Practice of Self-Medication with Antibiotics Among the Adult Inhabitants in Dhaka City

Introduction

The World Health Organization has emphasized that selfmedication must be correctly taught and controlled as the selfmedication is a great threat for the health globally WHO, [1]. Antibiotic self-medication is highly prevalent in the developing countries due to easy availability. Resistance to commonly used antimicrobial drugs is remarkably high in countries where antibiotics are not restricted Sallam, et al. [2]. There are some other reasons like wider availability of medicine, greater choice of treatments, in preventing or reliving miner symptoms or condition, ailment was minor and financial constraint Jain, et al. [3]. Antibioticresistant infections also contribute to the financial burden on health care systems Gelband, et al. [4]. A study conducted in Bangladesh in 2014 found that 26.69% in Rajshahi city experienced self-medication with highest percentage of self-medicated medicines were metronidazole (50.43%), azithromycin (20.75%), ciprofloxacin (11.53%), amoxicillin (10.37%) and tetracycline (7.49%) respectively. The key reasons for the self-medication of antibiotics was the pre-experience (45.82%), Biswas, et al. [5]. A cross sectional study conducted in 2017 in Dhaka city found that undergraduate medical students were found to practice more selfmedication (78.1%) than the non-medical students (55.1%) Nasir, et al. [6].

Reason and Factors Influencing Self-Medication with Antibiotics

Parents medicate to their children to save money or to avoid a trip to doctor’s office Bennadi [7]. A number of reasons for selfmedication such as saving money and availability of drugs in drug shops are responsible for growing trend of self-medication Oluyemi [8]. Many studies showed that limited purchasing capability is a major determinant for self-medication with antibiotics in India, Nigeria, Philippines, Latino adults in the United States of America, and the non-Arab population in the United Arab Emirates. Pharmacy staff behavior can be a factor that puts patients at risk for self-medication with antibiotics Oluyemi, et al. [8,9]. Inappropriate Antibiotic and Nonprescription use of antibiotics can range from 19 percent to well over 90 percent outside the United States and Europe, Vietnam, in Saudi Arabia and Syria, pharmacies dispensed antibiotics without a prescription Van Boeckel, et al, [10].

OTC Drugs

Over the Counter (OTC) drugs are non-prescription drugs that are not normally covered by a Medicare Prescription Drug Plan. OTC medications are legal, non‐prescription substances taken for the relief of discomforting symptoms. Although OTC drugs are believed to be safe and effective, indeed they are not. They mask the underlying disease and may cause several adverse effects Parikh, et al. [11]. A prescription is an order that is written by the physician to tell the pharmacist what medication your patient wants to take Inlander, et al. [11,12]. Drugs that destroy microbes, prevent their multiplication or growth, or prevent their pathogenic action – Differ in physical, chemical, pharmacological properties, differ in antibacterial spectrum of activity, differ in their mechanism of action.

Worldwide Antibiotic Resistance Rates and Trends

In the United States, more than 2 million infections and 23,000 deaths are due to antibiotic resistance each year and in Europe, an estimated 25,000 deaths CDC, [13]. Antibiotic-resistant infections also contribute to the financial burden on health care systems Gelband Quet, et al. [4,14]. A vast majority (93%) of the patients were totally unaware of the possibility of side-effects Teck, et al. [15-17].

Parental Knowledge About Antibiotic Use/Discontinuation in Bangladesh

High percentage of parents thought that antibiotics could cure infections caused by viruses and also cold, fever and sore throat. Resistance to commonly used antimicrobial drugs are remarkably high in countries where antibiotics are not restricted Sallam, et al. [2]. In Bangladesh, increasing rates of antimicrobial resistance andthe prevalence of self-medication is thought to be high, as a result, minor illnesses are treated with antimicrobials which have potentially harm the individual Gutema, et al. [18- 21,3]. Many older adults independently manage their prescription and nonprescription (OTC) medications Keshari, et al. [22,23]. A majority of the prescribers diagnose infection by clinical assessment and suspect a microbial etiology Faiz, et al. [24].

Methods and Materials

The study is a Cross-sectional descriptive study andit was helpful to describe the current conditions and situations based on the impressions and views of the respondents of the study (Thomas et al., 2005). The study location was Azimpur, lalbagh, Kamrangirchar belongs to Zone-5 of Dhaka South City Corporation. These areas are highly populated, and it was feasible to find people or respondents from every economic status like lower, middle and higher socioeconomic. The total study duration was 10 months from May 2019 to February 2020.

Study Population

The target population was adult age group (18 or more than 18 years old). Both male and female were selected from any religion and socioeconomic status. Pre-tested, semi structured interview questionnaires. This balance was useful for a comprehensive analysis. Data was entered in Microsoft Excel and analysis was done by using descriptive statistics in Microsoft Excel 2010 and SPSS version 20.

Ethical Consideration

Permission was taken from Institutional Review Board (IRB) of American International University-Bangladesh (AIUB), the committee on activities involving human subjects.

Results

Distribution of the Respondents’ Socio-Demographic Variables

Among the total (140) participants, 37.9% participants were between the 18 and 28 years old, 33.6% between the 29 and 39 years old, 20.7% between the 40 and 50 years old, 5.7% between the 51 and 61 years old and 2.1% were 62 years and above. Among the respondents, 56.4% participants were male and 43.6% were female and among them 64.3% were married and 35.7% were unmarried. It reveals that the participants’ education level was as illiterate 6.4%, primary 10.7%, secondary 14.3%, SSC 13.6%, HSC 15.0%, graduation 20.0%, masters and other higher degrees also 20%. Graduation, masters and other higher degree holder participants were more in numbers than others.

