Abstract
Aim: To investigate the value of hyponatremia as a predictive marker for complicated appendicitis.
Methods: PubMed, Embase, Web of Science and Scopus databases were searched for studies published up to 5 June 2024. Studies reporting serum sodium levels in patients with complicated and non-complicated appendicitis and studies reporting the association between baseline hyponatremia and complicated appendicitis were included. A random-effects meta-analysis was performed.
Results: Twenty-two studies met the eligibility criteria. Serum sodium levels were measured at arrival or preoperatively in all included studies. Meta-analysis of data from 17 studies showed that preoperative sodium levels were significantly lower in patients with complicated appendicitis vs uncomplicated appendicitis [Mean Difference (MD): -2.58 95% confidence intervals (CI): -3.51, -1.66 I2 = 98%]. A pooled analysis of 18 studies demonstrated a statistically significant association between preoperative hyponatremia and complicated appendicitis [Odds Ratio (OR): 4.11 95% CI: 3.07, 5.51 I2 = 93%]. Results remained significant on subgroup analysis for adult and pediatric populations. However, the MD was higher and the OR was higher in the subgroup of pediatric patients.
Conclusion: Hyponatremia was identified as a potential predictor for complicated appendicitis. The association between hyponatremia and complicated appendicitis seems to be stronger in pediatric patients as compared with adults.
Keywords: : complex appendicitis, electrolyte, perforated appendicitis, serum sodium
Plain language summary
Article highlights.
Appendicitis is one of the most common surgical emergencies and early identification of complicated appendicitis can improve patient care.
Methods
We conducted a systematic review and meta-analysis of the literature by searching PubMed, Embase, Web of Science and Scopus databases for studies.
Studies reporting serum sodium levels in patients with complicated and non-complicated appendicitis or reporting the association between baseline hyponatremia and complicated appendicitis were included.
Results
22 studies were included in the review.
The pooled analysis showed that preoperative sodium levels were significantly lower in patients with complicated versus uncomplicated appendicitis.
We also found a statistically significant association between preoperative hyponatremia and complicated appendicitis.
Importantly, it was noted that the association between hyponatremia and complicated appendicitis was stronger in pediatric patients.
Conclusions
Hyponatremia can be a useful marker for predicting complicated appendicitis.
The primary imitation of the current literature is the retrospective nature of data. Hence, further prospective studies are needed to improve the evidence.
1. Introduction
Appendicitis is one of the most prevalent surgical emergencies, with more than a million appendectomy procedures performed annually [1,2]. Up to 25% of patients who present with appendicitis have complications such as perforation, gangrene or abscess formation [2,3] that may lead to adverse after-effects, namely paralytic ileus, post-surgery infections and prolonged hospital stays [1–4].
While uncomplicated appendicitis can be managed by nonoperative antibiotic treatment, the applicability of this nonsurgical method for complicated cases remains a subject of debate [2,5,6]. Delay in operative treatment of complicated appendicitis may result in significant morbidity and longer hospitalization times. Therefore, early identification and proactive management of complicated cases could prevent inappropriate reliance on medical-only strategies [1,3,7]. Therefore, timely differentiation between cases of complicated and uncomplicated appendicitis is crucial for optimal patient care [3,6].
Computed tomography (CT) scans play a crucial role in enhancing diagnostic specificity of appendicitis cases [8,9]. However, the use of abdominopelvic CT scans in the evaluation of pediatric appendicitis is subject to more stringent criteria [5,8] due to ionizing radiation exposure. Nevertheless, over a third of children still undergo CT scans before the surgery [10]. Therefore, there is a need for reliable preoperative markers of complicated appendicitis that will allow enhanced diagnostic precision without resorting to surgical intervention or ionizing radiation [11].
Numerous studies report using conventional biomarkers like blood counts, inflammatory markers like C-reactive protein, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, monocyte-eosinophil ratio and serum electrolyte levels like sodium and potassium to distinguish between complicated and uncomplicated appendicitis with varied results [12–14]. Similarly, a number of scoring systems have been developed, like the Alvarado score, pediatric appendicitis score, appendicitis inflammatory response score and the Tzanakis score, to distinguish between complicated and uncomplicated appendicitis [15–18]. While the sensitivity and specificity of these scores are variable, studies show that the Appendicitis Inflammatory Response score may have the highest discriminating power in predicting complicated appendicitis in children. Nevertheless, scoring systems require multiple measurements and do not offer rapid assessment of complicated appendicitis [16]. Therefore, identifying new biomarkers remains a subject of substantial continuous research. Hyperfibrinogenemia [19], ischemia modified albumin [20], pentraxin-3 [21], hyperbilirubinemia [22], neutrophil gelatinase-associated lipocalin [23], IL-6 [23,24] and leucine-Rich α-2-glycoprotein 1 (LGR-1) [25,26]. However, a potential limitation of these biomarkers is that their testing may not be readily available in all healthcare setups worldwide. Therefore, there is a need for a simple, commonly available biomarker that can facilitate the identification of complicated appendicitis.
