Supplement_2024
In vitro characterisation of antioxidant, anti-aging, anti-alzheimer, anti-obesity, antidiabetic activities of silver nanoparticles synthesised from salvia willeana
Emrah Caylak 1, Gokhan Nur 2
1 Department of Biochemistry, Faculty of Medicine, Girne American University, Kyrenia, Cyprus, 2 Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Iskenderun Technical University, Hatay, Turkey
DOI: 10.4328/ACAM.22120 Received: 2024-01-18 Accepted: 2024-03-15 Published Online: 2024-03-19 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S1-7
Corresponding Author: Emrah Caylak, Department of Biochemistry, Faculty of Medicine, Girne American University, Kyrenia, Cyprus. E-mail: emrah333@hotmail.com P: +90 544 613 49 99 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0408-9690 Other Author ORCID ID: Gokhan Nur, https://orcid.org/0000-0002-5861-8538
Aim: In this study, we used silver nanoparticles (AgNPs/Sw) synthesized from Salvia willeana to investigate the plant’s antioxidant properties and protective activities against aging, Alzheimer, obesity, and diabetes.
Material and Methods: Post-synthesis characterisations of AgNPs/Sw were confirmed using UV, FTIR, XRD and SEM methods. Firstly, aqueous, methanol and chloroform extracts of S. willeana were prepared, and the methanol extract was found to have the highest phenolic content. Therefore, methanol extract was used in all analyses of our study. We analysed the lipid peroxidation inhibitory activity, 1,1-Diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging capacity, and iron reducing antioxidant power (FRAP) of AgNPs/Sw to determine their antioxidant properties. Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and amyloid-beta (Aβ) aggregation inhibition assays were performed to evaluate the anti-Alzheimer effects of AgNPs/Sw. Additionally, α-amylase, pancreatic lipase, and α-glucosidase inhibition activity tests were conducted to assess the protective effects of AgNPs/Sw against obesity and diabetes.
Results: Silver nanoparticles synthesised using S. willeana extract enhance the antioxidant, anti-aging, anti-Alzheimer, anti-obesity, and antidiabetic activities of the plant extract.
Discussion: AgNPs/Sw can be applied for therapeutic purposes in medicine.
Keywords: Salvia Willeana, Silver Nanoparticles, Antioxidant, Anti-Aging, Anti-Alzheimer, Anti-Obesity, Antidiabetic
Introduction
Salvia willeana grows endemically only in Cyprus and has been used for years as a functional tea that provides health benefits to prevent disease by strengthening human immunity. It is also used for abdominal pain, colds, and nausea. Compounds such as caffeic acid oligomers, phenolic, flavonoid and fatty acid derivatives have been isolated from S. willeana. Salvia spp. has been characterised as having antioxidant/antibacterial/anti-inflammatory/anti-diabetic/anti-aging, and tumour suppressor properties due to their isolated phenolic and flavonoid chemical compositions [1-3]. The phytochemical content of S. willeana extract (SwE) has not been extensively analysed.
Recent scientific studies about nanoscience can make important contributions to medicine, including the diagnosis, treatment, and prevention of diseases, as well as drug development. Nanoparticles (NPs) have been found to be effective as antimicrobial, antioxidant, antifungal, anticancer, and anti-diabetic agents in the treatment of diseases. Green synthesis is preferred over chemical reactions for obtaining nanoparticles due to its cost-effectiveness, environmental friendliness, and ease of preparation. Silver nanoparticles (AgNPs) are commonly used in health studies due to their unique optical, electrical, and thermal properties, as well as their antioxidant, antimicrobial, antifungal, and high catalytic activities [4].
Natural herbal products are commonly used to treat diseases, including Alzheimer’s disease, obesity and diabetes. One treatment strategy for these diseases is to inhibit the enzymes, and Salvia spp. is a promising research topic due to their potential inhibitory effects on enzymes. Thus, our study aims to examine the in vitro antioxidant activity of SwE and silver nanoparticles (AgNPs/Sw) and their protective effects against aging, Alzheimer’s disease, obesity, and diabetes.
Material and Methods
All chemicals and silver-nitrate (AgNO3) used in the study were obtained from Merck (Germany). S. willeana was collected in May 2023 from the Troodos Mountain in Nicosia. Some of them were kept at the University Pharmaceutical Research Institute. They were dried and grounded with an electric grinder.
Preparation of S. willeana extract
Firstly, aqueous, methanol and chloroform SwE were prepared [5]. For aqueous extraction, 50 g powdered S. willeana was added to a balloon flask and diluted with 250 mL distilled water. The mixture was boiled (15 min), cooled (20°C), and filtered through Whatman No. 1 filter paper. It was stored in the refrigerator (+4°C).
For methanol extraction, 50 g S. willeana powder was extracted with 95% methanol and filtered 5-7 times. It was then filtered through a Whatman No. 4 filter paper and concentrated using a rotary evaporator (IKA RV 10, Germany) at 50°C. It was dried and stored in a refrigerator (+4°C).
For chloroform extraction, 50 g S. willeana powder was placed in a balloon flask, and 300 mL chloroform was added. It was boiled (4 h) and filtered using Whatman No. 40 filter. It was concentrated in a rotary evaporator at 50°C, washed with warm hexane, yielding 4.55%.
Phytochemical analysis of SwE
The phytochemical analysis of SwE, they were resuspended in sterile phosphate-buffered saline (pH 7.2) to 200 mg/mL final concentration.
The total phenolic content of SwE was determined using the Folin-Ciocalteu method [5]. A blue solution was obtained by adding 50 μL each SwE to 5 mL Folin-Ciocalteu reagent and 5 mL Na2CO3. Then it was incubated (20°C/1 h), and the absorbance was measured at 760 nm using UV spectrophotometer (Shimadzu UV 1800 UV, Japan). Gallic acid was used as reference material, and the result was expressed as mg-gallic acid/g-SwE.
The total flavonoid content of the SwE extracts was determined using the aluminium-chloride method [5,6]. Briefly, 60 μL SwE were mixed with 4 mL distilled water and 20 μL aluminium-chloride reagent. The final volume was adjusted to 5 mL with pure methanol. It was incubated (20°C/30 min), and the absorbance was measured at 430 nm, spectrophotometrically. Quercetin was used as a reference chemical, and the result was expressed as mg-quercetin/g-SwE.
The alkaloid content of SwE was analysed using the bromocresol-green (BCG) method and produced yellow-coloured solution [5,6]. 200 μL SwE was diluted with 2 N HCl to 2000 μL final volume. It was washed triplicate with 10 mL chloroform in separating funnel, and then neutralised with 0.1 N NaOH. After 10 min, 5 mL BCG solution and 5 mL phosphate-buffer were added. After shaking thoroughly, we made 10 mL chloroform dilutions of SwE. We measured its absorbance at 470 nm, spectrophotometrically. The results were calculated used the formula [alkaloids=(Abs-0.048)/0.021], expressed as mg-SwE/mL.
In our study, as well as in another study [5], the highest phenolic content was found in the methanol extract (Table 1). Therefore, we used the methanol extract for all analyses.
Synthesis of AgNPs
Commercial AgNO3 was purchased to synthesise AgNPs. In a 1000 mL beaker, 500 mL AgNO3 and 50 mL SwE were added and stirred using magnetic stirrer (40-60°C/30 min). It was treated with ultrasound (3 h). As a result of the synthesis, the colour was changed from colourless to brown. It was then centrifuged with distilled water 10000×g/5 min, filtered, and dried in an oven (50°C/48 h). Absorbance was measured at 350-700 nm spectrophotometrically [7].
Evaluation of antioxidant activity
We analysed the lipid peroxidation inhibition, DPPH, and FRAP capacity of AgNPs/Sw [5,6]. The lipid peroxidation inhibition as MDA was determined by the thiobarbituric acid (TBA) test. Concentration series of AgNPs/Sw (50-100-150-250-500 mg/L) were prepared with 97% ethanol. A mixture 200 μL each of AgNPs/Sw, FeCl3, EDTA, H2O2 and ascorbic acid was added to a test tube and vortexed. It was then incubated (37°C/1.5 h), 1.2 mL TBA (28%) was added, and centrifuged (3000×g/15 min). The pellet was mixed with 1.2 mL TBA and boiled (100°C/10 min). After cooling on ice, the supernatant was discarded, and the absorbance was measured at 532 nm, spectrophotometrically. The results were expressed as pmol/mg-AgNPs/Sw.
To analyse the DPPH, first concentration series of AgNPs/Sw described above was prepared in 3.9 ml ethanol with DPPH. It was then vortexed (1 min), and incubated (20°C/1 h). The absorbance was measured at 517 nm, spectrophotometrically. Vitamin C was used as a reference sample. Each measurement was repeated three times. Equation 1 (Eq-1) was used to calculate the %inhibition DPPH. %inhibition=[(Acontrol-Asample)/Acontrol]×100.
The FRAP assay was performed preparing concentration series of AgNPs/Sw described above. 3.9 ml FRAP reagent (acetate buffer (pH 3.6)/tripyryltriazine in HCl/FeCl3) and 0.1 mL AgNPs/Sw were added in a test tube. After incubating (20°C/30 min), we measured the absorbance at 593 nm, spectrophotometrically. Trolox (TEAC) was used as a reference chemical, and FRAP activity was expressed as mg-TEAC/g-AgNPs/Sw.
Evaluation of anti-aging activity
The anti-aging effects of AgNPs/Sw were determined by assaying their anti-collagenase/elastase/hyaluronidase/tyrosinase activities.
In anti-collagenase assay [8], 0.5 mg azo dye-impregnated collagen, 400 μL Tris-HCl (0.1 M/pH 7), and 50 μL AgNPs/Sw were vortexed in a tube. Then, 50 µl collagenase (200 U/mL) was added, incubated (43°C/1 h), and centrifuged (3000×g/10 min). Its absorbance was measured at 550 nm, spectrophotometrically. Epicatechin gallate was used as a reference chemical.
To determine anti-elastase levels [8], in a test tube, 20 μL AgNPs/Sw was mixed with 80 μL Tris-HCl (0.1 M/pH 8) and 40 μL elastase. It was incubated (37°C/10 min. The reaction was initiated by adding 60 µL N-succinyl-(Ala)-3-nitroanilide. The absorbance was measured at 410 nm, spectrophotometrically. Oleanolic acid was used as reference chemical.
In anti-hyaluronidase assay [8], 20 μL AgNP/Sw and 20 μL hyaluronidase (8 mg/mL) were put in a test tube and then incubated (37°C/20 min). Next, 40 μL calciumchloride was added and incubated again (37°C/20 min). Then, 100 μL hyaluronic acid was added and incubated (37°C/40 min). 40 μL potassium tetraborate tetrahydrate and 4 μL NaOH were added to the solution. It was heated in a water bath (100°C/3 min). Finally, 1200 μL dimethylaminobenzaldehyde was added, cooled (20°C), and incubated (37°C/20 min). The absorbance was measured at 585 nm, spectrophotometrically. Indomethacin was used as reference chemical.
To determine anti-tyrosinase [8], 20 μL AgNP/Sw, 220 μL sodiumphosphate buffer (0.1 M/pH 6.8), 20 μL tyrosinase (1500 U/mL), and 40 μL L-tyrosine were added to the wells of a microtiter plate, and incubated (37°C/12 min). The reaction was stopped by placing the plate on ice. The absorbance was measured at 490 nm with microplate reader (Epoch2 Microplate Spectrophotometer, BioTech, USA). Alpha-kojic was used as reference compound.
Evaluation of anti-Alzheimer activity
The anti-Alzheimer effect of AgNPs/Sw was determined using acetylcholinesterase (AChE)/butyrylcholinesterase (BChE)/amyloid-beta (Aβ) aggregation inhibition assays.
In the determination of AChE/BChE inhibitions [9], hydrolysis of acetylthiocholine iodide (ATCh1) by AChE/BChE yields a 5-thio-2-nitrobenzoate anion as yellow complexes with 5,5’-dithiobis-2-nitrobenzoic acid (DTNB). 20 μL AgNPs/Sw, 300 μL sodiumphosphate buffer (100 mM/pH 8.0), 20 μL DTNB and 40 μL AChE (0.22 U/mL)/BChE (0.1 U/mL) were added to a test tube. The mixture was vortexed and incubated (37°C/10 min), and then 50 μL ATChl was added to initiate the reaction. After incubation (37 °C/15 min) the absorbance was recorded at 412 nm, spectrophotometrically. Galantamine hydrobromide was used as reference chemical.
For the Aβ-aggregation assay, thioflavin T (ThT) fluorescence test was performed [10]. Briefly, 40 μL AgNPs/Sw, 500 μL Aβ42 and 500 μL sodiumphosphate buffer (50 mM/pH 7.4) were added to a test tube, and incubated (37°C/48 h). 10 μL ThT-containing glycine/NaOH buffer (50 mM/pH 9.2) was added. Fluorescence intensities were measured at excitation-446 nm/emission-490 nm with a microplate fluorometer (Twinkle LB970, Germany). Curcumin was used as reference chemical. Fluorescence intensities were recorded and the percentage inhibition of Aβ-aggregation was calculated: %inhibition=(1-IFi/IFc)×100, where IFi and IFc were the fluorescence intensities at absorbances in the presence and absence of AgNPs/Sw, respectively.
Evaluation of anti-obesity activity
α-Amylase/pancreatic lipase inhibition assays were used to determine anti-obesity effects of AgNPs/Sw.
In α-amylase inhibition assay using 3,5-dinitrosalicylic acid (DNSA) method [9], DNSA reagent was prepared by mixing 12 g sodiumpotassiumtartratetetrahydrate in 8.0 mL NaOH and 20 mL DNSA. In a test tube, 500 μL AgNPs/Sw and 500 μL α-amylase (0.5 mg/ml) in sodiumphosphate buffer (0.02 M/pH 6.9) were mixed, and incubated (30°C/10 min). Then, 400 μL starch (1%) was added, and incubated again. The reaction was initiated adding 400 μL DNSA reagent in water-bath (85-90°C/10 min). It was cooled (20°C), and diluted in 10 mL distilled water. The absorbance was measured at 540 nm, spectrophotometrically. Acarbose was used as reference chemical and the results were calculated using Eq-1.
In pancreatic-lipase inhibition assay using p-nitrophenyl butyrate (PNPB) method [11], PNPB solution was prepared mixing 8.4 μL PNPB stock solution and 10 mL acetonitrile final volume. 250 μL AgNPs/Sw, 100 μL pancreatic-lipase (0.1 mg/mL) and 50 μL PNPB, and incubated (37°C/30 min). The hydrolysis amount of p-nitrophenol from PNPB by lipase enzyme was measured at 405 nm, spectrophotometrically. Orlistat was used as standard chemical, and the results were calculated using Eq-1.
Evaluation of antidiabetic activity
To determine the anti-diabetic effects of AgNP/Sw, α-amylase and α-glucosidase were determined (α-amylase enzyme assay was performed in the anti-obesity tests, above).
In α-glucosidase assay [9,12] using maltose as substrate. 80 μL AgNP/Sw, 2 mL maltose (2%) as subtrate and 2 mL α-glucosidase (1 U/mL) in phosphate buffer (10 mM/pH 8.0) were placed in a test tube, and incubated (37°C/5 min). The reaction was initiated by adding 100 µL methanol. The mixture was then placed in a water bath (2 min) and cooled (20°C). Absorbance values were measured at 695 nm, spectrophotometrically. α-Glucosidase inhibition was calculated using Eq-1.
Statistical analysis
SPSS (Statistical Package for Social Sciences) 25.0 was used, and data were analysed and compared by one-way analysis of variance (ANOVA) followed by post-hoc Tukey test. p<0.05 was considered statistically significant. Data are expressed as mean±SD.
Ethical approval
All the reagents used in this study were prepared, used, and disposed of according to the set laboratory guidelines and the material safety. Since no animals/humans were used during the study, it was stated by the university ethics committee that there was no need to get approval from the ethics committee.
Results
The assays to determine the total phenolic/flavonoid and/or alkaloid content in SwE were performed and the results are presented in Table 1. In our study, UV, FTIR, XRD and SEM techniques were used to control the green synthesis and catalytic activity of AgNPs/Sw. UV spectrophotometer was used to check the synthesis of AgNPs/Sw in at 300-700 nm, nm, and a sharp peak at 455 nm was observed (Figure 1A). FTIR spectroscopy was used to identify the secondary metabolites formed by the reaction of SwE with Ag ions. FTIR analysis revealed significant absorption peaks for AgNPs/Sw (Figure 1B).
The crystal structure and nanostructure of AgNPs/Sw were confirmed by XRD analysis. Confirmation of the crystal structure of 5 peaks for AgNPs/Sw presented in Figure 2A. They were possible due to the presence of Bragg reflection planes (111), (200), (220), (222) and (311). The morphology of the green synthesised AgNPs/Sw was confirmed by SEM. As shown in Figure 2B, they had a polymorphic appearance as granular clusters. SEM analysis for AgNPs/Sw revealed that their size was around 40 nm.
To determine their antioxidant properties of AgNPs/Sw, the in vitro effects of AgNPs/Sw on the inhibition of lipid peroxidation (MDA), DPPH, and FRAP capacity were analysed (Table 2). The anti-aging effects of AgNPs/Sw on collagenase/elastase/hyaluronidase/tyrosinase enzymes and the anti-Alzheimer/anti-obesity/antidiabetic inhibitory activities of AgNPs/Sw were shown in Table 3.
Discussion
Herbal medicines have become an integral part of complementary health care in the prevention and treatment of disease. Green synthesis of metal nanoparticles, a method of producing nanoparticles from medicinal plants, is a promising strategy in the medical world. In our research, silver nanoparticles were green synthesised using S. willeana in a highly efficient, cost-effective and simple process.
Phenolic compounds, which occur as secondary metabolites in plants, have been reported with their antioxidant, anti-aging, anti-Alzheimer’s, anti-obesity and anti-diabetic properties, help to reduce the development of many chronic diseases and cancer [3, 4]. Ercetin et al. [13] investigated the cholinesterase inhibition of S. willeana, and reported high flavonoid/phenolic contents in the plant leaves (547.55±3.12 and 300.24±1.23 mg/g, respectively). We and El Hajaji et al. [5] found that methanolic SwE had the highest phenolic content. Therefore, the methanolic extract was preferred in all subsequent analyses and procedures of our study.
In our study, after the synthesis of AgNPs/Sw, we checked the synthesis and catalytic activities of them using UV, FTIR, XRD and SEM techniques. UV spectroscopy confirmed the synthesis by the presence of an absorption peak at around 455 nm was ensured by plasmon resonance electrons on the surface of the nanoparticles [7]. FTIR was used to identify the secondary metabolites formed by the reaction of SwE with Ag ions and by the absorption peaks due to AgNPs/Sw synthesis and nanoparticle reduction, capping and stabilisation. The crystal structures and nanostructures of the synthesised S. willeana silver nanoparticles were confirmed by XRD analysis. The peak position, height and width determined by XRD analysis determine the nanocrystalline structure and purity of the nanoparticles. The morphology of AgNPs/Sw was confirmed by SEM, and they had a polymorphic appearance as granular clusters. Similar results also have been observed in previous studies on Salvia spp. [14, 15].
Reactive oxygen species (ROS) are highly reactive molecules produced during normal physiological metabolism in the human body. They can damage cells and cause lipid peroxidation, playing a role in chronic disease development [16]. Plant-synthesised nanoparticles effectively scavenge ROS, reducing oxidative stress. Studies have shown that S. willeana contains phytochemical components such as phenol, flavonoid, saponin, and alkaloid, which may be responsible for the biological reduction of Ag+2 ions in synthesised AgNPs and their beneficial effects. It has been observed that medicinal plants with high levels of antioxidant phytochemicals can enhance the inhibitory effects of silver green synthesis on lipid peroxidation [5]. Few studies have investigated the antioxidant, anti-aging, anti-Alzheimer, anti-obesity, and anti-diabetic activities of S. willeana [13, 17]. This study is the first to investigate the effect of silver nanoparticles synthesised using S. willeana. Ercetin et al. [13] conducted a study on S. willeana, and they measured the highest antioxidant properties in DPPH activity were observed in the methanol extracts prepared from the leaves and flowers of the plant (67.94±0.003% and 45.07±0.001%, respectively). Our study found that the level of MDA was significantly lower in AgNPs/Sw samples at 500 mg/mL concentration (649.56±62.24 pmol/mg). %Inhibition of DPPH and FRAP activities were higher in the same concentration of AgNPs/Sw (50.68±3.17%, TEAC-mg/g-AgNPs/Sw). This may be attributed to the high levels of phenolic and flavonoid compounds present in S. willeana, and it can suppress the formation of ROS and up-regulate antioxidant defence by chelating trace elements involved in ROS production [1, 2].
Recent scientific studies have focused on the anti-aging effects of herbs in preventing skin aging caused by internal and external factors. ROS production in the skin can cause oxidative stress, leading to damage to biological functions such as lipid membrane peroxidation, DNA destruction, and cell death; which contribute to skin aging, can activate dermal enzymes such as collagenase and elastase. These enzymes can break down and degrade the skin’s structures [8]. Hyaluronic acid (HA) is abundant in the dermis and epidermis layers of the skin. However, hyaluronidase, an enzyme that degrades HA and increases during the aging process, can be detrimental [18]. We investigated the anti-aging effects of AgNPs/Sw determining their anti-elastase/collagenase/hyaluronidase/tyrosinase. Previous studies have shown anti-aging enzyme activities for Salvia spp.: S. aytachii inhibited the activities of collagenase, elastase, and tyrosinase enzymes, or S. officinalis extract had inhibitory activity against hyaluronidase.