Knowledge about Antibiotic Resistance among Medicated and Non-Medicated Group

The result demonstrates that 37 participants out of 79 (46.8%) consulted doctor and other 42 participants out of 79 (54.2%) didn’t consult reg. doctor. Among the 42 participants who didn’t consult MBBS/reg. doctor 14 participants (17.7%) visited local pharmacy and took suggestion/medicines, 10 participants (12.7%) consulted quack/village doctor/medical assistant, 9 participants (11.4%) medicated from home stored medicine/family/friends, 3 participants (3.8%) consulted doctor of alternative medicine (Homeopathy/Uniani/Ayuryeda/Others) and 6 participants (7.6) did other health seeking behavior (Figures 1 & 2).

Figure 1: Status of antibiotic use in last 12 months.

Figure 2: Gender based knowledge about antibiotics.

Antibiotics Medication and Gender

Status of antibiotic use among the antibiotic users: The rate of self-medication with antibiotics (53.16%) is higher than the use of antibiotics (Figure 3) prescribed by doctors (46.84%). Selfmedication number was higher in male (31.65%) than the female (21.52%) and alternatively the number of antibiotics prescribed by doctor was higher in female (29.11%) than the male (17.72%).

Antibiotic Medication and Education Level

Education plays an important role to grow up the level of health awareness. In this study, most of the persons whom education levels were “Primary” (11.39%) used antibiotics as self-medication in higher rate and most of the persons whom education level was “Master” (16.46%) used antibiotics as prescribed by reg. doctors in higher rate. Practice of antibiotic prescribed by doctors is gradually higher in higher education group and gradually lower in lower education group. Alternatively practice of self-medication with antibiotics is higher in lower education level and lower in higher education level (Figure 4). Practice of self-medication is higher in male persons (59.52%) and comparatively lower in female parsons (40.48%). Practice of self-medication is higher in married people (59.52%) and comparatively lower in unmarried people (40.48%). (Figure 4). Practice of self-medication is higher in lower education level (illiterate 4.76%, primary 21.43%, secondary 19.05%, SSC 16.67%, HSC 14.29%, graduation/honors 16.67% and masters and other higher degrees 7.14%).

Figure 3: Antibiotics Medication and Gender.

Figure 4: Self-medication with antibiotics and education level.

Antibiotic Medication and Income Level

Income is a vital factor to improve the health seeking behavior. In this study, most of the persons whom income level were BDT>40000 to 60000(15.19%) and BDT >80000(12.66%) used antibiotics as prescribed by doctor. But most of the persons whom income level were BDT<=20000(24.05%) used antibiotics as selfmedication. Practice of self-medication with antibiotics is higher in lower income level and practice of antibiotic prescribed by doctor is higher in higher income level (Figures 5 & 6).

Figure 5: Antibiotic medication and Income Level.

Figure 6: Medication Type and occupation among antibiotic users.

Gender and Source of Self-Medication with Antibiotics

The most common source of antibiotic for self-medication was “bought from private pharmacy without prescription” for male (38.10%) and for female (14.29%). ‘Previously stored antibiotics’ for male (11.90%) and for female (14.29%). ‘From family and friends’ for male (7.14%) and for female (9.52%) and other sources were for male (2.38%) and for female (2.38%) (Figure 7). The highest rate of used antibiotics for self-medication is Metronidazole (21.4%), secondly Ciprofloxacin (19.0%), Thirdly Azithromycin (16.7%). Cloxacillin (9.5%), Amoxicillin (7.1%), Cefixime (7.1%), Cefuroxime (2.4%), other antibiotics (2.4%) and under not sure (14.3%).

Figure 7: Gender and source of self-medication with antibiotics.

Use of Antibiotics (Self-Medication) and Diseases

Metronidazole was most commonly used for Dysentery (21.43%), Secondly Ciprofloxacin was used for Fever (11.90%) and Common cold (7.14%). Thirdly Azithromycin was used for Fever (4.76%), for Sore throat (4.76%), for Sinusitis (2.38%), for Injury (2.38%). Amoxicillin used for Common cold (4.76%) and for Cough (2.38%). Cloxacillin was used for Injury (4.76%). Cefixime was used for Sore throat (2.38%), for Cough (2.38%) and for Dental infection (2.38%). Cefuroxime was used for Sore throat (2.38%), other antibiotics were used for Dermatological condition (2.38%) and under not sure 7.14% for Fever and 4.76% for Dental Infection. Most of the people (whom taken antibiotic as self-medication) were taken antibiotic due to Dysentery fever (Figure 8).

Discontinuing Antibiotics after Starting with Self- Medication

Majority of the participants didn’t stop taking antibiotics (incomplete course of treatment) (59.52%), and some participants stopped taking antibiotics without completing the course of antibiotic (33.33%) and 7.14% participants were not sure (Figure 9).

Figure 8: Use of antibiotics (self-medication) and diseases.

Figure 9: Continuity antibiotics after starting with self-medication.

Cure Diseases after Self-Medicating with Antibiotics

30.95% participants reported that they were not cured after taking antibiotics (self-medication) although majority of the participants 66.67% reported that they cured from diseases after taking antibiotics (self-medication), 2.38% participants were not sure (Figure 10). The association between the gender and antibiotic use and that is statistically significant (P-value = .024). There is relationship among self-medication with antibiotics group, antibiotics prescribed by doctor and no use of antibiotics group. The association between the income level and antibiotic use and that is statistically significant (P-value = .017). There is relationship among self-medication with antibiotics, antibiotics prescribed by doctor and no use of antibiotics group with income level. Practice of antibiotics varies on the income level. Income has an effect on use of antibiotic practice.The association between the education level and antibiotic use and that is statistically significant (P-value = .002). There is relationship among self-medication with antibiotics, antibiotics prescribed by doctor and no use of antibiotics group with education level. There is relationship of self-medication with antibiotics, antibiotics prescribed by doctor with education level.

