grases F, Costa-Bauzá A, Gomila I, Serra-Trespalle S, Alonso-Sainz F, del Valle JM. Melamine Urinary Bladder Stone. Urology. 2009;73(6):1262–3.

4. Sofer M, Kaver I, Greenstein A, Bar Yosef Y, Mabjeesh NJ, Chen J, et al. Refinements in treatment of large bladder calculi: simultaneous percutaneous suprapubic and transurethral cystolithotripsy. Urology. 2004;64(4):651–4.

5. Shah HN, Hegde SS, Shah JN, Mahajan AP, Bansal MB. Simultaneous transurethral cystolithotripsy with holmium laser enucleation of the prostate: a prospective feasibility study and review of literature. BJU Int. 2007;99(3):595–600.

6. Kara C, Resorlu B, Cicekbilek I, Unsal A. Transurethral cystolithotripsy with holmium laser under local anesthesia in selected patients. Urology. 2009;74(5):1000–3.

7. Philippou P, Moraitis K, Masood J, Junaid I, Buchholz N. The management of bladder lithiasis in the modern era of endourology. Urology. 2012;79(5):980–6.

8. El-Halwagy S, Osman Y, Sheir KZ. Shock wave lithotripsy of vesical stones in patients with infravesical obstruction: an underused noninvasive approach. Urology. 2013;81(3):508–10.

9. Bhatia V, Biyani C. Extracorporeal shock wave lithotripsy for vesical lithiasis : initial experience. Br J Urol. 1993;71(6):695–9.

10. Husain I, el-Faqih SR, Shamsuddin A, Atassi R. Primary extracorporeal shockwave lithotripsy in management of large bladder calculi. J Endourol. 1994;8(3):183–6.

11. Kostakopoulos A, Stavropoulos NJ, Makrichoritis C, Picramenos D, Deliveliotis C. Extracorporeal shock wave lithotripsy monotherapy for bladder stones. Int Urol Nephrol. 1996;28(2):157–61.

12. Sharma R, Dill CE, Gelman DY. Urinary bladder calculi. J Emerg Med. 2011;41(2):185–6.

13. Chen Y, DeVivo MJ, Lloyd LK. Bladder stone incidence in persons with spinal cord injury: determinants and trends, 1973-1996. Urology. 2001;58(5):665–70.

14. Benway BM, Bhayani SB. Lower urinary tract calculi. Campbell-walsh urology. 10th ed. Philadelphia: Saunders. 2007. p. 2521–2527.

15. Sánchez-Martín FM, Hostalot AM, Santillana JM, Angerri O, Millán F, Villavicencio H. Extraction of a bladder stone in a child as described by the renaissance physician Cristóbal Méndez. Actas Urol Esp. 2014;38(7):476–82. Spanish.

16. Philippou P, Volanis D, Kariotis I, Serafetinidis E, Delakas D. Prospective comparative study of endoscopic management of bladder lithiasis: is prostate surgery a necessary adjunct? Urology. 2011;78(1):43–7.

17. Bhatia V, Biyani CS. A comparative study of cystolithotfipsy and extracorporeal shock wave therapy for bladder stones. Int Urol Nephrol. 1994;26(1):27–31.

18. McAteer JA, Evan AP. The acute and long-term adverse effects of shock wave lithotripsy. Semin Nephrol. 2010;28(2):200–13.

19. Sun XZ, Zhang ZW. Shock wave lithotripsy for uric acid stones. Asian J Surg. 2006;29(1):36–9.

20. Al-ansari A, Shamsodini A, Younis N, Jaleel OA, Al-Rubaiai A, Shokeir AA. Extracorporeal shock wave lithotripsy monotherapy for treatment of patients with urethral and bladder stones presenting with acute urinary retention. Urology. 2005;66(6):1169–71.

21. Telha KA, Alkohlany K, Alnono I. Extracorporeal shockwave lithotripsy monotherapy for treating patients with bladder stones. Arab J Urol. 2016;14(3):207–10.

22. Kilciler M, Sümer F, Bedir S, Ozgök Y, Erduran D. Extracorporeal shock wave lithotripsy treatment in paraplegic patients with bladder stones. Int J Urol. 2002;9(11):632–4.


The effect of balanced electrolyte solution versus normal saline in the prevention of hyperchloremic metabolic acidosis in diabetic ketoacidosis patients: a randomized controlled trial

Keywords: balanced electrolyte solution, diabetic ketoacidosis, hyperchloremic acidosis, normal saline, standard base excess, strong ion difference

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.1542 • Med J Indones. 2017;26:134–40• Received 25 Aug 2016 • Accepted 06 Feb 2017

Corresponding author: Dita Aditianingsih, [email protected]


Dita Aditianingsih, Anne S. Djaja, Yohanes W.H. GeorgeDepartment of Anesthesiology and Intensive Therapy, Faculty of Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia

Clinical Research


ABSTRAK

Latar belakang: Resusitasi cairan menggunakan normal saline (NS) dapat menimbulkan efek samping asidosis metabolik hiperkloremik. Cairan balanced electrolyte solution (BES) yang komposisinya lebih mendekati plasma darah dengan konsentrasi klorida lebih rendah menjadi alternatif cairan resusitasi. Studi ini menilai efek asidosis hiperkloremik pada pasien ketoasidosis diabetikum (KAD) yang diresusitasi dengan menggunakan normal saline dan balanced electrolyte solution (BES).

Metode: Sebuah uji klinis acak tertutup tunggal dilakukan di Instalasi Gawat Darurat (IGD) RSUPN Cipto Mangunkusumo. 30 subjek dengan GDS >250 mg/dl, pH arteri <7,35 mg/dl, dan keton darah positif dirandomisasi menjadi kelompok kontrol (normal saline/NS) dan kelompok perlakuan menggunakan BES. Analisa data dilakukan dengan program SPSS dengan uji T dan uji Mann-Whitney untuk membandingkan rerata nilai aktual dan delta standard base excess (SBE) dan strong ion difference (SID) antara kedua kelompok pasien KAD tersebut. Parameter lain yang dianalisis pada jangka waktu spesifik adalah pemeriksaan kesadaran, gula darah sewaktu, tanda vital, analisa gas darah, laktat, elektrolit, dan keton darah.

Hasil: Rerata SID kelompok BES lebih tinggi secara signifikan daripada kelompok NS (p<0,05) pada setiap jam. Rerata SBE kelompok BES lebih tinggi secara signifikan daripada kelompok NS mulai 18 jam (-4,88±5,69 vs -9,68±5,64; p=0,009), 24 jam (-3,99±4,27 vs -8,7± 5,35; p=0,023), dan 48 jam (-4,06±4,11 vs -7,01±5,46; p=0,009). Selisih nilai BES dan SID tiap pengukuran dengan nilai awal jam 0 (delta BES dan delta SID) lebih tinggi pada kelompok BES, tetapi tidak signifikan.

Kesimpulan: Penelitian ini menunjukkan bahwa balanced electrolyte solution (BES) sebagai cairan alternatif untuk resusitasi pasien KAD dapat mengurangi efek asidosis hiperkloremik dengan rerata aktual dan delta SID dan SBE yang lebih tinggi, tetapi tidak secara signifikan lebih superior dibandingkan dengan normal saline.

ABSTRACT

Background: In resuscitation, normal saline could cause hyperchloremic metabolic acidosis, while balanced electrolyte solution is a crystalloid fluid resembling blood plasma with lower chloride content. This study compared the effect of normal saline and balanced electrolyte solution Ringerfundin (BES) as the resuscitation fluid in diabetic ketoacidosis (DKA) patients. Parameters applied in this study were standard base excess (SBE) as resuscitation’s result indicator and strong ion difference (SID) to measure chloride’s influence in developing hyperchloremic acidosis.

Methods: A prospective, randomized, single blind controlled trial was conducted at the Emergency Department of Cipto Mangunkusumo Hospital. Thirty subjects with blood sugar >250 mg/dl, arterial pH <7.35 mg/dl, and positive blood ketone were randomly allocated to receive either normal saline (NS) or RingerfundinÒ (BES) as the standardized resuscitation protocol. Data analysis was performed using the unpaired T-test and the Mann Whitney test to compare the SBE and the SID means between both groups. Additional parameters were the level of consciousness, blood sugar level, vital signs, blood gas analysis, lactate, electrolyte, and blood ketone.

Results: The mean SID in the BES group was significantly greater than the NS group of all measurements (p<0.05). The BES group had significantly higher mean SBE compared to the NS group at 18 hours (-4.88±5.69 vs -9.68±5.64; p=0.009), 24 hours (-3.99±4.27 vs -8.7±5.35; p=0.023), and 48 hours (-4.06±4.11 vs -7.01±5.46; p=0.009). BES resulted in non-significant higher delta SBE and SID than NS. Additional parameters were not different between both groups.

Conclusion: This study showed that fluid resuscitation of DKA patients with BES resulted in slightly but not significantly higher mean actual SBE and SID than NS. suggesting that BES as an alternative fluid resuscitation to prevent hyperchloremic acidosis in diabetic ketoacidosis patients was not superior to NS.


Aditianingsih, et al.Fluid resuscitation with balanced electrolyte solution in diabetic ketoacidosis

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Diabetic ketoacidosis (DKA) remains as one of the major complications of diabetes mellitus. This condition is associated with significant metabolic changes and a high mortality rate. Diabetic ketoacidosis is defined as an accumulation of ketone bodies in the circulation of patients due to uncontrolled diabetes mellitus with insulin resistance. It was accompanied by severe fluid depletion and electrolyte imbalance, which are associated with metabolic acidosis. Common etiologies of diabetic ketoacidosis include infection, discontinued insulin therapy, and new onset diabetes.1,2 Diabetic ketoacidosis is a life-threatening condition as the mortality rate of DKA is relatively high, which is between 15–51%. The major causes of death include unresolved severe metabolic acidosis, septic shock, and circulatory failure.2

The practice of large volume of fluid administration is found during perioperative condition and fluid resuscitation in DKA. Scheingraber et al3 conducted a research on two groups consisted of 12 subjects undergoing gynecology surgical procedure. The control group received normal saline perioperatively, while the other group received ringer lactate fluid. Both received similar volume of fluid, which was 30 mL/kg/hour. This study showed that the hyperchloremic metabolic acidosis and higher post-operative complications were observed in the normal saline group.3 Based on the American Diabetes Association (ADA), the highest priority of diabetic ketoacidosis management is the replacement of the fluid deficit with isotonic crystalloid solution, such as normal saline. Normal saline is widely used as it contains high chloride concentration, pH of 5.5 incomparable with physiological pH. Moreover, as fluid resuscitation, it is associated with hyperchloremia.1,2 Hyperchloremic acidosis is a form of metabolic acidosis, associated with an increase in plasma chloride concentration. This may occur in aggressive resuscitation with high chloride concentration fluid, or due to impair chloride excretion in the kidneys. Hyperchloremia will worsen the condition of metabolic acidosis, increase inflammatory cytokines, and impair renal function. The balanced electrolyte solution (BES) is known to have electrolyte contents similar to physiological condition, and is suggested to be used during management of diabetic ketoacidosis patients. Mahler et al4 mentioned that patients with diabetic ketoacidosis receiving normal

saline solution had higher chloride concentration in comparison with patients receiving BES.Van Zyl et al5 presented the normalization of pH was non-significantly faster in DKA patients resuscitated with ringer’s lactate instead of normal saline. The pH or chloride level is poor reflections of resolution of DKA. The severity of metabolic acidosis was calculated by the standard base excess (SBE), and the improvement of SBE was associated with better outcome in critically ill patients.6 The strong ion difference (SID) was calculated to show the influence of chloride level on hyperchloremic metabolic acidosis. The aim of this present study was to compare balanced electrolyte solution (BES) Ringerfundin® to normal saline in inducing of hyperchloremic metabolic acidosis in DKA, based on mean SID and SBE as primary endpoints.