Traditionally, S. willeana have been also used as an alternative treatment agents in Alzheimer’s disease, helping delay metabolic pathways or inhibiting enzymes in increased biochemical reactions [19]. In vitro studies on Alzheimer have shown that AChE leads to the formation of amyloid fibrils, resulting in the conversion of toxic acetylcholinesterase-beta-amyloid peptide (Aβ) complexes in brain cells,and BchE activity is elevated in various brain regions of Alzheimer’s patients. AChE and BchE are recognized as suitable targets for Alzheimer’s treatment [10]. Intensive research is currently underway to find drugs or plant extracts that can inhibit cholinesterases, and Salvia spp. have been examined for their cholinesterase inhibitory activities. S. eriophora and S. mirzayanii extracts exhibited inhibitive activity against AChE and BChE enzymes [9,20]. Yilmaz et al. [1] reported that S. aytachii extract inhibited AChE and S. viridis extract inhibited BChE. Ercetin et al. [13] investigated the cholinesterase inhibition of S. willeana. The highest acetylcholinesterase/butyrylcholinesterase inhibitory potentials were measured in ethyl acetate and aqueous extracts prepared from the plant. In our study, AgNPs/Sw inhibited AchE and BChE by 26.48±4.6% and 25.87±3%, respectively, while the reference compound, galantamine was 90.52±6%. We also investigated the Aβ aggregation inhibition effect of AgNPs/Sw. AgNPs/Sw and curcumin inhibited Aβ42 aggregation by 25.42±5.9% and 67.37±7%, respectively. No similar studies using Salvia spp. were found in the literature. Boonsin et al. [20] researched the effects of Gryllus bimaculatus plant extract on Aβ aggregation and reported that concentrations of extract (1 and 10 mg/mL) inhibited Aβ aggregation by 18.90% and 22.92%, respectively.
Obesity is a widespread problem, and increases the risk of diabetes, cardiovascular and liver diseases. The aim of obesity treatment is to prevent excessive absorption of fat and sugar [21,22]. In this study, we examined α-amylase and pancreatic-lipase inhibitor activities as anti-obesity functional markers. Previous studies have reported that certain flavonoids, particularly those containing methoxy groups, can inhibit pancreatic lipase activity, thereby inhibiting the digestion and absorption of dietary fats [23]. The α-glucosidase enzyme plays a crucial role in carbohydrate digestion and absorption. Excess sugar is converted into fat and stored in the body, leading to obesity. Research has shown that polyphenols found in plants exhibit anti-obesity and antidiabetic effects by inhibiting α-glucosidase in vitro [24,25]. Mahdi et al. [24] reported the antidiabetic activity of α-amylase (IC50:104.58±0.06 mg/mL) in S. officinalis extracts. Assaghaf et al. [25] investigated the essential oils of S. officinalis and demonstrated in vitro inhibition of α-amylase and lipase with IC50 values of 69.23±0.1 and 37.3±0.03 µg/ml, respectively. In our study, we found that AgNPs/Sw inhibited α-amylase and lipase by 27.84±7.5% and 35.46±6.9%, respectively.
Diabetes Mellitus is a hereditary disease that results in an increase in the production of free radicals due to increased insulin use in the body. Our study examined the α-amylase and α-glucosidase, the carbohydrate digestion enzymes because the inhibition of those enzymes can be effective in treatment of diabetes. Plant extracts have been found to be effective enzyme inhibitors, such as the α-glucosidase inhibitory activity of S. officinalis extract [24,25]. We found that AgNPs/Sw inhibited α-glucosidase by 43.57±8.7%, compared to the standard acarbose inhibition of 82.47±8.3%.
Conclusion
On the island of Cyprus, S. willeana is traditionally used to treat respiratory, digestive, rheumatism, heart, skin, gynaecological diseases, and various cancers. In vitro studies on the Salvia species have shown that the plant extract contains phenolic compounds having antioxidant activity against ROS that occur in the body. Recently, there has been hope that nanoparticles produced through green biosynthesis of metal nanoparticles using medicinal plant extracts could be used in medicine to treat diseases. Our study showed that Ag-NPs/Sw had a potential to prevent and treat diseases due to their antioxidant anti-aging, anti-Alzheimer’s, anti-obesity, and antidiabetic properties that protect cells. Therefore, it is believed that they can offer numerous benefits to humanity in the field of medicine. It is recommended that future researches could enhance our understanding of the potential health benefits of Salvia spp., and nanoparticles.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Unexpected effect of upper eyelid blepharoplasty on lid position
Şule Berk Ergun
Department of Ophthalmology, Ankara City Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.22146 Received: 2024-02-13 Accepted: 2024-03-15 Published Online: 2024-03-19 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S8-11
Corresponding Author: Şule Berk Ergun, Department of Ophthalmology, Ankara City Hospital, Ankara, Turkey. E-mail: suleberk@yahoo.com P: +90 532 607 59 45 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6698-8440
This study was approved by the Ethics Committee of Ankara City Hospital (Date: 2023-12-17, No: E1-23-4565 )
Aim: The study aims to evaluate upper eyelid position after upper eyelid blepharoplasty by measuring margin-reflex distance 1 (MRD1).
Material and Methods: Patients who applied to the Oculoplasty Clinic of our hospital and underwent upper eyelid blepharoplasty between January 2021 and March 2022 were retrospectively scanned. Patients whose preoperative and postoperative 3rd month photographs were obtained were included in the study. Patients who had simultaneous ptosis surgery, internal or external browpexy, fat pack removal, or botulinum toxin injection within the last 6 months were not included in the study. MRD1 was measured using digital photographs with the help of a special program, and the values before surgery and 3 months after surgery were compared.
Results: Thirty-eight eyes of 19 patients (12 female, 7 male) were included in the study. The average age of the patients was 65.1 ± 6.01 (56-78). While the mean MRD1 value was 2.374 ± 0.755 mm before surgery, it was 2.501 ± 0.772 mm in the 3rd month after surgery. This difference was found to be statistically significant (p=0.022).
Discussion: Anticipating a change in MRD1 following blepharoplasty surgery will facilitate a more accurate determination of postoperative eyelid position. A significant increase in MRD1 was observed in the 3rd month after upper lid blepharoplasty surgery, and it is recommended that this effect should not be ignored when planning surgery.
Keywords: Blepharoplasty, Dermatochalasis, Margin-Reflex Distance
Introduction
In recent years, the frequency of upper eyelid blepharoplasty surgeries for cosmetic or medical reasons has been steadily increasing. Alongside this trend, patients’ post-surgical expectations have also risen. The position of the upper eyelid is a result of the complex interaction of multiple forces. These include the delicate balance between eyelid muscles, mechanical forces such as dermatochalasis and brow ptosis, as well as afferent neurological tone [1, 2]. It has been traditionally accepted in upper eyelid surgery that the margin reflex distance 1 (MRD1) typically cannot be altered solely by blepharoplasty surgery [3]. However, there are studies, albeit limited in number, that suggest otherwise [4-7].
Blepharoplasty surgeries performed at our clinic are for medical reasons, often involving cases with visual field limitations. Hence, the consideration that the extent of skin removal might impede the visual field, specifically reaching a point where it would accumulate above the eyelashes, raised the query: “Might there be a rise in lid position upon removal of this conspicuous tissue?” This study was designed with this question in mind. The potential alteration in MRD1 post-blepharoplasty in this patient group could influence surgical outcomes, particularly in cases with mild ptosis, knowing the possibility of such changes postoperatively is important, as it may prevent additional procedures such as simultaneous ptosis surgery. The primary aim of this study, designed with this consideration, is to evaluate the upper eyelid position after upper eyelid blepharoplasty by measuring MRD1 and comparing it with preoperative values.
Material and Methods
Patients who underwent upper eyelid blepharoplasty at the Oculoplasty Clinic of our hospital between January 2021 and March 2022 were retrospectively reviewed. Patients with a history of botulinum toxin injections in the last year and those undergoing simultaneous ptosis surgery, internal or external brow lifting, or intervention on fat pads were excluded from the study.
Age, gender, and MRD1 values obtained from patients’ medical records and digital photographs were recorded before surgery and at the 3-month postoperative follow-up.
Before taking a photograph encompassing the entire face with the patient seated, a round colored label with a diameter of 9 mm was placed between the eyebrows to serve as a reference when adjusting the measurement scale. Care was taken to ensure the frontalis muscle was not contracted. Image analysis was performed using ImageJ Software (ImageJ program 1.42; National Institutes of Health, Bethesda, MD), considering previous studies in the literature [8, 9].
Statistical analyses were performed using SPSS 25.0 software. The distribution of data was assessed using the Kolmogorov–Smirnov and Shapiro-Wilk tests. Descriptive statistics were used for demographic data; correlation analysis and paired samples t-test were performed for the evaluation of MRD1 before and after surgery. Pearson correlation coefficients were used to study the association between the two groups. A p-value of <0.05 was considered statistically significant.
Ethical Approval
The study was approved by the Ethics Committee of Ankara City Hospital (Date: 2023-12-17, No: E1-23-4565 ).
Results
A total of 38 eyes of 19 patients, 12 of whom were female (63.2%) and 7 male (36.8%), were included in the study. Table 1 shows patient demographics as well as preoperative and postoperative MRD1 measurements following blepharoplasty at 3 months. The mean age of the patients was 65.1 ± 6.01 years (range: 56-78). The mean MRD1 value was 2.374 ± 0.755 mm preoperatively and 2.501 ± 0.772 mm at 3 months postoperatively, with this difference being statistically significant (p=0.022). Besides the statistical significance of the difference in MRD1 values preoperatively and postoperatively, there was a nearly perfect significant positive correlation between these values (r=0.909, p<0.001). No complications were observed in any of the surgeries.
Discussion
In recent years, the demand for upper eyelid blepharoplasty has been on the rise. At our clinic, this procedure is conducted not for cosmetic purposes but for medical reasons, with visual field limitations being the primary determinant. Therefore, it was thought that the mechanical effect of this prominent tissue, which reaches a level that piles up above the eyelashes, would be eliminated, allowing the levator and Muller muscles to lift the eyelid more comfortably. The position of the upper eyelid is a result of the complex interaction of multiple forces, including the delicate balance between eyelid muscles, the amount of dermatochalasis and brow ptosis, as well as afferent neurological tone [1, 2]. However, despite the assumptions that mechanical depressor effects decrease and the orbicularis oculi muscle (OOM) may weaken as a result of upper eyelid blepharoplasty, the net effects of mechanical-neurological interactions on eyelid position have not been definitively determined [3, 10].
In the study, which was designed with the idea that the possible change in MRD1 after upper eyelid blepharoplasty surgery would affect the results of the surgery, a significant increase in MRD1 was observed as a result of the evaluation of digital photographs before and 3 months after surgery.
Similarly, in the study by Tanju et al., statistically significant increases in MRD1 were observed following blepharoplasty surgery [5]. Additionally, Bunyada et al. emphasized that in their study, approximately 15% of patients experienced a decrease of >1 mm in MRD1 after upper eyelid blepharoplasty, with a higher likelihood of this decrease observed in those who underwent OOM resection. While upper blepharoplasty stands as a frequently conducted procedure in aesthetic surgery, consensus on the management of the OOM remains elusive. Although there are studies suggesting that OOM resection leads to a reduction in MRD1, it has also been noted that it does not create a significant difference in the long term [11, 12]. Since muscle removal does not offer additional benefits, preservation of the muscle is generally recommended [13].
In our study, the preservation of the OOM may have contributed to the observed increase in MRD1 rather than a decrease. When considering the explanation of MRD1 increase as the removal of mechanical effects of the skin tissue, it can be hypothesized that the OOM may exert an elevating effect on eyelid position upon relief of its own weight. However, due to its deeper location compared to the skin, its vectorial weight effect would be less than that of the skin. This is the author’s own interpretation, and no studies have been found in the literature that examine these mechanical balances in terms of the surface area or weight of the excised skin or the OOM. However, interventions on the OOM have been associated with potential damage to deeper elastic fibers or even the levator aponeurosis [14]. This mechanism may explain the increased likelihood of MRD1 decrease with the excision of the OOM.
Anticipating a change in MRD1 following blepharoplasty surgery will facilitate a more accurate determination of postoperative eyelid position. Considering that cases performed in our clinic are primarily driven by medical necessity rather than cosmetic concerns, the unexpected increase in MRD1 can be explained as a result of the removal of mechanical weight exerting influence on the eyelid following anterior lamellar resection, allowing the levator and Muller muscles to lift the eyelid more comfortably. Particularly in cases with significant dermatochalasis where simultaneous ptosis surgery is also planned, it is important to consider this effect.
Limitation
One of the limitations of the study can be stated as the small number of cases. This was due to the fact that a single type of surgical method was chosen in order to minimize the factors that could affect the results, and cases were excluded from the study if additional procedures were performed during surgery. Another limitation can be considered as not evaluating the eyebrow position, but it has been shown before; in cases with dermatochalasis, changing the eyebrow position manually does not affect MRD1 measurements, therefore no change is expected after surgery [15].
In future large-scale studies on this topic, enlightening additional information could be obtained by examining the area or weight of the excised tissue along with assessing whether the OOM was excised.
Conclusion
A significant increase in MRD1 was observed at 3 months post upper eyelid blepharoplasty surgery, suggesting that this effect should not be overlooked during surgical planning.
Acknowledgment
I would like to extend my gratitude to Dr. Önder Eraslan for his contributions to the statistical analysis.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
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Evaluation of cardiac and non-cardiac side effects of low dose oxytocin used during caesarean section
Emine Aslanlar
Department of Anesthesiology and Reanimation, Faculty of Medicine, Selcuk University, Konya, Turkey
DOI: 10.4328/ACAM.22151 Received: 2024-02-16 Accepted: 2024-03-16 Published Online: 2024-03-19 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S12-16
Corresponding Author: Emine Aslanlar, Department of Anesthesiology and Reanimation, Faculty of Medicine, Selcuk University, Konya, Turkey. E-mail: draslanlar@gmail.com P: +90 555 621 98 30 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3849-9137
This study was approved by the Ethics Committee of Selçuk University Faculty of Medicine Clinical Research Ethics Committee (Date: 2020-07-09, No: 2020/17)
Aim: Low-dose administration (<5 units) of oxytocin used in the prophylaxis of postpartum haemorrhage has been recommended because of its haemodynamic side effects. We aimed to analyse the cardiac and non-cardiac side effects of oxytocin, which we prefer to administer 2 units as a low dose, in a large patient population.
Material and Methods: In this observational drug study, patients aged 18-40 years with ASA II physical status scheduled for elective caesarean section under spinal anaesthesia were included. Oxytocin 2 unit intravenous bolus in 5-10 seconds was administered after placenta removal. 23 unit/1000 ml oxytocin infusion was started to be administered within 4 hours after bolus. Cardiac side effects such as hypotension, tachycardia, arrhythmia, T-negativity, ST depression and other adverse effects such as nausea-vomiting, headache, flushing, burning sensation on the face, metallic taste on the tongue after oxytocin bolus were assessed.
Results: The study included 417 patients. Tachycardia was the most common cardiac side effect with a rate of 42.9%, while T-negativity was the least common cardiac side effect with a rate of 1%. Hypotension was observed in 14.6%, chest pain in 10.1% and dyspnea in 5.5%. Headache was the most common non-cardiac side effect (21.6%). The most common type of headache was throbbing (12.5%). Nausea-vomiting occurred in 13.7%, metallic taste on the tongue in 9.4%. 56 patients required methylergonovine. The estimated blood loss was 618.5 ± 326.3 ml.
Discussion: Cardiac and non-cardiac side effects can be seen even with low dose (2 unit) oxytocin administered bolus in 5-10 seconds.
Keywords: Cesarean, Low Dose Oxytocin, Cardiac Effect, Non-Cardiac Effect
Introduction
Oxytocin is the primary drug used in the prevention and treatment of postpartum haemorrhage [1]. Current guidelines for oxytocin administration during caesarean are diverse, leading to considerable variability in global clinical practice. With unspecified rate and total dose, the World Health Organisation recommends 20 international unit/litre (IU/L) infusion of oxytocin, and the American Academy of Obstetricians and Gynaecologists recommends infusing between 10-40 IU/L. The Royal College of Obstetricians and Gynaecologists recommends that 10 IU oxytocin bolus should be abandoned due to haemodynamic side effects, and instead the bolus dose should be 5 IU and administered slowly [2].
Vascular endothelial cells possess oxytocin receptors. The interaction between oxytocin and the endothelial receptor results in vasodilation through nitric oxide. Vasodilation is the first cardiovascular event that develops after oxytocin use and results in hypotension. Oxytocin causes vasodilatation in peripheral vessels but vasoconstriction in coronary vessels. Chest pain, ST depression and T negativity on ECG may be observed in the patient due to myocardial ischaemia developing as a result of coronary vasospasm. After 2 maternal deaths due to cardiovascular instability were reported with 10 IU bolus of oxytocin, the bolus was reduced to 5 IU [2]. The observation of side effects even in 5 IU bolus applications has led to studies at lower doses. Doses lower than 5 IU have been shown to further reduce hemodynamic side effects without affecting blood loss. In addition, oxytocin may result in nausea-vomiting, headache and flushing. Oxytocin is on the list of ‘high alert drugs’ due to cardiac and non-cardiac side effects [3].
Despite more than 60 years of use, there is a need for further research and refinement of the use of this agent [3]. There were very few studies in the literature in which a 2 IU bolus was administered [4]. Therefore, we aimed to determine the incidence of side effects of 2 IU bolus oxytocin in a larger patient population.
Material and Methods
The patient was included from December 2020 to April 2022. Informed consent was obtained from all participants. Patients aged 18-40 years, with ASA II physical status, who were planned to undergo caesarean section under spinal anaesthesia under elective conditions were included in this study. Patients who underwent emergency caesarean section or general anaesthesia, had heart disease, pulmonary embolism or chronic respiratory disorders, and ASA > II were excluded. Cases that met the study conditions but failed spinal anaesthesia or returned to general anaesthesia were excluded from the study.
Demographic data, including age, height, weight, body mass index, comorbidities, gestational hypertension, and gestational diabetes mellitus, were collected. Patients were placed in a 15° left lateral tilt position to prevent aortic-caval compression syndrome. Standard monitoring was carried out, including non-invasive blood pressure, pulse oximetry, and electrocardiography. Blood pressure was measured every two minutes. After providing antisepsis, spinal anesthesia was applied with a 25 G Quincke-tipped spinal needle through the L3-L4 or L4-L5 intervertebral space in sitting position. Hyperbaric bupivacaine (%0.5) 9-10 mg and fentanyl 10 mcg was injected intrathecally. Surgery was allowed to start when the sensory block level was T6 dermatome and above. Spinal anesthesia induced hypotension episodes were treated with ephedrine 10 mg. Atropine 0.5 mg was administered when bradycardia developed.
1 IU/1 ml oxytocin was obtained by adding 4 ml isotonic solution to 5 IU/1 ml oxytocin, 2 IU of which was used for bolus administration and the remaining 3 IU was added to the solution containing 20 IU oxytocin (20 IU+3 IU) and a total infusion dose of 23 IU/1000 ml was prepared. Following delivery of the fetus, the placenta was removed and oxytocin was administrated as 2 IU IV bolus in 5-10 seconds. After bolus administration, 23 U/1000 ml oxytocin infusion was started to be administered over 4 hours. The obstetrician assessed uterine tone after removing the placenta and performing uterine massage. Methylergonovine 0.25 mg was administered intramuscular if uterine tone was inadequate.
It was evaluated whether cardiac side effects such as hypotension, tachycardia, arrhythmia, T negativity, ST depression developed after oxytocin bolus administration. Blood pressure and heart rate last measured before oxytocin bolus administration were considered as baseline values and changes were compared with these baseline values. A 20% decrease in blood pressure was considered hypotension and a 20% increase in heart rate was considered tachycardia. The patient was asked about the presence of chest pain and shortness of breath, which are cardiac side effects, and they were evaluated as present or absent.
The presence of symptoms such as nausea-vomiting, headache/type/localisation, flushing, burning sensation on the face, metallic taste on the tongue were evaluated by asking the patient. The type of headache was classified as throbbing, compressive, blunt, and the localisation of headache was classified as frontal, temporal, occipital, and diffuse. Nausea and vomiting, burning sensation, the metallic taste on the tongue were assessed as present or absent. Flushing was evaluated by a clinician as present or absent.
Estimated blood loss was calculated according to the following formula using the haematocrit level at baseline and 4 hours after cesarean; estimated blood loss (mL) = estimated blood volume × (preoperative haematocrit – postoperative haematocrit)/preoperative haematocrit. The estimated blood volume was calculated as 85.16 ml/kg.
Ethical Approval
The ethics committee approval of this observational drug study was obtained from Selçuk University Faculty of Medicine Clinical Research Ethics Committee (Date: 2020-07-09, No: 2020/17) and Turkish Pharmaceuticals and Medical Devices Agency (20-AKD-103).
Results
803 patients who delivered by cesarean section in our hospital were evaluated. The study included 417 patients who met the inclusion criteria. Demographic data of patients are shown in Table 1. While tachycardia was the most common cardiac side effect with a rate of 42.9%, T-negativity was the least common cardiac side effect with a rate of 1%. Hypotension was observed in 14.6%, chest pain in 10.1% and dyspnea in 5.5% of 417 patients (Table 2). Headache was the most common non-cardiac side effect with a rate of 21.6%. When we classified headache by type, throbbing type (12.5%) and compressive type (7.9%) were the most common; when we classified headache by region, frontal (8.4%) and diffuse headache (7.2%) were the most common. After headache, other common non-cardiac side effects were nausea and vomiting (13.7%), metallic taste on the tongue (9.4%) and burning in the face and ears (8.4%). The other side effects were shown in Table 3. 56 patients needed methylergonovine because of inadequate uterine tone (Table 1). The estimated calculated blood loss was 618.5 ± 326.3 ml.