Serum sodium levels are one of the most widely studied single biomarkers of appendicitis. It is one of the routine investigations conducted in any healthcare setup and is readily available even in small laboratory settings. However, evidence on the predictive value of hyponatremia for complicated appendicitis is unclear, and prior systematic reviews on the clinical value of serum sodium levels included just seven studies [14,27]. Therefore, this study aimed to review the existing literature to determine whether serum sodium levels can be used as a marker for complicated appendicitis.
2. Materials & methods
The review was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [28]. The protocol was registered at PROSPERO, with the number CRD42023482911.
2.1. Search strategy
A comprehensive search was performed by the two reviewers (HS & LS) in PubMed, Embase, Web of Science and Scopus databases using appropriate keywords and Boolean operators. The initial search was completed on 30th October 2023, and the updated search was completed on 5th June 2024. No limitations were applied on the publication date. The following search query was used to search the literature: “(((sodium) OR (hyponatremia)) AND ((appendix) OR (appendicitis))) AND (((((complicated) OR (perforated)) OR (infected)) OR (gangrenous)) OR (complex))”. The search was run on all the selected databases and the results were collated and deduplicated using EndNote software. Two reviewers independently screened the title and abstract of each study for relevance based on the inclusion and exclusion criteria. Relevant studies were downloaded, and their full-texts were assessed for eligibility. Google Scholar was additionally screened for grey literature and references of included studies to rule out any missed literature. All instances of differences between reviewers were settled by discussion.
2.2. Eligibility criteria
Inclusion criteria were as follows:
Human studies of all age groups.
Studies reporting on serum sodium levels in individuals with and without complicated appendicitis.
Studies reporting the risk of complicated appendicitis with the presence of hyponatremia.
Complicated appendicitis confirmed by intra-operative or histopathological findings.
Studies following a randomized controlled, cohort, case-control, or cross-sectional study design.
Published in peer-reviewed journals.
English-language studies.
Exclusion criteria were as follows:
Studies of appendicitis patients simultaneously undergoing additional gastrointestinal surgeries.
Studies not clearly defining complicated appendicitis.
Case reports, editorials, commentaries and letters.
Studies with incomplete or duplicate data.
In cases of duplicate data in two or more articles, the study with the largest sample size was selected. In case of missing data, the corresponding author of the study was contacted once via email.
2.3. Quality assessment & data management
Two reviewers (HS & LS) assessed the methodological quality of the observational studies using the Newcastle Ottawa Scale (NOS) [29]. Points were awarded for the representativeness of the study cohort, comparability of groups and measurement of outcomes, with a maximum score of nine points. Disagreements between reviewers were settled by discussion.
Two reviewers (HS & LS) independently collected data from included studies. A preformatted data extraction form was used to retrieve the following details: study authors, year of publication, location, study type, exclusion criteria, timing of measurement of sodium, cut-off of hyponatremia, sample size, sample age, male patients, serum sodium level in the groups and definition of complicated appendicitis. The odds ratio (OR) and 95% confidence intervals (CI) of the association between hyponatremia and complicated appendicitis were also extracted. If the ratio was not reported, it was calculated from the raw data presented by the study. Disagreements between the reviewers were resolved by discussion.
2.4. Data analysis
The meta-analysis was done using ‘Review Manager’ (RevMan, version 5.3). Two meta-analyses were conducted. The first analysis compared the serum sodium levels between patients with complicated and uncomplicated appendicitis. Mean difference (MD) and 95% CI were obtained by pooling data from all studies. The second analysis calculated the pooled OR of the risk of complicated appendicitis with hyponatremia. Heterogeneity was measured by I2 statistics. I2 values between 0 and 25% indicated negligible heterogeneity, 25–75% indicated moderate heterogeneity and ≥75% indicated substantial heterogeneity. Publication bias was examined by funnel plots. p < 0.05 indicated statistical significance. Sensitivity analysis was done by excluding one study at a time and examining its effects on the pooled outcome. Subgroup analysis was conducted for adult and pediatric patients.
3. Results
PRISMA-based flowchart of study selection is shown in Figure 1. The comprehensive literature search identified 383 articles. Of them, 236 studies were removed during deduplication, 147 were screened by the reviewers and 37 were selected for full-text review. A total of 22 studies [5,7,30–49] met the eligibility criteria and were included in the meta-analysis.
Figure 1.
Study flowchart demonstrating each step of the study selection process.