METHODS

This was a single blind randomized controlled trial conducted at the Emergency Department of Cipto Mangunkusumo Hospital, Jakarta, Indonesia, on May to October 2013. The protocol of this study has been approved by Medical Ethics Committee of Universitas Indonesia (No. 315/H2.F1/ETIK/2013). The management of diabetic ketoacidosis in this study was in accordance with the guideline from the Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta.

Inclusion criteria were patients with diabetic ketoacidosis aged 18–65 years old, agreed to participate in the study, had blood sugar level during hospital admission >250 mg/dL, had positive ketone bodies in the blood, and had arterial blood pH less than 7.35. Exclusion criteria were subjects with respiratory failure requiring mechanical ventilation, end-stage renal disease on hemodialysis, congestive heart failure, corrected sodium >158 or <120 mg/dL, myocardial infarction with signs of heart failure, traumatic brain injury with cerebral edema signs, and liver failure. The CONSORT flow diagram of this study is shown in Figure 1.

Subjects following inclusion and exclusion criteria were randomly allocated to the groups. The intervention given from the pharmacy for each subject was concealed. Subjects received peripheral


Figure 1. CONSORT flow diagram

and central intravenous access, nasogastric tube, and urinary catheter. Vital signs, blood pressure, heart rate, respiratory rate, level of consciousness, central venous pressure (CVP), diuresis, and hydration status were monitored hourly. Random

blood glucose level was monitored hourly for the first six hours, then 12 hours, 24 hours, 36 hours, and 48 hours. Arterial blood gas analysis, lactate, and electrolyte were measured every two hours for the first six hours, then 12 hours, 24 hours, 36 hours, and 48 hours. Blood ketone was evaluated every six hours for the first 48 hours. Blood urea nitrogen (BUN) and creatinine level were measured every 24 hours for the first 48 hours. Corrected sodium was measured by formula:6

Corrected sodium = measured sodium + (random blood glucose - 100) x 0.016

Subjects received adequate antibiotics if there were signs of infection, oxygen supplementation if pO2<80 mmHg, and heparin if there was disseminated intravascular coagulation (DIC) or severe hyperosmolarity (>380 mOsm/L). Management of the patients included fluid resuscitation, insulin, potassium, and bicarbonate correction, as showed in Figure 2. Subjects were followed up until 28 days to measure the renal functions.

Data collected in this study were baseline characteristics, consciousness level, mean arterial pressure (MAP), CVP, blood glucose level, arterial pH, ketone bodies, BUN, creatinine, mortality rate, and SBE. Corrected sodium, potassium, chloride, calcium, magnesium, were measured to be calculated as the SID by formula:

SID = [Na+] (mEq/L) + [K+] (mEq/L) +[Ca++] (mEq/L) + [Mg++] (mEq/L) - [Cl-] (mEq/L)

SBE and SID between the two groups were compared, while other parameters were reported descriptively.

An intention-to-treat analysis was performed on subjects receiving at least six hours of fluid study. Data was analyzed using the Statistical Program for Social Sciences (SPSS) version 16.0. The data normality was tested using the Saphiro-Wilk test. The unpaired t-test was used for normal distribution data and the Mann Whitney test was used for non-normal distribution data.

. RESULTS

Subjects’ characteristics along with several measured parameters are shown in Table 1. There

Fluids/hour Insulin Potassium Bicarbonate

0

1 2 3 4 5 6

etc.

Continue depends

on the condition

1 Litre IV fluid in ½ h,

continue 500 ml in ½

h 1 L IV fluid 1 L IV fluid 1 L IV fluid 500 IV fluid 500 IV fluid

Following

fluid resuscitation depends

on fluid

On second hour: Boluses 180mU/kgBW continue with insulin infusion 90 mU/kgBW/h If blood glucose <200mg/dl, decrease insulin infusion 45mU/kgBW/h. If blood glucose 200-300mg/dl in 12 hours, continue insulin infusion 1-2 U/h, and sliding scale every six hours. with insulin SC: <200 mg: 5 U 200-250 :10U 250-300:15U >350: 20U

Potassium chloride infusion 50 meq/6 h If potassium level : <3 : 75meq/6h 3-4.5 : 50 meq/6h 4.5-6 : 25 meq/6h >6 : stop

If pH: <7 : 100 meq 7-7.1 : 50 meq >7.1 : stop (Bicarbonate 100mEq HCO3 + KCL 25 mEq) (Bicarbonate 50mEq HCO3 +K 12.5 mEq)

If blood glucose <200, change to Dextrose 5%

After sliding every six hours, change to daily fixed dose

insulin SC

If could take oral intake, change to postassium slow

release PO

Increasing pH will be followed by

decreasing potassium level,

bicarbonate administration

should be accompanied with

potassium administration

Figure 2. Management protocol of diabetic ketoacidosis at Cipto Mangunkusumo Hospital (Adapted from American Diabetes Association. Diabetes Care. 2006;29;2743)1

IV=intravenous; SC=subcutaneus; PO=per orally

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Analysed (n=15) Excluded from analysis (n=0)

Lost to follow-up (n=0) Discontinued intervention (n=0)

Lost to follow-up (give reasons) (n=0) Discontinued intervention (n=0)

Analysed (n=15) Excluded from analysis (n=0)

Analysis

Follow-Up

Received normal saline (NS) (n=15) Did not receive NS (n=0)

Received Balanced Electrolyte Solution (BES) (n=15) Did not receive BES (n=0)

Allocation

Assessed for eligibility (n=30)

Excluded (n=0)

Randomized (n=30)

Enrollment


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were significant differences of mean SBE (Figure 3) and mean SID (Figure 4) between both groups were observed. The BES group had significantly higher SBE compared to the NS group at 24 hours (-3.99±4.27 vs -8.7±5.35; p=0.023), and at 48 hours (-4.06±4.11 vs -7.01±5.46; p=0.009), while mean SID in the BES group was significantly greater than the NS group at all measurements (p<0.05).

NS group(n=15)

BES group (n=15)

SexMale 5 (33.33%) 6 (40%)Female 10 (66.67%) 9 (60%)

DM type 1 2 (13.33%) 1 (6.67%)DM type 2 12 (80%) 13 (86.66%)Other type 1 (6.67%) 1 (6.67%)DKA etiology

Infection 11 (73.33%) 9 (60%)New onset DM 1 (6.67%) 1 (6.67%)Discontinued therapy

1 (6.67%) 2 (13.33%)

Others 2 (13.33%) 3 (20%)Age (years)* 56 (25, 65) 57 (23, 65)Mean arterial pressure (mmHg)*

83.3 (70,100) 80 (45, 107)

Central vein pressure (mmHg)*

8.73 (3, 12) 9.17 (4, 12)

Random blood glucose (g/dL)*

508 (271, 842) 467 (325, 1043)

Keton bodies (mmol/L)* 3.1 (0.7, 6.8) 3.8 (0.7, 5.7)

pH* 7.34 (7.23, 7.39) 7.31 (7.02, 7.44)Lactate (mmol/L)* 2.2 (1.1, 20) 1.95 (1.2, 14.6)Albumin (mg/dL)* 2.97 (2.15, 4.47) 2.87 (1.77, 4.96)SGOT (g/dL)* 24.5 (06, 325) 23 (11, 124)BUN (mg/dL)* 25.4 (15.7, 163) 54.8 (20.8, 270)Creatinine (mg/dL)* 0.75 (0.55, 1.72) 1.1 (0.5, 4.1)

SGPT (g/dl)* 17.5 (6, 44) 22 (10, 225)Total fluid resuscitation (liter)*

6.23 (4.3, 8.2) 6.23 (4.1, 8.4)

Table 1. Subjects’ characteristics of both groups during in-terventions

NS= normal saline group; BES= balanced electrolyte solu-tion group; DKA= diabetic ketoacidosis; SGOT= serum glu-tamic oxaloacetic transaminase; BUN= blood urea nitrogen; SGPT=serum glutamic-pyruvic transaminase. Categorical data was presented in frequencies (percentage). * Numerical data was presented in median (min, max), test-ed by Mann-Whitney-U test

Figure 3. Mean actual values of SBE of the NS group and the BES group. Data was presented in mean±SD, tested by un-paired t-test, *p<0.05 was significant. SBE= standard base excess; NS= normal saline group; BES= balanced electrolyte solution group; SD= standard deviation

Figure 4. Mean actual values of SID of the NS group and the BES group. Data was presented in mean±SD, tested by un-paired t-test, *p<0.05 was significant. SBE=standard base excess; NS=normal saline group; BES=balanced electrolyte solution group; SD=standard deviation

Since the baseline of SID was significantly higher in the BES group, the mean increase (delta) between the actual values SID and SBE at the every timepoints measurement to baseline values at hour 0 was calculated. The delta value of SID and SBE (Table 2) were not significantly higher in the BES group at all measurements.

Of 30 subjects, 25 subjects survived up to 28 days after admission, four subjects (two subjects in each group) died within 28 days, and one subject died within 48 hours. Furthermore, one subject suffered from cardiopulmonary arrest and had a return of spontaneous circulation within the first 48 hours. There was no difference of mortality between groups, and the benefit of BES over mortality was not analyzed because of the study design and small number of samples.


DISCUSSION

Stewart et al7 mentioned that two variables influencing acid-base balance can be grouped into independent and dependent variables. The independent variables were carbon dioxide pressure (pCO2), SID, and non-volatile weak acid (albumin effect). The dependent variables were [H+], [OH-], [HA], [A-], [HCO3

-], and [CO32-]

ions. Therefore, pH, as the negative logarithm of hydrogen ion [H+], was a function of three variables, which were pCO2, SID, albumin effect. SID or sodium-chloride effect was described as the difference between total strong cation (sodium, potassium, magnesium, calcium) and total strong anion (chloride). Potassium, magnesium, and calcium were usually neglected due to its small value.7 The cause of acid-base disturbance could be measured quantitatively by using the Stewart-Fencl formula. This formula utilized SBE, SID effect, albumin effect, and unmeasured anion effect. The first step was to identify the SBE based on blood gas analysis, followed by determining the sodium-chloride or SID effect. Albumin acts as a weak acid; therefore, the level of albumin effect might cause acid-base imbalance. The unmeasured anion (UA) effect is the concentration of lactate, ketone, phosphate and other unidentified ions. It can be derived as the difference of SBE with SID and the albumin effect.6

Metabolic acidosis was characterized by the decreasing pH and bicarbonate level, which was caused by decreased SID or increased weak

acids concentration. Mean SID in the BES group had more superior values significantly than in the NS group at every hour. Mean hourly SBE in the BES group were mostly higher than in the NS group, and the significant difference occurred at 18, 24, and 48 hours (illustrated in Figure 3 and Figure 4).