Discussion
In this study, tachycardia 42.9%, hypotension 14.6%, ST depression 2.6%, T negativity 1%, headache 21.6%, nausea-vomiting 13.7% were observed after 2 IU oxytocin bolus administration.
Oxytocin is the most commonly used uterotonic drug to prevent uterine atony, the most common cause of postpartum bleeding and it has traditionally been used in higher doses. However, recent studies have shown that lower doses may be as effective as higher doses [2, 5, 6]. Many studies over the last two decades have failed to reach a consensus on the ideal dose and route of administration [3, 7]. There is compelling evidence to support the use of a combination of bolus and infusion doses for efficacy and safety. According to a meta-analysis of 37 studies, there was some evidence to recommend 3-5 IU bolus and 0.25-1 IU/min infusion to achieve optimum effects, while there was insufficient evidence for high doses (> 5 IU bolus or infusion ≥ 1 IU/min) [8]. The latest guideline recommends an initial bolus dose of 1 IU and if uterine tone is insufficient after 2 minutes, a 3 IU bolus is recommended [2]. Since there are few studies on 2 IU bolus administration in the literature, we preferred this dose in our study.
Oxytocin has a short half-life as 4-10 minutes and requires continuous intravenous infusion for efficacy [9]. According to pharmacokinetics, the therapeutic plasma concentration of a drug is rapidly achieved by first administering a bolus followed by a maintenance infusion. Therefore, Stephens and Bruessel recommended a bolus dose followed by infusion in their systematic review of oxytocin dosing in cesarean delivery [10]. In a study investigating haemoglobin changes after delivery, 40 IU of oxytocin infused within 30 minutes was found to be as effective as 60 and 80 IU of oxytocin infused in the same period. Duffield et al. infused oxytocin at 2.5 IU/h and 15 IU/h after a 1 IU bolus and showed that increasing infusion doses had no extra contribution to improving tone or reducing blood loss [11]. In our study, our infusion protocol (23 IU / 4 h) was organised according to the doses in the last guideline (2.5-7.5 IU/h) [2]. Oxytocin infusion has been reported to reduce postpartum haemorrhage compared to bolus administration alone, reducing the need for transfusions and additional uteronics. However, the optimal duration of oxytocin infusion after the onset of uterine tone is unknown [2]. In our study, we started infusion immediately after the bolus dose.
Oxytocin-induced hypotension results from vasodilatation mediated by oxytocin receptors in the vascular endothelium, mainly by calcium-dependent stimulation of the nitric oxide pathway. It also leads to a mild negative inotropic effect, probably by modulating acetylcholine release from intrinsic cardiac cholinergic neurones [3]. Butwick et al. reported that hypotension developed approximately 22% after 1 IU bolus and 27% after 3 IU boluses in their study. The reason for the high rates of hypotension in their study compared to our study may be due to the different definitions of hypotension; we defined a 20% decrease from baseline as hypotension, while Butwick et al. defined a 10% decrease as hypotension [5]. First, the rate of administration appears to correlate with the incidence of oxytocin-induced hypotension. In studies in which 5 U oxytocin was administered as a “rapid” bolus, the incidence of hypotension was found to be 100% [12], whereas the same amount of oxytocin was administered in 15 seconds, the incidence of hypotension was found to be 50% [5]. Farber et al., who administered the same amount of oxytocin within 4 minutes and did not observe hypotension in any patient, pointed out that the rate of administration rather than the dose is important to protect against haemodynamic side effects of oxytocin [13]. The fact that hypotension was observed in our study in which a lower dose was administered more rapidly (5-10 sec) supports the thesis of Farber.
Oxytocin decreases systemic vascular resistance by relaxing vascular smooth muscle and tachycardia is observed as a compensatory response to this decrease. Apart from this reflex response, another cause of tachycardia is that oxytocin affects atrioventriculer conduction and myocardial repolarization through oxytocin receptors in the myocardium [3]. Sartain et al. observed tachycardia in 57.5% of patients when they administered oxytocin 5 IU bolus in 5-10 seconds, while this rate was 27.5% when they administered oxytocin 2 IU bolus. [14]. We administered oxytocin 2 IU in approximately the same amount of time, but our tachycardia rate (42.9%) was higher. This may be related to the infusion of phenylephrine, which had the ability to cause reflex bradycardia in the aforementioned study. The high rate of tachycardia in our study may also be due to the dehydration of the patients due to prolonged fasting (>8 hours). Because of the recommendation that “clear liquid can be drunk until the last 2 hours before the operation” could not be put into routine practice in our hospital.
The effect of oxytocin on the ST segment is dose-dependent. In a randomised study, ST depression occurred in 8% of patients when oxytocin was administered as a 5 IU bolus and in 22% of patients when oxytocin was administered as a 10 IU bolus [15]. In recent years, the dose for PPH prophylaxis has been reduced due to awareness of the transient haemodynamic changes and dose-dependent ST depression following intravenous oxytocin. Rudingwa et al. administered 2.5 IU oxytocin within 1 minute and found ST depression as 4.8% [16]. In this study in which relatively similar doses were administered for a longer period of time, the ST depression rate was found to be higher than the rate in our study. The reason for this may be that they captured ST depression more clearly with holter monitoring. The haemodynamic effects of oxytocin also depend on the route of administration and dose. When 3 IU oxytocin was administered in 15 seconds, ST depression was observed in 7.5% of the patients, whereas no ST depression was observed when the same dose was administered in 5 minutes [17].
While the incidence of headache was 12% in the study in which oxytocin 5 IU bolus was administered [18], it was 28% in the study in which 10 IU bolus was administered [9] and 21.6% in our study. In the study by Bekkenes et al. in which oxytocin 1 IU bolus was administered, the headache rate was found to be very low (4.8%) [16]. In a meta-analysis, headache was reported in 14% (142 of 991) patients [19]. As far as we could reach in the literature, the type of oxytocin-induced headache has not been classified. The majority of headaches were of the throbbing type, followed most frequently by the compressive type. Oxytocin is known to activate the NO pathway in vascular endothelium [20]. Extensive studies have shown that NO is associated with many types of primary headache, including migraine, cluster and tension-type headache [21].
Rabow et al. reported that oxytocin caused global vasodilatation by reducing vascular tone in both large and small arteries [22]. The occurrence of flushing even at low doses is an indication of how potent the drug has a vasodilator effect [23]. In the study comparing 0.5 and 5 IU oxytocin, flushing rates were found to be 17% and 29% respectively [24]. In our study, the rate of flushing was 3.4% and the rate of burning in the face-ears was 8.4%. Although the pathophysiology of both effects is based on vasodilation, the difference in the rates may be due to the fact that the presence of flushing depends on the observation of the investigator and flushing may not be noticeable in dark-skinned patients.
Elbohoty et al. administered oxytocin as 10 IU bolus followed by 20 IU/4 hour infusion and 13% of patients required ergometrine [9]. The bolus dose in this study was 5 times our bolus dose, while our infusion protocol can be considered similar. In another study with 2 times the bolus dose and half the infusion dose in our study (5 IU bolus and 20 IU/10 hour infusion), the rate of additional uterotonic requirement was 16% [24]. Stålberg et al. did not start the infusion immediately but only administered a bolus of 2.5 IU oxytocin and 13.8% needed ergometrine [25]. These results suggest that the main factor determining the need for additional uterotonic is the infusion dose rather than the bolus dose.
Limitation
Further haemodynamic monitoring could have been performed, but we wanted to demonstrate the side effect profile that could be noticed without going beyond the routine monitoring performed in obstetric anaesthesia.
We could have evaluated the duration and severity of the headache.
Conclusion
Cardiac and non-cardiac side effects can be seen even with low dose (2IU) oxytocin administered bolus in 5-10 seconds.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
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2. Heesen M, Carvalho B, Carvalho JCA, Duvekot JJ, Dyer RA, Lucas DN et al. International consensus statement on the use of uterotonic agents during caesarean section. Anaesthesia. 2019;74(10):1305-1319.
3. Balki M, Tsen L. Oxytocin protocols for cesarean delivery. Int Anesthesiol Clin. 2014;52(2):48-66.
4. Gallos ID, Papadopoulou A, Man R, Athanasopoulos N, Tobias A, Price MJ et al. Uterotonic agents for preventing postpartum haemorrhage: A network meta-analysis. Cochrane Database Syst Rev. 2018;12(12):CD011689.
5. Butwick AJ, Coleman L, Cohen SE, Riley ET, Carvalho B. Minimum effective bolus dose of oxytocin during elective Caesarean delivery. Br J Anaesth. 2010;104(3):338-343.
6. Khan M, Balki M, Ahmed I, Farine D, Seaward G, Carvalho JC. Carbetocin at elective Cesarean delivery: a sequential allocation trial to determine the minimum effective dose. Can J Anaesth. 2014;61(3):242-248.
7. West R, West S, Simons R, McGlennan A. Impact of dose-finding studies on administration of oxytocin during caesarean section in the UK. Anaesthesia. 2013;68(10):1021-1025.
8. Tantry TP, Karanth H, Anniyappa S, Shetty PK, Upadya M, Shenoy SP et al. Intravenous oxytocin regimens in patients undergoing cesarean delivery: A systematic review and network meta-analysis of cluster-based groups. J Anesth. 2023;37(2):278-293.
9. Elbohoty AE, Mohammed WE, Sweed M, Bahaa Eldin AM, Nabhan A, Abd-El-Maeboud KH. Randomized controlled trial comparing carbetocin, misoprostol, and oxytocin for the prevention of postpartum hemorrhage following an elective cesarean delivery. Int J Gynaecol Obstet. 2016;134(3):324-328.
10. Stephens LC, Bruessel T. Systematic review of oxytocin dosing at caesarean section. Anaesth Intensive Care. 2012;40(2):247-252.
11. Duffield A, McKenzie C, Carvalho B, Ramachandran B, Yin V, El-Sayed YY et al. Effect of a high-rate versus a low-rate oxytocin ınfusion for maintaining uterine contractility during elective cesarean delivery: A prospective randomized clinical trial. Anesth Analg. 2017;124(3):857-862.
12. Langesaeter E, Rosseland LA, Stubhaug A. Haemodynamic effects of repeated doses of oxytocin during Caesarean delivery in healthy parturients. Br J Anaesth. 2009;103(2):260-262.
13. Farber MK, Schultz R, Lugo L, Liu X, Huang C, Tsen LC. The effect of co-administration of intravenous calcium chloride and oxytocin on maternal hemodynamics and uterine tone following cesarean delivery: A double-blinded, randomized, placebo-controlled trial. Int J Obstet Anesth. 2015;24(3):217-224.
14. Sartain JB, Barry JJ, Howat PW, McCormack DI, Bryant M. Intravenous oxytocin bolus of 2 units is superior to 5 units during elective Caesarean section. Br J Anaesth. 2008;101(6):822-826.
15. Jonsson M, Hanson U, Lidell C, Nordén-Lindeberg S. ST depression at caesarean section and the relation to oxytocin dose. A randomised controlled trial. BJOG. 2010;117(1):76-83.
16. Rudingwa P, Vijayakumar K, Panneerselvam S. Exploring cardiac effects after oxytocin 2.5 IU or carbetocin 100 mcg – a randomized controlled trial in women undergoing planned caesarean delivery. Eur J Anaesthesiol. 2023;40(6):453.
17. Bhattacharya S, Ghosh S, Ray D, Mallik S, Laha A. Oxytocin administration during cesarean delivery: Randomized controlled trial to compare intravenous bolus with intravenous infusion regimen. J Anaesthesiol Clin Pharmacol. 2013;29(1):32-35.
18. Rosseland LA, Hauge TH, Grindheim G, Stubhaug A, Langesæter E. Changes in blood pressure and cardiac output during cesarean delivery: The effects of oxytocin and carbetocin compared with placebo. Anesthesiology. 2013;119(3):541-551.
19. Sun H, Xu L, Li Y, Zhao S. Effectiveness and safety of carboxytocin versus oxytocin in preventing postpartum hemorrhage: A systematic review and meta-analysis. J Obstet Gynaecol Res. 2022;48(4):889-901.
20. Bahr MH, Abdelaal Ahmed Mahmoud M Alkhatip A, Ahmed AG, Elgamel AF, Abdelkader M, Hussein HA. Hemodynamic effects of oxytocin and carbetocin during elective cesarean section in preeclamptic patients under spinal anesthesia: A randomized double-blind controlled study. Anesth Pain Med. 2023;13(1):e128782.
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Emine Aslanlar. Evaluation of cardiac and non-cardiac side effects of low dose oxytocin used during caesarean section. Ann Clin Anal Med 2024;15(Suppl 1):S12-16
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Evaluation of neutrophil lymphocyte ratio as a venous risk factor in patients with primary familial erythrocytosis
Alpay Yeşilaltay
Department of Hematology, Faculty of Medicine, Baskent University, Istanbul Research Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.22152 Received: 2024-02-16 Accepted: 2024-03-17 Published Online: 2024-03-19 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S17-21
Corresponding Author: Alpay Yeşilaltay, Department of Hematology, Faculty of Medicine, Baskent University, Istanbul Research Hospital, 34662, Istanbul, Turkey. E-mail: alpay.yesilaltay@hotmail.com P: +90 507 240 42 84 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3784-5739
This study was approved by the Ethics Committee of Baskent University Faculty of Medicine (Date: 2024-02-06, No:KA24/65)
Aim: Primary Familial Erythrocytosis (PFE) is an inherited disorder characterized by polycythemia. Studies have shown that these patients are frequently predisposed to atherosclerosis and thromboembolic complications. In our study, we aimed to analyze the risk of atherosclerosis in PFE patients using the Neutrophil-to-Lymphocyte Ratio (NLR), which is considered a potential predictive factor for atherosclerosis in recent years.
Material and Methods: A total of 50 patients, including 2 females and 48 males diagnosed with polycythemia, were enrolled in the study. All patients tested negative for JAK2 V617F and Exon 12 mutations, and their EPO levels were within the normal range, leading to the diagnosis of PFE. Patients with high EPO levels and/or positive JAK analyses, those with any history of cancer, those undergoing active chemotherapy, and those with cardiac and respiratory diseases were excluded from the study. Hemogram evaluations of all patients were conducted in the absence of active infection that could affect neutrophil and lymphocyte counts. The ratio of neutrophil counts to lymphocyte counts in patients was evaluated and analyzed.
Results: The NLR threshold was accepted as 2.3 for increased risk of atherosclerosis. NLR > 2.3 was observed in 94% of the patients included in the study (except for 3 patients). The mean NLR value for all patients was found to be 2.86.
Discussion: NLR has been interpreted as an early indicator of atherosclerosis, particularly in recent studies on cardiovascular diseases. It is known that PFE predisposes individuals to atherosclerosis, thromboembolism, and cardiovascular diseases. Considering the early onset of PFE and its genetic transmission, we believe that NLR could serve as an early determinant parameter for atherosclerosis in this disease.
Keywords: Neutrophil, Lymphocyte, Atherosclerosis, Erythrocytosis
Introduction
The most important parameter that regulates erythropoietin secretion under normal conditions in the body is the haemoglobin level in erythrocytes. Under hypoxic conditions, HIF-1 (hypoxic inducible factor-1) is the major transcription gene responsible for the transcription of the EPO gene. This factor is hydroxylated and bound to VHL protein with the help of PHD protein in normoxaemic states. Afterwards, this bound structure is removed from the environment as a degree in the proteasome system. Furthermore, under hypoxaemic conditions, HIF-1 alpha binds to the EPO gene together with HIF-1 beta, leading to EPO formation and consequently an increase in erythrocyte levels [1].
Erythrocytosis is defined by an increase in haematocrit above the upper limit of normal. According to the latest WHO 2016 criteria, polycythemia is accepted as Hb 16.5 g/dL in males and above 16 g/dL in females, and haematocrit is accepted as 49% in males and 48% in females [2].
Erythrocytoses occur clinically as congenital or acquired and are classified as primary (autonomous, due to bone marrow progenitor cell defects) or secondary (due to increased EPO or other erythropoietic factors). Primary erythrocytoses characterised by low or subnormal EPO levels are divided into two groups: hereditary (EPO receptor mutations) and acquired (polycythemia vera), whereas secondary erythrocytoses characterised by high EPO levels may occur due to hereditary causes, low tissue oxygenation, some tumours, renal diseases, adrenal cortical hyperfunction and androgen therapy [3].
Primary familial erythrocytosis (PFE) occurs as a result of isolated and abnormal proliferation of erythroid cells in the bone marrow. This disease is typically inherited in an autosomal dominant pattern, Clinically isolated erythrocytosis, normal leukocyte and platelet counts, low serum EPO level (<10mU/ml), normal haemoglobin-oxygen dissociation curve (normal p50) and increased sensitivity to EPO in erythroid cells in in vitro stem cell cultures are present. Over 160 mutations related to PFE have been identified. However, the genetic cause is known in approximately 70% of patients and the other patients are referred to as idiopathic erythrocytosis. In this day, a total of 8 different EPO receptor mutations have been identified [4].
As of today, OMIM classification is used in PFE classification based on genetic causes. According to this classification, some groups have a higher cardiovascular risk. One of these is the well-known Chuvas polycythemia, which was found in a region in Russia. Comparatively, this group has been the most studied group of patients with PFE and increased cardiovascular risk and thrombus have been clearly proven [5].
Hyperviscosity, which increases with the increase in red blood cells and haemotocrit in PFE patients may cause early morbidity and mortality. The Chuvash Cohort is the most comprehensive study in terms of defining clinical features.This study demonstrated decreased survival with increased arterial and venous thrombosis and haemorrhagic events in patients with Chuvash polycythemia [5].
Neutrophil-to-lymphocyte ratio (NLR) is a biomarker calculated as a simple ratio between neutrophil and lymphocyte counts in peripheral blood measurements [6]. Neutrophils are the first line of the immune response against pathogens and secretes proinflammatory and immunomodulatory cytokines and chemokines. Other cells of the immune system; dendritic cells (DC), B cells, NK cells, CD4, CD8, γδ T cells and, mesenchymal stem cells interact with neutrophils [7].
An isolated increase in the number of neutrophils with a relatively unchanged or unchanged number of lymphocytes favours neutrophils in the Neutrophil/Lymphocyte Ratio (NLR). The N/L ratio increases in bacterial or fungal infections, acute stroke, myocardial infarction, atherosclerosis, severe trauma, cancer, postoperative complications, and tissue damage that activates SIRS. In the Rotterdam study [8] NLR levels were shown to be independently and significantly associated with the risk of all-cause mortality. It has been suggested that the early increase in NLR after acute physiological stress (<6 h) may make NLR important as an earlier marker of acute stress than other laboratory parameters (e.g. white blood cell count, bacteraemia, CRP). However, although increased NLR is an independent prognostic factor of morbidity and mortality in several diseases, its normal ratio is still a matter of controversy [9]. A large retrospective case-control study [9] reported that normal NLR values in an adult, healthy non-elderly population can range from 0.78 to 3.53, while the Rotterdam study reported that the mean NLR in the general population was 1.76. It was also found that the mean NLR was significantly higher in males (mean 1.88) than in females (mean 1.68) and that individuals older than 85 years (mean NLR 2.13) had significantly higher NLR rates compared to individuals aged 45-54 years (mean NLR 1.63) [8].
Several studies have shown that NLR may be predictive of cardiovascular events [10]. In the general healthy population, an NLR > 4.5 has been suggested to predict coronary artery disease as an independent marker. Furthermore, the same study showed that using the NLR allowed the Framingham Risk Score (FRS) to accurately classify individuals in the intermediate risk category as having a lower or higher probability of cardiovascular mortality [10]. Recent evidence has shown that NLR has predictive value for disease severity and mortality across the spectrum of acute coronary syndromes, independent of the revascularisation procedure, and may be associated with other conventional risk factors. It was emphasised in the study that NLR should be accepted as 1-2 in normal population, and between 2.3- 3.0 should be considered as grey zone and especially as a warning for atherosclerosis [11].
The prognostic values of NLR have also been analysed in diabetic patients, showing that NLR independently predicts major adverse cardiac events in these patients. In a cohort of 324 elderly patients, an NLR greater than 3.68 significantly predicted atherosclerotic carotid plaque formation.[12].
Another study reported that in hospitalised hypertensive patients over 80 years of age, high NLR, especially for values > 2.97, may be an independent predictor of all-cause 3-month mortality[13].It is immunologically accepted that the reason for the increase in NLR in cardiovascular diseases is inflammation and oxidative stress in the pathophysiology of atherosclerosis and endothelial dysfunction and the disruption in homeostasis between IL-1 and its antagonists as a result of activation of the NPL3 inflammasome [14].
However, as new data on the role of non-myeloid inflammatory cells, especially T lymphocytes and monocytes, in the immune thrombosis process have become available, it has been shown that T-reg lymphocytes are involved in the regulation of the prothrombotic effect of activated neutrophils in the process of fibrin formation and dissolution. Based on this information, the neutrophil to lymphocyte ratio (NLR) can be considered as the synthesis of these two opposing actions in thrombotic events and may play a role as a prognostic marker of cardiovascular events in PV, as shown in the general population and in a small series of patients with ET [15].
Thrombotic events are an important complication and the most common cause of mortality in patients with PV. Therefore, early assessment of the risk of occurrence and progression of thrombotic events and early intervention may be effective in improving the prognosis of patients with PV. Damage to vascular endothelial cells may induce aggregation of platelets and thrombosis as a result of increased neutrophil count and inflammation [16].
Material and Methods
Patients
We retrospectively included 50 polycythaemic patients (2 women, 48 men) who were admitted to the Haematology Outpatient Clinic of Başkent University Medical Faculty Istanbul Hospital and diagnosed as PFE. Patients with JAK2 (+) (V617F and Exon 12), malignancy with high EPO level, known lung and cardiac diseases were excluded. The age range of the patients was 18-70 years. Complete blood count was analysed in healthy periods of all patients in the absence of active infection and Neutrophil/Lymphocyte ratio and counts were determined.