Study details are presented in Supplementary Table S1. The majority of the studies were retrospective, and three were prospective cohort studies. The included studies were from a range of countries, namely the USA, Mexico, Brazil, New Zealand, Egypt, Greece, the UK, Sweden, Croatia, Turkey, Saudi Arabia, China, Japan and Pakistan. All studies were published between the years 2016 to 2023. Ten studies were done exclusively on pediatric patients; two reported data on both adult and pediatric populations, while the remaining studies included only adult patients. In all studies, patients underwent laparoscopic or open appendectomy. Serum sodium levels were measured at arrival or preoperatively in all included studies. Seventeen studies reported baseline sodium levels in complicated and uncomplicated appendicitis, while 18 studies reported the association between preoperative hyponatremia and complicated appendicitis. Hyponatremia was defined as serum sodium levels of <134–136.5 mEq/l. A detailed definition of complicated appendicitis used by the studies is presented in Supplementary Table S1. In general, complicated appendicitis was identified by the intra-operative presence of perforation, gangrene, peritonitis, and/or abscess with or without histopathological evidence of perforation. On examining the quality of studies, the reviewers rated 12 studies with six stars on NOS while the remaining were rated with eight stars (Table 1). No disagreements were documented between the reviewers for quality assessment.
Table 1.
Risk of bias analysis of included studies. Quality assessment of included studies based on Newcastle Ottawa Scale.
| Study | Representativeness of cohort | Comparability of groups | Outcome measurement | Total score | Ref. |
|---|---|---|---|---|---|
| Wu et al. (2023) | 4 | 2 | 2 | 8 | [31] |
| Poston et al. (2023) | 4 | 2 | 2 | 8 | [30] |
| Messias et al. (2023) | 4 | 2 | 2 | 8 | [37] |
| Elgendy et al. (2023) | 4 | 2 | 2 | 8 | [7] |
| Cetinkaya et al. (2023) | 4 | – | 2 | 6 | [5] |
| Alfehaid et al. (2023) | 4 | – | 2 | 6 | [34] |
| Walsh et al. (2022) | 4 | – | 2 | 6 | [39] |
| Turhan et al. (2022) | 4 | – | 2 | 6 | [38] |
| Symeonidis et al. (2022) | 4 | – | 2 | 6 | [49] |
| Shuaib et al. (2022) | 4 | 2 | 2 | 8 | [32] |
| Sheen et al. (2022) | 4 | – | 2 | 6 | [36] |
| Qureshi et al. (2020) | 4 | – | 2 | 6 | [33] |
| Ozdemir et al. (2022) | 4 | 2 | 2 | 8 | [43] |
| Maqbool et al. (2022) | 4 | – | 2 | 6 | [42] |
| Duman et al. (2022) | 4 | – | 2 | 6 | [45] |
| Pogorelić et al. (2021) | 4 | – | 2 | 6 | [44] |
| Pérez-Soto et al. (2021) | 4 | – | 2 | 6 | [40] |
| Heymowski et al. (2021) | 4 | 2 | 2 | 8 | [35] |
| Lindestam et al. (2020) | 4 | 2 | 2 | 8 | [41] |
| Yang et al. (2019) | 4 | 2 | 2 | 8 | [47] |
| Besli et al. (2019) | 4 | – | 2 | 6 | [46] |
| Pham et al. (2016) | 4 | 2 | 2 | 8 | [48] |
Meta-analysis of the data from 17 studies showed that preoperative sodium levels were significantly lower in patients with complicated vs uncomplicated appendicitis (MD: -2.58 95% CI: -3.51, -1.66). High heterogeneity was present in the meta-analysis (I2 = 98%) (Figure 2). No gross asymmetry was seen on the funnel plot (Figure 3). On subgroup analysis, complicated appendicitis was associated with lower serum sodium levels in both adult (MD: -1.32 95% CI: -1.81, -0.84 I2 = 73%) and pediatric populations (MD: -3.72 95% CI: -5.03, -2.41 I2 = 98%) (Figure 2). The association of serum sodium levels with the severity of appendicitis remained both in subgroups and in overall results significant after the sensitivity analysis.
Figure 2.
Meta-analysis of difference in preoperative sodium levels between complicated and uncomplicated appendicitis with subgroup analysis for adult and pediatric patients. Effect estimates of each study are represented by green squares and horizontal line indicates the 95% confidence intervals (CI). Black diamond at the bottom of each analysis indicates the pooled effect size.
IV: Inverse variance; SD: Standard deviation.
Figure 3.
Funnel plot examining publication bias for difference in preoperative sodium levels. Dotted line in the center indicates the value of the pooled mean difference (MD).
SE: Standard error.
A pooled analysis of 19 studies demonstrated a statistically significant association between preoperative hyponatremia and complicated appendicitis (OR: 4.11 95% CI: 3.07, 5.51 I2 = 93%) (Figure 4). No gross asymmetry was seen on the funnel plot (Figure 5). The association was significant for both adult (OR: 3.09 95% CI: 2.09, 4.56 I2 = 91%) and pediatric (OR: 5.34 95% CI: 3.30, 8.63 I2 = 93%) populations (Figure 4). The OR remained significant for both subgroups and the overall result on sequential exclusion of studies during sensitivity analysis.
Figure 4.
Meta-analysis of the association between preoperative hyponatremia and complicated appendicitis with subgroup analysis for adult and pediatric patients. Effect estimates of each study are represented by red squares and horizontal line indicates the 95% confidence intervals (CI). Black diamond at the bottom of each analysis indicates the pooled effect size.