In terms of fluid management for diabetic ketoacidosis, the effect of large fluid resuscitation administered for the patients would influence the SID calculation. Normal saline administered for the patients had SID=0 because of the same numbers of strong positive and negative ions. The result of fluid resuscitation with SID=0 was that the physiological ions would suffer from volume dilution as well as the addition of sodium and chloride ions at the same time. For example, in the plasma, there was 140 mEq/L sodium ions, 100 mEg/L chloride ions; therefore, the SID plasma = 140 mEq/L – 100 mEq/L = 40 mEq/L. If 1 L of normal saline given to the patient with 3 L blood volume, then there would be a dilution with (140x3 mEq/L+154 mEq/L)/(3+1) = 143 mEq/L sodium ions, and (100x3 mEq/L + 154 mEq/L)/(3+1) = 113.5 mEq/L. Therefore, the present SID was 143 mEq/L – 113.5mEq/L = 29.5 mEq/L, while the normal SID was 38-44 mEq/L.8,9 Decreased SID causes the plasma to be acidotic; defined as a dilutional metabolic acidosis due to normal saline or hyperchloremic metabolic acidosis. Even though SBE showed a significant difference only at 18 hours, 24 hours, and 48 hours, the mean SBE among the BES group was always higher than the NS group.

Delta values* of standard base excess Delta values* of strong ion differenceNS Group

(n=15)BES Group

(n=15)p

NS Group(n=15)

BES Group(n=15)

p

2-hour -0.1 (-2.5, 3.7) 4.6 (-22.3, 11.3) 0.33 -2.05 (-12.3, 2.3) -0.87 (-12.5, 12.6) 0.184-hour 4.1 (-0.2, 6.6) 7 (-24.3, 11.2) 0.373 -3.35 (-15.4, 1.1) -2.15 (-11.5, 4.38) 0.4886-hour 4.1 (-0.1, 7) 8 (-21.8, 8.8) 0.118 -1.75 (-15.4 , 0.6) -2.5 (-12.6, -0.3) 0.81712-hour 5.5 (1.7, 10.7) 7.4 (-22.8, 12.7) 0.404 -2.3 (-14.5, 2.4) -0.97 (-13, 4.6) 0.69518-hour 4.8 (-1.3, 11.7) 10.5 (-20.9, 21) 0.337 -2.05 (-13.6, 6.3) 0.81 (-11.5, 4.5) 0.17924-hour 5.8 (-0.8, 11.3) 11.3 (-21.6,20.4) 0.564 -5.1 (-15.0, 3.0) -1 (-10.9, 4.4) 0.40136-hour 7.3 (1.7, 12.8) 9.9 (-20.7, 20.4) 0.073 -1.9 (-40.9, 6.9) -1.2 (-10.4, 5.2) 0.12248-hour 6.9 (2.4, 12.1) 12.1 (-22.4, 22.5) 0.492 -2.45 (-40.9, 6.6) -0.43 (-9.19, 6.6) 0.806

Table 2. Delta values of standard base excess and strong ion difference

NS= normal saline group; BES= balanced electrolyte solution group, *Delta value was the difference between the values at specific time-points compared baseline values at 0-hour. Data was presented in median (min, max), tested using the Mann-Whitney-U test, p<0.05 was significant

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Two types of metabolic acidosis are mineral (anorganic) and organic metabolic acidosis. Anorganic metabolic acidosis was caused by increased anions which could not be metabolized (e.g. hyperchloremic acidosis); while organic metabolic acidosis was caused by metabolism disorder (e.g. lactic acidosis, diabetic ketoacidosis). Each type of metabolic acidosis had different consequences and managements. Mineral acidosis managements included rapid elimination from the body (by diuretic or renal replacement therapy), or alkalinization (e.g. bicarbonate administration). For example, in hyperchloremic acidosis, inorganic acid has to be disposed through the kidney.10 SID can be influenced by renal excretion and electrolyte contents inside the body; therefore, subjects requiring hemodialysis were excluded. Creatinine and BUN level was highly varied between two groups, but they did not differ significantly. It showed that renal function and its direct influences in metabolic acidosis were comparable in this study.5,11 Albumin is an non-volatile weak acid, controlled by the liver and dominated by the albumin. Thus, subjects with liver failure were excluded. Since both groups showed no significant difference of liver function test, which was also proven by similar albumin concentrations within a normal range, albumin level was not considered to affect the acidosis. There was no difference in the severity of liver and kidney dysfunction that could impact SID between both groups.

As mentioned earlier, there was pCO2, albumin effect, and UA effect, in which each of them contributes to the SBE value. pCO2 was influenced by ventilation, but subjects requiring mechanical ventilation were excluded in this study. If albumin effect and UA effect were neglected, SBE value in the BES group would have more superior result than the NS group. This could be attributed to SID in the BES group was significantly higher than in the NS group. Nevertheless, even though SID in the BES group was significantly higher at all time points, this study found that SBE in the BES group was only significantly higher at 18, 24, and 48 hours than in the NS group. This might be due to the higher unmeasured anion factor in the BES group than in the NS group. Unmeasured anion as the one resulted from cell metabolisms, for instance lactate, ketone bodies, and phosphate, or

anions acquired from the environment, such as salicylate and methanol. In the BES group, there was one subject with creatinine level ≥4 mg/dL, one subject with creatinine level 3–4 mL/dL, and three subjects with creatinine level 2–3 mg/dL. Meanwhile, in the NS group there were four subjects with creatinine level 2–3 mg/dL. Therefore, subjects in the BES group were suspected to have signs of renal insufficiency. The result of this renal insufficiency was deposition of unmeasured anions, such as sulfate and phosphate, which created masking effect of SID to SBE. The other cause of insignificant SBE difference in the earlier hours was the degree of sepsis severity between two groups, which were not standardized in this study. Septic mediators as the primary cause of DKA also played a role in contributing unmeasured anions such as lactate to acidosis condition.11 This explained the non-significant mean pH difference between the two groups in our study. The pH is a weak endpoint of diabetic ketoacidosis resolution since it was influenced by respiratory alkalosis due to hyperventilation in sepsis condition, loss chloride due to vomiting or large gastric residual volume that common in diabetic gastroparesis.5

Both groups had nearly similar characteristics. Mean MAP between the two groups was relatively adequate (>65 mmHg) with no significant difference, except mean MAP at 24 hours. No significant difference between the two types of fluid resuscitation was observed due to the isotonic crystalloid solution of both fluids. Additionally, there was no total volume difference between two groups. There was no significant mean CVP difference between the two groups, except at six hours. This occurred due to similar characteristics between two types of solution, which were isotonic to plasma and similar total volume given to the subjects.4,8 The distribution of lactate level was varied although there was no significant difference between both groups. This might be attributable to the two types of solution; normal saline and BES, did not contain any lactate. Lactate and ketone bodies were monitored in this study. There was no significant differences of both anions in both groups. Lactate in both groups had wide variability: 1.1–20 mmol/L to 0.9–2 mmol/L in the NS group, and 1.2–14.6 mmol/L to 0.8–6.9 mmol/L towards the end in the BES


group. These wide variabilities were due to tissue hypoperfusion, causing ineffective cell metabolism.9,11

There was no significant mean random blood glucose (RBG) and mean ketone bodies difference between both groups at every hour during interventions. Five subjects had recurring diabetic ketoacidosis after 48 hours (two subjects in each group died within 28 days and one subject died within 48 hours), caused by the discontinued insulin therapy (78%) as the most cause of DKA in this study, other than infection, and non-infection medical illness.12,13 All of them received sodium bicarbonate due to pH less than 7.1 following diabetic ketoacidosis protocol in this study and died within 28 days. One subject suffered from cardiopulmonary arrest following sodium bicarbonate administration. This should be handled carefully because increased pH would shift the dissociation curve to the left, diminishing tissue oxygen delivery. Fluid overload (intrvascular volume expansion) due to hypernatremia, which might also cause mortality.10,13

A limitation of this study is the baseline of SID in the BES group is higher than in the NS group; therefore, the superiority of BES could not be concluded based on significant mean actual SID and SBE, delta SID and BES. Other limitations are the small number of subjects and a single institution. BES could be utilized as an alternative fluid resuscitation, but it should be reviewed further in a larger population and other hospitals or institutions with different protocol.

In conclusion, fluid resuscitation of DKA patients with BES results in a significantly higher SBE and SID means as compared to NS. However, the higher delta SBE and SID were not significant, suggested that BES as an alternative fluid was not superior to NS in preventing hyperchloremic acidosis in diabetic ketoacidosis patients.


REFERENCES

1. Kitabchi AE, Umpirezz GE, Miles JM, Fisher JN. Hyperglycemic crisis in adult patients with diabetes. Diabetes Care. 2009;32(7):1335–43.

2. Diabetes.org.uk [Internet]. Joint british diabetes societies inpatient care group. The management of diabetic ketoacidosis in adult [update: 2013 Sep; cited 2014 Nov]. Available from: http://www.diabetes.org.uk/Documents/Adults/Guidelines.htm).

3. Scheingraber S, Rehm M, Sehmisch C, Finsterer U. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologyc surgery. Anesthesiology. 1999;90(5):1265–70.

4. Mahler SA, Conrad SA, Wang H, Arnold TC. Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patient with diabetic ketoacidosis. Am J Emerg Med. 2011;29(6):670–4.

5. Van Zyl DG, Rheeder P, Delport E. Fluid management in diabetic-acidosis--Ringer’s lactate versus normal saline: A randomized controlled trial. QJM. 2012;105(4):337–43.

6. Park M, Noritomi DT, Maciel AT, de Azevedo LC, Pizzo VR, da Cruz-Neto LM. Partitioning evolutive standard base excess determinants in septic shock patients. Rev Bras Ter Intensiva. 2007;19(4):437–43s.

7. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol. 1983;61(12):1444–61.

8. Bellomo R, Naka T, Baldwin I. Intravenous fluids and acid base balance. Contrib Nephrol. 2004;144:105–18.

9. Badr A, Nightingale P. An alternative approach to acid base abnormalities in critically ill patients. Contin Educ Anaesth Crit Care . 2007:7(4):107–11.

10. Kellum JA. Determinants of blood pH in health and disease. Crit Care. 2000;4(1):6–14.

11. Levraut J, Grimaud D. Treatment of metabolic acidosis. Curr Opin Crit Care. 2003;9:260–5

12. Randall L, Begovic J, Hudson M, Smiley D, Peng L, Pitre N, et al. Recurrent diabetic ketoacidosis in inner-city minority patients: behavioral, socioeconomic, and psychosocial factors. Diabetes Care. 2011;34(9):1981–96.

13. Price DA. Case study: recurrent diabetic ketoacidosis resulting from spurious hypoglycemia: a deleterious consequence of inadequate detection of partial strip filling by a glucose monitoring system. Clinical Diabetes. 2009;27(4):164–6.


http://www.diabetes.org.uk/Documents/Adults/Guidelines.htm

http://www.diabetes.org.uk/Documents/Adults/Guidelines.htm

Widyahening, et al.Primary care physician’s education

141

Does the establishment of universal health coverage drive the foundation of postgraduate education for primary care physicians?

