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Hyponatremia as a marker of complicated appendicitis: A systematic review
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Hyponatremia as a marker of complicated appendicitis: A systematic review Dimitrios Giannis a, Evangelia Matenoglou b, Dimitrios Moris c,* a
Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, 41110, Greece Medical School, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece c Duke Surgery, Duke University Medical Center, Durham, 27710, NC, USA b
article info
abstract
Article history:
Background: Acute appendicitis, the most common cause of acute surgical abdomen, is
Received 6 August 2019
associated with intra-abdominal complications, such as perforation, that increase
Received in revised form
morbidity and mortality. Early and accurate preoperative diagnosis of complicated
30 December 2019
appendicitis mandates the identification of new diagnostic markers. This systematic re-
Accepted 6 January 2020
view summarizes current literature on the adoption of hyponatremia as an early diagnostic
Available online xxx
and predictive marker of complicated appendicitis. Methods: Pubmed, Cochrane Library, Scopus, Google Scholar, WHO Global Health Library,
Keywords:
System for Information on Grey Literature, ISI Web of Science, EBSCOHost and Virtual
Hyponatremia
Health Library were searched in accordance with the PRISMA guidelines in order to identify
Appendicitis
original human studies investigating the association between hyponatremia and the
Perforation
presence or development of complicated appendicitis.
Complication
Results: A total of 7 studies conducted in 6 different countries were identified. A prospective
Diagnostic marker
diagnostic accuracy study reported a strong association between hyponatremia and complicated appendicitis in children. The largest sample size study performed in adults reported a significant association between hyponatremia and perforated or gangrenous appendicitis. Conclusions: The admission serum sodium level measurement, a routinely performed, lowcost test, should be taken into account in patients with clinical presentation compatible with acute appendicitis and suspicion of underlying complications. Future well-designed prospective diagnostic accuracy studies are required to further establish the association between hyponatremia and perforated appendicitis. © 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Introduction Appendicitis is the most common cause of acute surgical abdomen, with an estimated lifetime prevalence of 7e8%.1,2 Despite advances in diagnosis and treatment, it is still associated with significant morbidity (10%) and mortality (1e5%).3 Acute appendicitis severity ranges between mild inflammation to severe gangrene with perforation and local or widespread intra-abdominal contamination.4 The underlying
pathophysiological process involves appendiceal luminal obstruction, mainly due to appendicoliths, foreign bodies or lymphoid hyperplasia, and mucus accumulation-induced luminal distention and bacterial overgrowth.4,5 Subsequently, venous and lymphatic vessels impaired drainage results in arterial supply impairment and ischemic tissue necrosis.4,5 Eventually, in some patients, necrotic tissue perforation occurs resulting in local (abscess) or extensive (peritonitis) complications.4,5
* Corresponding author. E-mail addresses: [email protected] (D. Giannis), [email protected] (E. Matenoglou), [email protected] (D. Moris). https://doi.org/10.1016/j.surge.2020.01.002 1479-666X/© 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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By definition, complicated appendicitis includes perforation of the appendix, empyema or abscess formation, and finally fecal peritonitis.6 Perforation is an important factor of patient morbidity and is associated with increased frequency of postsurgical complications.7e10 Appendiceal rupture is associated with increased risk of developing postoperative complications, such as ileus, intra-abdominal abscess or wound infection as well as prolonged hospitalization.7,9 Bonadio et al. reported significantly shorter length of stay, lower post-admission complications (wound infection, intraabdominal abscess) rate and fewer unscheduled readmissions in surgically treated perforated appendicitis patients versus those who received medical management.11 Thus, early preoperative identification and surgical intervention in patients with perforated appendicitis has important clinical implications. Previous studies have identified advanced age, male gender, presence of comorbidities, fever (>37.5 C), tachycardia (>100 bpm), markedly elevated CRP (>50 mg/L), leukocytosis (>10/nL), neutrophil count > 85%, symptom duration >24 h, duration of abdominal pain >48 h to be associated with complicated appendicitis.12e14 Gosain et al. in their prospective study in 247 children, including 53 patients with ruptured appendicitis, reported African American race, duration of symptoms > 48 h, presence of fecal on computerized tomography (CT) and WBC> 19,400 cells/ml to be significantly associated predictors of ruptured appendicitis.5 Utilization and combination of these diagnostic markers resulted in the development of scoring systems, but many of them appear unreliable when applied in the populations other than the initial study population.5 The accurate and early preoperative diagnosis of perforated appendicitis mandates the identification of new diagnostic modalities. Recently, hyponatremia has been investigated as a potential diagnostic marker of complicated appendicitis presence as well as a predictive marker of postoperative intra-abdominal complications after management of gangrenous (complicated) appendicitis.12e18 Preoperative hyponatremia, a common electrolyte disorder, is associated with increased 30-day morbidity and mortality and should be considered as a marker of prognostic value for perioperative complications in the surgical population.19 The underlying pathogenesis involves proinflammatory cytokines such as interleukins IL-1b and IL-6, milestone mediators of severe inflammatory response, in the development of hyponatremia through antidiuretic hormone (ADH) secretion.20,21 Despite the presence of previous literature investigating the association between hyponatremia and severe forms of inflammatory reactions, their exact pathophysiologic correlation remains to be elucidated. In order to identify and summarize all available data regarding to the importance of hyponatremia as an early diagnostic and predictive marker of complicated appendicitis, we performed a systematic literature search of the available bibliography. Our study provides additional information to emergency department physicians and surgeons who frequently are in diagnostic dilemma in cases of suspected complicated appendicitis.