IV: Inverse variance; SE: Standard error.
Figure 5.
Funnel plot examining publication bias for the association between preoperative hyponatremia and complicated appendicitis. Dotted line in the center indicates the value of the pooled odds ratio (OR).
SE: Standard error.
4. Discussion
This study demonstrated that hyponatremia may serve as a potential predictor for complicated appendicitis in all age groups of patients.
Accurately distinguishing between complicated and uncomplicated appendicitis in the preoperative setting has been a matter of intense research in the past few decades [12–14]. Surgical guidelines state that complicated appendicitis should be treated urgently while uncomplicated appendicitis may be conservatively managed with antibiotics [50]. CT imaging seems to be an essential step in the diagnosis of complicated appendicitis that is characterized by distinct features like extraluminal air, abscess, appendicolith and periappendicular fluid. However, CT has the disadvantage of using ionizing radiation, and cannot reliably rule out complicated appendicitis [51], which further emphasizes the need to identify new reliable differentiators for this disease.
Our results showed that mean serum sodium levels were significantly lower in patients with complicated appendicitis, with the MD between the two of 2.58 mEq/l. The results of the meta-analysis, using study-specific cut-offs, demonstrated a significant association between preoperative hyponatremia and a risk of complicated appendicitis. The absence of publication bias and the stability of the outcomes on sensitivity analysis further confirmed the credibility of our results. While the included studies differed in their conclusions, with some reporting non-significant results, overall, no study was found to be an outlier in the meta-analysis.
The results of our study are in concurrence with prior reviews [14,27] examining the role of hyponatremia in assessing the risk of complicated appendicitis. However, there are several major differences between our results and the previously published reviews. Both these studies [14,27] only included seven articles each. By conducting an updated literate search, we were able to include 22 studies, significantly improving the statistical power of the analysis and the reliability of the evidence. Moreover, the study of Giannis et al. [14] was only a systematic review, and no meta-analysis was conducted. They were able to include just four studies on pediatric and three on adult populations and could not provide any statistical evidence on the efficacy of hyponatremia as a biomarker for complicated appendicitis. The review of Anand et al. [27] assessed the role of hyponatremia in children only and did not include studies on adult patients. Furthermore, their meta-analysis only compared serum sodium levels between complicated and uncomplicated cases of appendicitis and did not generate ORs for the risk of complicated appendicitis with a specific cut-off of hyponatremia. In contrast to the previous reviews, our study not only provides evidence of the utility of hyponatremia as a biomarker in both adult and pediatric populations but also generates pooled OR values for the risk of complicated appendicitis with a specific cut-off of hyponatremia.
Classification of appendicitis as complicated or uncomplicated is based on histopathological or intraoperative findings [52,53]. Appendicitis is usually considered complicated if it becomes perforated and gangrenous, causing abscess formation or purulent peritonitis [53]. In our review, all included studies used intraoperative or histopathological findings to identify complicated appendicitis. However, some minor variations could have impacted the results.
Another area of concern is the high heterogeneity that was observed in our meta-analyses. This was partly expected as the included studies involved patients from different regions, and with different levels of severity of appendicitis. Secondly, we used crude serum sodium values for the meta-analysis. Serum sodium levels are easily altered by comorbidities, especially metabolic diseases, and other treatments [54]. Without detailed data from all included studies, we could not run a detailed subgroup or meta-regression analysis to explore the causes of heterogeneity. However, one obvious differentiator was the age of the population. A subgroup analysis based on the age of the patients showed that the MD for sodium levels was smaller in adults as compared with pediatric cases. Similarly, the risk of detecting complicated appendicitis based on preoperative hyponatremia was higher in pediatric as compared with adult populations. Hyponatremia was associated with a threefold risk of detecting complicated appendicitis in adults, while in pediatric patients, the risk was fivefold. One possible reason for this difference could be that adults usually have other comorbidities and are frequently on medications that can alter sodium levels even in uncomplicated cases [36]. This could diminish the association between hyponatremia and complicated appendicitis.
The observed reduction in serum sodium levels and increased risk of hyponatremia in patients with complicated appendicitis can be attributed to the inflammatory process and the release of pro-inflammatory cytokines associated with severe pathology. Indeed, hyponatremia is also seen with other inflammatory pathologies like pneumonia, meningitis and encephalitis [55]. Evidence shows that inflammatory cytokines are key in releasing vasopressin from the pituitary gland in severe inflammatory conditions. It involves the activation of the Janus tyrosine kinases (JAK)-signal transducer and activator of transcription JAK-STAT pathway by circulating cytokines, leading to non-osmotic secretion of vasopressin. Vasopressin, in turn, acts on the kidneys, promoting excess water reabsorption, diluting the sodium concentration in the blood and causing hyponatremia [55]. Therefore, monitoring serum sodium levels in patients with appendicitis could offer valuable insights into the degree of inflammation and the likelihood of complications. This physiological understanding is crucial for clinicians, as it provides a basis for considering hyponatremia as an indicator of the severity of appendicitis. Early recognition of this association could prompt clinicians to expedite diagnostic evaluations and interventions for patients with hyponatremia, potentially improving outcomes by timely addressing complications.