The Chi square test showing that there is no association between education and self-medication with antibiotics and no use of antibiotics (P-value= .357). Statistically there is no significant. There was strong association between the education and antibiotic user prescribed by doctor and that is statistically significant (P-value = .012). There is relationship of antibiotics prescribed by doctor with education level. There was strong association between the income level and antibiotic user prescribed by doctor and that is statistically highly significant (P-value = .000). There is a strong relationship of antibiotics prescribed by doctor with income level. Practice of antibiotics prescribed by doctor varies on the income level. Higher income leads to the visit of registered doctor and proper practice of antibiotic use (prescribed by doctor).

Figure 10: Rate of cure after self-medicating with antibiotics.

Discussion

A study conducted in Rajshahi city of Bangladesh in 2014 found that 347 (26.69%) out of 1300 participants in Rajshahi city experienced self-medication with antibiotics Biswas, et al. [5]. The percentage of self-medication has been increased more than previous years which is very alarming. The selection of antibiotics in a study conducted in Dhaka city found that the reasons behind the self-medication was ‘minor illness’ (40%) and ‘confidence on self-knowledge’ (33%) among the medical students; whereas the main reason among non-medical students was ‘need immediate relief’ (24%) Nasir, et al. [6]. Antibiotic-resistant infections also contribute to the financial burden on health care systems Gelband, et al. [4]. Antibiotic prescribed by doctor group 13.57% know more about antibiotic resistance than self-medication 4.29%. The rate of self-medication with antibiotics (53.16%) is higher than the use of antibiotics prescribed by doctors (46.84%). Another study conducted on “Self-medication with antibiotics in Lithuania” in 2006 found higher prevalence of self-medication with antibiotics Berzanskyte, et al. [25]. It might be a global problem especially in developing countries Sallam, et al. [2].

Self-decision by previous experience/confidence was higher in age group 40-50 years. A study found that the parents who medicate their children do so in order to save money or to avoid a trip to doctor’s office Bennadi, [26-41]. Another study found that a number of reasons could be counted for self-medication such as strong desire of self-care, feeling of sympathy towards family members in sickness, previous experience of having antibiotic, lack of health services, saving money, ignorance, misbelieves, extensive advertisement and availability of drugs in other than drug shops are responsible for growing trend of self-medication and most importantly weak implementation of regulation related to medicines Oluyemi [8]. Most of the people (whom taken antibiotic as self-medication) were taken antibiotic due to Dysentery fever. Ciprocin, Metronidazole and Azithromycin, Cloxacillin and Amoxicillin were mostly used as 500mg dose. Daily frequency of taking antibiotics twice daily was most frequently practiced and the Ciprocin was highly practiced twice daily and secondly Azythromycin. Thrice daily was also most common for Metronidazole.Another study conducted in Bangladesh in 2014 also found that the highest percentage of self-medicated antibiotics was metronidazole (50.43%) followed by azithromycin (20.75%), ciprofloxacin (11.53%), amoxicillin (10.37%) and tetracycline (7.49%) respectively. The key reasons for the self-medication of antibiotics was the pre-experience (45.82%), suggestions from others (28.24%) and knowledgeable of the antibiotics (16.14%) Biswas, et al. [10].

There was strong association between the gender and antibiotic use and that is statistically significant (P-value = .024). The association between the income level and antibiotic use and that is statistically significant (P-value = .017). The association between the education level and antibiotic use and that is statistically significant (P-value = .002). There is strong association between the education and antibiotic users (self-medication and prescribed by doctor) and that is statistically highly significant (P-value = .000). Statistically there is no association. There was strong association between the income level and antibiotic user prescribed by doctor and that is statistically highly significant (P-value = .000). There was a strong relationship of antibiotics prescribed by doctor with income level. Income has an important effect on use of antibiotic practice (prescribed by doctor.

Conclusion

The practice of self-medication is higher in lower income andeducation level as these groups might have less knowledge about side effects and it is statistically significant also. The most common self-medicated antibiotics were Metronidazole, secondly Ciprofloxacin and thirdly Azythromycin. Antibiotics were selfmedicated mostly for the Dysentery, Fever, Common cold and Sore throat. Most of the participants’ source of antibiotics for selfmedication was private pharmacy and bought antibiotics from the pharmacy without prescription. Visiting pharmacy was the most common health seeking behavior among the participants who selfmedicated with antibiotics.

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Disabled Afghan Refugees in Iran: Beginning for the Future

Introduction

Afghan refugees’ population is estimated at over 950,000 in Iran [1,2] and most of them are living in urban areas [2] and out of camps [3] where are considered unsafe and poor environments [4]. It has been well known that delivering services are directly or indirectly affected by demographic characteristics of the refugees’ population [5,6], for example, the prevalence of chronic diseases can be higher in the older population [6]. On the other hand, providing services such as combined primary care and mental health have more obstacles when we are in contact with specific populations such as refugees [7] mostly as a result of differences in their attitude and believe [4]. Although as a result of the new registration system in Iran named Amayesh, more demographic characteristics and information has been collected [8] and few studies had performed on the health status of Afghan refugees in Iran [9] (as main purpose [4,5,10] or as a part [11-14] of those studies), there is, unfortunately, no accurate data and information regarding the prevalence of disability, its incidence and sociodemographic characteristics of disabled Afghan refugees in Iran. This may partly be because of the out-of-camp living of Afghan refugees in Iran [3] which makes data collection harder. The United Nations High Commissioner for Refugees (UNHCR) and The State Welfare Organization of Iran (SWO) are collaborating to provide rehabilitation services, assistive devices and equipment, and rehabilitation and treatment costs for disabled refugees in Iran [1,2]. Accessing that information will help SWO and other partners for better service deliveries and the sustainability of projects in the future. The main objective of our descriptive study is providing and obtaining sociodemographic characteristics of disabled Afghan refugees participating in a joint project of UNHCR and SWO in Golestan province, Iran between June until December 2015.