Keywords: family medicine, general practice, primary care physician, universal health coverage, postgraduate training

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.1857 • Med J Indones. 2017;26:141–51• Received 09 Feb 2017 • Accepted 31 May 2017

Corresponding author: Indah S. Widyahening, [email protected]


Indah S. Widyahening,1 Rodri Tanoto,1 Fedri Rinawan,2 Elsa P. Setiawati,2 Zorayda E. Leopando3

1 Department of Community Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia2 Department of Public Health, Faculty of Medicine Universitas Padjajaran, Bandung, Indonesia3 Department of Family and Community Medicine, University of the Philippines, Manila, Philippines

Systematic Review


ABSTRAK

Latar belakang: Pengembangan program pendidikan pasca sarjana bagi dokter di layanan primer di negara yang telah mencapai Jaminan Kesehatan Semesta (JKS) sangat penting dipelajari dalam mendukung negara berkembang yang sedang menuju pencapaian JKS tahun 2030. Review ini bertujuan mendapatkan gambaran pendidikan pasca sarjana bagi dokter di layanan primer di negara-negara yang telah mencapai JKS.

Metode: Sebuah review terhadap literatur yang dipublikasi dan dokumen resmi yang diperoleh dari laman berbagai organisasi kesehatan dan perkumpulan dokter di layanan primer regional maupun global seperti World Health Organization (WHO), World Organization of Family Doctors (WONCA), European Forum for Primary Care, European Union of General Practitioners (GP)/Family Physicians (FP), European Academy of Teachers in GP/Family Medicine (FM), serta laman organisasi dokter praktik umum/keluarga di berbagai negara. Daftar negara yang telah mencapai JKS diidentifikasi melalui basis data WHO dan International Labor Organization.

Hasil: Sejumlah 72 negara yang telah mencapai JKS berhasil diidentifikasi. Pendidikan pasca sarjana bagi dokter di layanan primer ditemukan di 62 (86%) negara. Pernyataan bahwa pengembangan pendidikan terkait dengan kebijakan JKS ditemukan pada 11 (18%) negara. Terdapat berbagai nama program, yang tersering “general practice” dan “family medicine”. Di 33 negara (53%), pendidikan wajib diikuti oleh mereka yang ingin berpraktik di layanan primer. Lama pendidikan berkisar antara 2–6 tahun, dengan jumlah terbanyak tiga tahun.

Kesimpulan: JKS bukanlah alasan utama pengembangan pendidikan pasca sarjana bagi dokter di layanan primer. Akan tetapi, hampir semua negara yang telah mencapai JKS berupaya serius mengembangkan pendidikan tersebut sebagai bagian dari reformasi kesehatan dalam meningkatkan derajat kesehatan nasional.

ABSTRACT

Background: Studying the formation of postgraduate training in primary care within countries which has attained Universal Health Coverage (UHC) is important to support the development of similar training in low-and middle-income countries aiming to achieve UHC by 2030. This review aims to describe the state of postgraduate training for primary care physicians in UHC-attaining countries.

Methods: A literature review of published literature and official documents from the websites of regional and global health/primary care organizations or societies such as World Health Organization (WHO), World Organization of Family Doctors (WONCA), European Forum for Primary Care, European Union of General Practitioners (GP)/Family Physicians (FP), European Academy of Teachers in GP/Family Medicine (FM), as well as the websites of GP/FP organizations in each of the respective countries. The list of UHC attained countries were identified through WHO and International Labor Organization databases.

Results: A total number of 72 UHC-attained countries were identified. Postgraduate education for primary care physicians exists in 62 countries (86%). Explicit statements that establish primary care postgraduate training were corresponded with the policy on UHC is found in 11 countries (18%). The naming of the program varies, general practice and family medicine were the commonest. In 33 countries (53%), physicians are required to undertake training to practice in primary level. The program duration ranged from 2–6 years with 3 years for the majority.

Conclusion: Although UHC is not the principal driving force for the establishment of postgraduate training for primary care physicians in many countries, most UHC-attaining countries make substantial endeavor to ensure its formation as a part of their health care reform to improve national health.



Since the 1978 Alma Ata declaration of “Health for All” by countries attending the International Conference on Primary Health Care jointly organized by the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF), most nations acknowledged that health provision is a fundamental human right and that primary health care is the key to ensure the fulfillment of adequate health.1 However, although people are generally healthier, wealthier and live longer today than 39 years ago, health inequity persisted in many countries. The failure to achieve “health for all” has propelled a campaign for Primary Health Care Reforms which comprised universal health coverage (UHC) reforms, service delivery reforms, public policy reforms, and leadership reforms.2

In September 2015, the United Nations General Assembly launched the Sustainable Development Goals (SDGs) which included the third goal “to ensure healthy lives and promote well-being for all at all ages” that should be achieved in 2030.3 It is believed that development of systems capable of delivering health rely on the existence of health financing mechanisms that offer universal access to health. One of the targets to accomplish the goal is “the attainment of universal health coverage which includes financial risk protection, access to quality essential health-care services and access to safe, effective, quality and affordable essential medicines and vaccines for all”.4

According to WHO, universal coverage is defined as “access to key promotive, preventive, curative, and rehabilitative health interventions for all at an affordable cost, thereby achieving equity in access.” The principle of financial-risk protection ensures that the cost of care does not put people at risk of financial catastrophe. A related objective of health-financing policy is equity in financing: households contribute to the cost of health care on the basis of ability to pay.5

Reform in service delivery in order to support the affordable cost and equity in access incorporates the availability of health care providers competent in delivering a person-centered, continuing, comprehensive and integrated health service; it is responsible for a defined population and able to coordinate support from hospitals, specialized services and civil society organizations.2 Therefore, the establishment of special training

program for primary care physicians (general practitioner or family physician) is considered integral to primary health care (PHC) reforms in some countries.6

Even though this discipline is well established and mainstreamed in most developed nations, it is still relatively new in low and middle-income countries. Studying the formation of postgraduate training in primary care within countries which have attained UHC is important to support the development of such education in low-and middle-income countries aiming to achieve UHC by 2030. In this review, we aim to describe the existence of the postgraduate training for primary care physicians in countries which have attained UHC.

METHODS

This study is a review of academic literature and official documents, both nationally and internationally. Review also includes secondary data collection from publicly available data and reports by major international organizations such as International Labor Organization (ILO) and WHO.

Identification of countries which have attained universal health coverageA report by Stuckler et al5 identified 58 countries which have achieved UHC based on the following criteria.1 Healthcare legislation explicitly states that the entire population is covered under a specific health plan, including availability of package of services with identifiable year (and such legislative articles can be identified online);2 More than 90% of the residents of those country must have access to skilled attendance at birth and health care insurance (i.e. social health insurance, state coverage, private health insurance, and employer-based insurance), which serve as broader proxy indicators for access to care, using the latest data available and based on the ILO threshold.

To identify additional countries which meet the Stuckler criteria of attaining UHC, the list is updated using the ILO databases on social health protection coverage,7 supplemented with the data about access to skilled attendance at birth from the WHO Global Health Observatory data

http://mji.ui.ac.id


143

repository.8 Fourteen countries were added, thereby increasing to 72 countries included in this report.

The literature review methodsTo identify the existence of postgraduate training for primary care physicians in the 72 UHC-attaining countries, online literature search was conducted using medical databases such as Medline and Google Scholar in February 2017. The keywords “postgraduate training” AND (“primary care” OR “general practice” OR “family medicine”) both as medical subject headings (MeSH) terms and free-texts, were utilized to identify reviews, surveys and country specific reports with regards to the establishment of postgraduate training on primary care/general practice/family medicine in those countries. A hand search was also conducted on the websites of regional and global health/primary care organizations or societies such as WHO, WONCA, European Forum for Primary Care, European Union of GP/FP, European Academy of Teachers in GP/FM, etc, as well as on the websites of GP/FP organizations in each respective country.

To explore the connection between establishment of primary care physician postgraduate

Andorra* Costa Rica Kuwait Rwanda‡Antigua* Croatia Kyrgyzstan§ SingaporeArgentina Cuba§ Lithuania SlovakiaArmenia§ Cyprus Luxembourg Slovenia§Australia Czech Republic Malaysia South AfricaAustria Denmark Malta South KoreaAzerbaijan† Estonia§ Mauritius* Spain§Bahrain Fiji† Moldova§ Sri LankaBelarus‡ Finland Mongolia‡ SwedenBelgium France Netherlands SwitzerlandBosnia Herzegovina Germany New Zealand TaiwanBotswana Greece Norway Thailand§Brazil Hungary Oman Tunisia‡Brunei Darussalam Iceland Panama United Arab Emirates (UAE)Bulgaria Ireland Poland Ukraine§Canada Israel Portugal§ United KingdomChile Italy Qatar Uzbekistan‡China Japan Rumania§ Venezuela

Table 1. Availability of primary care physician post-graduate education in the countries which attained universal health coverage

Bold= Primary care physicians post-graduate education are available; *= no information on the availability of post-graduate education for primary care physicians; †= post-graduate education is in-development; ‡= no post-graduate education; §= the establishment of post-graduate education corresponds to the policy on UHC

education with UHC, another literature search was conducted using the terms “universal health coverage” OR “universal coverage” AND the name of each of the countries in the list. We concluded the relationship between the establishment of primary care specialist in one country and UHC policy if we found any statement specifying that primary care physician postgraduate education was started or endorsed as part of the UHC implementation policy in the respective countries.

RESULTS

Postgraduate education for primary care physicians exists in 62 of 72 countries (86%) which attained UHC as shown in Table 1 although in Austria and Brunei Darussalam it is not recognized as specialist degree. The existence of the education could not be determined in Andorra, Antigua, and Mauritius. Only in 11 of 62 countries (18%) showed explicit statement that the establishment of primary care postgraduate education corresponded with the policy on UHC. Statements that education is established or reinforced as part of health care reforms through primary health care movement was



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Yes

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No

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Yes

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Yes

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Taiw

an14

2–14

5Fa

mily

Med

icin

e19

79Ye

sPG

Y13

Yes

Yes

Stro

ngTh

aila

nd14

6–14

9Fa

mily

Med

icin

e19

98N

oPG

Y13

Yes

Yes

Wea

kUn

ited

Arab

Em

irat

es (U

AE)28

, 99,

150

Fam

ily M

edic

ine

1994

-PG

Y13

Yes

-St

rong

Ukra

ine15

1–15

3Fa

mily

Med

icin

e19

92N

oPG

Y12

Yes

Yes

Stro

ngUn

ited

King

dom

19, 1

54–1

56Ge

nera

l Pra

ctic

e19

77Ye

sPG

Y33

Yes

Yes

Wea

kVe

nezu

ela16

, 157

–159

Fam

ily M

edic

ine

and

Gene

ral C

ompr

ehen

sive

M

edic

ine

1980

(FM

)20

06 (G

CM)

No

PGY3

3Ye

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sSt

rong

Tabl

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Cha

ract

eris

tics o

f the

pri

mar

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re p

hysi

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pos

t-gr

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found in several countries such as Brazil, China and South Africa. Other statement found was the recognition of the need for professional development of generalist physicians as a distinct medical discipline with its own training which can be identified in pioneering countries for the development of general practice/family medicine, such Canada, United Kingdom, Australia, and the Netherlands. Becoming members of regional organization requiring countries to adhere to standard in health care including training of primary care physicians was also influential in the establishment of training on primary care physicians as observed in the east of Europe and Arab gulf countries.