There are certain limitations of the review. Foremost is the predominant retrospective nature of the data, which introduces bias. Secondly, not all studies excluded patients with endocrine and metabolic disorders who could have altered sodium levels. Further, there was little information provided by the studies on electrolyte-altering medications like diuretics, which could have skewed the results. Thirdly, there were minor discrepancies in the cut-offs of hyponatremia which makes the comparison biased.
5. Conclusion
To conclude, the present study is the most updated systematic review and meta-analysis examining the role of hyponatremia in predicting complicated appendicitis. We were able to analyze 22 studies after a detailed literature search. Two separate meta-analyses were conducted. In the first, it was noted that mean serum sodium levels were significantly lower by 2.58 mEq/l in cases of complicated appendicitis as compared with uncomplicated appendicitis. In the second meta-analysis, based on study-specific cut-offs, we noted a significant association between preoperative hyponatremia and risk of complicated appendicitis. The absence of publication bias and the stability of the results on sensitivity analysis lends credibility to the results of our review. Our results suggest that hyponatremia could be a predictor for complicated appendicitis in clinical practice. The advantages of using serum sodium levels as a biomarker are its ready availability, regular use in all healthcare setups worldwide and low cost of measurements. Therefore, it could be readily used by surgeons for early assessment of appendicitis. A lower serum sodium levels could indicate complicated appendicitis suggesting the need for early intervention. However, at this point, the exact cut-off for hyponatremia suggestive of complicated appendicitis is unclear. Further studies to generate population-specific cut-offs are needed. This would help better identify complicated appendicitis based on the population characteristics.
The current evidence also suggested that hyponatremia could be a better biomarker with a stronger association with complicated appendicitis in children as compared with adults. Our meta-analysis showed that hyponatremia was associated with a threefold risk of detecting complicated appendicitis in adults, but in pediatric patients, the risk was fivefold. Hence, lower serum sodium levels in children should generate stronger suspicion of complicated appendicitis as compared with adults, prompting early intervention. Nevertheless, the current evidence should be interpreted cautiously due to its limitations. The high heterogeneity is a major restraint in the interpretation of results. Furthermore, most of the available evidence is retrospective, and most of the studies failed to exclude patients with endocrine and metabolic disorders, which could have altered the results. Indeed, only further prospective studies can provide higher-quality evidence on the role of hyponatremia in predicting the risk of complicated appendicitis. Future prospective, multi-centric studies that use a standard definition of complicated appendicitis are needed. They should consider electrolyte-altering medication like diuretics and exclude patients with endocrine and metabolic disorders. They should also conduct separate analyses for adult and pediatric age groups and examine the risk of complicated appendicitis with different cut-offs of hyponatremia, providing sensitivity and specificity values for each cut-off. Such research could provide reliable evidence on the role of hyponatremia in predicting the risk of complicated appendicitis.
Supplementary Material
Supplemental material
Supplemental data for this article can be accessed at https://doi.org/10.1080/17520363.2024.2403332
Author contributions
H Shia contributed to the study conception and design. H Shia and L Shen data collection and analysis were performed. The first draft of the manuscript was written by H Shia. All authors read and approved the final manuscript.
Financial disclosure
The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.
References
Papers of special note have been highlighted as: • of interest; •• of considerable interest
- 1.Arbell D, Udassin R. Should we disconnect perforated and nonperforated appendicitis in children? Ann Surg. 2008;247:553–554. doi: 10.1097/SLA.0b013e3181661790 [DOI] [PubMed] [Google Scholar]
- 2.Benedetto G, Ferrer Puchol MD, Llavata Solaz A. Suspicion of acute appendicitis in adults. The value of ultrasound in our hospital. Radiologia. 2019;61:51–59. doi: 10.1016/j.rx.2018.08.007 [DOI] [PubMed] [Google Scholar]
- 3.Aanning HL. Nonperforated versus perforating appendicitis. Ann Surg. 2008;247(3):554; author reply 554-5. doi: 10.1097/SLA.0b013e31816617b8 [DOI] [PubMed] [Google Scholar]