Materials and Methods

Data Collection

This study was a part of a joint project for disabled Afghan refugees in Iran between UNHCR, the Bureau for Aliens and Foreign Immigrants Affairs (BAFIA) of the Ministry of Interior of Iran, and SWO in 14 Provinces between June until December 2015 (project number: UNHCR 15/IRN/SWO/180). Golestan province is located in the northeast of Iran and for this project. we had 40 disabled Afghan refugees recruited based on information and profile of disabled Afghans in Gorgan city Welfare Administration. In total, there were 136 disabled Afghan refugees have been registered in the Golestan Welfare Administration. We included the first 40 individuals with a complete profile and passed a special commission to approve their disability type and its severity. During the project, two Afghan facilitators were trained by the province Welfare Organization to collect data and facilitate the delivery of rehabilitation services including individual and family education, assistive devices, medical follow-up, and providing basic needs.

Ethics Approval

Afghan refugees’ Information and data were used and analyzed by agreement of the Golestan Welfare Administration. All attention was paid to information confidentiality.

Statistical Analysis

The STATA SE v.12 (STATA Corporation, College Station, Texas) was used for analysis. We were cross-tabulated sociodemographic characteristics of the study population to calculate and present total and by sex prevalence.

Results

There were 40 individuals including 28 men with a mean age of 31.89 ± 18.07 (age range 8-72 years) and 12 women with a mean age of 19.67 ± 14.36 (age range 1-57 years). Most of the individuals (40.00 %) belong to the age group of 11-20 years old and single (72.50 %). Half of the sample lived in the urban area and 82.50% of them did not have any educations and were mostly unemployed (72.50 %). There was no individual with a university education. Almost all of the individuals lived in the rental house (95.00 %). There were not any individuals without a caretaker, but 75.00 % of them were cared for by one of the family members of which, 62.50 % of them were cared by their father and only 25 % were self-helped. Only 7 individuals had another disabled in their family (Table 1). In total, 42.50 % of individuals had Physical and motor disabilities. There were 42.50 % of individuals had a severe disability Table 2 showed information regarding disability types and severity among men and women. From 40 individuals, there were more men with physical and motor (35.71 %) and mental retardation (32.14 %) disabilities. Among 12 women, about 58% had physical and motor disabilities. In both sex, individuals with severe disability was more prevalent (men= 42.50 %, women= 50 %).

Table 1: Sociodemographic Characteristics.

Note: Results are presented as n (%) or mean ± standard deviation.

PCI: Percutaneous Coronary Intervention; CABG: Coronary Artery Bypass Graft; PAD: Peripheral Arterial Disease; CRF: Chronic Renal Failure; TIA: Transient Ischaemic Attack; CVI: Cerebrovascular Insult; CEA: Carotid Endarterectomy; CAS: Carotid Artery Stenting; CTA: Computer Tomographic Angiography.

Table 2: Disability Characteristics.

At the beginning of this project, none of the individuals had healthcare insurance. But, during the project they could get the Salamat Health Insurance booklet (the universal public health coverage scheme in Iran) [1], therefore we did not show this information. Of 40 individuals, none of them had official training.

Discussion

Up to our search and knowledge, there were no published papers regarding disabled Afghan refugees’ status in Iran. This is a descriptive study as a part of a joint project between SWO, UNHCR, and BAFIA on disabled Afghan Refugees in Golestan province, Iran. There were 40 disabled Afghan refugees with mostly physical and motor disabilities who had received rehabilitation services and basic needs. Most of the individuals were without education and unemployed which can hinder any sustained empowerment of them. There are different partners with UNHCR for protecting, educating, health, and increasing the self-reliance of Afghan refugees in Iran [1,2]. This is a golden opportunity when Iran health system is faced with a high burden [4], so this capacity can be used to decrease the expenditure of the national health system [14], a succession of the international project, and the probability of the individual’s empowerment as an ultimate goal of the projects. Although only 12 women were in this project, we must consider cultural barriers, different attitudes, and being a refugee to participate in society [4]. In addition, service delivery for refugees living out of the camp is more difficult than residence in camps although they settled in urban areas and cities [6], and living space can affect individual’s health through their insight and type of relationship with those environments [15]. Although access to the number of health services such as family planning is the same for all individuals in Iran, the study showed lower usage by Afghans [4]. Therefore, programs and projects must-have elements and factors to integrating refugees into those societies besides providing rehabilitation, treatment costs, assistive devices, and environment adjustments.

Having one family member as a caretaker, although can reduce disability side effects and can lead to low family income especially when a father or mother with older ages becomes a caretaker and there might be an ambiguous future for them after losing their caretaker. This can also, besides low socioeconomic status, unemployment, and low grades of education may increase food insecurity [16] which may aggravate disability. Therefore, having an insurance system that covers both treatment and rehabilitation costs and pension payments can help them to have a better quality of life. Comprehensive health insurance would be one way for lowering out-of-pocket payments for using rehabilitation and health care services when it is almost the same as other citizens’ insurance. Health insurance in itself may not guarantee better access to health services for refugees. Since this coverage is at the very beginning steps, studies must be carried (both qualitative and quantitative) to discover accessibility, advantages, disadvantages, barriers, and the attitudes of refugees using services. Iran’s government has started to repatriate Afghan refugees but on the other hand, education, medical treatments, work, and economy have been reported as the main concerns of refugees to return to Afghanistan [8]. This situation may become more prominent for disabled refugees. Therefore, more comprehensive planes and dedicated projects to empower refugees are needed to facilitate repatriation. Changing trends from no education for girls towards educating them at any costs, as a result of staying in Iran during the past years, can be used as an opportunity for a succession of educational projects [8], although most of our disabled refugees remained without education. A program such as family planning and reproductive health was successful in the Afghan refugee society through shifting attitudes and beliefs [3] which indicates the possibility of making changes among them to achieve disability prevention.