Table 2 displayed the features of the primary care physician postgraduate education in the 62 countries. The name of the program varies; general practice and family medicine were mostly described. In Argentina, Norway, and Venezuela, two postgraduate programs with different name exists. In Czech Republic, there are two separate groups of GPs, who never work in combined practices: GPs for adults and practitioners for children and adolescents, each with their own training program. The mandatory status of the program for those who wants to practice in primary health care could be ascertained in 33 of 62 (53%) countries. The duration of the program ranges from 2–6 years, in which three years is the most common.

DISCUSSION

Postgraduate education for primary care physicians exists in 86% countries which attained UHC. The link between the establishments of postgraduate education and the UHC implementation policy is explicitly stated in only 18% of the countries.

In many industrialized countries like Canada, United Kingdom, Australia, or the Netherlands, the postgraduate education for primary care physicians have been established since the 1960s or 1970s. It was fostered as a response to the declining general practice due to the rapid development of medical specialization in the first half of the twentieth century. The age of specialization resulted in the fragmentation of medical care which led to deterioration of doctor-patient relationship. A new kind of generalist

with special training and qualifications armed with a defined set of skills is needed.9 The Alma-Ata declaration in 1978 which emphasized the importance of PHC to achieve “Health for All”1 further expanded the development of special training of primary care physicians in the wider part of the world since successful PHC systems usually involve a primary care doctor with postgraduate training in family medicine or general practice.2

Evidences from various studies on the effectiveness of strong PHC showed that with PHC specialist physicians holding the central role, there is an improvement of various health outcomes and with better use of health cost. A systematic review by Engström et al10 reported that an increase in the number of, or ratio of primary health care specialist physicians compared to total number of doctors, was significantly associated with lower mortality rates, neonatal death rate, rate of low birth weight; increased life expectancy and decreased total mortality and stroke. The same review also revealed that higher proportions of primary care physicians were associated with lower payments for both in-hospital and out-of-hospital care while a greater supply of family doctors was significantly associated with lower reimbursements for outpatient care.

The reason why in some countries in this study, the establishment of postgraduate training for primary care physicians is linked to the effort in attaining the UHC could be found in a review by Kruk et al11 This review described how primary care strengthening contributed to increased access to services as well as equity in access and outcomes. Primary care emerged as foundation for health systems strengthening in the developing world, by improving cost efficiency and responsiveness. Similar observation has also been emphasized by Barbara Starfield.12

Our study is the first attempt to find link between the establishment of training for primary care physicians with universal health coverage. However, we acknowledged limitations of our study. The main source of limitation is that it relied heavily on the published literature which in some countries are very limited and outdated. Our decision to only including literature in English also limited information from the non-English speaking countries.

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In conclusion, although UHC is not the principal driver of the establishment of postgraduate primary care physician education in many countries, most UHC-attaining countries made substantial endeavor to ensure the formation of those trainings as part of their health care reform to improve the national health.


AcknowledgmentThe authors appreciate the valuable inputs from Hadyana Sukandar and Dwi Agustian during the literature review process and the development of report.

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Targeting pro-protein convertase subtilisin kexin-9 as a novel therapy of hypercholesterolemia

Keywords: low density lipoprotein, PCSK-9 inhibitor, pro-protein convertase subtilisin kexin-9

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.1443 • Med J Indones. 2017;26:152–7• Received 08 May 2016 • Accepted 09 Jun 2017

Corresponding author: Anwar Santoso, [email protected]


Bambang Dwiputra,1 Anwar Santoso,1 Kian K. Poh2

1 Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Indonesia - National Cardiovascular Center Harapan Kita, Jakarta, Indonesia

2 Department of Cardiology, National University Heart Centre, Singapore

Review Article


ABSTRAK

Menurunkan kadar kolesterol low density lipoprotein (LDL) merupakan salah satu bagian dari prevensi primer dan sekunder pada pasien dengan penyakit jantung koroner. Meskipun demikian, tidak semua pasien berhasil mencapai target LDL mereka sesuai yang dianjurkan oleh guideline. Selama 10 tahun terakhir, kadar LDL yang tinggi dalam plasma diketahui berhubungan dengan peningkatan kadar pro-protein convertase subtilisin kexin 9 (PCSK-9). Mutasi fungsional gen PCSK-9 yang menghilangkan fungsi-nya akan menyebabkan penurunan kadar PCSK-9 plasma dan berhubungan dengan kadar LDL yang rendah serta penurunan risiko kardiovaskular. Penemuan PCSK-9 telah memicu peneliti untuk menciptakan obat peghambat PCSK-9 untuk menurunkan kolesterol LDL. Beberapa uji klinis tahap III menunjukkan hasil yang menjanjikan terkait efikasi penghambat PCSK-9 untuk menurunkan kadar LDL. Tulisan ini akan mendiskusikan peran PCSK-9 dalam metabolisme LDL dan efikasi penghambat PCSK-9 untuk menurunkan kadar LDL plasma.

ABSTRACT

Reducing low density lipoprotein (LDL) cholesterol level is an established primary and secondary prevention strategy for coronary heart disease. However, not all patients are able to achieve their LDL targets as recommended by the guidelines. Over the last 10 years, high plasma LDL level is known to be associated with a higher level of pro-protein convertase subtilisin kexin-9 (PCSK-9). Loss-of-function mutations in the PCSK-9 gene is associated with lower plasma LDL level and cardiovascular risk. Since its discovery in 2003, PCSK-9 has triggered many researchers to design a PCSK-9 inhibitor to reduce LDL cholesterol through competitive inhibition of this molecule. Some phase III clinical trials have showed promising results of PCSK-9 inhibitor efficacy in lowering LDL level and improving clinical outcome. This article aims to discuss the role of PCSK-9 in LDL metabolism and the efficacy of PCSK-9 inhibitor in reducing plasma LDL level.


Dwiputra, et al.PCSK-9 as target of dyslipidemia therapy

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Hypercholesterolemia is an established risk factor for cardiovascular diseases that increase the incidence of myocardial infarction and death. Reducing plasma low density lipoprotein (LDL) levels by administering statin therapy has already been proven to reduce morbidity and mortality of cardiovascular disease. The return on expenditure achieved for lipid therapy in Asia (REALITY-Asia) study1 demonstrated that only 38% of patients with coronary heart disease managed to reach their LDL targets (at that time, of less than 100 mg/dL). In addition, of the approximately 20 million patients receiving statin therapy, 10–20% of them can not tolerate the drug, mainly due to musculoskeletal side effects.

A landmark study by Cohen et al2 found that the concentration of plasma LDL was determined by pro-protein convertase subtilisin kexin-9 (PCSK-9). The PCSK-9 is an enzyme produced by the liver, kidney mesenchymal cells, small intestine, and colon epithelial cells. This protein regulates cholesterol homeostasis by binding epidermal growth factor-like repeat A domain of the LDL receptor and leading to a lysosomal degradation. It is demonstrated that a loss-of-function mutation in PCSK-9 gene leads to a lower PCSK-9 plasma level and thus associated with low LDL levels and cardiovascular risk reduction. First discovered in 2003, translational researchs aimed to make PCSK-9 a target for LDL cholesterol reduction. Several phase-III clinical trials on monoclonal antibodies of PCSK-9 have demonstrated promising results in lowering LDL cholesterol levels.

Structure and regulation of PCSK-9 Pro-protein convertase subtilisin kexin-9 is a member of subtilysin-like serine protease family consisting of 9 members. The first eight members (proprotein convertase -1 (PC1), PC2, furin, PC4, PC5, paired basic amino acid cleaving enzyme-4 (PACE-4), PC7, and subtilysin kexin isozyme-1) break down protein precursors of growth factors, hormones, receptors, and transmembrane transcription factors prior to secretory pathway.3 Instead, PCSK-9 increases endosomal and lysosomal degradation of cell surface receptors that regulate lipid metabolism. PCSK-9 is a glycoprotein composed of 692 amino acids with a molecular weight of 73 kDa. Its structure consists of four domains (prodomain, catalytic domain, cysteine terminal and histidine C-rich terminal) (Figure 1).4

PCSK-9 is synthesized as a zymogen that undergo an autocatalytic breakdown process in the endoplasmic reticulum (FAQ152SIPK site).3 This process is needed for maturation and secretion of protein after emerging from the endoplasmic reticulum. In the extracellular pathway, the PCSK-9 secreted from the transgolgi network, internalize the cell-surface LDL receptors in clathrin-coated endosomes to further degrade them. This process requires cytosolic adaptor binding protein called autosomal recessive hypercholesterolemia (ARH) protein. In the intracellular pathway, PCSK-9 are exposed directly to the lysosome along with LDL receptors and they become degraded simultaneously.5 The catalytic subunit of PCSK-9 binds to epidermal growth factor (EGF-A) on the human LDL receptor.

Low intracellular cholesterol levels will induce the sterol regulatory element binding protein-2 (SREBP-2) to increase expression of the LDL receptor gene. This increases circulating LDL cholesterol uptake. Meanwhile, SREBP-2 can also induce the expression of PCSK-9 that leads to LDL receptor degradation and thus limits the cholesterol uptake in the liver. This process will prevent excessive cholesterol uptake in order to maintain cholesterol homeostasis.

PCSK-9 and LDL cholesterolThe LDL cholesterol plays a central role in foam cell formation and initiates the process of atherosclerosis. In normal metabolic processes, circulating LDLs undergo hepatic clearance through LDL receptors in hepatocyte cell surface. The mutation of LDL receptor found in familial hypercholesterolemia cases will increase premature cardiovascular events. This increased expression is regulated in transcription level through SREBP-2 and through PCSK-9 and the

Figure 1. PCSK-9 structure. LDL-C: low density lipoprotein cholesterol. SP: signal peptide. Reprinted with permission from Schulz et al.4


inducible degrader of LDL receptor (IDOL) after translation.3 PCSK-9 bound to the LDL receptor will thus initiate lysosomal degradation of the LDL receptor meanwhile IDOL will reduce it through lysosomal and poliubiquitination pathway.

Initially, the documentation of the relationships between LDL, LDL receptors, and PCSK-9 level were observed in animal studies. Lagace et al6 found that the injection of pure PCSK-9 resulted in a significant reduction in the LDL receptors on the surface of rat hepatocytes. Mice with high PCSK-9 activity appeared to have a lower number of LDL receptors. Both of these findings were accompanied by low serum LDL levels. Other studies in cultured cells and parabiotic mice also found that PCSK-9 triggered extracelullar LDL receptor degradation through an intermediary adapter protein (ARH) on hepatocytes and lymphocytes.