- 4.Livingston EH, Woodward WA, Sarosi GA, Haley RW. Disconnect between incidence of nonperforated and perforated appendicitis: implications for pathophysiology and management. Ann Surg. 2007;245:886–892. doi: 10.1097/01.sla.0000256391.05233.aa [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Cetinkaya E, Bayazitli SM, Göktaş A, et al. A new, simple marker for predicting complicated appendicitis in patients with normal white blood cell count indicator; LUC. Ulus Travma Acil Cerrahi Derg. 2023;29:872–876. doi: 10.14744/tjtes.2023.60196 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Shin DH, Cho YS, Cho GC, et al. Delta neutrophil index as an early predictor of acute appendicitis and acute complicated appendicitis in adults. World J Emerg Surg. 2017;12:32. doi: 10.1186/s13017-017-0140-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Elgendy A, Khirallah MG, Elsawaf M, Hassan HS, Ghazaly M. Acute appendicitis in children: is preoperative hyponatremia a predictive factor of perforation/gangrene? A prospective study. Pediatr Surg Int. 2023;39:281. doi: 10.1007/s00383-023-05561-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Cho JH, Akers MJ, Siavoshi M, Gress T, Thompson EC. Features on computed tomography that correlate with acute appendicitis. Am Surg. 2023;89:2876–2879. doi: 10.1177/00031348211054076 [DOI] [PubMed] [Google Scholar]
- 9.Moris D, Paulson EK, Pappas TN. Diagnosis and management of acute appendicitis in adults: a review. JAMA. 2021;326:2299–2311. doi: 10.1001/jama.2021.20502 [DOI] [PubMed] [Google Scholar]
- 10.Koo HS, Kim HC, Yang DM, Kim SW, Park SJ, Ryu JK. Does computed tomography have any additional value after sonography in patients with suspected acute appendicitis? J Ultrasound Med. 2013;32:1397–1403. doi: 10.7863/ultra.32.8.1397 [DOI] [PubMed] [Google Scholar]
- 11.Borruel Nacenta S, Ibáñez Sanz L, Sanz Lucas R, Depetris MA, Martínez Chamorro E. Update on acute appendicitis: typical and untypical findings. Radiologia. 2023;65(Suppl. 1):S81–S91. doi: 10.1016/j.rxeng.2022.09.010 [DOI] [PubMed] [Google Scholar]
- 12.Yesilalioglu S, Az A, Sogut O, Ergenc H, Demirel I. Systemic inflammatory markers for distinguishing uncomplicated and complicated acute appendicitis in adult patients. North Clin Istanbul. 2023;10:507–513. doi: 10.14744/nci.2022.79027 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Sengul S, Guler Y, Calis H, Karabulut Z. The role of serum laboratory biomarkers for complicated and uncomplicated appendicitis in adolescents. J Coll Physicians Surg Pak. 2020;30:420–424. doi: 10.29271/jcpsp.2020.04.420 [DOI] [PubMed] [Google Scholar]
- 14.Giannis D, Matenoglou E, Moris D. Hyponatremia as a marker of complicated appendicitis: a systematic review. Surgeon. 2020;18:295–304. doi: 10.1016/j.surge.2020.01.002 [DOI] [PubMed] [Google Scholar]; •• Previous systematic review assessing hyponatremia as a predictor of complicated appendicitis in both adult and children.
- 15.Awan AR, Khan ZU, Saleem H, et al. A comparison of the accuracy of Tzanakis and Alvarado Score in the diagnosis of acute appendicitis: a systematic review and meta-analysis. Surgeon. 2024;22(5):e164–e170. doi: 10.1016/j.surge.2024.04.013 [DOI] [PubMed] [Google Scholar]
- 16.Macco S, Vrouenraets BC, de Castro SMM. Evaluation of scoring systems in predicting acute appendicitis in children. Surgery. 2016;160(6):1599–1604. doi: 10.1016/j.surg.2016.06.023 [DOI] [PubMed] [Google Scholar]
- 17.Pogorelić Z, Mihanović J, Ninčević S, Lukšić B, Elezović Baloević S, Polašek O. Validity of appendicitis inflammatory response score in distinguishing perforated from non-perforated appendicitis in children. Child (Basel, Switzerland). 2021;8:309. doi: 10.3390/children8040309 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Pogorelić Z, Rak S, Mrklić I, Jurić I. Prospective validation of Alvarado score and pediatric appendicitis score for the diagnosis of acute appendicitis in children. Pediatr Emerg Care. 2015;31:164–168. doi: 10.1097/PEC.0000000000000375 [DOI] [PubMed] [Google Scholar]
- 19.Zhao L, Feng S, Huang S, et al. Diagnostic value of hyperfibrinogenemia as a predictive factor for appendiceal perforation in acute appendicitis. ANZ J Surg. 2017;87:372–375. doi: 10.1111/ans.13316 [DOI] [PubMed] [Google Scholar]
- 20.Singh A, Pogorelić Z, Agrawal A, et al. Utility of ischemia-modified albumin as a biomarker for acute appendicitis: a systematic review and meta-analysis. J Clin Med. 2023;2:5486. doi: 10.3390/jcm12175486 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Oztan MO, Aksoy Gokmen A, Ozdemir T, Müderris T, Kaya S, Koyluoglu G. Pentraxin-3: a strong novel biochemical marker for appendicitis in children. Am J Emerg Med. 2019;37:1912–1916. doi: 10.1016/j.ajem.2019.01.010 [DOI] [PubMed] [Google Scholar]
- 22.Pogorelić Z, Lukšić AM, Mihanović J, Đikić D, Balta V. Hyperbilirubinemia as an indicator of perforated acute appendicitis in pediatric population: a prospective study. Surg Infect (Larchmt). 2021;22:1064–1071. doi: 10.1089/sur.2021.107 [DOI] [PubMed] [Google Scholar]
- 23.Kakar M, Delorme M, Broks R, et al. Determining acute complicated and uncomplicated appendicitis using serum and urine biomarkers: IL-6 and neutrophil gelatinase-associated lipocalin. Pediatr Surg Int. 2020;36:629–636. doi: 10.1007/s00383-020-04650-y [DOI] [PubMed] [Google Scholar]
- 24.Lin W-Y, Lee E-P, Chen C-Y, Guo B-C, Lin M-J, WuH-P. Changes in levels of serum cytokines and chemokines in perforated appendicitis in children. Int J Mol Sci. 2024;25:6076. doi: 10.3390/ijms25116076 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Tintor G, Jukić M, Šupe-Domić D, Jerončić A, Pogorelić Z. Diagnostic utility of serum leucine-rich α-2-glycoprotein 1 for acute appendicitis in children. J Clin Med. 2023;23:2455. doi: 10.3390/jcm12072455 [DOI] [PMC free article] [PubMed] [Google Scholar]; • Provides evidence on a newly developed salivary biomarker for predicting complicated appendicitis.