Limitations and Strengths

The main limitations were the unwillingness of refugees and their families to participate and attend in disability assessment commissions and projects in addition to difficulties to have accurate information when asking sensitive questions such as housing and employment status. We were not able to collect income information of refugees since they did not have regular and monthly paid jobs. These limits may be partially or completely due to fear of returning to Afghanistan [16]. Although we had training sessions for our facilitators, a longer period of education with more materials would increase their competence. Inability to have and involve undocumented disabled refugees [17] in this and similar projects was another problem since they live in the society, not in camps. As a strength, we used Afghan facilitators to make better trust and tackle the language and ethnic barriers.

Conclusion

Although joint programs are comprehensive and may lead to better service delivery to those marginalized groups including refugees, cooperating organizations and sectors need to be in line with the goals of those programs.

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Biomarker of Cerebral Injury S100 During Carotid Endarterectomy

Introduction

Carotid Endarterectomy (CE) is a surgical procedure that has been widely accepted as the appropriate means to reduce the likelihood of Ischaemic Stroke (IS) in the setting of severe carotid artery stenosis. A possible complication of the surgery may be IS. The main cause of a cerebrovascular insult is reduced blood flow through the brain during cross clamping of the Internal Carotid Artery (ICA). Immediate and correct recognition of insufficient collateral flow is crucial for a good outcome of the vascular surgery [1]. General use of a temporary vascular bypass (shunt) during surgery increases the complexity of the endarterectomy and may injure the vascular wall, leading to thromboembolism [2]. This implies the need for neuromonitoring to select patients who will benefit from shunt insertion [3]. Patients undergoing CEA under Local Anaesthesia (LA) are monitored clinically, preferably with neuromonitoring, which enables a more appropriate shunt insertion than other methods [4].

This is not possible in patients undergoing surgery in general anaesthesia, and therefore a suitable method of good neurological monitoring is being sought for these patients. Objective value of methods of monitoring patients during CEA was evaluated by studying serum levels of biochemical markers of brain injury. One of the most investigated is the serum protein S100B [5]. The neuroprotein S100B is a subunit of calcium-binding protein B identified in astroglia and Schwann cells. S100B’s function has yet to be fully explored and defined. At nanomolar concentrations, S100B stimulates axon development and neuronal survival. At micromolar levels, it causes apoptosis and increases the production of inflammatory cytokines [6]. Even during clinically atypical CEA, S100B in peripheral blood is a sensitive sign of Blood-Brain Barrier (BBB) failure and ischemic brain injury [7,8]. Peak S100 B levels can be found as early as 20 minutes after brain injury. On the other hand, it has a biological half-life of 30 to 113 minutes and is eliminated quickly by the kidneys [9]. In the previous decade, concerns regarding mild, subclinical brain harm after carotid revascularization have been raised [10].

Cappocia [11] et al. analyzed SB100 values as continuous and categorical data and found that they can be correlated with subclinical brain injury to some extent. Sahlein [12]. Inserted a 6 French Fogarty catheter rostral to the jugular bulbus through the facial vein. Fifteen minutes after carotid artery blockage, S100B levels in the jugular bulbus were considerably higher compared to baseline values. Some studies linked slight cerebral injuries following CEA and a large increase in serum S100B levels [13,14]. Several studies have found a large increase in S100B levels after declamping [15,16], followed by a reduction in S100B levels 24 hours later [10,17]. Falkensammer [18] investigated the relationship between perioperative levels of the molecular marker S100B and the likelihood of subclinical abnormalities in cerebral function and mild cerebral injury following CEA. Aleksic [4] observed a small but considerable increase in arterial S100B levels during carotid ventricular declamping.

NIRS (near-infrared spectroscopy) is a technique for determining regional oxygen saturation (rSO2). NIRS monitoring was employed in our department during CEA in all patients. A near-infrared light (NIR) emitting element is placed on the skin above the forehead to perform NIRS. Because NIR light penetrates through human tissue, some of it passing through the skin, subcutaneous tissue, and bone. The cerebral parenchyma reflects some of the light that reaches the brain. At particular wavelengths, the reflectance of brain tissue is substantially determined by the concentration of oxygenated haemoglobin in the tissue. The device records the amount of reflected photons as a function of wavelength by detecting the reflected photons. The INVOS system determines tissue oxygenation by measuring the amount of reflected light at wavelengths of 730 and 810 nm and calculating the regional oxygen saturation of haemoglobin (rSO2 index, sometimes known as simply rSO2) [19]. The aim of this pilot investigation was to see if a raised serum S100B level or a decrease in rSO2 following carotid revascularization with CEA might be used to detect neurological instability in CEA patients. Increased serum S100B levels during CEA, we hypothesized, would be linked to neurological symptoms after surgery.

Patients and Methods

Study Population

A prospective observational study design was performed with patients admitted to the Department of Vascular Surgery of Novo mesto General Hospital who underwent CEA between. Sixty adults (41 men, 19 women) between the ages of 50 and 86 years who underwent 64 CEAs over a 12-month time period were studied. The approval of the National Medical Ethics Committee of the Republic of Slovenia was obtained; written informed consent was obtained from all the patients. Indications for CEA included ipsilateral neurological symptoms (stroke, Transient Ischaemic Attack [TIA], amaurosis fugax), with ≥50% ICA stenosis, and both symptomatic and asymptomatic patients with 70% to 99% stenosis.

Carotid Endarterectomy

Twenty-six patients were symptomatic, and all were scheduled to undergo CEA with regional anaesthesia achieved by the combination of superficial and deep cervical plexus block (100 mg levobupivacaine + 200 mg lidocaine). After carotid clamping, neurological assessment was performed by having the patient squeeze into the contralateral hand and speak. Neurological assessment was continuous throughout the operative procedure at 3-min intervals. The patients were assigned to one of two groups: those who developed neurological symptoms (neurological symptoms group) during clamping and those who did not (no neurological symptoms group). Criteria for the neurological symptoms group were development of motor weakness, slurring of speech, inability to respond appropriately to verbal commands, loss of consciousness, or seizure. These were also used as criteria for insertion of a shunt or anticipating a very short clamp time with primary closure. The patch closure was performed in 58 CEAs, with primary closure in 6.