Previous genetic studies have demonstrated that PCSK-9 had a pivotal role in maintaining cholesterol homeostasis. The gain-of-function mutation of PCSK-9 accelerates atherosclerosis process and leads to manifestation of cardiovascular events. A landmark study by Cohen et al2 compared coronary heart disease (CHD) incidence over 15 year observation in black dan white subjects with non-sense mutation of PCSK-9 (Y142X and C679X). Of the 3,363 black subjects observed, 2.6 percent had nonsense mutations in PCSK-9. This loss-of-function mutation were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9,524 white subjects observed, 3.2 percent had a sequence variation in PCSK-9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003). From this study, it was concluded that moderate lifelong reduction in the plasma level of LDL cholesterol (especially through PCSK-9 inhibition) was associated with a substantial reduction in the incidence of coronary events.

The mechanism of how PCSK-9 may affect plasma LDL levels are currently under investigation. Though previous studies had suggested ARH-mediated degradation of LDL receptor by PCSK-

9, this extracellular pathway was not found in fibroblasts.7 This suggests that there are other pathways mediating LDL receptor degradation. An animal study showed that active PCSK-9 can degrade the LDL receptor intracellularly. PCSK-9 binds to the region of EGF-A of the LDL receptors on the cell surface. This bond is stronger in an acidic environment inside endosome. From endosome, LDL receptors will be transported to the lysosome for degradation rather than recycled. These findings prove that PCSK-9 degrades LDL receptors through both extracellular and intracellular pathway.

The promises of PCSK-9 inhibitorThe discovery of PCSK-9 has encouraged experimental and clinical research on lowering LDL cholesterol (LDL-C) levels by targeting it for drug action. Large clinical trials have been conducted to test the efficacy and safety of PCSK-9 inhibitors. These first-in-class medications are humanized monoclonal antibodies that PCSK-9 acts. That inactivation results in decreased LDL-receptor degradation, increased recirculation of the receptor to the surface of hepatocytes, and consequently lowered the LDL cholesterol levels in the bloodstream.

By 2016, phase III trials had been completed for alirocumab and evolocumab. These phase III clinical trials results were reported in a number of different populations, including patients with statin intolerance, hypercholesterolemic patients on statin therapy, familial hypercholesterolemia subjects (both heterozygous and homozygous), hypercholesterolemic patients who are not taking lipid-lowering medications, and patients on monotherapy compared with ezetimibe (Table 1).

The efficacy and safety of alirocumab (SAR236553/REGN727) versus ezetimibe in patients with hypercholesterolemia (ODYSSEY MONO)8 trial recruited native hypercholesterolemia patients who had a 1% to 5% 10-year risk of cardiovascular death (scored by European systematic coronary risk estimation). This study included 103 patients, randomized to ezetimibe 10 mg daily or alirocumab 75 mg, injected every two weeks. If LDL-C was ≥70 mg/dL during 8-eight week observation, the alirocumab dose was uptitrated to 150 mg. Results showed that alirocumab reduced LDL-C by 47% compared to 16% by ezetimibe after 24 weeks. Apolipoprotein

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B (ApoB) and non-high density lipoprotein cholesterol (non-HDL-C) levels were also reduced by 37% and 41%, respectively in alirocumab group. In terms of adverse effect, there were no differences between the alirocumab group and the ezetimibe group. Moreover, evaluation of PCSK-9 inhibitor in patients with statin intolerance was conducted through ODYSSEY ALTERNATIVE trial.7 Three hundred and 14 patients were randomized to alirocumab 75 mg every 2 weeks, ezetimibe 10 mg daily, or atorvastatin 20 mg daily. After 24 weeks of treatment, alirocumab caused 45% LDL reduction compared to 15% in the ezetimibe group. Treatment-emergent adverse events

Trial Study population

Patients (n) Duration Background therapy Study drug LDL percent

reduction

ODYSSEY MONO8 HC 103 pts 24 weeks None EZE 10 mgAL 75 mg

15.647.2

ODYSSEY ALTERNATIVE7 Moderate to high CV risk.

Statin intolerant

314 pts 24 weeks None EZE 10 mgAL 75 mg

14.645.0

ODYSSEY COMBO I9 HC. High CV risk 316 pts 52 weeks Max-tolerated statin AL 75 mg 48.2ODYSSEY COMBO II10 HC. High CV risk 720 pts 104 weeks Max-tolerated statin EZE 10 mg

AL 75 mg20.750.6

MENDEL-211 HC, without statin use or statin

intolerance history

614 pts 12 weeks None EZE 10 mgEVO 140-420 mg

17.8-18.656.1-57.0

LAPLACE-212 HC, mixed dislipidemia

1896 pts 12 weeks Moderate-high intensity statin therapy

ATV 10 mg

SIMV 40 mg

ROSU 5 mg

ATV 80 mg

ROSU 40 mg

EZE 10 mgEVO 140-420 mgEVO 140-420 mg

EVO 140-420 mg

EZE 10 mgEVO 140-420 mgEVO 140-420 mg

19.0-23.961.4-62.562.4-66.2

+3.3-(+6.0)59.3-63.8

+2.8-(+7.6)16.9 -21.361.8-65.159.1-62.9

DESCRATES13 HC 901 pts 52 weeks DietDiet + ATV 10 mgDiet + ATV 80 mgDiet + ATV 80 mg

+ EZE

EVO 420 mgEVO 420 mgEVO 420 mgEVO 420 mg

51.554.746.746.8

GAUSS-214 Statin intolerant 307 12 weeks None, low dose statin, or LLT

EZE 10 mgEVO 140 mg

15.1-18.152.6-56.1

RUTHERFORD-215 HeFH 331 12 weeks Statin + LLT EVO 140-420 mg 55.7-61.3

Table 1. Phase III clinical trial results of alirocumab and evolocumab

HC= hypercholesterolemia; CV= cardiovascular; ATV= atorvastatin; SIMV= simvastatin; ROSU= rosuvastatin; LLT= lipid lowering therapy; EZE= ezetimibe; AL= alirocumab; EVO= evolucumab; HeFH= heterozygous familial hypercholesterolemia

were similar in the two2 groups, with rates of skeletal muscle-related events being lower in the alirocumab than in the atorvastatin group.

In high-cardiovascular risk patients, ODYSSEY COMBO I and II trials tested alirocumab as an additional therapy to statin.9,10 In ODYSSEY COMBO I, 316 patients were randomized to 75 mg alirocumab every two weeks or placebo. Meanwhile, ODYSSEY COMBO II randomized 720 patients to 75 mg alirocumab every two weeks or ezetimibe 10 mg daily. Both trials showed positive results in LDL-C reduction. After 24-week observation, alirocumab reduced LDL-C by


48% while the placebo group only 2% (COMBO I). In the case of COMBO II, the 75 mg alirocumab reduced 51% while the ezetimibe only 21% .

A number of phase III trials were also conducted to evaluate the clinical efficacy and safety of evolocumab. In the monoclonal antibody against PCSK-9 to reduce elevated LDL-C in subjects currently not receiving drug therapy for easing lipid levels-2 (MENDEL-2) study,11 614 patients with hypercholesterolemia were randomized to placebo, ezetimibe, evolocumab 140 mg biweekly, or evolocumab 420 mg monthly for 12-week observation. Evolocumab could reduce LDL-C by 56% to 57% compared to 18% to 19% with ezetimibe without differences in adverse events. The LDL cholesterol assessment with PCSK-9 monoclonal antibody inhibition combined with statin therapy (LAPLACE-2) study12 with 109 patients also confirmed that evolocumab (evolocumab 120 mg every two weeks or 420 mg once a month) reduced LDL-C by 66% to 75% (biweekly dose) and by 63% to 75% (monthly dose) in the moderate- and high-intensity statin groups compared to placebo. Moreover, biweekly evolocumab could lower non-HDL-C by 58% to 65%, apoB by 51% to 59% and lipoprotein a Lp(a) by 21% to 36% compared to placebo, with comparable reductions demonstrated in the monthly-dose group.

These positive results are consistent with the durable effect of PCSK-9 antibody compared to placebo (DESCARTES) trial findings.13 This trial gives evolocumab 420 mg every four weeks or placebo to 901 randomized hypercholesterolemic patients with LDL-C ≥75 mg/dL and already on atorvastatin 10 to 80 mg daily (with or without ezetimibe). After 52 weeks, evolocumab reduced LDL-C by 57% compared to placebo, ranging from 49% to 62% depending on background lipid-lowering therapy (atorvastatin alone or in combination with ezetimibe). Eighty-two percent of the patients on evolocumab were able to achieve an LDL-C goal of <70 mg/dL. There were no differences in terms of adverse events across groups. In addition, comparison of evolucumab with ezetimibe was also performed in goal achievement after utilizing an anti-PCSK-9 antibody in statin intolerant subjects (GAUSS-2) trial.14 Of 307 randomized hypercholesterolemic and statin intolerant patients, evolocumab

140 mg every twotwo weeks reduced LDL-C by 56% and 55% in the every- two2- weeks and monthly doses, respectively. In addition, evolocumab reduced apoB by 46% and Lp(a) by 24% to 26%.

Moreover, the reduction of LDL cholesterol with PCSK-9 inhibition in heterozygous familial hypercholesterolemia disorder study-2 (RUTHERFORD-2), a multicenter, randomized, double-blind, placebo-controlled trial, recruited 331 heterozygous familial hypercholesterolaemia patients (18–80 years of age) who were on stable lipid-lowering therapy for at least four weeks.15 They randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every two weeks, evolocumab 420 mg monthly, or subcutaneous placebo every two weeks or monthly for 12 weeks. Compared to placebo, evolocumab led to a significant reduction in mean LDL cholesterol in 12 weeks (every two weeks dose: 59,2% reduction [95% CI 53,4–65,1], monthly dose: 61,3% reduction [53,6–69,0]; both p<0·0001) and at the mean of weeks 10 and 12 (60,2% reduction [95% CI 54,5–65,8] and 65,6% reduction [59,8-71,3]; both p<0,0001). In this study, evolocumab was well tolerated, with adverse events occurrence similar to placebo.

Despite the promising results of many clinical trials available which tested PCSK-9 inhibitors, the price of this new-class drugs are still expensive. For example, alirocumab was launched at a list price of $14,600 per patient per year while evolocumab costs $14,100 per patient per year. Therefore, the cost effectiveness and public health cost efficiency issues need to be considered when prescribing this class of therapy.

In conclusion, advance research in PCSK-9 successfully showed a vital role of this protein in regulating LDL receptors. Suppression of PCSK-9 production was correlated to lower LDL levels. Inhibiting PCSK-9 with PCSK-9 inhibitors has gained attention over the past five years, encompassing positive results of phase-III clinical trials. Nonetheless, cost-effectiveness of this new drug should be evaluated in order to increase public access.

Confict of interest The authors affirm no conflict of interest in this study.