- 26.Tintor G, Jukić M, Šupe-Domić D, Jerončić A, Pogorelić Z. Diagnostic accuracy of leucine-rich α-2-glycoprotein 1 as a non-invasive salivary biomarker in pediatric appendicitis. Int J Mol Sci. 2023;23:6043. doi: 10.3390/ijms24076043 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Anand S, Krishnan N, Birley JR, Tintor G, Bajpai M, Pogorelić Z. Hyponatremia-a new diagnostic marker for complicated acute appendicitis in children: a systematic review and meta-analysis. Child (Basel, Switzerland). 2022;9:1070. doi: 10.3390/children9071070 [DOI] [PMC free article] [PubMed] [Google Scholar]; •• Previous meta-analysis assessing hyponatremia as a predictor of complicated appendicitis in children.
- 28.Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Int J Surg. 2021;88:105906. doi: 10.1016/j.ijsu.2021.105906 [DOI] [PubMed] [Google Scholar]
- 29.Wells G, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Accessed October 30 2020. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp [Google Scholar]
- 30.Poston LM, Leavitt T, Pope S, et al. Pre-appendectomy hyponatremia is associated with increased rates of complicated appendicitis. Surg Open Sci. 2023;13:88–93. doi: 10.1016/j.sopen.2023.05.001 [DOI] [PMC free article] [PubMed] [Google Scholar]; • Largest study assessing hyponatremia as a predictor of complicated appendicitis.
- 31.WuZ, Zhao L, Feng S, Luo J. Hyperfibrinogenemia and hyponatremia as predictors of perforated appendicitis in children: a retrospective cohort study. Int J Colorectal Dis. 2023;38:72. doi: 10.1007/s00384-023-04362-4 [DOI] [PubMed] [Google Scholar]
- 32.Shuaib A, Alhamdan N, Arian H, Sallam MA, Shuaib A. Hyperbilirubinemia and hyponatremia as predictors of complicated appendicitis. Med Sci (Basel, Switzerland). 2022;10:4–11. doi: 10.3390/medsci10030036 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Qureshi MU, Iqbal A, Habib M, et al. Hyponatremia as a marker of complicated appendicitis. J Ayub Med Coll. 2022;34:274–278. doi: 10.55519/JAMC-04-S4-9982 [DOI] [PubMed] [Google Scholar]
- 34.Alfehaid MS, Babiker AM, Alkharraz AH, et al. Elevated total and direct bilirubin are associated with acute complicated appendicitis: a single-center based study in Saudi Arabia. BMC Surg. 2023;23:1–7. doi: 10.1186/s12893-023-02258-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Heymowski A, Boström L, Dahlberg M. Plasma sodium and age are important markers of risk of perforation in acute appendicitis. J Gastrointest Surg. 2021;25:287–289. doi: 10.1007/s11605-020-04753-w [DOI] [PubMed] [Google Scholar]
- 36.Sheen J, Bowen J, Whitmore H, Bowling K. Hyponatremia as a marker of complicated appendicitis: a retrospective analysis. Cureus. 2022;14:5–10. doi: 10.7759/cureus.26672 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Messias B, Cubas I, Oliveira C, et al. Usefulness of serum sodium levels as a novel marker for predicting acute appendicitis severity: a retrospective cohort study. BMC Surg. 2023;23:1–7. doi: 10.1186/s12893-023-02224-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Turhan VB, Unsal A, Öztürk B, Ozturk D, Bulus H. Predictive value of serum sodium level in determining perforated appendicitis. Ulus Travma ve Acil Cerrahi Derg. 2022;28:290–295. doi: 10.14744/tjtes.2021.69670 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Walsh A, Lala S, Wells C, Upadhyay V. Hyponatremia an indicator of complicated appendicitis in children: starship experience. ANZ J Surg. 2022;92:747–752. doi: 10.1111/ans.17425 [DOI] [PubMed] [Google Scholar]
- 40.Pérez-Soto RH, Ponce de León-Ballesteros G, Álvarez-Bautista F, Trolle-Silva AM, Medina-Franco H. Thrombocytosis and hyponatremia as predictors of complicated acute appendicitis. predictors of appendicitis. J Surg Res. 2021;261:369–375. doi: 10.1016/j.jss.2020.12.050 [DOI] [PubMed] [Google Scholar]