Statistical evaluation
GraphPad Prism 9.5.0 statistical package programme was used for data analysis. The variables belonging to the patient group to be included in the study were given as mean and standard deviation. One-Sample t test was used to test whether the N/L ratio was different from 2.30. The correlations between two continuous variables were evaluated by Pearson correlation analysis. A value of p<0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Baskent University Faculty of Medicine (Date: 2024-02-06, No:KA24/65).
Results
Fifty patients were included in the study, 2 of these patients were female and 48 patients were male. The mean haemoglobin of the patients was 17.7 gr/dl and the mean haemotocrit was 52.5%. The mean WBC value was 8,835 x109/L, neutrophil and lymphocyte counts were 6,035×109 /L and 1,9×109/L respectively. Notrophil/lymphocyte ratio of all patients was 2.86 (Table.1). While NLR ratio above 2.3 was considered significant, only 3 patients had NLR below this value. This value was found to be above 2.3 in all other patients. There was no statistically significant difference between the patients in the comparison of NLR within the whole group (Table 2). As seen in Table 2, it was tested whether the NLR variable of the patients was different from the value of 2.30, which is considered normal in the population, and it was found that the NLR variable was statistically significantly different from the value of 2.30 (p=0.010). Accordingly, it is possible to say that the mean of the NLR variable obtained for our sample is considerably higher (4.28) than the accepted value of 2.30 (Figure 2). As seen in Table 3, when the correlations between the variables are analysed, it can be said that there is a positive correlation between NLR and WBC (r = 0.280, p = 0.049) and PMN (r = 0.478, p = 0.000) variables and a negative correlation with the lymphocyte (r = -0.566, p = 0.000) variable.
It can be also said that; there is a positive correlation between the HB variable and HET (r = 0.675, p = 0.000), a positive correlation between the HET variable and LENF (r = 0.352, p = 0.012), a positive correlation between the WBC variable and PMN (r = 0.935, p = 0. 000) and LENF (r = 0.516, p = 0.000) variables, and there is a positive correlation between PMN variable and Lymphocyte (r = 0.354, p = 0.012) variable.
Discussion
Unlike polycythemia vera, PFE does not involve the bone marrow. Thus, there is no risk of transformation to other bone marrow malignancies such as Myelofibrosis or Leukaemia. This advantageous feature also brings some disadvantages. The most important of these is the reluctance to follow up patients in Hematology outpatient clinics due to the fact that they are not accepted as a hematological disease, and the reluctance to follow up patients in Internal Medicine and Cardiology outpatient clinics due to their polycythemia, in a manner to leave the patients hanging. The fact that they are polycythaemic makes them particularly prone to venous thromboembolism. Increased diastolic load on the heart due to increased viscosity creates a tendency to cardiovascular and cerebral thromboembolism in patients. At the same time, considering the familial transmission of the disease, it is a disease that can cause serious mortality, especially at a young age. A study has shown that a haematocrit value above 45% in females and 48% in males increases the risk of MI 3 times more than the normal population [14].
The limit of polycythaemia in PFE is not different from other polycythaemias. The fact that the disease is an interdisciplinary disease and does not belong to a branch has also reflected the number of studies in this field. The number of studies showing the cardiovascular and thromboembolic events and risk of this disease is very few in the literature and most of the studies include Polycythemia Vera patients. In one of the few studies, it was shown that high haematocrit was an independent factor for cardiovascular risk in PFE patients [17]. The treatment of the disease is intermittent phlebotomy, which has been shown to reduce complications in the literature [18].
Atherosclerosis is still one of the leading causes of mortality in the world. Therefore, NLR has recently been suggested to have an early predictive value at the very beginning of early atherocycotic events. NLR has recently been emphasised in both cardiovascular mortality in atherosclerosis and cancer studies. However, it was also used as a marker of early infection in the earlier period before CRP, especially in COVID 19 infection [19].
NLR has been used in PV patients for the same reasons, as polycythemia predisposes to atreosclerosis and early thromboembolic events. This study showed that the absolute number of neutrophils and lymphocytes was higher (mean: 6.9 × 10^9/L, p = 0.022) and lower (mean: 1.3 × 10^9/L, p = 0.002) in the univariate analysis of NLR, respectively, resulting in an overall higher NLR. The significant finding of the study was the linear correlation between the absolute number of lymphocytes and the risk of events [20]. It was shown in the study that patients with lymphocyte counts lower than 2 × 10^9/L at baseline were at risk for venous thrombosis, and as lymphocyte counts increased, the risk for venous thrombosis gradually decreased. These changes were found to be consistent with the adverse prognostic tendency of neutrophils, indicating that the risk increases as neutrophil counts increase [21]. Although the role of lymphocytes in the underlying pathophysiological process here is unclear, lymphocytes modulate the activity and attraction of innate immune cells during clot dissolution, a special subset of T-reg lymphocytes that accumulate in venous thrombi and are vital for clot dissolution has recently been identified. These mechanistic studies have suggested an active interaction between innate and adaptive immune systems in venous thrombosis [22]. We did not find any study similar to our study in PFE patients in the literature reviews we performed during our study. Therefore, our study is the first study investigating NLR in PFE patients.
In our study, we found a statistically significant increase in NLR with a mean of 2.8 in almost all PFE patients. Thus, we suggest that PFE patients are prone to early atherocyclosis and cardiovascular complications. Studies have not clearly demonstrated how polycythemia initiates atherosclerosis independent of hyperlipidaemia. The most important of these is diastolic dysfunction, which occurs in all polycythaemic patients with an increase in cardiac load and end diastolic pressure due to increased blood viscosity. We have demonstrated diastolic dysfunction and increased carotid intima-media thickness in PFE patients in a TÜBİTAK project in this group of patients [23].We would like to get an answer to the question of whether NLR as a marker of atresclerosis can be helpful in the monitoring of atherosclerosis in future studies. In future studies, we think that NLR follow-up may be useful especially in patients who reach target haematocrit levels with phlebotomy. A decrease in N/LR can be expected after increased neutrophils in increased inflammation are rendered normocytemic by phlebotomies. PFE is common and the pathophysiology of the disease remains many questions. It is possible that the results of large-series studies will contribute to the world of science and increase the quality of life of patients by prolonging their survival.
Conclusion
PFE patients present with polycythaemia and in the light of limited studies, it has been accepted to cause atherosclerosis and cardiovascular events. Recently, NLR has been recognised as a very early marker of inflammation during the proinflammatory phase and has been used especially in atherosclerotic diseases. It is increasingly recognised that increased neutrophil count in the early period increases NLR and its early use may be a harbinger of atherosclerosis. In our study, we evaluated NLR which has never been performed in PFE patients before. In almost all patients, the result was above 2.3, which is considered to be the normal limit. Thus, our data suggest that PFE patients may be prone to atherosclerosis.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Alpay Yeşilaltay. Evaluation of neutrophil lymphocyte ratio as a venous risk factor in patients with primary familial erythrocytosis. Ann Clin Anal Med 2024;15(Suppl 1):S17-21
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Lesser toe deformity; hammer and claw toe in the same foot toes side by side
Burak Kuşçu 1, Fatih Doğar 2, Kaan Gürbüz 3
1 Department of Orthopedics and Traumatology, Pazarcık State Hospital, Kahramanmaras, 2 Department of Orthopaedics and Traumatology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, 3 Department of Orthopedics and Traumatology, Kayseri City Education & Research Hospital, Kayseri, Turkey
DOI: 10.4328/ACAM.21571 Received: 2023-01-01 Accepted: 2023-02-07 Published Online: 2023-07-04 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S22-24
Corresponding Author: Burak Kuşçu, Department of Orthopedics and Traumatology, Pazarcık State Hospital, Kahramanmaras, 46760, Pazarcık, Kahramanmaraş, Turkey. E-mail: dr.burakkuscu@hotmail.com P: +90 507 192 73 13 F: +90 344 311 31 35 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1082-2206
Hammer toe and claw toe deformities are common in the geriatric age group and significantly impair patients’ quality of life. There are numerous treatment options, ranging from conservative to surgical. A patient may have claw toe or hammer toe deformity for a variety of reasons. In this case report, we present the first instance of a hammer and claw toe deformity occurring in two adjacent toes on the same foot in a young male patient.
Keywords: Lesser Toe, Deformity, Hammertoe, Claw Toe
Introduction
Lesser toe deformities are common forefoot deformities, negatively affecting the patient’s quality of life due to pain and severity of the deformity. Hammer toe and claw toe are the most common deformities among these deformities and constitute the majority of forefoot surgical interventions [1]. The literature varies in its definition of lesser toe deformity [2]. These deformities occur secondary to many different underlying pathologies that can be listed according to their frequency as hallux valgus, long metatarsal, intrinsic imbalance and neurological anomalies [3].
The claw toe is defined by the elongation of the metatarsophalangeal joint. A hammer toe is defined by flexion of the proximal interphalangeal joint. The flexibility of these joints may help distinguish between these abnormalities. When deciding on the surgical treatment for lesser toe deformities, it is very essential to correctly understand the deformity and the factors that cause its formation.
Lesser toe deformities are more common in women, but their incidence increases with age in both sexes [1]. These deformities occur with various combined deformities of the metatarsophalangeal (MTP) joint, proximal interphalangeal (PIP) joint, and distal interphalangeal (DIP) joint. However, the distinctive deformity occurs at the metatarsophalangeal joint [2]. While the PIP joint is in flexion and the DIP joint is in extension in the hammer toe, there is no spasticity or deformity in the MTP joint in the early stage. On the other hand, in the claw toe, the PIP and DIP joint are in the flexion defect, while the MTP joint is in the hyperextension position. These two deformities are generally evaluated in the same group and treated in the same way in daily practice [4].
Numerous factors contribute to the emergence of these deformities. Narrow-toed shoes, which bend the toes at the tip, and high-heeled shoes, which cause hyperextension of the MTP joint, likely explain why women suffer from these deformities in greater numbers [5]. The biomechanical imbalance between the intrinsic flexor and long extensor muscles that developed over time plays a significant role in the emergence of deformity [1].
Although the claw toe deformity is usually bilateral and in more than one toe, hammer toe deformities occur in isolation and are most frequently seen in the second toe. Conservative methods are often tried first. Taping, non-steroidal anti-inflammatory drugs and wide-toed shoes are used. Surgical treatment is applied in patients who are not successful with conservative treatment.
In cases such as ours, where the hammer and claw toe deformities present in the same lesser foot, it is never an easy goal to determine the most appropriate surgical treatment strategy. The purpose of this study was to present a different clinical appearance of a hammer and claw toe in the same foot toes side by side and their surgical results.
Case Report
A 26-year-old male patient with no known chronic disease was admitted to our clinic with complaints of deformity of the toes, forefoot pain that increased with the use of shoes, and inability to obtain suitable shoes. On physical examination, MTP joint of the 2nd toe of the right foot was in the hyperextension position, PIP joint was flexible, DIP joint flexion deformity was fixed. In the same foot side toe, there was a rigid flexion deformity of the PIP joint in the 3rd toe, while the DIP joint was in the flexible and extension position (Figure 1). The patient was evaluated clinically together with routine radiographs and surgery was planned with the diagnosis of claw toe for the 2nd toe and hammer toe for the 3rd toe.
Under peripheral regional anesthesia, first, a z-shaped incision was applied to the MTP joint capsule between 2-3 metatarsals for the 3rd toe hammer toe deformity. The extensor hallucis longus was elongated fractionally with the Z-plasty technique. A percutaneous tenotomy was performed on the flexor digitorum longus at the level of the DIP joint. After the tenotomy, the two ends of the FDL tendon, which was split longitudinally, were transposed to the dorsal MTP joint and fixed to the proximal medial and lateral of the third proximal phalanx. It was observed that the 3rd toe MTP joint and PIP joint deformity improved. After careful soft tissue dissection with a linear incision made from the dorsal for DIP joint flexion contracture, a retrograde Kirshner wire of 1.2 mm was performed for temporary fixation. In the continuation of the operation, after careful soft tissue dissection with a linear incision made from the dorsal PIP joint for the 2nd toe claw toe deformity, a Kirshner wire of 1.2 mm was also performed for temporary fixation. Since it has been reported in the literature that DIP joint flexion deformity may develop frequently in the early post-operative period after PIP joint arthrodesis in surgical techniques applied for Lesser toe deformities, percutaneous tenotomy was applied to the 2nd toe flexor digitorum longus from the plantar face at the DIP joint level (Figure 2).
A short leg splint was applied for 4 weeks postoperatively. At the end of the 4th week, with the removal of splints and implants, active and passive exercises of the foot and ankle including the forefoot were started and continued for 3 weeks with a physiotherapist (Figure 3). Time to return to work of this patent was approximately 3 months.
Discussion
Although the claw and hammer toe deformities are presented separately in the literature in various studies, the clinical appearance and surgical results of a hammer and claw toe in the same foot toes side by side are presented for the first time in this case report, which clarifies these two often confused deformities. This makes our case unique because of two different formation mechanism deformities seen in the same foot.
Numerous soft-tissue and osseous techniques for the correction of hammer and claw toes followed. Lesser toe abnormalities are extremely common and are routinely treated in orthopedic practice. Despite the long history of scientific publications and the prevalence of these deformities, there is a dearth of surgically guiding literature. Relevant randomized controlled trials are uncommon due to the difficulties associated with establishing homogenous patient groups, constraints associated with grading distinct stages of the pathophysiologic process, and limited reproducibility. The absence of significant clinical complications associated with these deformities may also explain the paucity of prospective studies. In practice, a variety of different surgical procedures can be used to achieve satisfactory results.
While Girldston-Taylor surgery is applied for unfixed flexible hammer toe deformity, fractional lengthening can be performed with capsulotomy and EDL Z-plasty for MTP joint contracture, which is sometimes seen together. In fixed hammer toe deformity, clinically good results can be obtained with PIP joint arthrodesis or resection interposition arthroplasty [2,6].
Treatment of an unfixed flexible claw toe deformity is similar to that of an unfixed flexible hammertoe deformity. However, dorsal capsulotomy and EDL z-plasty are more frequent in claw toes because MTP joint deformities are fixed compared to hammer toes. In some cases, additional FDL tenotomy may be required to correct DIP joint contracture. In fixed claw toe deformity, there is a defined Weil osteotomy technique [2,3]. The reasons for applying small joint fixation using k-wire in addition to soft tissue procedures for the patient presented in this case report were low risk of early and long-term post-op complications, short surgical time, low infection rate, and early time to return to work.
Conclusion
Depending on the surgeon’s theoretical knowledge and practical competence, the aim should be to correct the deformity, eliminate pain and increase the patient’s quality of life in a way that fully meets the patient’s needs, regardless of which surgical treatment method is applied.
Ethical Approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Informed Consent
The authors certify that they have obtained all appropriate patient consent forms under the terms of national medical laws. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that his name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be quaranteed. The study was conducted in accordance with the principles of the Declaration of Helsinki.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Montgomery HC, Davies MB. Common disorders foot and ankle. Surgery. 2016;34(9):475-81.
2. Schrier JC, Verheyen CC, Louwerens JW. Definitions of hammer toe and claw toe: An evaluation of the literature. J Am Podiatr Med Assoc. 2009;99(3):194-7.
3. Dhukaram V, Hossain S, Sampath J, Barrie JL. Correction of hammer toe with an extended release of the metatarsophalangeal joint. J Bone Joint Surg Br. 2002;84(7):986-90.
4. Barakat MJ, Gargan MF. Deformities of the lesser toes- how should we describe them? The Foot. 2006;16(1):16-18
5. Coughlin MJ. Lesser toe abnormalities. Instr Course Lect. 2003;52:421-44.
6. Losa Iglesias ME, Becerro de Bengoa Vallejo R, Jules KT, Trepal MJ. Meta-analysis of flexor tendon transfer for the correction of lesser toe deformities. J Am Podiatr Med Assoc. 2012;102(5):359-68.
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Burak Kuşçu, Fatih Doğar, Kaan Gürbüz. Lesser toe deformity; hammer and claw toe in the same foot toes side by side. Ann Clin Anal Med 2024;15(Suppl 1):S22-24
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Imaging modalities in early diagnosis of splenic ectopic pregnancy: A case report
Pham Hong Duc 1, 2, Pham Huu Khuyen 3, Quach Van Kien 4, Nguyen The Anh 5
1 Department of Radiology, Saint Paul Hospital of Hanoi, 2 Department of Radiology, University of Hanoi Medical, 3 Department of Medical İmaging and Nuclear Medicine, Viet Duc Hospital, 4 Department of Digestive Surgery, Viet Duc Hospital, 5 Department of Intensive Care and Poison Control, Vietnam Soviet Friendship Hospital, Ha Noi, Vietnam
DOI: 10.4328/ACAM.21737 Received: 2023-04-21 Accepted: 2023-05-30 Published Online: 2023-07-08 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S25-28
Corresponding Author: Nguyen The Anh, Department of Intensive Care and Poison Control, Vietnam Soviet Friendship Hospital, 100000, Ha Noi, Vietnam. E-mail: theanhhstc@gmail.com P: +849 8855 59 29 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1152-047X
Splenic ectopic pregnancy is extremely rare but carries a high risk of life-threatening intraperitoneal bleeding. Here, we present a 40-year-old woman presenting with vaginal bleeding. Although the intrauterine device (IUD) had been in place for 6 years, urinary and serum tests were positive for pregnancy. However, transvaginal ultrasound showed an empty uterus, no apparent adnexal masses or free fluid. An abdominal ultrasound was subsequently performed, which revealed a viable gestational sac in the spleen. Magnetic resonance imaging (MRI) that did not induce ionizing radiation was also performed, confirming the diagnosis of this splenic pregnancy. The gastrointestinal surgeon completed a laparotomy, which successfully removed the spleen’s superior pole containing an ectopic pregnancy.
Keywords: Splenic Pregnancy, Ectopic Pregnancy, Ultrasound, MRI, Partial Splenectomy
Introduction
The most common site of ectopic implantation is within the fallopian tube, accounting for 95.5% of all ectopic pregnancies, the remaining extra-tubal ectopic pregnancies include ovaries and abdomen, accounting for 3.2% and 1.3%, respectively [1]. Abdominal pregnancies in various extra-pelvic organs have been described, with the spleen being one of the rarest sites. A systematic review of the literature by Poole A et al. showed that in 225 abdominal ectopic pregnancies, splenic gestations accounted for only 5.3%. The remaining sites were divided into the following categories in descending order of the number of reported cases: pouches around uterus (24.4%), uterus-adnexa (24.0%), multiple abdominal organs (12.9%), omental (11.1%), bowel-appendix (6.7%), hepatic (5.8%), retroperitoneal (4.5%), abdominal wall (3.1%) and others (2.2%) [2].
Primary splenic pregnancy was common at a young maternal age (27.3-28.7), with few births (the average parity was 1.1) [2]. As with other abdominal pregnancy sites, splenic pregnancy occurred with several risk factors, including a history of pelvic inflammatory disease, endometriosis, in vitro fertilization (IVF), previous pelvic surgery, previous ectopic pregnancy, utero-tubal anomalies, and intrauterine device (IUD) [3,4]. Most cases of symptomatic splenic pregnancy are diagnosed between the 6th and 8th weeks of gestation and tend to occur earlier than in other sites of the abdomen [2,5,6], but later than tubal ectopic pregnancy [1]. Kalof et al. postulated that most splenic pregnancies at clinical presentation are 2.0 and 3.5 cm in size, and suggested that the risk of rupture in ectopic gestation exceeds this size [6].
Herein, we would like to present a case, preoperatively diagnosed by abdominal ultrasound and MRI as a splenic pregnancy with live embryos implanted at the superior pole of the spleen in a middle-aged woman who had an IUD in situ, successfully treated by partial splenectomy before its rupture.
Case Report
A 40-year-old woman, gravida 2 para 2, was admitted to the Obstetrics and Gynecology Department due to intermittent vaginal bleeding and vague pain in the lower abdomen for several days. The patient had a history of regular menses (28-day cycle), and her last menstruation was 6 weeks prior. She denied a history of pelvic inflammatory disease, tubal surgery or a previous ectopic pregnancy, except for a copper IUD 6 years ago.
At admission, she had neither vomiting nor fever, physical examination showed no abdominal tenderness or rigidity and a blood pressure of 110/60 mm Hg. Bimanual examination indicated a normal cervix and minimal bleeding discharge with no tenderness of the uterus or adnexa.
Urine pregnancy test showed positive results and serum beta-human chorionic gonadotropin (βHCG) showed 34,279 IU/L (normal <5.3). Blood laboratory tests were unremarkable with a normal red blood cell count of 4.5 T/l (4.0-5.2). However, transvaginal ultrasound revealed a normal-sized uterus with a 7.6 mm thick endometrium, but with an IUD, no identifiable intrauterine gestational sac and no signs of ectopic tubal pregnancy, normal bilateral ovaries and no free fluid in the pouch of Douglas.
After suspecting an extra-tubal pregnancy, further pan-abdominal ultrasound was performed to look for uncommon implantation sites. The splenic parenchyma at the superior aspect showed an ill-defined heterogeneous cystic mass measuring 36 x 47 mm, which contained an 11 mm gestational sac containing an embryo with a crown-to-rump length of 7.2 mm (equivalent to 6 weeks 4 days fetus), and fetal heart movement was confirmed at 145 beats/min (Figure 1). Abdominal ultrasound also noted the absence of free fluid in the perisplenic space.
Although an abdominal ultrasound strongly identified a splenic pregnancy, an abdominopelvic MRI was performed to obtain additional information. This technique confirmed the existence of a mixed cystic lesion measuring 28 x 37x 46 mm, accompanied by perilesional edema of the splenic parenchyma. No other abnormalities were found in the abdomen and pelvis (Figure 2). A diagnosis of primary splenic pregnancy was made.