Cerebral Oximetry

The cerebral oximeter INVOS 5100C (Somanetics) was used to measure simultaneous, bilateral rSO2 throughout the procedure. During surgery, brief and variable degrees of cerebral ischaemia occur during cross-clamping of the ICA [20,21]. The pre-clamping bilateral rSO2 value and the lowest ipsilateral measurement after ICA clamp placement were recorded. Inter subject variability in rSO2 index values is well known and was noticed in this study. To facilitate comparison of rSO2 changes after carotid cross-clamp among all patients, and to determine the magnitude of rSO2 change that was associated with a change in neurological function, the rSO2 data were normalised by calculating a percentage change in rSO2 reading during cross-clamp periods in each patient according to a formula (Figure 1). On the basis of previous studies [22], a decrease in rSO2 of ≥12% was considered clinically significant.

Figure 1: Thus, a change of rSO2 reading from a mean preclamp value of 60% saturation to a minimal (after cross-clamp) of 54% saturation according to this formula would represent a 10% decrease in rSO2 reading (percentage change = 10%).

Serum Biomarker of Brain Injury

Venous blood samples were obtained for each patient preoperatively (basal sample, preclamp), immediately after the end of the procedure (declamp), and 12 hours, 24 hours, and 48 hours after the surgery. Samples were allowed to clot. Blood samples were centrifuged within 30 minutes, and serum was stored at –20°C until assayed in duplicate in a single batch within 6 months. The concentrations of protein S100B and NSE were measured by automated electrochemiluminescence assay (Cobas e411 analyser, Roche Diagnostics, Mannheim, Germany). The lower limit of detection for protein S100B was 0.005 μg/L. The upper reference limit of protein S100B was set at 0.105 μg/L, representing the 95th percentile of the healthy population. The reference limit was provided by the manufacturer of the assay and verified by the laboratory. We compared the baseline value with the sample taken immediately after the end of the procedure. An increase of 25% was considered abnormal [11].

Statistical Analysis

The lowest values of rSO2 and highest values of S100B were used for comparison between the no neurological symptoms and neurological symptoms groups. The baseline characteristics of patients who developed neurological symptoms were compared with the patients with no symptoms using the chi-square test or Fisher exact test, where appropriate. In the case of continuous variables, the independent samples t-test or Mann-Whitney test was used. Of these results Positive Predictive Value (PPV), Negative Predictive Value (NPV), positive Likelihood Ratio (LR+), Negative Likelihood Ratio (LR-) and Diagnostic Odds Ratio (DOR) with 95% Confidence Intervals (CI) were calculated. ROC curve analysis was applied to identify the threshold values of parameters and the Area Under the Curve (AUC) values were compared. Statistical analysis was performed with R 3.5.2 statistical software (R Foundation for Statistical Computing, Vienna, Austria). A p-value less than 0.05 was considered as statistically significant.

Results

Baseline Characteristics

In this study, 64 CEAs were performed under regional anaesthesia. There were 41 (67%) men and 19 (33%) women; patient mean age (±SD) was 70.9 ± 8.5 years (range, 50-86 years). Two men and two women were operated bilaterally. Fifty-nine per cent of the CEAs were performed for asymptomatic disease, in comparison with 41% for symptomatic disease.

Demographics, Anatomy, and Pre-Operative Variables

There were no differences (Table I) in diabetes mellitus, hypertension, smoking, hypercholesterolaemia, coronary artery bypass graft, and chronic renal failure or peripheral artery disease between those with and without neurological symptoms. There were no significant differences in rates of overall prior carotid intervention, symptomatic features, contralateral carotid stenosis grade, or pre-operative diagnostics between the two groups. However, ipsilateral carotid stenosis grade of 50–69% (43% vs. 12%) were more common in those with neurological symptoms and ipsilateral carotid stenosis grade of 70–89% (57% vs. 88%) were more common in those without neurological symptoms (P = .056).

Table 1: Baseline characteristics of no neurological symptoms (NS-) and neurological symptoms (NS+) group.

Note: Results are presented as n (%) or mean ± standard deviation.

PCI: Percutaneous Coronary Intervention; CABG: Coronary Artery Bypass Graft; PAD: Peripheral Arterial Disease; CRF: Chronic Renal Failure; TIA: Transient Ischaemic Attack; CVI: Cerebrovascular Insult; CEA: Carotid Endarterectomy; CAS: Carotid Artery Stenting; CTA: Computer Tomographic Angiography.

Operative and Post-Operative Variables

Neurological deterioration after carotid clamping occurred (neurological symptoms group) in 7 (10.9%) operations. Neurological change resolved after insertion of an intravascular shunt. The median [1stQ, 3rdQ] duration of carotid cross-clamping were 23.2 [19.8, 28.9] minutes and 20.9 [12.4, 29.2] minutes in the no neurological and neurological symptoms groups, respectively (Table 2). This difference was not statistically significant (P=.519). A prosthetic patch was used in 58 (90.6%) procedures and primary closure in 6 (9.4%) procedures.

S100B

Table 2: Operative in post-operative factors in patients without Neurological Symptoms(NS-) and patients with Neurological Symptoms (NS+) during CEA.

Note: Results are presented as median [interquartile range].

CEA = carotid endarterectomy; rSO2 = cerebral oxygen saturation; S100B = protein S100B.