Materials and methods Search strategy and articles selection process This systematic review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and in compliance with the protocol agreed and approved by all authors.22 A comprehensive literature search was performed independently by two authors (DG and EM) in Pubmed (Medline), Cochrane Library, Scopus, Google Scholar, WHO Global Health Library (GHL), System for Information on Grey Literature (SIGLE), ISI Web of Science, EBSCOHost and Virtual Health Library to identify relevant articles. Except for Google Scholar and EBSCOHost, all of the databases were searched by using the following search algorithm: (hyponatremia OR hyponatraemia OR sodium) AND (appendi*) AND (complic* OR sever* OR prognos* OR diagnosis OR diagnostic OR predict* OR marker). Google Scholar was searched by using the following conditions in the advanced search method: (‛‛Find articles with all the words: appendicitis, with at least one of the words: hyponatremia hyponatraemia, where my words appear: anywhere in the article’’). EBSCOhost was searched by using the algorithms “Hyponatremia AND appendicitis'’, “Hyponatraemia AND appendicitis”, “Appendicitis AND sodium’’ in title and abstract search mode. In addition, a manual search using snowball methodology was executed, by searching through the references of the included articles, relevant reviews and articles in PubMed to avoid missing any important data. Original human studies investigating the association between hyponatremia and the presence or development of complicated appendicitis were considered eligible. There was no restriction regarding to publication date, age, sex, ethnicity, sample size, race, country or language. Exclusion criteria were: (1) any study without full-text availability, (2) non-primary studies such as reviews, systematic reviews and meta-analyses, (3) non-peer reviewed publications (theses, book chapters, conference posters), (4) animal studies, (5) studies without extractable data and (6) duplicated or overlapping datasets.
Data extraction A standardized data extraction template was developed and modified according to an initial pilot testing. Two authors (DG and EM) independently extracted the appropriate and available data parameters in the corresponding extraction sheet columns. The following data were extracted for each included study: Basic information about the articles (names of authors, publication year, country of first author, journal, study design, inclusion and exclusion criteria), important patient characteristics (age, gender, sample size, condition), laboratory findings (serum sodium levels, definition of hyponatremia) and outcomes associated data (definition of complicated appendicitis by the study, cases and controls subgroups sample sizes and number of patients with hyponatremia for
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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Figure 1 e Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart process.
each subgroup). Studies for which we could not obtain missing information (after at least two contact attempts via email) are classified as “no data available (NA)”. Any incongruence in the results of extraction was discussed thoroughly until a consensus was achieved and a third reviewer (DM) was consulted if needed.
Quality assessment tools The National Heart, Lung and Blood Institute (NHLBI) quality assessment tools23 were used in order to evaluate the quality of included studies. The choice of appropriate tool, one for case control studies and one for observational cohort and cross-sectional studies, was based on each individual study and its corresponding design. Both tools measure the internal validity and quality of studies in a similar manner consisting of 12 and 14 criteria respectively and each criterion question is answered as “yes”, “no”, “cannot determine”, “not reported”, “not applicable”. Two authors (DG and EM) independently applied the aforementioned rules in order to guide a cumulative rating for each study defined as “poor”, “fair” or “good”.
Any differences or discrepancies throughout the process were discussed and if needed the senior reviewer (DM) was consulted in order to achieve consensus among the reviewers.
Statistical method Categorical data on outcome of interest were tabulated and statistical measures reported by the studies’ authors (univariate analysis odds ratio, multivariate analysis odds ratio with 95% confidence interval, diagnostic sensitivity and specificity) were extracted. In addition, crude odds ratios with 95% confidence interval were calculated for studies with available data.