The initial surgery was an exploratory laparoscopic examination. In the upper pole of the spleen, a pregnant formation 3×4 cm in size with villous tissue, deeply embedded in the spleen parenchyma and bleeding easily, was revealed. Clearly revealing the splenic pedicle, the splenic artery branch to the upper pole is ligated, temporarily cross-clamping the inferior pole artery and manual compression, which collects blood into the vein to collapse the spleen. Subsequently, an anatomic resection of the upper pole of the spleen is performed and hemostasis with Prolene 3.0 suture. Excellent hemostasis was achieved and the abdomen was closed after washout with the a drain placed in the peri-splenic region. Postoperatively, the patient was transferred to the Intensive Care Unit for monitoring, before stepping down to the surgical ward 2 days later where the rest of her recovery was uneventful. The ß-hCG levels decreased to 908.83 IU/L 6 days after the surgery. The pelvic drain was removed on the 3rd day, and the patient was discharged on the 5th day after the operation. She had an uneventful recovery at home, and her ß-hCG levels returned to normal 4 weeks after surgery.
On sectioning in half, there was a corresponding oval mass with well-delineated but non-encapsulated dimensions of 20 x 25 x 35 mm, containing cystic and pinkish-white soft tissue mixed with dark red hemorrhages. Microscopic examination demonstrated numerous chorionic villi and intermediate trophoblasts invading the splenic parenchyma (Figure 3). No malignant cells were found.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Discussion
Due to the strong peristalsis of the intestine and the dynamics of the intraperitoneal fluid flow, it is possible to carry fertilized ovum from the cul-de-sac to different abdominal cavities. The spleen provides a smooth and flat surface of the thin capsule along with its abundant blood flow nature and accessibility in the supine position, making it a relatively sustainable site for the zygote implantation. This explains why most of the pregnant masses are implanted under the capsule, protruding outward and often beyond the border of the spleen, and their location can be anywhere from the upper pole to the lower pole and hilum [6].
Although the spleen is a favorable environment for embryonic growth, unfortunately the spleen parenchyma cannot distend to support the blastocyst growth and cannot accommodate placental attachment. Therefore, splenic pregnancy is rarely detected at the end of the first trimester [5]. In complicated cases, patients complain of acute severe abdominal cramping or typically present with left upper abdominal pain radiating to the left shoulder, followed by signs of peritonitis and unstable hemodynamic status leading to urgent splenectomy [2,6].
Nowdays, imaging modalities are always available to help in early diagnosis to identify the implantation site of an ectopic gestational sac. Once a woman with a missed period has an abnormally elevated β-hCG and no intrauterine pregnancy on transvaginal ultrasound, the diagnosis of an ectopic pregnancy can be established, even in the absence of histopathology of uterine curettage. Several cases have demonstrated that ultrasound combined with computed tomography (CT) plays a role in the early diagnosis of splenic ectopic pregnancy.
Ultrasound should be considered as the standard imaging tool of first choice. Screening pan-abdominal ultrasound can reveal a gestational sac-like echo image in the spleen, and color Doppler imaging can also show increased vascularity around the sac [3,7]. Rarely, embryos with a live fetal heart can be seen, as was in our case. Wu et al. published recently the first case of splenic pregnancy accurately diagnosed by ultrasound prior to treatment [8].
To confirm the results of an abdominal ultrasound, CT or MRI should be employed because they play an important role as diagnostic evidence and a detailed assessment of ectopic gestations, which helps to make management decisions. Although abdominal CT provided accurate diagnosis in most of previous case reports, it carries a risk of radiation exposure, therefore, MRI can be considered. Moreover, this method is increasingly available and useful in earlier or unruptured abdominal pregnancy. Our case was similar to that of Makrigiannakis et al, wherein both abdominal sonography and MRI verified the presence of an embryonic sac in the splenic parenchyma [5].
In unruptured splenic ectopic pregnancy cases, even if a patient with ruptured splenic pregnancy is hemodynamically stable or a non-surgical candidate, splenic preservation should be considered whenever possible because of its functional benefit. Several studies have been published showing successful conservative splenic treatment using minimally invasive approaches, and non-surgical management in combination with intramuscular methotrexate administration has been mentioned, including laparoscopic injection of methotrexate in the embryonic sac, CT-guided yolk sac aspiration with local injection of methotrexate, followed by ultrasound-guided percutaneous KCl injection, ultrasound-guided methotrexate injection [7], selective embolization of the splenic vessels feeding ectopic pregnancy by methotrexate [5] and partial splenectomy or splenorrhaphy [4] as well as our aforementioned case.
Conclusion
In reproductive-age females with abnormally elevated β-hCG levels and no intrauterine or pelvic pregnancy detected on transvaginal ultrasound, it is advisable to examine patients using other imaging modalities, such as abdominal sonography, CT or MRI, to detect any upper abdominal pregnancies. In rare abdominal ectopic gestations, early successful diagnosis is essential because of the high risk of uncontrollable life-threatening intraperitoneal bleeding. Partial splenectomy is the treatment of choice with the benefit of splenic preservation, especially in unruptured splenic pregnancy.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Conflict of interest
The authors declare no conflict of interest.
Funding: None
References
1. Bouyer J, Coste J, Fernandez H, Pouly JL, Job-Spira N. Sites of ectopic pregnancy: A 10 year population-based study of 1800 cases. Hum Reprod. 2002;17(12):3224-30.
2. Poole A, Haas D, Magann EF. Early abdominal ectopic pregnancies: A systematic review of the literature. Gynecol Obstet Invest. 2012; 74(4): 249-60.
3. Yagil Y B-RN, Amit A, Kerner H, Gaitini D. Splenic pregnancy: The role of abdominal imaging. J Ultrasound Med. 2007;26(11):1629-32.
4. Antequera A, Babar Z, Balachandar C, Johal K, Sapundjieski M, Qandil N. Managing Ruptured Splenic Ectopic Pregnancy Without Splenectomy: Case Report and Literature Review. Reprod Sci. 2021;28(8):2323-30.
5. Makrigiannakis A, Raissaki M, Vrekoussis T, Patramani S, Makrygiannakis F, Kholcheva N, et al. Splenic pregnancy treated with transcatheter embolization and methotrexate. Arch Gynecol Obstet. 2021;303(1):55-9.
6. Kalof AN, Fuller B, Harmon M. Splenic pregnancy: A case report and review of the literature. Arch Pathol Lab Med. 2004;128(11):e146-8.
7. Python JL, Wakefield BW, Kondo KL, Bang TJ, Stamm ER, Hurt KJ. Ultrasound-guided percutaneous management of splenic ectopic pregnancy. J Minim Invasive Gynecol. 2016;23(6):997-1002.
8. Wu L, Jiang X, Ni J. Successful diagnosis and treatment of early splenic ectopic pregnancy: A case report. Medicine (Baltimore). 2018;97(17):e0466.
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Pham Hong Duc, Pham Huu Khuyen, Quach Van Kien, Nguyen The Anh. Imaging modalities in early diagnosis of splenic ectopic pregnancy: A case report. Ann Clin Anal Med 2024;15(Suppl 1):S25-28
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Breast necrosis in a patient with COVID-19
Hakan Baysal 1, Begumhan Baysal 2, Gulnur Erdem 2, Gozde Kır 3, Orhan Alimoglu 1
1 Department of General Surgery, 2 Department of Radiology, 3 Department of Pathology, Faculty of Medicine, Istanbul Medeniyet University, Goztepe Prof Dr Suleyman Yalcin City Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.22038 Received: 2023-11-05 Accepted: 2023-12-22 Published Online: 2023-12-26 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S29-31
Corresponding Author: Hakan Baysal, Department of General Surgery, Istanbul Medeniyet University, Goztepe Prof Dr Suleyman Yalcin City Hospital, Fahrettin Kerim Gokay Street, Istanbul, Turkey. E-mail: hakanbaysal_tr@yahoo.com P: +90 532 345 21 08 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3604-6177
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious and pathogenic coronavirus that was detected in late 2019. It is a systemic disease that affects the entire body and is associated with various complications. Endothelial inflammation due to coronavirus disease (Covid-19) can affect the entire vascular system leading to thrombosis and vasculitis. A seventy-eight-year-old woman was admitted with complaints of sudden pain and color change in the right breast, suggestive of breast necrosis, in the first week of Covid infection. The necrosis did not regress, and simple mastectomy was performed. Herein, we present a case of unilateral breast necrosis that developed in a patient with Covid-19, which we have treated. In a disease like COVID-19 that affects all systems, a complete evaluation should be done, including the breasts.
Keywords: Breast Necrosis, Covid-19, Vasculitis
Introduction
Coronavirus disease (COVID-19) emerged in December 2019 and spread rapidly worldwide [1]. It affects multiple systems in the human body and causes symptoms depending on the damage caused. Vasculitis, vasculitis-like processes, and coagulopathy have been reported as a result of Covid-19 [2]. Breast involvement and multicentric breast abscesses have also been reported [3]. In addition, primary necrotizing fasciitis of the breast was reported with the late presentation of the patient in the initial days of the pandemic [4]. We present a case of breast necrosis that developed in a Covid-19 patient, which has not been previously reported in literature.
Case Report
A seventy-eight-year-old woman was admitted to the emergency department with complaints of severe pain and discoloration of the right breast in November 2021. She was diagnosed with Covid-19 one week prior to admission. The patient had a 20 year history of hypertension. No breast pathology was reported in the patient or her family histories. The patient had extensive hyperemic, painful, ecchymotic and bullous lesions (Figure 1a). Laboratory findings revealed neutrophilic leukocytosis and elevated lactate dehydrogenase (250 U/L), C-reactive protein (80 mg/L), and fibrinogen (800 mg/dl). Serum lipase was 210 U/L (normal 10–140 U/L). Among the hematological tests, haemoglobin, hematocrit, prothrombin time, activated partial thromboplastin time, international normalized ratio (INR), protein C, protein S and protein electrophoresis were normal respectively. D-Dimer levels (normal value < 0.55 mg/L) remained high between 6-10 mg/L. Bilateral ground-glass appearance and consolidations on thoracic computed tomography (CT) was consistent with a diagnosis of viral pneumonia. The patient was hospitalized for multidisciplinary follow-up, and treated with a double-dose inactivated vaccine, along with antiviral (Flavipavir) and antiaggregant (acetylsalicylic acid) therapy. On the 10th day, her PCR (Polymerase Chain Reaction) test result was negative, and cultures of discharge of breast bullous lesions and blood were sterile. Right breast ultrasound showed increased echogenicity of the skin and the subcutaneous fatty layers. Contrast-enhanced magnetic resonance imaging (MRI) revealed diffuse edema in the right breast and a hypovascular area, suggesting necrosis, in the retroareolar area (Figure 2). Tru-cut biopsy results were consistent with inflammatory lesions suggestive of fat necrosis. During follow-up, severe hemorrhagic necrosis continued at 15–20 cm, covering the nipple diametrically (Figure 1b). A simple mastectomy was performed due to progressive necrosis (Figure 1c). The pathology results showed total hemorrhagic infarction, microabscess formation, thrombi in medium and large vessels, and leukocytoclastic vasculitis (LCV). Grossly, large areas of hemorrhagic necrosis were observed in the breast skin and parenchyma (Figure 3). Post-operatively, the patient reported no new symptoms on follow-up for two years.
Discussion
Covid-19 is a SARS-CoV-2 syndrome that can affect all organs, including the circulatory system. Endothelial cell inflammation occurs in arteries, arterioles, capillaries, venules, and veins, inducing pathological events such as tissue hypoperfusion, injury, thrombosis, and vasculitis. Mechanisms that facilitate these events include an antiphospholipid syndrome-like state, complement activation, systemic endothelial infection with viral spread, viral RNA absorption with immune thrombosis, coagulation pathway activation mediated by hypoxemia and immobility. The morbidity and mortality associated with Covid-19 have been attributed to an exogenous immune response. In vitro and in vivo data have shown that complement activation plays a critical role in the pathogenesis and disease severity in SARS-CoV and SARS CoV-2 [5]. There are 3 main independent but overlapping pathways for complement activation: classical, Lectin, and alternative pathways. With the activation of these pathways, severe localized tissue damage or systemic involvement and multi-organ failure may develop, as in our case, with endothelial pathogenesis and thromboinflammation. It has been stated that complement activation contributes significantly to thrombotic microangiopathies (TMA). The endotheliopathy that occurs here is the prototype of TMA-mediated damage induced by C5b-9. Significant microvascular accumulation of C4d and C5b-9, the primary enzymatic initiator of the Lectin pathway in mannan-binding lectin serine protease 2 (MASP-2) complement activation, has been reported in the skin and lungs of patients. Extensive endothelialitis with endothelial adherence and platelet-rich fibrin thrombosis in large and small arterial vessels has been reported [6]. In autopsy results of patients with COVID-19, macro-and microvascular thromboses, in all major organ arteries, arterioles, capillaries, and venules, have been revealed [7]. Thrombosis often accompanies vasculitis, but may be the cause of tissue damage in obliterated arteriolite [8]. Some types of vasculitides associated with Covid-19 have been reported in literature. These are LCV, IgA, and Kawasaki disease-like types of vasculitis. The treatment of vasculitis includes corticosteroids, monoclonal antibodies, immunosuppressive drugs, anticoagulants, antiplatelet agents, and immunoglobulins. The choice of drug mainly depends on the type of vasculitis and the affected organ [9]. In 6% of patients with Covid-19-related skin lesions, these may result in necrosis. Our patient presented with breast necrosis related to Covid-19, which has not been reported in literature, and the progressive necrosis was thought to be associated with a vasculitis-like and thrombotic process.
Conclusion
An exogenous immune response has been identified in mortality and morbidity associated with Covid-19. Thrombosis and developing vasculitis due to thrombotic microangiopathies seen in complications are responsible for many pathological conditions. Except for a few cases of Covid-19 breast involvement reported in the literature, we report our case as the first case of progressive breast necrosis. Additional studies are needed to fully elucidate the underlying mechanism of breast necrosis that may develop in patients with Covid-19 and to establish a definitive treatment protocol.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Liu YC, Kuo RL, Shih SR. COVID-19: The first documented coronavirus pandemic in history. Biomed J. 2020;43(4):328-33.
2. Iba T, Connors JM, Levy JH. The coagulopathy, endotheliopathy, and vasculitis of COVID-19. Inflamm Res. 2020;69(12):1181-9.
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Pulmonary arterial hypertension in a child with stage IV neuroblastoma after autologous stem cell transplant: A case report
Tran Kiem Hao 1,2,3, Nguyen Thi Kim Hoa 2,4, Bui Binh Bao Son 5,6
1 Department of Intensive care, Pediatric Center, Hue Central Hospital, Hue, 2 Department of Pediatrics, The Faculty of Medicine, Duy Tan University, Danang, 3 Department of Health, Hue Healthy Affair, Hue, 4 Department of Pediatric Oncology-Hematology and transplant, Hue Pediatric Center, Hue Central Hospital, Hue, 5 Department of Pediatric Pulmonology, Hue Pediatric Center, Hue Central Hospital, Hue, 6 Department of Pediatrics, Hue University of Medicine and Pharmacy, Hue University, Hue, Viet Nam
DOI: 10.4328/ACAM.22056 Received: 2023-11-21 Accepted: 2023-12-22 Published Online: 2023-12-26 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S32-35
Corresponding Author: Nguyen Thi Kim Hoa, Department of Pediatric Oncology-Hematology and Transplant, Hue Central Hospital, Hue, Viet Nam. E-mail: kimhoa.fmi@gmail.com P: +84 935 645 83 6 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2525-4368
Pulmonary hypertension (PH) is a potentially fatal condition associated with increased pulmonary vascular resistance and elevated right ventricular pressure after hematopoietic stem cell transplantation (HSCT). Herein we report a 3-year-old girl with stage-IV neuroblastoma who developed PAH at the day 52nd after autologous HSCT. She had good response to oxygen, diuretics, endothelin receptor antagonist and sildenafil.
Keywords: Pulmonary Arterial Hypertension, Stem Cell Transplantation, Children
Introduction
Pulmonary arterial hypertension (PAH) is an unusual and life-threatening condition associated with increased pulmonary vascular resistance and elevated right ventricular pressure [1, 2]. PAH is defined by a pulmonary artery pressure (PAP) that exceeds 25 mmHg at rest and over 30 mmHg during activity [3]. Elevated pulmonary artery pressures could cause permanent changes in the pulmonary vasculature, right ventricular failure and death. At the initial time, PAH may be asymptomatic or present with non-specific symptoms such as respiratory distress, fatigue. Therefore, the diagnosis is very challenging, and it could be mis-diagnosed [1, 3-5]. The diagnosis requires a high degree of suspicion [6]. The most commonly reported pathological types of PH in HSCT recipients are pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD), depending on the site of endothelial injury [1, 4]. PH therapy can be disease specific or supportive [2]. At this moment, the drugs used to treat PH are all accepted for PAH [2, 4]. Early diagnosis and timely treatment could allow improved clinical outcome with normalisation of PAP [5].
Case Report
A 3 year-old female with stage IV neuroblastoma achieved partial remission after 8 course Rapid- Cojec. She underwent autologous transplant with conditioning regimen of busulfan and melphalan. Neutrophile and platelet engraftments were administered on day +25 and +35 respectively. At Day +52, she presented with cough, anorexia, vomiting, dyspnea, and fatigue. Physical examination showed the following: temperature 37.5oC, pulse rate 160 bpm, blood pressure 95/60 mmHg and respiratory rate 45 bpm, with nasal, intercostal and subcostal retraction. Lung sounds increased at both sides, and hepatomegaly was 3cm under subcostal margin. Oxygen saturation was 85% by pulse oximeter on room air. Key lab evaluations showed increased Pro-BNP: 9646 pg/ml (cutoff value < 125 pg/ml), full blood count, blood biochemistry (LDH, CRP, liver, kidney function) and coagulation tests were normal. The chest radiography and CT scan didn’t demonstrate any lesions at her lungs (Fig.1 and Fig.2). ECG revealed right axis deviation and heart ultrasound showed an increased pulmonary artery pressure (systolic 80mmHg and mean 45 mmHg), and dilated right ventricle and right atrium (Fig.3). Before transplant, she was evaluated and the heart ultrasound examination was normal. In addition, pro-BNP was normal. At this time, her peripheral blood smear and biochemical finding revealed no evidence for microangiopathic hemolytic anemia. Therefore, PAH related to primary respiratory disease or chronic thromoboembolic pulmonary hypertension was further excluded. The patient was diagnosed secondary PAH to HSCT, and was treated with diuretics (furosemide 1mg/kg/day + spironolactone 1mg/kg/day), endothelin receptor antagonist (bosetan: 2mg/kg every 12 hours), enalapril (0.1mg/kg/day), digoxin (30mcg/kg/day, divided three times) and sildenafil (3mg/kg/day, divided three times). After 18 days, her pulmonary artery pressure returned normal value. Her heart rate and Pro-BNP returned normal. She did not have hepatomegaly and respiratory distress anymore. We stopped oxygen and digoxin, continued to use diruetics + sidenafil + Bonsetan + enalapril for one month. Then, she received radiotherapy at her tumor bed with 21.6 Gy. After finishing radiation, she was discharged and used 13 cis-retino acid for 6 months according to treatment regimen in high risk neuroblastoma. One year later, she is still healthy.
Discussion
The first case with PAH as a complication after transplant was reported in 1984 by Troussard et al [7]. This was a 12-year-old boy who underwent HSCT for relapsed acute lymphoblastic leukemia and was reported autopsy findings consistent with PH. Since then, there were some other cases were reported [7].
The lung is a major target organ for infection, toxicity and inflammation prior and after allogeneic and autologous HSCT. After transplantation, there are some common pulmonary complications, such as infectious pneumonia, acute respiratory distress syndrome, pulmonary edema, diffuse alveolar hemorrhage, heart failure, interstitial pneumonitis, idiopathic pneumonia syndrome, bronchiolitis obliterans, and organizing pneumonia [1]. PH is rarely included in the differential diagnosis of respiratory distress post-transplantation and can be easily omitted.
Early identification and diagnosis of PAH is very important so that we could provide the right treatment immediately before right-sided heart failure and irreversible cardiac compromise [1]. In HSCT patients, family history could be unrevealing because most risk factors are associated with HSCT therapy or complication in these patients [1]. These factors could be infection, malignancy, immune dysregulation, epithelial damage (caused by radiation, conditioning regimen), endothelial damage, genetic/biochemical, pro-inflammatory cytokine release and cell-mediated damage [5].
The initial respiratory symptoms of PAH are shortness of breath, fatigue, weakness, hypoxemia, and these signs could be vague and difficult to attribute specifically to PAH in the post-transplantation patient. Edema and ascites could develop in the later stages from increased venous congestion [8].
In our case, at D+52 after autologous transplant, the patient was presented with cough, anorexia, vomitting, dyspnea, and fatigue. Examination showed increased respiratory rate and increased lung sound at both sides. Her oxygen saturation was 85%. With these symptoms, at the beginning, we thought patient had viral pneumonia. However, after receiving the normal result of chest radiography, we had to think of another diagnosis. Particularly when combining with other symptoms, such as: elevated heart rate, hepatomegaly, we ordered some tests including heart ultrasound, ECG, Pro-BNP, LDH, CRP, liver, kidney function and Bilirubine. With the result of ECG showed right axis deviation, heart ultrasound demonstrated an increased pulmonary artery pressure (systolic 80mmHg and mean 45 mmHg), dilated right ventricle and right atrium and pro-BNP increased (9646 pg/ml), we concluded that the patient had PAH secondary to HSCT. For this case, in the beginning, we did not expect to diagnose PAH with her symptoms (since this was the first case with PAH we met in our hospital), and we had to wait the result of some lab tests. However, the time to wait PAH diagnosis was short and could be acceptable. Analysing the reasons to cause PAH in our case, we thought about conditioning regimen with busulfan and melphalan which have been described to cause endothelial injury [5].