Median [1stQ, 3rdQ] baseline serum levels of protein S100B in the asymptomatic patients and symptomatic patients were 0.030 [0.021, 0.053] and 0.037 [0.025, 0.060], respectively. There were no significant differences in baseline preclamp concentrations of protein S100B between the patients (P = .456; Mann-Whitney U test). Percentage of increase in S100B parameter at different timeframes for the no neurological symptoms and neurological symptoms groups are depicted in Figure 2. The median serum S100B level increase was 36.2% [6.9%, 79.0%] (median [1stQ, 3rdQ]) in the neurological symptoms group, compared with –2.7% [–30.9%, 25.5%] (median [1stQ, 3rdQ]) in the no neurological symptoms group. The highest increase of serum S100B protein was 209%. The increase was significantly different between the groups (P = .040; Mann-Whitney U test) (Figure 2). This finding indicates that neurological instability that occurs after clamping correlates with the increase in S100B level. Neurological change could be predicted as a function of a 25% increase of S100B marker. Applying this technique, the Area Under the Curve (AUC) was 0.7393 (95% confidence interval CI = [0.5472, 0.9315]), and the diagnostic sensitivity and specificity were 71.4% and 75.4%, respectively. The threshold for S100B of 22.5% increase was optimal to identify patients with neurological symptoms (Figure 3 & Table 3).

Figure 2: Percentage of increase in S100B parameter at different timeframes for the no neurological symptoms and neurological symptoms groups.

Figure 3: ROC curve for performance of S100B declamp percentage change in prediction of neurological symptoms. The closest top left point is at threshold value 22.5% with sensitivity of 71.4% and specificity of 75.4%. The area under the curve is 74% (95% CI: 55-93%).

Cerebral Oxygen Saturation

The decrease in rSO2 from the preclamp to cross-clamp period on the ipsilateral side was not statistically significant between the groups. The median rSO2 decrease was 15% [6%, 21%] (median [1stQ, 3rdQ]) in the neurological symptoms group vs. 10% [6%, 19%] (median [1stQ, 3rdQ]) in the no neurological symptoms group (P=.675, Mann-Whitney U-test). The correlation between changes in rSO2 and neurological symptoms was analysed and by ROC analysis, a cut-off of rSO2 decrease of 13.4% was determined to be optimal for identifying patients with neurological symptoms, AUC = 0.5489, 95% CI = [0.3327, 0.7651]. Sensitivity and specificity were 57.1% and 63.2%, respectively (Figure 4 & Table 3).

Table 3: Results of ROC curve analysis with threshold values.

Note: Results are presented as value (95% CI).

AUC: Area Under The Curve; rSO2: Cerebral Oxygen Saturation; S100B: Protein S100B.

Figure 4: ROC curve for performance of rSO2 post-clamp percentage change in prediction of neurological symptoms. The area under the curve is 55% (95% CI: 33-77%).

Contralateral Carotid Occlusion

There were no statistically significant differences between contralateral carotid occlusion and neurological symptoms (P=1), contralateral carotid occlusion and serum S100B increase (P=.466), or contralateral carotid occlusion and rSO2 fall (P=.418).

Prediction of Neurological Symptoms

The PPV for the prediction of neurological symptoms during the CEA was 16% for the rSO2 parameter; for the S100B parameter the values were 26% for declamp, 22% for 12h post-operative, 19% for 24h post-operative, and 14% for 48h post-operative. The NPV for the rSO2 parameter and S100B parameter at different timeframes were 92%, 96%, 91%, 92% and 91%, respectively (Table 4). However, in terms of LR considered as minimally predictive, the declamp S100B parameter had amongst other measurements the highest LR+ (2.9, 95% CI: 1.5-5.6) and lowest LR- (0.4, 95% CI: 0.1- 1.2). Also in terms of DOR, this parameter performed best (7.7, 95% CI: 1.4-44.0).

Table 4: Performance of rSO2 and S100B parameters in prediction of neurological symptoms.

Note: Results are presented as value (95% CI).

rSO2: cerebral oxygen saturation; S100B: Protein S100B; PPV: Positive Predictive Value; NPV: Negative Predictive Value; LR+: Positive Likelihood Ratio; LR-: Negative Likelihood Ratio; DOR: Diagnostic Odds Ratio

Peri-Operative Outcomes

Two (3.1%) perioperative strokes occurred. The single major stroke happened on day 6, and the patient had decreased responsiveness to verbal commands and developed left hemiplegia. The diagnosis of stroke was based on the clinical and computed tomography finding of a focal ipsilateral ischaemic cerebral infarct with a patent CEA site on angiography. The patient was asymptomatic. The other patient had mild neurological deficits with complete recovery without re-exploration of the carotid artery. The patient was symptomatic. Both patients were shunted, and had normal rSO2, and increased S100B markers.

Discussion

The key conclusion of this pilot investigation was that increased serum levels of S100B protein, a brain marker, were associated with increased neurological instability. A statistically significant difference was only revealed by decapitation measurements and disregarded by 12-, 24-, and 48-hour post-operative measurements. The early mechanism of S100B release, which happens minutes later, is still unknown. The low amount of hypoperfusion associated with carotid artery occlusion may cause minor blood-brain barrier disruption, which could explain the early rise of serum S100B. [12,23]. Although S100B been linked to cerebral ischaemia, developing it into a biomarker for differential diagnosis in clinical practice has been problematic [24,25]. Several writers have claimed that elevated levels of S100B in the blood are not unique to stroke, claiming that the rise occurs in other neurological disorders with similar symptoms [26].

During carotid clamping, seven (10.9%) of the patients who needed shunting developed cerebral ischaemia (neurological deficit). These findings for CEA in conscious patients are similar to those reported by Hans [27] (10%), Evans [28] (9.7%), Calligaro [29] (7.2%), Stroughton [30] (14%), and Rockman [31] (11%). Of the 7 patients who required shunting due to a lack of compensatory blood flow, five patients were in the S100B-positive group. With a sensitivity of 71.4 percent and a specificity of 75.4 percent, we were able to predict neurological alterations in connection to an increase in the S100B marker. A 22.5 percent rise in neurological symptoms was used as the threshold value. Because of the lengthy test process, measuring serum S100B protein for perioperative neuromonitoring is currently not possible. Existing assays lack sensitivity and are difficult to use, and they often take 3 hours to complete. For the measurement of S100B protein, a quick and sensitive immunoassay would be required.