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https://www.ncbi.nlm.nih.gov/pubmed/?term=PCSK9+inhibition+with+evolocumab+(AMG+145)+in+heterozygous+familial+hypercholesterolaemia+(RUTHERFORD-2)%3A+a+randomised%2C+double-blind%2C+placebo-controlled+trial


Leadership in doctor-patient relationship: Implementation on patient’s case management in primary care

Keywords: doctor, leadership, primary care

pISSN: 0853-1773 • eISSN: 2252-8083 • https://doi.org/10.13181/mji.v26i2.1877 • Med J Indones. 2017;26:158–66• Received 01 May 2017 • Accepted 14 May 2017

Corresponding author: Retno A. Werdhani, [email protected]


Retno A. WerdhaniDepartement of Community Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia

Brief Communication


ABSTRAK

Dalam perannya sebagai care coordinator, seorang dokter membutuhkan perencanaan, pengorganisasian, pelaksanaan, dan evaluasi. Gaya kepemimpinan transformasional disebut-sebut sebagai gaya kepemimpinan yang cocok untuk pelayanan kesehatan karena kemiripannya dengan pendekatan patient centered. Penatalaksanaan yang disusun dan dijelaskan akan sesuai dengan kebutuhan pasien serta dapat disepakati dan dilaksanakan bersama sesuai peran masing-masing. Dalam melakukan pekerjaan, seorang pemimpin perlu melakukan berbagai aspek terkait proses manajerial untuk melaksanakan kegiatan yang perlu dilaksanakan dalam rangka pencapaian tujuan yang telah dirumuskan. Proses pengelolaan yang sama juga dapat dilakukan oleh seorang dokter dalam melaksanakan berbagai kegiatan yang diperlukan untuk mencapai target pengelolaan masalah kesehatan pasien. Kegiatan-kegiatan tersebut meliputi membuat perencanaan sampai dengan membangun jaringan kerja. Dokter diharapkan memiliki kompetensi kepemimpinan klinis dan kepemimpinan transformasional dalam menunjang kinerja mereka sebagai care coordinator dengan cara pengelolaan kasus yang holistik, komprehensif, terintegrasi, dan bersinambung, serta membina relasi dengan memanfaatkan berbagai sumber daya untuk kepentingan pasien.

ABSTRACT

As a care coordinator, primary care physicians (PCP) need planning, organizing, implementation, and evaluation. A model of leadership in medicine needs to be implemented in primary care. Transformational leadership is defined as a leadership style that is suitable for health services. It is similar to a patient-centered approach. Case management should be well prepared and explained in accordance with patient needs, can be agreed upon, as well as implemented with appropriate respective roles. A leader needs to do various aspects related to the managerial process for carrying out the required activities. The same process can also be done by PCPs to achieve patient’s target management. Such activities include planning up to building networks. PCPs are expected to have leadership competencies and transformational leadership to support their performance as care coordinators. This can be obtained through a holistic, comprehensive, integrated, and continuous approach, as well as building relationships with other stakeholders.


Werdhani.Leadership in doctor-patient relationship

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Morbidity and mortality are still problems, especially in developing countries. These include not only infectious diseases, but also non-infectious or degenerative as well as re-emerging diseases. Various efforts have been made, such as improving access to health care, community empowerment and setting the millenium development goals and sustainable development goals, however these efforts are still not adequate. Additional strategies have been proposed and improved, such as standardization, accreditation, health policy reform, universal coverage reform, and strengthening health resources.1

Modern medical services need teamwork, which implies that it also requires individuals with leadership competency.2 Doctors who work at primary healthcare become the forefront in all efforts to ensure sustainable health management. In managing health problems, doctors must cooperate with various individuals, both medical and non-medical, as well as patients and their families.3,4 In their role as care coordinators, doctors must experience the stages of planning, organization, implementation, and evaluation. All of these elements comprise part of an overall healthcare service system at a healthcare service facility or organization that calls for a clinical leadership competency and are expected to bring positive effects on the quality of the services provided.5

Healthcare system and primary careThe healthcare system consists of three levels. The first is the macro level, which is at the government/legislative level and consists of health policy and health investment policy, health finance system, standardization, continuing education, and inter-sector coordination. The second is the meso level, which is at the health facility level and consists of health service/patient’s flow, health provider expert, evidence-based and prevention-based medicine, information systems, and connection with community resources. The third is the micro level, which consists of patient empowerment and doctor-patient relationship. All levels of healthcare system will need leadership capacity, and this article will focus more on the micro level.5,6 There are also needs in primary care as written in Primary Health Care Now More Than Ever by World Health Organization (WHO).1 Primary health care needs to establish person-centered care, comprehensive and integrated responses as well as continuity of care, closer

to people, responsible for a well identified population, organizing networks and primary care team as a hub of coordination.1,7 –8

Care coordinatorOne of a doctor’s roles in patient’s health management is to be a care coordinator.3 McDonald9 defines a care coordinator as an individual who is responsible for conducting activities related to patient’s health management which involves two or more participants (including the patients), in an organization, in order to improve the patient’s quality of life and the quality of health services.10 The definition emphasizes the need for doctors to establish cooperation with various individuals, including patients, families, and other healthcare providers in managing diseases. This principle is in line with democracy-based health development, which is performed in the spirit of partnership and inter-sector collaboration.11

The terms coordinator itself contains leadership elements. Leadership is an action, not position.12 Being a doctor means doing an action, not having a position. Why? Because it is the duty and functions of a doctor to motivate, engage, collaborate, and influence individuals’ as well as their behavior to live healthy. Therefore, it is in accordance with WHO five stars doctor as a community leader because naturally a doctor is a leader for the community and does something for the community, regardless their structural position.13,14

Some clinicians consider leadership skills as necessary only for those doctors in a formal management role, not as practitioners.15 In primary care case management, coordination is needed between doctor and patient / family, nurses, other health providers, or other activities unit, to solve the patient’s health problems. Therefore, primary care physicians should at least have the capability of interpersonal communication, inter-professional, teamwork, and clinical administration. These abilities are reflection of the clinical leadership competencies, with doctors as the center of health care services provider to patients and leading multidisciplinary healthcare teams.15,16

Coherence between transformational leadership and doctor-patient interactionTead17 defines leadership as a combination of various person’s behaviors to encourage others and be able to complete entrusted tasks. Bass


and Avalio18 define transformational leadership as the leader’s efforts to transform the needs of followers to one level higher. Through transformational leadership, followers can achieve performance exceeding their leader’s expectations. This theory is based on the idea that innovative, inspirational, and proactive leaders have the ability to motivate others and to pursue high standards and long-term goals.12 The transformational leader realizes that empowerment, communication, strong values, and mutual respect are the most important things to improve quality. In medicine, the transformational leadership type is more suitable because doctor-patient relationship is a dynamic, trust, and voluntary relationship. There is also internal motivation from patients and doctors to communicate with each other, and doctors should also have charisma, inspire, as well as be proactive in serving patients.19

The values of transformational leadership and value-based diagnostics are central to the clinical leadership development program. Clinical leadership is the leadership from physicians and by physicians, to initiate and implement changes, aimed to reach patient management target. The role of physicians in clinical leadership is to determine the direction, management of resources, and motivation while maintaining the clinical role. Therefore, clinical leadership is integrated into daily medical practice and become part of the clinical role because they are directly involved in health care to patients.19,16 National Health System United Kingdom20 divides the clinical leadership competence framework into five dimensions: Demonstrating personal qualities, working with others, managing services, improving services, and setting direction. By applying these five dimensions, it is hoped that a practicing physician, especially a primary care physician, is able to have self-directed development, build networks, make plan and manage resources, innovate, as well as contribute to the improvement of healthcare service based on evidence.20

The essential role of a doctor is to create a healthy and productive people. In order to achieve this goal, the doctor needs to work together with various people who share the same vision and mission, give positive influence to each other, and be willing to motivate each other. Such

image is in accordance with the ideal practices of transformational leadership among doctors at all levels, from the micro level to the macro level. All efforts to create a healthy society must be supported by policies and facilities, which can assist doctors in fulfilling their duties.

There is a term in family medicine called a patient-centered approach. There is a relationship between a leader and his followers in leadership that is similar to the relationship between a physician and his patient. One characteristic of transformational leadership is the ability to explore ideas, concerns, and expectations of followers. It is identical to a patient-centered approach, where the doctors need to explore the ideas, concerns, and expectations of patients. Both leaders and doctors should respect, understand and care about their followers or patients’ problems. The transformational leader explains the vision and goals of the organization and encourage followers to achieve organizational goals together by sharing tasks and agreed responsibilities. On the other side, doctors are also expected to explain the goals and objectives of treatment and to encourage patients to control the disease together with mutually agreed target/clinical outcome. A transformational leader motivates followers to reach a higher level. It is identical to the task of motivating patients to change their behavior to become healthier. Such is the resemblance between transformational leadership and a patient-centered approach (Table 1).16,19,21

A doctor as the leader and implementation in doctor-patient relationshipIn fulfilling the duties, a leader must take several aspects in the management process for the purpose of designing the activities, which need to be performed in order to achieve the team’s common goals. A doctor can also apply the same management process when designing the treatment and intervention, which need to be performed to achieve the targets, related to the patient’s health management. The process starts from planning up to creating a professional network, as described in Figure 1.

PlanningPlanning is defined as a systematic activity to identify and specify the goals of a project, the set of actions that need to be taken to achieve the goals,

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Table 1. Transformational leadership and patient centered approach

Figure 1. Leadership in Doctor – Patient Relationship

the steps that need to be taken, the methods of implementation, and the human resources that need to be employed to perform the actions to achieve the goals. Planning must be performed in an integral, holistic, and meticulous manner; must ensure a unity of understanding, attitude, and course of action; and must be followed up by concrete actions. Planning covers a number of specific activities consisting of identifying the types of activity, determining the priority scale, preparing time and cost estimates, appointing the individuals in charge of each activity, distributing jobs, and stating the procedures for evaluation.22

In daily practice, the doctor would normally design a disease management plan according to the anamnesis, physical examination, and supporting examinations by applying a systematic process of thinking and careful establishment of a diagnosis. This principle must be adopted so that the doctor

and the patient can perform the planned activities more effectively to achieve their common goals of solving the patient’s health problems. The entire planning process must be documented by medical information system, accessible to all individuals involved.

Providing informationInformation gives intensification to exchanges of ideas, opinions, and thoughts related to the decisions and policies taken to solve problems. This process requires the commitment of all parties involved and comprehensive information from the leader. The process of information exchange must be performed in two directions.22 This kind of approach is expected to take place in a doctor-patient relationship. The interpersonal relationship between doctor and patient is similar to between leader and follower, which generates specific communication patterns of doctor-patient relationship. A doctor needs to devise an effective pattern of communication with the patient and other individuals involved, achieving a unity of vision and mission in their determined effort to cure the patients’ health problem.

Any plan for health management must specify the roles and duties of all individuals involved in the process including the doctor, nurses, other healthcare providers, patient, family members, and community (if required). The doctor, who leads the whole process of information exchange, selects the right model of information exchange. Communication failure often leads to misunderstandings, inflicts losses, and even leads to disastrous effects. Such consequences can and actually occur in daily medical practices in various forms, such as allegations of malpractice even in a situation where the doctor has followed applicable professional standards.