Regarding treatment, the initial purpose of therapy aims at optimizing cardiac function, especially if PAH has resulted in right ventricular compromise. The treatment could be a combination of some medicines, such as diuretics, afterload-reducing agents, intravenous inotropes, pulmonary vasodilator therapy, oxygen therapy, inhaled nitric oxide, calcium channel blockers, phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostanoids. For our patient, she was treated with diuretics, endothelin receptor antagonist, enalapril, digoxin and sildenafil. After 18 days, her pulmonary artery pressure returned normal value. We stopped oxygen and digoxin and continued to use diruetics + sidenafil + Bonsetan + enalapril for one month. She had good response.
According to Ozyoruk, he reported one case with high risk neuroblastoma appeared PAH after autologous transplant with Bul+Mel conditioning. The patient was treated with a similar therapy, including enalapril, furosemide, sildenafil and iloprost inhaler, and he had good response. It has been reported that sildenafil effectively reduces pulmonary artery pressure, improves cardiac function and does not cause adverse reactions in children [4]. However, if diagnosis delays, the prognosis is very poor. Levy reported 22 patients who were diagnosed severe pulmonary hypertension after HSCT with a fatal outcome in 32%. All the patients who were diagnosed died later, whereas pulmonary hypertension always resolved in those who had a rapid diagnosis allowing timely administration of targeted therapy [5]. Therefore, the most important thing is how to diagnose timely and provide treatment properly to normalise pulmonary pressure and improve survival [3, 5].
Aggressive and timely up-front combination therapy allowed normalisation of pulmonary pressure and improved survival.
Conclusion
Pulmonary arterial hypertension is rare complication of cardiorespiratory failure after pediatric hematopoietic stem cell transplant. It is crucial to diagnose and provide treatment immediately before right-side heart failure and irreversible cardiac compromise.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Dandoy CE, Hirsch R, Chima R, Davies SM, Jodele S. Pulmonary hypertension after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19(11):1546-56.
2. Beghetti M, Gorenflo M, Ivy DD, Moledina S, Bonnet D. Treatment of pediatric pulmonary arterial hypertension: A focus on the NO-sGC-cGMP pathway. Pediatr Pulmonol. 2019;54(10):1516-1526.
3. Houtchens J, Martin D, Klinger JR. Diagnosis and management of pulmonary arterial hypertension. Pulm Med. 2011;2011:845864.
4. Ozyoruk D, Kibar AE, Surucu M, Azak E, Emir S, Cetin, II, et al. Pulmonary arterial hypertension in a child with stage-IV neuroblastoma after autologous hematopoietic stem cell transplantation and review of the literature. Pediatr Transplant. 2015;19(7):E185-8.
5. Levy M, Moshous D, Szezepanski I, Galmiche L, Castelle M, Lesage F, et al. Pulmonary hypertension after bone marrow transplantation in children. Eur Respir J. 2019;54(5).
6. Jodele S, Hirsch R, Laskin B, Davies S, Witte D, Chima R. Pulmonary arterial hypertension in pediatric patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Biol Blood Marrow Transplant. 2013;19(2):202-7.
7. Troussard X, Bernaudin JF, Cordonnier C, Fleury J, Payen D, Briere J, et al. Pulmonary veno-occlusive disease after bone marrow transplantation. Thorax. 1984;39(12):956-7.
8. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493-537.
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Tran Kiem Hao, Nguyen Thi Kim Hoa, Bui Binh Bao Son. Pulmonary arterial hypertension in a child with stage IV neuroblastoma after autologous stem cell transplant: A case report. Ann Clin Anal Med 2024;15(Suppl 1):S32-35
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Foreign body aspiration
Suat Konuk, Emre Bacaksız
Department of Chest Diseases, Faculty of Medicine, Bolu Abant İzzet Baysal University Hospital, Bolu, Turkey
DOI: 10.4328/ACAM.22060 Received: 2023-11-30 Accepted: 2024-03-18 Published Online: 2024-03-19 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S36-38
Corresponding Author: Suat Konuk, Department of Chest Diseases, Faculty of Medicine, Bolu Abant İzzet Baysal University Hospital, Bolu, Turkey. E-mail: suatkonukk@windowslive.com P: +90 507 341 01 26 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8240-4775 Other Author ORCID ID: Emre Bacaksız, https://orcid.org/0000-0002-4914-2080
Bronchoscopic evaluation was performed on the patient who applied to Bolu Abant İzzet Baysal University Chest Diseases Clinic and could not achieve clinical and radiological improvement with antibiotic treatment. During bronchoscopy, the middle lobe of the right lung was observed to be approximately 30% occluded. Since the suspicion of aspiration could not be excluded, thoracic surgery consultation was requested and rigid bronchoscopy was performed. Chicken bone was removed from the right main bronchus. In our case, the aspirated chicken bone did not cause serious respiratory distress because it did not completely obstruct the right main bronchus, but it did lead to chronic respiratory tract infection. Definitive diagnosis of foreign body aspirations is made by bronchoscopy. One of the most important criteria for the indication of bronchoscopy is clinical suspicion.
Keywords: Aspiration, Bronchoscop, Chicken Bone
Introduction
Foreign body aspirations (FBA) are typically observed in children and are often associated with acute respiratory distress, although they can sometimes remain asymptomatic. In adults, FBA is rare. Symptoms in adults may include severe coughing, chest pain, and shortness of breath, but cases can also be asymptomatic. Initially, silent cases may later manifest as a clinical picture involving persistent lung infections, bronchiectasis, or lung abscess.
Case Report
A 57 years old male patient presented with a one-month history of cough and yellowish sputum. He was admitted for further investigation. It was revealed that his symptoms did not improve despite receiving pneumonia treatment at an external center. The patient, who had refused bronchoscopy at the external center, underwent a sputum culture and a fungal culture for three days. Increased bilateral rales were heard on auscultation, particularly on the right side. A chest CT was requested, revealing a hyperdense appearance consistent with a foreign body in the right intermediate bronchus and accompanying bilateral consolidated areas.
The patient and his family were informed about the possibility of a foreign body, bronchoscopy consent was obtained, and the procedure was scheduled. During bronchoscopy, all lobes and segments of the left lung were clear, while the right intermediate bronchus was almost completely obliterated by vegetative lesions. Multiple forceps biopsies, brush biopsies, and lavage were performed from this area, and the obtained materials were sent for cytology, microbiology, and pathology. As the suspicion of aspiration could not be ruled out, consultation with thoracic surgery was sought, and rigid bronchoscopy was performed. A chicken bone was extracted from the right intermediate bronchus. The patient’s symptoms improved after the procedure, and he was discharged.
Discussion
Tracheobronchial foreign body aspirations (FBA) are more common in the pediatric age group but can also occur in adults. In adults, FBA is often observed in the 6th and 7th decades of life when protective airway mechanisms may decrease [2, 3, 4]. Diagnosis is typically based on detailed history, physical examination, and, in most cases, the results of radiological findings. However, there are situations where radiological findings may not provide clear guidance. Common symptoms in adults include severe coughing, chest pain, shortness of breath, and cyanosis [3, 5]. However, depending on the type, size, and location of the foreign body, there may be no symptoms, or it can lead to severe respiratory distress. Late complications may include lung abscess, atelectasis, obstructive pneumonia, bronchiectasis, empyema, bronchopleural fistula, pneumothorax, and esophageal erosion [2, 3]. In our case, the aspirated chicken bone did not completely obstruct the right intermediate bronchus, thus not causing severe respiratory distress but leading to chronic respiratory tract infection.
Sometimes, a foreign body may remain asymptomatic for an extended period. The longest reported duration for a foreign body to remain in the tracheobronchial tree is 40 years[6]. When suspecting foreign body aspiration, posterior-anterior and lateral chest X-rays, along with physical examination, are essential. However, chest X-rays may not always lead to a conclusive diagnosis. If the aspirated foreign body is radiopaque, it can be easily visualized on chest X-rays. Secondary radiological findings include air trapping on chest X-rays taken after postobstructive atelectasis or expiration. In adults, aspiration often occurs in the right hemithorax, whereas in the 0–15 age group, both hemithoraxes are equally affected [6, 7]. In all cases where there is suspicion of foreign body aspiration, the most appropriate treatment is the removal of the foreign body under general anesthesia through rigid bronchoscopy [7]. This method is generally safe for extracting foreign bodies from the airways. However, in cases where a significant amount of time has passed since the aspiration, the procedure may be more challenging due to the fibrotic parenchymal tissue that has developed in the surrounding area. For sharp and pointed foreign bodies, manipulations during bronchoscopy should be performed carefully, considering the possibility of peripheral migration. If foreign bodies in peripheral bronchi cannot be reached with rigid bronchoscopy or in patients with restricted neck movement due to cervicofacial or maxillofacial pathology, fiberoptic bronchoscopy (FOB) may be preferred. In our case, as the foreign body was not described in the patient history, attempts were made to biopsy the dark-colored lesion during the FOB procedure, and its rigidity was noticed at that time, leading to the suspicion of a foreign body.
After the removal of the foreign body, patients should be observed for some time for hemoptysis and subglottic edema. In cases where the foreign body cannot be removed during the first bronchoscopy session, the procedure may be repeated 2-3 times. If unsuccessful, the patient may be referred for thoracotomy [1, 8]. Due to diagnostic delays, if a foreign body remains in the lung for an extended period, irreversible damage such as bronchiectasis, obstructive emphysema, recurrent pneumonia, bronchial stenosis, lung abscess, pleural effusion, empyema, bronchopleural fistula, endobronchial polyp, and rib osteomyelitis may develop [7, 8].
In a study by Şenaylı and colleagues in Turkey, which aimed to examine foreign body aspirations and determine the overall situation, 14 articles were retrospectively analyzed. From 1973 to 2007, 6633 patients were investigated for foreign body aspiration, and foreign bodies were found in 5014 patients. In cases of unsuccessful bronchoscopies, 46 thoracotomies were performed, and 9 tracheotomies, 4 pneumothoraces, and 7 cardiac arrests were reported. The most commonly encountered foreign bodies were identified as seeds and needles [9]. Delayed foreign body aspirations can lead to irreversible damage in the lungs and bronchi, and situations requiring pulmonary resection may arise. In a series of 23 cases treated surgically due to delayed foreign body aspiration, Duan and colleagues reported that they were able to remove the foreign body with bronchotomy in six cases and that lung resection was required in 17 cases [10]. Foreign body aspiration may be more common in adults with neurological diseases, alcohol and sedative drug use, epileptic seizures, facial trauma, and those undergoing general anesthesia[6].
Conclusion
The definitive diagnosis of foreign body aspirations is typically made through bronchoscopy. One of the most crucial criteria for indicating bronchoscopy is to have clinical suspicion. Anamnesis, physical examination, and radiological evaluations are usually sufficient to suspect foreign body aspiration. However, in cases where no clinical findings or history are detected but there are lung issues, considering foreign body aspiration may still necessitate the indication for bronchoscopy. If successful removal of the foreign body cannot be achieved through bronchoscopy, surgical procedures should be considered.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Yıldızeli B, Yüksel M. In: Yüksel M, Kalaycı G, editor. Trakeobronşiyal yabancı cisim aspirasyonları [Tracheobronchial foreign body aspirations]. 1st ed., Istanbul: Özlem Grafik Matbaacılık. 2001.pp.677-87.
2. Başoglu A, Çelik B, Demircan S, Akdag AO, Gündogdu B, Kaya S, et al. Erişkinlerde trakeobronşiyal yabancı cisimler [Tracheobronchial foreign bodies in adults]. J Exp Clin Med. 2004;21(3):117-22.
3. Pingarrón Martín L, Morán Soto MJ, Sánchez Burgos R, Burgueño García M. Bronchial. Impaction of an implant screwdriver after accidental aspiration: Report of a case and revision of the literature. Oral Maxillofac Surg. 2010;14:43-7.
4. Kısacık E, Gülhan E, Sırmalı M, Sarıca E, Türüt H, Karasu S, et al. Trakeobronşiyal yabancı cisim aspirasyonları: 261 Olgunun Analizi. [Tracheobronchial foreign body aspirations: Retrospective analysis of 261 cases]: Solunum Hastalıkları. 2004;15(2):86-91.
5. Umesan UK, Chua KL, Balakrishnan P. Prevention and management of accidental foreign body ingestion and aspiration ın orthodontic practice. Ther Clin Risk Manag. 2012;8:245-52.
6. Limper AH, Prakash UBS. Tracheabronchial Foreign Bodies In Adults. Ann Intern Med 1990;112:604-9.
7. Dübüş T, Demiryontar D, Uzman Ö. Yetişkinde Trakeobronşiyal Yabancı Cisim Aspirasyonu: İki Olgu Sunumu [Tracheobronchial foreign body aspiration in adults: Two case reports]. İstanbul Tıp Dergisi. 2011;12(1):49-52.
8. Çapan N, Alıcı Oİ. Trakeabronşiyal Yabancı Cisim Aspirasyonları [Tracheobronchial foreign body aspirations]. Solunum Hastalıkları. 2009;20(1):39-42.
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Suat Konuk, Emre Bacaksız. Foreign body aspiration. Ann Clin Anal Med 2024;15(Suppl 1):S36-38
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Rare case of hand bony involvement of sarcoidosis in a palestinian woman: A case report
Neveen Shalalfa 1, Saleh Shalalfa 2, Ahmad Bitawi 2, Zuhair Nazar Mohammed 3, Salam Noman Hattawi 4, Javid Mohammadzadeh Azarabadi 5
1 Department of Family Medicine, Faculty of Medicine, Palestine Polytechnic University, Hebron, Palestine, 2 Department of Orthopedic Surgery, Faculty of Medicine, Alquds University, Ramalla, Palestine, 3 Department of Health and Medical Laboratory Technologies, Faculty of Medicine, Northern Technical University Kirkuk, Iraq, 4 Department of Renal Diaylsis Techniquies, Faculty of Health and Medical Technical, Northern Technical University, Kirkuk, Iraq, 5 Department of Orthopedics and Traumatology, Faculty of Medicine, Baskent University, Ankara, Turkey
DOI: 10.4328/ACAM.22064 Received: 2023-12-05 Accepted: 2024-01-15 Published Online: 2024-02-02 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S39-42
Corresponding Author: Javid Mohammadzadeh Azarabadi, Department of Orthopedics and Traumatology, Faculty of Medicine, Baskent University, Ankara, Turkey. E-mail: dr_jma_md@yahoo.com P: +90 538 038 79 83 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2393-3535
Sarcoidosis is a multisystem inflammatory illness with no recognised cause. Non-caseating granulomas are a characteristic of this illness. Bilateral hilar lymphadenopathy and lung infiltration are the most typical presentations. However, the disease is quite diverse and has an unexpected clinical outcome. Less often, there is bone involvement but considered serious and significant. Involvement of the bone is present in 1–15% of sarcoidosis patients. Hand involvement in sarcoidosis is uncommon and Sarcoid lesions of the hand occur in only around 0.2 percent of cases. We describe a case of sarcoidosis in Palestine with a history of finger swelling, radiographic and magnetic resonance imaging (MRI) findings showed bony involvement for increasing the awareness of the medical team and population.
Keywords: Sarcoidosis, Hand Involvement, Bone Involvement, Finger Swelling, Treatment
Introduction
Sarcoidosis is an inflammatory disorder with non-caseating granulomas that affects multiple organ systems and has no known cause, Tuberculosis, leprosy, syphilis, Wegener granulomatosis, multiple myeloma, lymphoma, and other diseases are among the differential diagnoses of cases [1]. Bilateral hilar lymphadenopathy and lung infiltration are the most typical presentations; however, the disease is quite diverse and has an unexpected clinical outcome [2]. There are frequent musculoskeletal symptoms. Less often, there is bone involvement. [3] Involvement of the osseous system is present in 1–15% of sarcoidosis patients [2,4].
Hand involvement in sarcoidosis is uncommon and when it occurs, it usually presents as tenosynovitis, dactylitis, nodules, and osteoarticular bone deterioration [5]. Occasionally, however, sarcoidosis is diagnosed based on irregular symptoms. Soft-tissue swelling in the hands, for example, without serious systemic disease is an uncommon symptom, but it may suggest subcutaneous sarcoid involvement. These swellings can appear in a variety of ways, posing challenges for orthopedic surgeons who encounter them [1].
Sarcoid lesions of the hand occur in just around 0.2 percent of cases. Bone lytic lesions are seen in the majority of these cases [6], with tendon, muscle, and subcutaneous soft-tissue involvement occurring infrequently. In addition, sarcoid dactylitis, which is characterized by non-caseating granulomas invading the phalanges and adjacent soft tissue, is well recognized [3]. Skin involvement is seen in 9 percent to 37 percent of systemic sarcoidosis patients, subcutaneous involvement is a less common manifestation [1]. Diagnostic imaging methods are crucial. Radiological examinations indicated cortical anomalies, sclerotic or destructive lesions (including also joints), and cystic and punched-out lesions [2].
In Palestine, sarcoidosis is commonly recognized as a rare disorder, with bone involvement even rarer. Herein, we report a case of hand bony involvement of sarcoidosis in a 58-year-old woman. This case was diagnosed using clinical findings, and correlated radiographic imaging.
Case Report
A 58-year-old lady presented with progressive, painful swellings in the left index finger of her hand for four months. She had a pre-existing diagnosis of sarcoidosis and had been consistently taking medication. Although she discontinued corticosteroids 3 month ago, her finger was swollen completely (Figure 1). It was tough, tender, firm, and had well-demarcated borders. Routine laboratory studies indicated a uric acid level of 4.3mg/dl, urea of 33.6 mg/dl, normal triglyceride, and normal kidney and liver function test and total cholesterol. Hand X-ray and MRI were done. The findings were matching with dactylitis as a diagnosis for this case (Figure 2). Chest X-ray was also done and confirmed the diagnosis (Figure 3).
Ethical considerations:
Ethical committee approval of the polytechnic university was taken, and a written consent form the patient was also taken, the patient also given her consent for her image and clinical information to be reported in the journal, the patient understand that her name will not be published.
Discussion
Most patients are aged 20–45 years, although recently an increase in new onset of sarcoidosis in people older than 60, especially women, has been reported [2]. Sarcoidosis can affect multiple organs, most often the lungs, lymph nodes, eyes, and skin. Bone involvement is rare [7] which is present in 1–15% of sarcoidosis patients [2,4]. Skin involvement is seen in 9 percent to 37 percent of systemic sarcoidosis patients. Subcutaneous involvement is a less common manifestation [1]. Sarcoid lesions of the hand occur in just around 0.2 percent of cases. Bone lytic lesions are seen in the majority of these cases [6], with tendon, muscle, and subcutaneous soft-tissue involvement occurring infrequently. In addition, sarcoid dactylitis, which is characterized by non-caseating granulomas invading the phalanges and adjacent soft tissue, is well recognized [3].
The most frequent manifestation of the bone in sarcoidosis patients is dactylitis. It appears in about 90% of the cases. The condition is generally bilateral and asymmetric, occurring most often in the middle and distal phalanges of the second and third digits [8]. Various circumstances can lead to dactylitis discovery. It is the most common clinical presentation, with swelling of one or more fingers that become purplish and may or may not be painful. Fluid accumulation in the skin and subcutaneous tissue, along with nail splitting, has also been reported [3]. In rare cases, it is discovered suddenly when radiography is performed for any other indications.
In our case, there is a female patient who had bone changes that were characteristic of osseous sarcoidosis and was diagnosed using an X-ray of the hand, which showed dactylitis. MRI showed extensive soft tissue mass lesion involving the whole index finger and extensive abnormal right bone marrow.
In terms of laboratory testing, higher erythrocyte sedimentation rate, and increased acetylcholinesterase levels are observed in a variable and nonspecific manner, independent of where the disease is located [4].
In our case, the patient doesn’t have any abnormal laboratory test results. However, in radiograph images, the lesion is found mainly in the index phalange. This kind of lesion most often occurs bilateral and asymmetric [3]. MRI mainly provides detailed information about fluid accumulation in the bone and mainly bone marrow and extension to soft tissues [7]. The involvement of small bones in the hands may be evident with MRI, as MRI may show a much more extensive process than one would see on the radiographs [7].
Conclusion:
This presented case demonstrate a bone lesions typical of osseous sarcoidosis. These lesions were severe and may cause noticeable bone damage with fluid accumulation in the soft tissues. This case is rare in this manifestation of sarcoidosis. The possibility of osseous sarcoidosis should be considered when a patient with radiographic signs also has a suggestive clinical context. With the correct diagnosis, suitable treatment can be provided early on, thereby avoiding unnecessary surgery that compromises the functional prognosis.
From an orthopedic point of view:
The significance of this case is that, although sarcoidosis commonly presents with typical signs and symptoms, unusual manifestations should not preclude the diagnosis. An atypical soft-tissue swelling in the hands may arouse the suspicion of sarcoid involvement of subcutaneous tissue so orthopedics must be aware of that all the time.