- 41.Lindestam U, Almström M, Jacks J, et al. Low plasma sodium concentration predicts perforated acute appendicitis in children: a prospective diagnostic accuracy study. Eur. J Pediatr Surg. 2020;30:350–356. doi: 10.1055/s-0039-1687870 [DOI] [PubMed] [Google Scholar]
- 42.Maqbool M, Khaliq F, Mehboob A, Anis S, Hussain M, Amjad M. Diagnostic value of serum urea, creatinine, sodium and potassium for complicated appendicitis - a one year retrospective study. J Ayub Med Coll. 2022;34:331–335. doi: 10.55519/jamc-02-9514 [DOI] [PubMed] [Google Scholar]
- 43.Ozdemir DB, Karayigit A, Dizen H, Unal B. Role of hyponatremia in differentiating complicated appendicitis from uncomplicated appendicitis: a comparative study. Eur Rev Med Pharmacol Sci. 2022;26:8057–8063. doi: 10.26355/eurrev_202211_30159 [DOI] [PubMed] [Google Scholar]
- 44.Pogorelić Z, Lukšić B, Ninčević S, Lukšić B, Polašek O. Hyponatremia as a predictor of perforated acute appendicitis in pediatric population: a prospective study. J Pediatr Surg. 2021;56:1816–1821. doi: 10.1016/j.jpedsurg.2020.09.066 [DOI] [PubMed] [Google Scholar]
- 45.Duman L, Karaibrahimoğlu A, Büyükyavuz BI, Savaş MÇ. Diagnostic value of monocyte-to-lymphocyte ratio against other biomarkers in children with appendicitis. Pediatr Emerg Care. 2022;38:E739–E742. doi: 10.1097/PEC.0000000000002347 [DOI] [PubMed] [Google Scholar]
- 46.Besli GE. Predictive value of serum sodium level in determining complicated appendicitis risk in children. Haydarpasa Numune Train Res Hosp Med J. 2019;59:35–40. doi: 10.14744/hnhj.2019.16013 [DOI] [Google Scholar]
- 47.Yang J, Liu C, He Y, Cai Z. Laboratory markers in the prediction of acute perforated appendicitis in children. Emerg Med Int. 2019;2019:1–4. doi: 10.1155/2019/4608053 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Pham XBD, Sullins VF, Kim DY, et al. Factors predictive of complicated appendicitis in children. J Surg Res. 2016;206:62–66. doi: 10.1016/j.jss.2016.07.023 [DOI] [PubMed] [Google Scholar]
- 49.Symeonidis NG, Pavlidis ET, Psarras KK, et al. Preoperative hyponatremia indicates complicated acute appendicitis. Surg Res Pract. 2022;2022:1836754. doi: 10.1155/2022/1836754 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Bom WJ, Scheijmans JCG, Salminen P, Boermeester MA. Diagnosis of uncomplicated and complicated appendicitis in adults. Scand J Surg. 2021;110:170–179. doi: 10.1177/14574969211008330 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Kim HY, Park JH, Lee YJ, Lee SS, Jeon J-J, Lee KH. Systematic review and meta-analysis of CT features for differentiating complicated and uncomplicated appendicitis. Radiology. 2018;287:104–115. doi: 10.1148/radiol.2017171260 [DOI] [PubMed] [Google Scholar]
- 52.Gomes CA, Nunes TA, Fonseca Chebli JM, Junior CS, Gomes CC. Laparoscopy grading system of acute appendicitis: new insight for future trials. Surg Laparosc Endosc Percutan Tech. 2012;22:463–466. doi: 10.1097/SLE.0b013e318262edf1 [DOI] [PubMed] [Google Scholar]
- 53.Di Saverio S, Podda M, De Simone B, et al. Diagnosis and treatment of acute appendicitis: 2020 update of the WSES Jerusalem guidelines. World J Emerg Surg. 2020;15:27. doi: 10.1186/s13017-020-00306-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Buffington MA, Abreo K. Hyponatremia: a review. J Intensive Care Med. 2016;31:223–236. doi: 10.1177/0885066614566794 [DOI] [PubMed] [Google Scholar]
- 55.Swart RM, Hoorn EJ, Betjes MG, Zietse R. Hyponatremia and inflammation: the emerging role of IL-6 in osmoregulation. Nephron Physiol. 2010;118:p45–p51. doi: 10.1159/000322238 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.