Furthermore, when compared to results acquired after carotid surgery under general anaesthetic, the observed rise in serum S100B protein during transverse clamp in LA was less pronounced (GA). In our study, the average rise in S100B was 12 percent. During CEA in the LA, Aleksic [4] observed a rise of 18% in serum S100B levels. Jaranyi [32] found a 170 percent increase in serum S100B levels in patients undergoing CEA while under GA. This indicates relevant global cerebral ischaemia. S100B levels and cerebral ischaemia alterations in patients undergoing CEA under LA are unlikely to apply to patients undergoing CEA under GA [29].

Symptomatic patients had greater preclamp S100B concentrations than asymptomatic patients. The median baseline serum S100B protein levels were 0.037 g/L and 0.030 g/L, respectively. The difference (P = 456) was not statistically significant. S100B protein peak levels could be identified as early as 20 minutes after cerebral injury. Its biological half-life ranges from 30 to 113 minutes, and it is quickly excreted by the kidneys. Concentrations return to near pre-clamp levels 24 hours after surgery, and by the third post-operative day, they recover completely. In our investigation, all symptomatic patients were operated on more than 72 hours after the onset of carotid symptoms. There were no expected significant variations in baseline S100B protein levels between asymptomatic and symptomatic individuals before surgery. Dragas [10] discovered that symptomatic patients had considerably greater preclamp S100B concentrations. He attributed this to greater embolic potential of symptomatic carotid plaques.

In the group with neurological symptoms, the decline in rSO2 from the preclamp to the cross-clamp period on the ipsilateral side was not significantly greater (P =675). Furthermore, the low AUC value shows that the link between rSO2 percentage reduction and neurological symptoms is at best shaky. In recognizing patients with neurological symptoms, the relative decline in rSO2 is neither sensitive (57.1%) nor specific (63.2%). These findings do not support cerebral oximetry as the sole monitoring modality during carotid endarterectomy. When comparing groups, the absolute lowest value of rSO2 on the contralateral side was statistically different (P =042). This has no clinical implications because baseline rSO2 measurements vary greatly between individuals [33,34]. The range of baseline rSO2 values is large, ranging from 47% to 86%. Rather than using absolute numbers, relative changes in rSO2 should be used [35]. One of the existing rSO2 monitoring’s drawbacks is that the oxygen sensor can only be utilized on hairless scalps.

Other areas of the brain may acquire focal cerebral ischaemia without the drop in rSO2 seen by the scalp sensors [20]. After an abrupt fall in blood flow in brain tissue (which may involve an exponential decrease in tissue oxygenation) with compensation for blood pressure variations, secondary dilatation of the microcirculation due to autoregulation or opening of collateral arteries occurs [36]. Even if intracranial collateral anastomoses exist, they are insufficient to sustain baseline intracerebral oxygen saturation in the brain. The presence of moderate reductions in rSO2 has not been linked to cerebral hypoperfusion severe enough to cause cerebral ischaemia [1]. The crucial rSO2 drop that the brain can endure is unknown.

One of the existing rSO2 monitoring’s drawbacks is that the oxygen sensor can only be utilized on hairless scalps. Other areas of the brain may develop focal cerebral ischaemia without a drop in rSO2 registered by the scalp sensors [20]. After an abrupt fall in blood flow in brain tissue (which may involve an exponential decrease in tissue oxygenation) with compensation for blood pressure variations, secondary dilatation of the microcirculation due to autoregulation or opening of collateral arteries occurs [36]. Even if intracranial collateral anastomoses exist, they are insufficient to sustain baseline intracerebral oxygen saturation in the brain. The presence of moderate reductions in rSO2 has not been linked to cerebral hypoperfusion severe enough to cause cerebral ischaemia [1]. The crucial rSO2 drop that the brain can endure is unknown.

A 13 percent (13.4 percent) reduction in rSO2 was found to be best for detecting individuals with neurological symptoms in our study, with sensitivity and specificity of 57.1 percent and 63.2 percent, respectively. The results were identical to those of Al- Rawi [21] and Mille [22], who used cut-off values of 13% and 12% (11.7%), respectively. There were 8 patients with contralateral carotid occlusion among them. One exhibited neurological symptoms, one had an elevated S100B level in the blood, and two had a considerable drop in rSO2. The need for a shunt is not consistently predicted by contralateral carotid occlusion. Two patients experienced a cerebrovascular insult (CVI). The patient suffering CVI during the procedure exhibited the largest rise in serum S100B protein of all the patients, but her rSO2 was normal. Higher blood S100B protein levels with a late peak are linked to more extensive cerebral injury. In patients with subclinical cerebral tissue death, serum levels are lower and peak increasingly earlier [37]. On the sixth day after the operation, the second patient developed a CVI. Although there was a considerable rise in serum S100B protein, rSO2 remained normal. The CVI attack was predicted by neurological instability and an elevated level of S100B. This was not the case with rSO2.

Limitations

The study had several limitations. First, despite the huge patient group, it was constrained by the small number of patients who experienced neurological symptoms during the surgery. Second, the reported higher S100B levels in the blood of hypertension patients relative to healthy controls made employing the S100B biomarker to diagnose cerebral ischaemia challenging [38]. In terms of serum S100B increase, we did not compare the hypertensive and nonhypertensive categories. Third, different surgeons may assess neurological signs differently during surgery.

Conclusion

Awake neuromonitoring has been found to provide a sensitive and direct evaluation of brain tissue perfusion and is specific to CEA under LA. Although there was a favourable connection between CEA and an increase in serum S100B protein, due to the long assessment time, serum S100B monitoring was not practicable (usually 3 hours). The small number of patients in the study makes it impossible to draw clear conclusions, particularly in the group of people who suffer from neurological problems. Future research will either support or refute our findings.

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