Acknowledgment
The authors thank Dr.Abdulrahman Marridi for their efforts and cooperation.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
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Neveen Shalalfa, Saleh Shalalfa, Ahmad Bitawi, Zuhair Nazar Mohammed, Salam Noman Hattawi, Javid Mohammadzadeh Azarabadi. Rare case of hand bony involvement of sarcoidosis in a palestinian woman: A case report. Ann Clin Anal Med 2024;15(Suppl 1):S39-42
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Overview of vasopressor and inotropic agents
Yasemin Hacanlı
Department of Cardiovascular Surgery, Faculty of Medicine, Harran University, Şanlıurfa, Turkey
DOI: 10.4328/ACAM.22004 Received: 2023-10-05 Accepted: 2023-11-06 Published Online: 2023-12-22 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S43-46
Corresponding Author: Yasemin Hacanlı, Department of Cardiovascular Surgery, Faculty of Medicine, Harran University, Şanlıurfa, Turkey. E-mail: yaseminhacan@hotmail.com P: +90 506 700 27 00 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4427-8149
Hypotension can often occur during and following anesthesia and surgery. Studies emphasize that end-organ ischemia during surgery is associated with morbidity, hypotension and mortality. Vasoactive agents and fluid volumes are often preferred to improve hypotension during surgery. Despite the widespread use of vasoactive agents, neither the substance nor the dose has been fully defined. Vasoactive agents are divided into two groups according to their functions: vasopressors and inotropes. These agents are believed to regulate end-organ perfusion. But, it also has side effects such as hyperlactataemia, tachycardia, tachyarrhythmias, ischemia and hyperglycemia. The likelihood and severity of these side effects depend on the agent used, its amount and duration. Our aim in this compilation is; To provide an overview of inotropic agents. To give information about ISO and dobutamine, which are inotropic agents, and to briefly touch upon their use in animal studies.
Keywords: Vasoactive Agents, Vasopressor, Inotropic Agents, Isoproterenol, Dobutamine
Introduction
Although the quality of care after surgical procedures has improved, the possibility of postoperative mortality and complications remains a serious threat [1]. Hypotension can often occur during and following anesthesia and surgery. Studies emphasize that end-organ ischemia during surgery is associated with morbidity, hypotension and mortality [2]. Vasoactive agents and fluid volumes are often preferred to improve hypotension during surgery [3]. Despite the widespread use of vasoactive agents, neither the substance nor the dose has been fully defined [4]. Vasoactive agents are divided into two groups according to their functions: vasopressors and inotropes [5]. These agents are believed to regulate end-organ perfusion [6]. Vasopressors act through the adrenergic system and increase blood pressure through vasoconstriction [5]. However, the volume of myocardial oxygen does not increase. This leads to reduced cardiac and systemic perfusion, leading to multiple organ failure and death due to cardiac arrest [7]. Inotropes act by increasing cardiac contractility [5]. The study on inotropes showed that their short-term use provided a neutral effect, while their long-term use led to adverse outcomes in patients hospitalized with acute HF [8]. For this reason, the use of most inotropic agents [especially phosphodiesterase (PDE) and catecholamines (Endogenous: Adrenaline, Noradrenaline, Dopamine and exogenous: Dobutamine, Isoproterenol, Phenylephrine, Milrinone) [9]] is not preferred unless there is hypoperfusion or hypotension [10].
It is possible to list hyperlactatemia, tachycardia, tachyarrhythmias, ischemia and hyperglycemia among the side effects of vasopressors and inotropes [11]. The likelihood and severity of these side effects vary depending on the agent used, its amount, and duration [12].
Isoproterenol (ISO)
Isoproterenol (ISO) is a cardiac β1 and β2 adrenoreceptor agonist with positive chronotropic and inotropic effects [13]. It is a synthetic catecholamine [14]. It has been shown to be successful in activating pulmonary veins, including in highly sedated patients, as well as extrapulmonary veins that trigger atrial fibrillation [13]. However, it plays a role in the synthesis of free radicals by triggering lipid peroxidation. This situation creates critical levels of oxidative stress in the myocardium, leading to infarction-like necrosis in the heart muscle and ultimately irreversible damage to the myocardial membrane [14]. It can lead to cardiac hypertrophy and myocardial apoptosis. The myocardial damage method created by ISO is preferred in examining the protective effect of many drugs on the heart, as it is similar to the pathological changes in heart tissue in the development of human heart failure [15].
Dobutamine
Dobutamine is a β-1 adrenergic agonist [17]. As a result of the fact that cardiomyocytes and inflammatories affect each other, the contractility of the heart decreases. In this case, dobutamine supplementation is preferred to increase cardiac output [18]. Dobutamine directly triggers β1 and α1 receptors, with poor affinity for β2 receptors [19]. In the myocardium, β-1 activates adrenergic receptors. and increases cardiac contractility. MoreoverIn doing so, it does so this without generating tachycardia and vasoconstriction [17]. At doses as lower as than <5 microgram/kilogram/minute (µg/kg/min), dobutamine can cause agonist and antagonist triggering of α1 receptors and vasodilation. However, at doses above >15 µg/kg/min, it may cause vasoconstriction [19]. The half-life of dobutamine is <2 minutes. The benefit depends on the dose-response relationship. The infusion administered in high doses should be used with caution as it may cause the formation of tachycardia [9]. While dobutamine is beneficial in the regulation of heart failure treatment in the short term, it has been explained that it may have the opposite effect in the long term [20].
The hemodynamic effects and adrenergic properties of ISO and dobutamine are briefly summarized in Table 1 [21].
Discussion
Today, various studies are being carried out to investigate the effects of cardiovascular diseases (CVD) on the diagnosis and treatment. In these studies, especially in experimental studies on animals, cardiac injury models were created by using various inotropic agents, methods, surgical techniques and drugs. Our aim is to touch upon some of the experimental daemage models of ISO and dobutamine on animals. ISO, a beta- adrenergic agonist, may play a role in the formation of necrosis similar to myocardial infarction (MI) in rats. This damage is thought to be similar to human myocardial differentiation [22]. In ISO-generated injury models, various biochemical parameters such as lactate dehydrogenase (LDH), creatine phosphokinase-MB (CK-MB) and aspartate transaminase (AST) are evaluated as well as the heart tissue structure to detect damage [23].
In their study, Fan et al. looked at AST, lactate dehydrogenase (LDH), CK and CK-MB levels in plasma to determine the detection of myocardial damage by ISO in male Sprague Dawley rats, and these parameters were higher in the ISO group [24]. Xing et al. induced MI by ISO in rats. When pathological changes in heart tissue in the ISO group were examined compared to the control group, myocardial necrosis and edema, infiltration of inflammatory cells and membrane damage were detected [25]. Another study examined ISO-induced MI damage in rats and found that ISO led to the production of oxidative free radicals that cause irreversible disruption of the cardiac myocyte membrane and myocardial cell death, leading to leakage of markers of heart damage [26]. Yang et al. injected the mice with ISO for two days. After this administration, serum cardiac troponinT (cTnT), CK-MB and LDH content increased and cardiac dysfunction was observed [27]. In another experimental study on rats, an increase in heart weight, heart-to-body weight ratio, malondialdehyde levels in heart tissue and serum, and TNF-a, IL-1β and IL-6 levels in heart tissue homogenates was observed in the ISO group compared to the control group. Decreases in superoxide dismutase and catalase levels have been reported [28].
Dobutamine is a β-1 adrenergic agonist [17]. As a result of the fact that cardiomyocytes and inflammatories affect each other, the contractility of the heart decreases. In this case, dobutamine supplementation is preferred to increase cardiac output [18]. While dobutamine is beneficial in the regulation of heart failure treatment in the short term, it has been explained that it may have the opposite effect in the long term [20]. Azuero et al. administered increasing doses of dobutamine to the piglets’ hearts [2.5–15 μg/kg (microgram/kilogram) body weight (min) dobutamine per minute (min), 0.007–0.044 μmol/kg/min (micromol/kilogram/min]. As a result of the application, an increase in left ventricular end-diastolic pressure, heart rate and lactate production was observed. Tissue acylcarnitine levels were higher in the dobutamine group than in the saline group [29]. In their study on dogs, Yi et al. administered low doses (0.01 μg/kg/min) and high doses (0.06 μg/kg/min) to the right coronary artery (RCA) for 15 minutes of hypoperfusion. While low-dose dobutamine administration showed positive results in hypoperfusion-infused right ventricular (RV) myocardial contractile function and cellular energy recovery, the same was not true for high-dose. Therefore, it is important to pay attention to the dosage application [30]. In the experimental study on rats, the rats were loaded with caffeine and dobutamine. Early ventricular contractions were reported in 7 of 8 rats and bidirectional ventricular tachycardia in 6 of 8 rats [31]. Kelm et al. gave rats a stress test with dobutamine. They measured LAD coronary artery velocity before and 72 hours after IR surgery. LAD coronary artery velocity before surgery was higher after dobutamine infusion [32]. In our previous study, we administered dobutamine IP (intraperitoneal) at 40 µg/mouse/day for 15 days to damage mouse hearts. To detect myocardial damage, troponin-I value was checked in addition to electrocardiography (ECG) images. The Troponin-I value was measured to be high in the dobutamine group. In addition, in the histopathological examination of the heart tissue, it was observed that the areas of necrosis in the myocytes were higher in the dobutamine group. Thus, our injury modeling was determined both biochemically and histopathologically [33].
Conclusion
Inotropes increase cardiac output by increasing cardiac contractility with their different functions. However, they show vasoconstrictive or vasodilative activations, which may vary depending on the substance used and the amount given. They have also been among the causes of increased short- and long-term deaths due to common side effects and unnecessary use. If attention is paid to approaches such as identifying the right patient and choosing the right inotrope, inotropes can be utilized in the best way [34].
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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9. Kislitsina ON, Rich JD, Wilcox JE, Pham DT, Churyla A, Vorovich EB, et al. Shock – classification and pathophysiological principles of therapeutics. Curr. Cardiol. Rev. 2019;15(2):102-–113.
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12. Baekgaard ES, Møller MH, Vester-Andersen M, Krag M. Use of vasoactive agents in non-cardiac surgery: Protocol for a scoping review. Acta Anaesthesiol Scand. 2023;67(1):120-122.
13. Oral H, Crawford T, Frederick M, Gadeela N, Wimmer A, Dey S, et al. Inducibility of paroxysmal atrial fibrillation by isoproterenol and its relation to the mode of onset of atrial fibrillation. J Cardiovasc Electrophysiol. 2008;19(5):466-70.
14. Karthick M, Prince PS. Preventive effect of rutin, a bioflavonoid on lipid peroxides and antioxidants in isoproterenol-induced myocardial infarction in rats. J Pharm Pharmacol. 2006;58(5):701-–7.
15. Wei H, Li H, Wan SP, Zeng QT, Cheng LX, Jiang LL, et al. Cardioprotective effects of malvidin against isoproterenol‐induced myocardial infarction in rats: A mechanistic study. Med Sci Monit. 2017;23:2007‐2016.
16. Ruffolo RR Jr. The pharmacology of dobutamine. Am J Med Sci. 1987;294(4):244-–8.
17. L’Heureux M, Sternberg M, Brath L, Turlington J, Kashiouris MG. Curr Cardiol Rep. 2020;22(5):35.
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19. Brener MI, Rosenblum HR, Burkhoff D. Pathophysiology and advanced hemodynamic assessment of cardiogenic shock. Methodist Debakey Cardiovasc J. 2020;16(1):7-–15.
20. Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vyasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll CardiolI. 2005;46(1)57-–64.
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34. Farmakis D, Agostoni P, Baholli L, Bautin A, Comin-Colet J, Crespo-Leiro MG, et al. A pragmatic approach to the use of inotropes for the management of acute and advanced heart failure: an expert panel consensus. Int J Cardiol. 2019;297:83-90.
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Yasemin Hacanlı. Overview of vasopressor and ınotropic agents. Ann Clin Anal Med 2024;15(Suppl 1):S43-46
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Mandibular Buccal Bifurcation Cyst with Radiologic and Histopathologic Features: Two Case Reports and a Literature Review
Rabia Duman Tepe 1, Hulya Cakir Karabas 1, Merva Soluk Tekkesin 2
1 Department of Oral and Maxillofacial Radiology, 2 Department of Oral Pathology, Faculty of Dentistry, Istanbul University, Istanbul, Türkiye
DOI: 10.4328/ACAM.22028 Received: 2023-10-28 Accepted: 2023-12-04 Published Online: 2024-01-24 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S47-53
Corresponding Author: Rabia Duman Tepe, Department of Oral and Maxillofacial Radiology, Faculty of Dentistry, Istanbul University, Vezneciler, Fatih, Istanbul, Türkiye. E-mail: rabia.dumantepe@istanbul.edu.tr P: +90 531 348 79 47 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9496-5441
This article aims to present the clinical, radiological, histological features and diagnostic criteria of mandibular buccal bifurcation cyst (MBBC) while adding two new cases to the literature. In our study, literature search was made on PubMed and Google Scholar. The following words were used for the search: (buccal bifurcation”OR“inflammatory collateral”OR paradental) and cyst. In addition, two cases were presented. The diagnosis of the cases was made by cone beam computed tomography (CBCT) and histological findings together. Histopathologic features of MBBC is identical to inflammatory odontogenic cysts. Therefore, the diagnosis should be made by the combination of clinical, radiographic, and histopathological features. Knowing this entity, especially in childhood, will guide clinicians in protecting the affected tooth while performing cyst treatment in most of the cases.
Keywords: Mandibular Buccal Bifurcation Cyst; Inflammatory Odontogenic Cyst; Inflammatory Collateral Cyst; Odontogenic Cyst; Cone Beam Computed Tomography
Introduction
Mandibular buccal bifurcation cyst (MBBC) is a rare inflammatory odontogenic cyst that was first described by Stoneman and Worth [1] in 1983 as ‘mandibular infected buccal cyst’. In 1992 WHO classification [2], it was mentioned under the entity of paradental cyst as inflammatory collateral/mandibular infected buccal cyst.
MBBC has been classified under the inflammatory collateral cyst (ICC) in the 2017 [3] and the last 2022 WHO classifications (Available from: https://tumourclassification.iarc.who.int/chapters/52).
ICC comprises about 5% of all odontogenic cysts and includes paradental cysts and MBBCs (Available at: https://tumourclassification.iarc.who.int/chapters/52). MBBC comprise 35% of all ICC and is found on the buccal aspect of mandibular first or second molars and are often bilateral (up to 25%). Paradental cysts (60%) are found on the distobuccal aspect of mandibular third molars [4,5]. The etiology is inflammation in the pericoronal tissues. Cyst formation may be exacerbated by food impaction or by an enamel projection on the buccal aspect of the tooth [6,7].
MBBC is most commonly associated with the permanent mandibular first molar tooth, and secondly with mandibular second molar tooth [8]. The cyst can sometimes be seen bilaterally [9]. It is usually seen in children aged between 4-14 years, and the associated tooth has either recently erupted or partially erupted. Symptoms may increase as the size of the lesion progresses [10]. Sometimes it presents with very few symptoms, and sometimes pain, swelling, and suppuration can be observed [11]. The most common symptom is swelling in the buccal of the associated tooth. Its characteristic features are increased periodontal probing depth and buccal deviation of the crown of the associated tooth [12]. On clinical examination, the molar tooth may be missing, or the lingual cusps of the associated tooth may appear abnormally higher than the buccal cusps. The affected tooth is vital [9]. In the case of secondary infection, there may be pain, pus discharge, and facial asymmetry due to edema around the teeth [13,14].
In the radiographic findings of MBBC, there is a radiolucent lesion on the buccal surface of the affected tooth. The periodontal ligament space and lamina dura of the associated tooth is intact, and the root apices are displaced towards the mandibular lingual cortex. The lesion may cause expansion of the mandibular cortex and the formation of a periosteal reaction [15].
The histopathologic features of MBBC are not specific and consist of non-keratinized stratified squamous epithelium and inflamed connective tissue wall [10].
The general treatment option is the enucleation of the cyst without tooth extraction. Recurrence is not frequently observed [9]. Enucleation with tooth extraction and marsupialization can be other treatment options [16]. This article aims to present the clinical, radiological, and histological features and diagnostic criteria of MBBC and to add two new cases to the literature.
Material and Methods
Literature search was made on PubMed and Google Scholar. The following words were used for the search: (buccal bifurcation”OR“inflammatory collateral”OR paradental) AND cyst. The search was limited to articles in English. Case reports with clinical and radiographic features compatible with MBBC were included in the study. Case reports related to third molar teeth were excluded from the study because most showed paradental cyst features and others had not enough information.
Case Report
Case 1
A 9-year-old male patient was admitted to the clinic with the complaint of swelling. In the intraoral evaluation, it was observed that the bilateral mandibular first molars had partially erupted and there was swelling in the buccal gingiva. Radiolucent lesions associated with the right and left mandibular first molars were observed in the panoramic radiograph (Fig. 1). CBCT was taken to examine the effect of the lesion on the surrounding tissues. CBCT images showed well-circumscribed hypodense lesions starting from the furcation region of the bilateral mandibular first molars and extending to the inferior and anteroposterior directions. The expansion was observed in the buccal cortex. Periosteal reaction was not observed. Tipping was observed in the lingual direction in the roots of the associated teeth and in the buccal direction in the crowns (Figure 1). A preliminary diagnosis of bilateral mandibular buccal bifurcation cyst was made.
Case 2
An 8-year-old male patient was admitted to clinic due to pain and swelling. In the intraoral evaluation, it was observed that the right mandibular first molar tooth had partially erupted and there was swelling in the buccal gingiva. A radiolucent lesion associated with the right mandibular first molar tooth was observed in the panoramic radiograph (Fig. 2). CBCT was taken to examine the effect of the lesion on the surrounding tissues. On CBCT images, a well-circumscribed hypodense lesion was observed starting from the furcation region of the right mandibular first molars and extending to the inferior and anteroposterior direction. It was observed that the lesion caused expansion and destruction of the buccal cortex. Periosteal reaction was not observed. Lingual tipping was observed in the roots of the associated tooth (Figure 2). A preliminary diagnosis of mandibular buccal bifurcation cyst was made.
Both cases showed similar histopathologic features which were composed of the squamous non-keratinised epithelial lining in a characteristic arcading pattern and inflamed cyst walls (Figure 3). The patients were diagnosed with buccal bifurcation cyst with all clinicopathologic features. In the control panoramic radiograph of both cases, new bone formation areas were observed within the lesion, and there was no evidence of recurrence (Case 1: 8-month folllow-up, Case 2: 12-month follow-up ).
Results
According to the results obtained in the literature search, a total of 81 MBBC cases were included in the study, and all findings were summarized in Table 1, Table 2, and Table 3. The age of the cases ranged from 6 to 17 years with the mean age of 8.4. Gender was specified in 75 cases and the majority of cases were male (n:49, 65.33%) while only 26 (34.66%) were female.
Symptom information was available in 52 cases. The most common symptom was swelling, reported in 27 (51.92%) cases. In 23 (44.23%) cases, both swelling and pain were present. Pain alone was observed in one patient, and pus discharge was observed in one patient. Vitality information was presented in 42 cases and 40 (95.23%) of them were vital. It was reported that one of the other 2 was devital and the other one had root canal treatment a month ago.
Location was reported in 80 cases. 27 (33.75%) cases were observed on the right side, 27 (33.75%) on the left side, and 26 (32.5%) bilaterally. In 80 cases, affected tooth number was given. The most common affected tooth was the mandibular first molar, which was reported in 69 (86.25%) cases, followed by the second molar tooth reported in 10 (12.5%) cases. In one case, the primary canine was associated with primary first and second molars. 23 bilateral cases were associated with the mandibular first molar (88.46%), while 3 cases were associated with the mandibular second molar (11.53%). Periosteal reaction was reported in 14 cases and no definite information was given in the remainder.
The treatment method was specified in 72 cases. Enucleation applied without tooth extraction was reported most frequently treatment method in 50 (69.44%) cases. The second most preferred method was enucleation with tooth extraction in 11 (15.27%) cases. While marsupialization was applied in 6 (8.33%) cases, the periodontal irrigation method was used in only one case. It was observed that 4 (5.55%) cases with small sizes were followed up without any procedure. No recurrence was reported in control radiographs in 47 cases. Overall, there were no recurrences reported in any of the cases in the literature.
Discussion
The clinical-radiographic differential diagnosis of MBBC includes lateral periapical cyst, lateral periodontal cyst, dental follicle, dentigerous cyst, periodontal abscess, odontogenic keratocyst, and eosinophilic granuloma [13]. Periodontal abscess and Langerhans cell histiocytosis can also cause an inflammatory periosteal reaction like MBBC. The most characteristic feature of MBBC in differentiating it from other lesions is that it pushes the roots of the affected tooth into the lingual. A dentigerous cyst is also in the differential diagnosis. However, the epicenter of a dentigerous cyst is different because a MBBC starts near the bifurcation region of the tooth and does not surround the crown, unlike a dentigerous cyst [9]. Hyperplastic dental follicles are enlarged normal follicles, surrounding the crown of the developing tooth and following the general outline of that tooth crown. Odontogenic keratocyst may be pericoronal and may resemble a dentigerous cyst in the early stages. It may appear similar to MBBC if adjacent to the roots but causes little enlargement of the mandible. A lateral radicular cyst is an odontogenic inflammatory cyst associated with a nonvital tooth. The epicenter is located close to the apex. Large cysts may extend into the furcation area and may be confused with MBBC. Large cysts may extend into the furcation area and may be confused with MBBC. However, MBBC is more expansile than a radicular cyst of the same size. A lateral periodontal cyst is an odontogenic cyst that occurs lateral to the tooth roots. It usually appears as inter-radicular radiolucency. The mandibular premolar region is the most common site. It is seen in the older age groups [15].
When MBBC is visualized on conventional radiographs, it presents as a normal lamina dura and superposed radiolucency on tooth roots. Since the lesion is non-endodontic origin, the periodontal space surrounding the roots and the lamina dura is observed as intact [13]. On periapical and panoramic radiographs, the cyst may sometimes appear to be located slightly distal to the furcation of the associated tooth [9]. However, it is not always easy to diagnose with conventional radiographs [42]. With cone-beam computed tomography (CBCT), the borders of the lesion, its effects on the surrounding tissues, and its characteristic features can be displayed more clearly. It is often observed as unilocular, well-defined radiolucency, starting from the furcation area of the associated tooth and spreading to the apex. Pompura et al. reported that cortical periosteal reaction was observed in 68.8% of MBBC cases [12,54]. CBCT may also be successful in demonstrating buccolingual enlargement caused by the cyst and lingual deviation of the buccal root of the crown of the associated tooth. In addition, occlusal radiographs can be used in MBBC imaging [12,16]. The lingual tipping of the roots, cortex expansion, and periosteal reaction can be observed on the occlusal radiography [9].