Planning Providinginforma.on Monitoring

Solvingproblems

Providingsupport Developing

Givingrewardand

apprecia.on

Managingconflict

Formingworkteams

Buildingprofessionalnetworks

Transformational Leadership Person Centered ApproachLeader – Follower Doctor – Patient/ClientExplore ideas, aspirations, and expectation of followers Explore ideas, concern, and expectation of patientRespect, understand, and care about follower’s problem Respect, understand, and care about patient’s problemExplain vision and goals of organization Explain goals and objectives of disease managementEncourage followers to achieve the goals Encourage patients to control diseaseTask sharing and agreed responsibility Mutual agreement on target/clinical outcomeMotivates follower to growth to higher level Motivates patient to change their behavior


MonitoringMonitoring is one of a leader’s duties, which involves assessment and correction to make sure that the common goals can be achieved effectively. Monitoring can be done both internally and externally. Internal monitoring consists of identifying indicators of success, examining the key success factors, raising specific questions, which are related to performance, encouraging team members to report any problems, and learning from failures. External monitoring consists of identifying customers’ needs based on situational changes, involving customers in information search, observing various events relevant to mutual goals, and learning from other people’s successes.22

In cases of daily patient’s management, a doctor needs to continuously gather relevant data and regularly evaluate the extent to which the treatments and interventions have been able to cure the patient’s health problems according to the set plan. A medical information system is required to record the data and the subsequent intervention plans by taking into account the patient’s current development. The results can be used for improving the quality of both short-term and long-term healthcare services.

Solving problemsA good leadership involves the ability to make various decisions, solve problems, take actions, employ various resources, and produce and adopt policies as solutions for certain problems. In order to achieve the goal, the leader and the followers must sit together and make decisions, which serve the interests of the organization, as well as the needs of the subordinates. Before a decision is made, both parties must consider all possible risks and identify the best solution whose performance will be part of the leader’s responsibility.22

The same analogy also applies to the doctor’s duty to cure the patient’s health problem. Before making any clinical decisions about the patient’s health problem, the doctor must consider all information, which has been gathered from many resources for the best interest of the patient. Any discussions which take place between the doctor and the patient before decision making is comparable to a counseling session in which the doctor invites

the patient, along with their family when needed, to make a decision together in order to solve the problems at hand by considering the patient’s preferences.

Providing supportProviding support is one of the expected duties of a leader as the reflection of consideration, acceptance, care, and concern for the followers. It is important for a leader to treat others with politeness, to show genuine concern, to be patient and helpful, to provide support when somebody is confused and distraught, to pay attention to followers’ complaints and problems, and to identify and maximize their potentials.22

A doctor must also show the same qualities to his or her patients. When interacting with a patient, the doctor is expected to actively listen to the patient’s complaints, show empathy, give support, and work together with the patient to solve the problem while at the same time identifying the potentials or resources, which can be employed to solve the problem.

DevelopingThis aspect is defined as the process of enhancing an individual’s knowledge, skills and capabilities which can improve performance both at present and in the future. Development can be gained from training, coaching, mentoring, and counseling. A leader must be able to select the most suitable forms of development according to the actions that will be taken, and the achieve target. There are several factors that need to be considered in terms of development, such as the need for development, the motivation for capacity building, the method for development and the procedures for evaluation.22

In a doctor-patient relationship, the doctor has an obligation to provide education, knowledge, counsel and coaching for individual patients, their families and the larger society as a form of capacity building. Such attempts must be undertaken to empower and enable the people to address their own health problems under the doctor’s supervision and his or her medical team.

Giving rewards and appreciationGiving rewards is defined as an action of giving praise or showing appreciation to a component of

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an organization that has achieved a certain level of effective performance. An acknowledgment from the leader will enhance motivation and strengthen the commitment to achieve common goals. A reward or appreciation may take concrete forms such as a raise in salary or job promotion.22

In daily interaction between a doctor and a patient, when the patient has reached a certain target (such as when the patient has been able to maintain his or her glucose level or blood pressure or when the complaints have been eased), the doctor can appreciate the patient’s commitment to follow the intervention scheme as planned before. In addition to praise, the doctor may also inform the patient about the benefits which the patient has gained or will gain from achieving a certain target. One of the greatest challenges in the medical world is to ensure long-term benefits of an intervention (such as disappearance of relapses, withdrawal of symptoms, or an absence of complications), which may not be immediately observed. As such, the patient must be continuously supported and encouraged to take the necessary measures to prevent relapses. The point is that the patients will be really motivated and feel the need to maintain their own health if they realize and know the benefits or have experienced the benefits themselves.

Managing conflictsConflicts may arise from the way an individual interprets, perceives, and responds to the environment. Another source of conflicts is lack of coordination among members of a team in terms of interdependence, confusion because of unstructured job descriptions, differences in task orientations, and a weak control system. A conflict may also take the form of a monotonous working environment, which will lead to excessive apathy if left unaddressed.22

Beside communication problems, another type of conflict that may arise in a doctor-patient relationship is an apathetic attitude of the patient that may arise when the problems persist and do not show any sign of improvement. This apathy might drive the patient to do things, which deviate from the agreed plan. Such conflicts may also arise when the patient is not well informed, does not know exactly what

to do, or does not realize the consequences of doing things that are not supposed to be done because the doctor does not give a clear or detailed explanation. In order to avoid this type of conflict, there must be a clear distribution of duties and responsibilities between the doctor and the patient. Furthermore, the doctor must have sufficient knowledge and skills in predicting various possible scenarios, so that a more effective prevention and monitoring scheme can be prepared.

Forming work teamsThis team might consist of several individuals or smaller teams, each of which possesses complementary skills and is strongly committed to achieve common goals. Each of them must also be equipped with a set of techniques, approaches, and orientations that are solidly based on scientific theories recognized and applicable in their respective fields. A leader’s duty to form a work team is also related to conflict management, because one of the ways to manage conflicts in a constructive way is by forming a solid work team.22

In order to provide high-quality medical services at a healthcare facility, a professional service team should be formed, which consists of doctors, nurses, pharmacists, nutritionists, and other healthcare providers. The team’s job is to cure patients’ health problems in an integrated way, according to the targets set for each individual patient. It is hoped that all elements within the team would support and complement each other for the best interest of the patients under the coordination of a doctor who is authorized to make clinical decisions if any clinical problems should occur. There must also be clear job distribution and procedures, which are mutually agreed and will be carried out together by all components of the team.

Building professional networksAs globalization continues to expand, the need for building networks has become more urgent. This current situation stimulates the development of an intensive communication network that “shrinks” the world. Building professional networks is associated with a variety of behaviors, which aims to enhance both the internal and external potentials of an organization. A leader must develop


the awareness and sensitivity to various needs by taking into account of the available opportunities and the stakeholders interests.22

In the context of doctor-patient interaction and healthcare services, the doctor and healthcare team, who have to deal with patients personally, must be aware of and sensitive to the patients’ needs in order to build both internal and external professional networks in a healthcare facility. By establishing professional networks, the otherwise inaccessible important external information can be made more accessible to all parties involved in order to ensure information accuracy and appropriate interventions. Establishing cooperation with a specialist or building networks among healthcare facilities, are other ways to build professional networks for the benefit of the patients.

Care coordination model Case management in primary care requires medical staff team as care coordinator who work and discuss case/health service issue, clarify each other task, contributes each other, and improve team building. Besides working among health professionals and patients, care coordinator also works closely with families and specialists for the benefit of patients. Case management assessment in a holistic (bio-psycho-socio-cultural approach), comprehensive (preventive oriented), integrated, and continuum are reported to head of health facility in a periodic meetings to identify issues that need to be changed/updated/clarified according to the needs of patients. As a form of social responsibility or expanding services, the care coordinator team can provide guidance to specific communities as well as identifying the resources that are useful to patients. This model will enhance creativity, closeness, satisfaction, commitment, concern for others, involved in determining the direction of the healthcare, and enhance self-leadership. It requires the support of meso-level management, information systems, and strengthening the leadership capacity of primary care physicians (Figure 2).

Function of primary care doctors as care coordinators can be improved by increasing the implementation of interdisciplinary services, strengthening the capacity of primary care physicians and exposure to manage

Figure 2. Care coordination model in primary care

interdisciplinary team, clarifying the service flow, job desk and responsibilities of each member of the health team, and improving information systems that can be accessed quickly and processed longitudinally to evaluate management goals.

Being a care coordinator is also beneficial as an involvement to determine the direction of service through regular meetings with fellow physicians for case discussions, making clinical guides, new standards or revisions according to current conditions, regular meetings with the head of the health facility to discuss patients’ complaints or to fix service flow and strengthening the role of each health provider involved, as well as regular meetings with management to deliver new/revised management guidelines and advocate why it needs policy/rule change. Therefore, the doctor will needs diplomacy skills, influence, leadership and effective communication capacities.

Activities such as regular meetings to discuss cases/patient’s complaints, contributions to

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Patient’s case management goals

Family medicine’s approach: - Holistic - Comprehensive - Integrative - Continuum

Network: - Other specialist - Referral

Clinical leadership: - Self improvement - Team based - Innovating - Direction contribution

Community: - Engagement - Resource utility - Empowerment - Social

responsibility

Primary care physician and team: - Case discussion - Content contribution - Job description - Team building

Support: - Healthcare system,

management and policy - Information system Follow-

up and monitoring - Capacity building in leadership

Head of health facility: - Coordination

meeting - Health service

development

Family: - Perception and

participation - Family meeting


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educational materials creation, guidelines, service flow, or other written guidance, develop recording / integrated data processing in order to avoid overlapping of recording/questions, and team building to develop agreed activities and monitor together, will increase creativity and relationship. This will enhance the relationship among team member that will impact on patient’s outcome.

The doctor plays complex roles as a practitioner, a colleague, and a leader for his or her patient, as well a link to the healthcare services management. Therefore, the ideal doctor needs to have a wide range of exposure to professional experiences, so that he or she would be able to understand the relationship between practical experiences (practical management) and healthcare services management (organizational management). Such exposure to various experiences can be attained by enhancing doctors’ capacity and competency in organizational behaviors, as well as their application to patient case management. This action may help health service reform based on patient needs by applying holistic, comprehensive, integrated, and continuous case management, as well as strengthening relationships by employing various resources for the best interest of the patient. This experiential exposure can be provided within the framework of a structured formal education for doctors who wish to work as practitioners and leaders as the forefront of high quality healthcare services, especially in primary healthcare.15

In conclusion, the doctor is expected to have two kinds of competencies: clinical leadership and transformational leadership, which can support their performance as the patient’s care coordinators and to ensure the continuation of services which cannot be performed by a single individual only. Care coordinators and clinical leadership will meet primary care needs as well as support to WHO primary health care reform. By having formal education/training on leadership competence, having a care coordinator in primary care with leadership spirit and competence, doing periodic evaluation, giving constructive feedback, solid teamwork, cooperation with the patient, family, community and other health workers, as well as networking, hopefully will improve the patient, family, and community’s quality of life.

Conflicts of InterestThere was no conflict of interest for this paper.

AcknowledgmentThe writer would like to thank dr. Muchtaruddin Mansyur, MS, SpOk, PhD, Dr. dr. Astrid W. Sulistomo, MPH, SpOk, Dr. dr. Herqutanto, MPH, MARS, Dr. Wirawan, MSL, MM, MSi, Dr. Ekowati Rahajeng, SKM, M.Kes, and Prof. Dr. dr. KRT. Adi Heru Sutomo, MSc.

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