MBBC histopathology is indistinguishable from radicular cyst. Because of its histopathologic similarity with inflammatory odontogenic cysts, the diagnosis should be made by clinical and radiological evaluation [16].
There are different approaches to the treatment method. There are two main approaches for the treatment of MBBC in the literature. The first is enucleation and curettage without tooth extraction, and the second is tooth extraction with curettage and enucleation [16]. David et al. [46] suggested a more conservative method described as ‘micro-marsupialization’. In this method, periodontal probing and irrigation of the buccal pocket with saline or hydrogen peroxide are performed. Daily saline irrigation is then continued. It was thought that creating a small opening with periodontal probing would reduce the pressure of the cyst and allow it to regress spontaneously. David et al. [46] also mentioned another conservative method called ‘automarsupialization’ and ‘self-dissolution’. This method is based on follow-up and states that microtraumas can cause spontaneous remission of the lesion. High bone remodeling capacity and rapid healing in children of the relevant age group may explain this method [16]. Zadik et al. [37] and Corona-Rodriguez et al. [36] mentioned spontaneous resolution cases in their studies. In small and asymptomatic cases, marsupialization may be a treatment option for the pediatric age group, thanks to its rapid bone remodeling capacity. However, larger lesions require surgery [55]. Some authors suggest that pulp vitality is at risk when tooth formation is complete, and endodontic treatment or extraction of the tooth is indicated when necessary. The most accepted approach in the treatment of MBBC is enucleation and curettage without tooth extraction. This conservative surgical method aims to protect the first and second molar teeth, which are important to keep in the mouth [13]. When the lesion is treated appropriately, it rarely recurs and has a good prognosis [56].
Conclusions
In this paper, we reported two additional cases consistent with most of the literature in terms of gender (male), common symptoms (swelling and pain), affected tooth (mandibular permanent first molar tooth) and prognosis (no recurrence). In addition, the clinical signs, symptoms, and treatment features of MBBC cases reported in the literature were complied. Knowing this entity, especially in childhood, will guide clinicians in protecting the affected tooth while performing cyst treatment in most of the cases.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Rabia Duman Tepe, Hulya Cakir Karabas, Merva Soluk Tekkesin. Mandibular Buccal Bifurcation Cyst with Radiologic and Histopathologic Features: Two Case Reports and a Literature Review. Ann Clin Anal Med 2024;15(Suppl 1):S47-53
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Effect of SARS-CoV-2 infection during pregnancy on maternal and perinatal mortality: A systematic review of cohort studies
Keltouma Oumbarek 1, Ahmed Kharbach 1, 2, Abdelmajid Lkoul 1, Mohamed Amine Baba 2, 3, Laila Lahlou 1, 3, Karim Sbaı Idrıssı 1, 4, Rachid Razıne 1, 4, Majdouline Obtel 1, 4
1 Department of Public Health, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, 2 Department of Nursing Sciences, High Institute of Nursing Professions and Technical Health, Agadir, 3 Department of Health Sciences Research, Faculty of Medicine and Pharmacy, Ibn Zohr University, Agadir, 4 Department of Public Health, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco
DOI: 10.4328/ACAM.21956 Received: 2023-09-07 Accepted: 2023-10-24 Published Online: 2023-12-05 Printed: 2024-03-20 Ann Clin Anal Med 2024;15(Suppl 1):S54-61
Corresponding Author: Keltouma Oumbarek, Department of Public Health, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco. E-mail: oumbarekeltouma@gmail.com P: +21 265 457 24 49 Corresponding Author ORCID ID: https://orcid.org/0009-0008-0413-6059
Aim: The aim of this systematic review was to examine cohort studies investigating the association of this infection with maternal and perinatal mortality, especially stillbirth.
Material and Methods: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines, a search was conducted on 3 databases: PubMed, Scopus and ScienceDirect for cohort studies published up to 24 April 2022 in English or French. Studies comparing the incidence of maternal or perinatal mortality among infected and uninfected pregnant women were retained (PROSPERO registration number: CRD42022341500).
Results: Initially, 2818 articles were identified, and 24 cohort studies were included. The overall population was 1511875 pregnant women. Of seventeen studies addressing maternal mortality, six reported a significant increase in death incidence among the exposed group (RR ranging from 13.3 to 22.26). Although, three studies found no significant difference (p ≥ 0.05). Eight studies reported no maternal deaths, of which 7 were conducted in the first year of the epidemic and 5 in a single center. The association of SARS-CoV-2 infection with perinatal mortality and stillbirth was not significant in 9/17 studies. However, 6/17 studies reported a significant association (RR ranging from 1.2 to 4.7).
Factors that may influence outcomes included disease severity, body mass index, ethnicity, previous morbidities, and gestational age at the time of exposure.
Discussion: The association between SARS-CoV-2 infection and maternal mortality was contrasting. Single-center studies revealed a low risk, while larger studies indicated a high risk of death. Furthermore, the association with perinatal mortality was less strong.
Keywords: SARS-CoV-2, Maternal Mortality, Perinatal Mortality, Stillbirths, Systematic Review
Introduction
Pregnant women were defined as a vulnerable population during the COVID-19 pandemic [1].
This is attributable to the physiological changes, which promote fetal development while reducing immunity and increasing the risk of infections [2]. Pregnant women are more likely than the general population to be admitted to intensive care units (ICUs) for infection by SARS-CoV-2 [3]. Disease severity is influenced by several factors such as maternal age, weight, comorbidities, parity, and ethnicity [4]. The probability of vertical transmission is low. However, adverse fetal outcomes have been noted [5], and pregnant women were more likely to die from COVID-19 than non-pregnant [6].
The probability of maternal death ranges from 0% to 15.78% in pregnant women infected with SARS-CoV-2 [7]. According to a living systematic review, they had an increased risk of maternal death (OR=6.09), and fetal death (OR=1.81) compared to pregnant women without the condition [4]. Furthermore, maternal mortality and stillbirth rates have increased during the COVID-19 pandemic compared to the pre-pandemic period [8]. This rise has varied among high-income countries and middle- and low-income countries [9].
Although fetal mortality has reduced in high-income countries, it is considered a poor outcome in women with COVID-19 [10]. According to the World Association of Perinatal Medicine (WAPM), perinatal death occurred in 4.1% of women infected with SARS-CoV-2 [5,11]. It occurs as a result of maternal or fetal complications [12]. SARS-CoV-2 induces placental vascular damage with episodes of hypoxia with a risk of adverse perinatal outcomes [10].
Despite evidence of an increased risk of maternal and perinatal mortality associated with COVID-19 status, multiple studies have reported that the incidence of maternal and fetal death was not statically different among test-positive and test-negative women [13].
The effect of SARS-CoV-2 infection on maternal and perinatal outcomes must be measured over the long term, given the emergence of new variants [14]. Therefore, the World Health Organization has recommended in its generic protocol: COVID-19 and pregnancy, 2022 (available at the WHO website), to search for comparative data among infected and uninfected pregnant women. These studies should be longitudinal to ensure long-term monitoring [1].
Many published studies have reported data from infected cohorts of pregnant women without comparison groups [15]. The primary objective of this systematic review is to examine comparative cohort studies that have investigated the association of SARS-CoV-2 infection status during pregnancy and the risk of maternal and perinatal mortality. The second objective is to identify factors that may influence this association.
Material and Methods
1.Search strategy
This systematic review was conducted in accordance with the PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [17]. The protocol was registered and published on PROSPERO (registration number: CRD42022341500).
Two authors (K.O. and A.K.) independently queried three databases: Scopus, PubMed and ScienceDirect. Concerning Scopus and PubMed, the search for articles was done using two queries, first: (“COVID-19” or “SARS-CoV-2” or “Coronavirus” and “maternal mortality” or “maternal death”) and secondly: (“COVID-19” or “SARS-CoV-2” OR “Coronavirus” and “perinatal mortality” or “perinatal death “or “stillbirth”). For ScienceDirect, the formula was as follows: ((“COVID-19” or “SARS-CoV-2” or “Coronavirus”) and (‘’maternal-death’’ or “maternal mortality” or “perinatal mortality” or “perinatal death” or “stillbirth”)).
2.Selection process
We included in this systematic review cohort studies published in English or French up to 24 April 2022. Initially, titles and abstracts were selected for relevant articles by 2 authors independently (KO and AK). Duplicate articles are eliminated using Zotero 6.0.18 (free version). A third reviewer (MO) was solicited to decide if there was disagreement between the two examiners. The included articles were retrieved in full text for further evaluation.
3.Eligibility criteria
Articles eligible for inclusion were comparative cohort studies that met the following criteria: 1) prospective or retrospective cohort studies; 2) studies that investigated the occurrence of maternal and/or perinatal death among pregnant women diagnosed with COVID-19 during pregnancy or at delivery (confirmed positive test) compared to pregnant women with negative test during the same investigation period.
Exclusion criteria were: 1) Studies comparing the risk of mortality in SARS-CoV-2 infected pregnant women with that of pregnant women in the pre-pandemic period or non-pregnant women of childbearing age. 2) Studies defined by their authors as cross-sectional, case-control, or cohort studies with no comparison group.
4.Outcomes and data collection process
This review compared SARS-CoV-2 infected and non-infected pregnant women with regard to the occurrence of the following outcomes:
a) Maternal mortality: death of a woman, either during pregnancy or childbirth, from any cause related to or aggravated by pregnancy, or within 42 days of the end of pregnancy [18].
b) Perinatal mortality: incorporate stillbirth and early neonatal mortality (death of a child born alive and within the first 7 days of life) [19].
c) Stillbirth: the birth of a baby without signs of life after 20 weeks of gestation [20].
The first author (K.O) collected data from the included studies. The collected information was verified by another author (A.K.). A third author (M.O.) was asked to decide in case of disagreement.
The results were presented in three tables. The first lists the characteristics of the included studies. The second and third tables show the results of the maternal mortality studies and the perinatal mortality studies respectively. Quantitative data were expressed as numbers and proportions (N; %), odds ratios, relative and adjusted relative risks (with 95% CI). Results were considered statistically significant (p<0.05). A narrative synthesis of the findings was performed.
Quality assessment of studies
The quality assessment was conducted by two independent reviewers, (K.O.) and (A.K.), using the JBI Cohort Study Critical Assessment Checklist, 2017 (available at the jbi.global website). This checklist, approved by the Joanna Briggs Institute Scientific Committee, assesses the quality of cohort studies according to 11 items: 1) Population and study groups; 2) and 3) Similarity and validity of exposure measurement; 4) and 5) Identification and managing of confounding factors; 6) and 7) Validity of outcome measurement; 8) to 10) Duration and continuity of follow-up 11) Statistical analysis quality. The checkboxes were: Yes, No, Unclear or Not applicable.
Agreement between the examiners was assessed using the statistical coefficient kappa (κ).
5.Statistical Analysis
Not applicable.
Results
1.Characteristics of included studies
Initially, 2818 articles were identified. After removing duplicates, screening by title and abstract and then by full text was performed according to the eligibility criteria. Finally, 24 cohort studies were included for the systematic review (Figure 1).
The total duration of these studies extended from January 13, 2020, to July 4, 2021 (Table 1). Eleven cohort studies had a prospective design [20, 30], twelve studies were retrospective [15, 31, 41], and there was one cohort with a retro-prospective design [42].
Fourteen studies were multicenter [20, 23, 26, 28, 31, 34, 36, 39, 41], including a multinational study [28]. Ten studies were single-center [15, 21, 22, 24, 25, 27, 29, 30, 40, 42].
The overall population included in this review was 1511875 pregnant women, with 30633 testing positive for SARS-CoV-2 infection and 1481242 testing negative.
Five studies focused on maternal death [20, 21, 31, 32, 42], seven on perinatal death [22, 24, 33, 36] and twelve on both mortalities [15, 25, 30, 37, 40].
2. Assessment of the quality of the studies
Included studies were assessed using the JBI Cohort Study Critical Assessment Checklist. The results of the study assessment were detailed in supplementary material.
For all studies, the study groups were recruited from the same population, and the exposure measure was similar and valid, with ambiguities in the two studies [22, 27]. Confounding factors were identified in most studies (20/22), while strategies to address these confounders were indicated in 65% of these studies (13/20). The validity of outcomes measurement and duration of participant follow-up were overall appropriate. Regarding the statistical analysis, regression was used in 45% of the studies (11/24).
The reviewers agreed that, in all, the included studies had a low risk of bias. The quality was considered “good” and the statistical coefficient of Kappa was κ = 0.71.
3. Association of SARS-CoV-2 infection during pregnancy with the risk of maternal mortality
As shown in Table 2, eight studies reported no maternal mortality [20, 25, 27, 29, 30, 32, 40]. In contrast, the occurrence of maternal death in pregnant women with SARS-CoV-2 was reported in nine cohort studies [15, 21, 28, 31, 37, 39, 41, 42].
Three of these studies concluded that there was a high association between SARS-CoV-2 exposure in pregnancy and the occurrence of maternal death [29, 38, 39]. However, a retrospective single-center study found no significant association between COVID-19 status and maternal mortality [15]. Indeed, a multinational study including 18 countries, showed that COVID-19 exposure during pregnancy was highly associated with an increased incidence of maternal mortality, with RR: 22.26 (2.88- 172.11) (95% CI) [28]. Similarly, based on analysis of data from 720 American hospitals, the risk of maternal death was 25.6 times higher among pregnant women with COVID-19 who delivered and 13.3 among all hospitalized pregnant women with COVID -19, including pregnancies that did not proceed to birth [37]. In addition, a cohort study conducted in 703 US hospitals found that women with a confirmed diagnosis of SARS-CoV-2 at the time of hospitalization for delivery had a 17-fold increased risk of death compared to the unexposed group [38].
Five cohort studies compared the incidence of maternal mortality among pregnant women exposed and unexposed to SARS-CoV-2 infection during pregnancy using the Chi2 test and or the Fisher’s exact test [21, 31, 39, 41, 42]. Of these, three studies found that there was an increased incidence of maternal death for pregnant women infected by the SARS-CoV-2 [21, 39, 41]. However, two studies reported that the rates of maternal death in the exposed group were slightly higher than in the unexposed group, but this difference was not statistically significant [31, 42].
To investigate factors influencing the association of SARS-CoV-2 infection during pregnancy with the risk of maternal mortality, four studies divided the study population into subgroups and assessed this association in each subgroup [28, 37, 39, 41]. Stratification variables included severity of infection, maternal age, race/ethnicity, body mass index, previous morbidities, and gestational age at exposure (Table 2).
4. SARS-CoV-2 infection during pregnancy and the risk of perinatal mortality
As presented in Table 3, seventeen cohort studies reported the occurrence of perinatal mortality in pregnant women diagnosed with COVID-19. Four of these studies reported a significant association between this exposure during pregnancy and the risk of stillbirth. This ranges from 1.2 to 4.7 [25, 33, 37, 38]. Also, a multicenter cohort study noted a significantly high incidence of stillbirths among the infected group (0.8%) compared with the matched uninfected group (0.1%), (p<0.05) [35]. In addition, the multinational study by Villar et al. observed that newborns born to exposed mothers had a high perinatal morbidity and mortality index (PMMI) compared with those born to unexposed mothers (RR= 2.14).
Using regression, three studies found an insignificant association between SARS-CoV-2 infection status during pregnancy and the risk of stillbirth [22, 34, 36]. In addition, five cohort studies concluded that there was no significant difference in fetal death incidence among the exposed and unexposed groups [23, 27, 39, 41]. Also, the variation in stillbirth incidence between asymptomatic women with SARS-CoV-2 and uninfected pregnant women was not statistically significant (p> 0.05) [26].
Factors influencing the association between SARS-CoV-2 infection and the risk of perinatal mortality or stillbirth were assessed in eight studies [23, 28, 34, 35, 37, 39, 41]. The risk of stillbirth was slightly higher in women aged ≥25 years, however, there was no significant difference between ethnic subgroups [37]. In addition, it was noted that symptomatic women and women with high body mass index or previous morbidities were more likely to have severe perinatal morbidity and mortality [28]. The influence of gestational age at infection on stillbirth incidence was discussed in four studies [34, 35, 40, 41].
Finally, two single-center studies reported that there were no stillbirths in the study population [24, 30].
Discussion
In the present review, six cohort studies showed that there was a high association between SARS-CoV-2 infection during pregnancy and the incidence of maternal death. According to a living systematic review and meta-analysis of eight studies, the probability of all-cause mortality in pregnant women with COVID-19 was higher compared to pregnant women without the disease [4]. Another meta-analysis indicated that the probability of maternal death related to SARS-CoV-2 infection is high (pooled OR: 7.05 [2, 41, 20, 65]) [43]. In contrast, a meta-analysis of six comparative studies showed that there was no significant difference in maternal mortality rates in relation to COVID-19 status (p=0.23) [13].
Eight included studies found no maternal deaths in pregnant women with SARS-CoV-2. Of these, seven were conducted during the first year of the pandemic and the majority were monocentric. Maternal death is an uncommon event requiring a large study population and a follow-up until six weeks after delivery to obtain valid results. Furthermore, the absence of symptoms may explain this finding; an included single-center study with no deaths indicated that 86.24% of infected women were asymptomatic [20]. Other systematic reviews reported that no maternal deaths occurred among infected women [43, 45]. Similarly, a meta-analysis of data of the early pandemic revealed no deaths among 348 cases recorded [46].
In the current review, countries concerned by the increase in maternal deaths related to COVID-19 were the USA in four studies [37, 39, 41], Romania [21], and eighteen countries included in a multinational study [28]. A meta-analysis of recent studies conducted in low-resource countries showed an increased incidence of death in pregnant women who tested positive [47]. Among the countries suffering most from this issue, Brazil recorded high maternal mortality rates during the outbreak [48].
Regarding the determinants of the association between SARS-CoV-2 infection and maternal mortality risk, symptomatic pregnant women or those with a history of morbidity or overweight had a high incidence of maternal death [28]. Similarly, a meta-analysis found that all 153 pregnant and postpartum women who died due to COVID-19 were symptomatic and suffered from morbidities such as diabetes, overweight, cardiovascular diseases, and asthma [9]. A systematic review of 14 articles showed that high BMI or comorbidities were risk factors for mortality associated with SARS-CoV-2 infection [49]. In our review, maternal age over 35 years increased the risk of maternal death [37]. In another systematic review, 41.7% of died infected mothers were older than 35 years [9].
In terms of perinatal death, six studies in this review found a significant association between SARS-CoV-2 infection during pregnancy and the risk of stillbirth. This is consistent with many systematic and meta-analyses, which have reported high odds ratio values (OR= 2.70) [50], (pooled OR 1.46) [43], (OR= 2.11) [51] and (OR =2.36 )[52]. In the opposite, nine included cohort studies revealed that SARS-CoV-2 exposure did not significantly influence the incidence of stillbirth. In agreement, this incidence was 1.1% in both groups according to a meta-analysis of six comparative studies [13]. Another meta-analysis found that the risk of fetal death from COVID-19 was extremely low [53].
In the current review, the probability of stillbirth was slightly higher among women over 25 years [37]. However, a discrepancy has been observed regarding the effect of severity of infection, gestational age, and weight on this probability. Indeed, an included multinational cohort study noted that symptomatic women with a high body mass index were more likely to have a perinatal death [28]. The fetal death rate was higher in asymptomatic or mildly affected women [39], and was not correlated with either BMI or gestational age [40]. Besides, the incidence of stillbirth was higher in women infected within 30 days of delivery [41]. While, it was higher among women infected in the first or second trimester [35]. This discrepancy can be explained by sample size limitations in monocentric studies and retrospective data collection, mainly under-recording of patient information.
Most studies in this review involved pregnant women infected at or near the time of delivery. A review of maternal and fetal outcomes related to COVID-19 showed that the third trimester was the most vulnerable period for infection [54].
Strengths and limitations of the study
This systematic review had several strengths and limitations. It included comparative cohort studies allowing for follow-up of outcomes in and without the exposure. In addition, cohort studies comparing outcomes with the pre-pandemic period were eliminated to avoid confounding the impact of the COVID-19 pandemic on healthcare services. However, the unavailability of some data or full-text articles reduced the number of included studies.
The overall study period was from the beginning of the pandemic until July 2021, which provided a large study population (1511875 pregnant women). However, the data collected did not cover new variants such as Omicron, which appeared for the first time on 9 November 2021. In addition, the influence of vaccination status was not studied because the SARS-CoV-2 vaccine was contraindicated for pregnant women during the early pandemic.
The retrospective design of many cohort studies did not provide a real-time follow-up of outcomes related to SARS-CoV-2 infection. Nevertheless, there were more prospective than retrospective studies.
Therefore, meta-analyses of recent large-sample multicenter studies are recommended to compare the effect of infection with different variants of SARS-CoV-2 and vaccine coverage on maternal and fetal outcomes, including maternal and perinatal mortality.
Conclusion
The findings of included cohort studies regarding the association of SARS-CoV-2 infection during pregnancy with the risk of maternal and perinatal mortality varied.
Studies covering the early months of the pandemic noted that the risk of maternal mortality was low. However, larger studies reported that women exposed to SARS-CoV-2 infection during pregnancy have a higher risk of maternal mortality than those unexposed. Factors that may influence this association include the severity of COVID-19 disease, co-morbidities, overweight, maternal, gestational age, and ethnicity. On the other hand, according to findings of studies that have addressed perinatal mortality, the association of SARS-CoV-2 infection and the risk of stillbirth was lower than the association of this condition with maternal death.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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