Results Literature search and eligible studies The initially proposed electronic database search yielded 4379 potentially eligible articles, of which 2020 were removed as
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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Table 1 e Summary of eligible studies associating hyponatremia and complicated appendicitis in children. Study
Country, Setting
Study design
Population, Age,Sex
Condition
CA definition
Hyponatr emia definition
Retrospective case-control
Children, N ¼ 403; Age: 11.39 ± 3.58a y; _:273 (67.7%) \:130 (32.3)
Appendicitis Perforated or gangrenous appendix, generalized peritonitis, and intra-abdominal abscess
<135 mEq/L
Lindestam et al., 2019 Sweden; Tertiary care hospital, Pediatric Surgery department
Prospective diagnostic accuracy study
Children, N ¼ 80; Age:1e14 y, 9.2 (7.3e11.1) y _:53 (66%) \:27 (34%)
Appendicitis Perforated appendicitis
136 mEq/L
Pham et al., 2016
USA; Tertiary care hospital, Pediatric Surgery department
Retrospective case-control
Children, N ¼ 392; Age 12 _:260 (66.3%) \:132 (33.7%)
135 mEq/L
Serradilla et al., 2018
Spain; Retrospective Tertiary care case-control Hospital, Pediatric Surgery department
Children, N ¼ 162
Appendicitis Perforated or gangrenous appendix, an intra-abdominal abscess, or fecal peritonitis (intraoperative finding) Gangrenous Intraabdominal appendicitis abscess (postappendectomy)
Besli et al., 2019
Turkey; Tertiary care hospital, Pediatric emergency department
<135 mEq/L
CA: complicated appendicitis. N (%) CA: number of patients (percent of total population) with complicated appendicitis. N (%) CA þ Hyponatremia: number of patients (percent of complicated appendicitis population) with complicated appendicitis and hyponatremia. NCA: noncomplicated appendicitis. N (%) NCA: number of patients (percent of total population) with noncomplicated appendicitis. N (%) NCA þ Hyponatremia: number of patients (percent of noncomplicated appendicitis population) with noncomplicated appendicitis and hyponatremia. Na level: Serum sodium level. a Corresponds to mean ± standard deviation; y: corresponds to median (interquartile range).
duplicates (by Endnote 7 (Thompson Reuter, USA) or manually) and 2359 were further screened for relevance. Among the 2359 papers, 2349 were removed after title and abstract screening according to the predefined inclusion and exclusion criteria. The remaining 10 studies were screened in full-text and 3 of them were excluded (1 conference poster without full text and 2 irrelevant articles). Finally, after manual searching and no additional study retrieval, 7 studies were included in the systematic review (Fig. 1).
Patient and included studies characteristics A total of 7 studies with 2682 patients were conducted in 6 different countries. All studies were designed and performed in tertiary care centers. The total number of adults (>18 years), included in 3 studies, was 1645 (61.3%) and the number of children (<18 years), included in 4 studies, was 1037 (38.7%). Case-control design was implemented in 5 studies, one study was prospective cohort and one was retrospective cohort. In
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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N (%) CA
N (%) CA þ Hyponatremia
245 (60.8%)
62 (25.3%)
15 (18.8%)
CA Na level
N (%) NCA
N (%) NCA þ Hyponatremia
136.11 ±3.03
158 (39.2%)
29 (18.4%)
13 (86.7%)
134 (132e136) y
65 (81.2%)
179 (46%)
112 (63%)
134 (132e136) y
54 (33.3%)
NA
NA
Na Level comparison between groups
Hyponatremia e CA association statistics
136.96 ±2.54a
p ¼ 0.004
11 (16.9%)
139 (137e140) y
p < 0.001
213 (54%)
71 (33%)
137 (135e138)
p < 0.01
Crude OR ¼ 1.51 (95% CI:0.92e2.47); Chi-Square test p ¼ 0.103; AUC: 0.580 (standard error 0.03, p ¼ 0.005; p < 0.05, 95% (CI:0.581e0.672). Cut-off value Na 138 mEq/L., Sensitivity 82.5%, Specificity 31.1%. Crude OR ¼ 31.9 (95%CI:6.3e161.9); Univariate logistic regression: OR ¼ 25.5 (95%CI:5.0e128); RR ¼ 15 (95%CI:3.7e62); Cutoff Na 136 mEq/L for diagnosing CA: Sensitivity 0.87 (95% CI, 0.60e0.98), Specificity 0.83 (95% CI, 0.72e0.91), AUC ¼ 0.93 Crude OR ¼ 3.34 (95%CI: 2.21e5.07); Multivariate logistic regression OR ¼ 3.1 (95%CI: 2.0e4.9)
108
NA
NA
NA
studies with available gender data we observed a male predominance (1572 out of 2436 patients of 5 studies, equal to 64.5%). Eligible studies patient characteristics are summarized in Table 1 (children) and Table 2 (adults).
Hyponatremia and complicated appendicitis association Our systematic search identified 4 eligible studies investigating the role of hyponatremia as a marker of the
NCA Na level
Crude OR ¼ 10, (95%CI: 4.68e21.36), p < 0,001; Multivariate logistic regression OR 8.143 (95%CI: 3.551e18.674), p < 0,001
presence13,16,17 or development of appendicitis complications15 in children. In total, 3 out of 4 eligible studies reported statistically significant results. In a retrospective case-control study (including 403 children) by Besli et al., complicated appendicitis was defined as the presence of perforation or gangrenous appendix, peritonitis or intra-abdominal abscess.17 Hyponatremia (Na <135 mEq/L) was nonsignificantly associated with complicated appendicitis (OR ¼ 1.51, 95% CI:0.92e2.47; Chi-Square test:
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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Table 2 e Summary of eligible studies associating hyponatremia and complicated appendicitis in adults. Study
€ ser et al., 2013 Ka
Kim et al., 2015
Wu et al., 2013
Country, Setting
Switzerland; Tertiary care hospital, Adult emergency department USA; Tertiary care hospital
Taiwan; Tertiary care hospital
Study design
Population, Age,Sex
Condition
Complicated Appendicitis (CA) definition
Hyponatremia definition
Retrospective case-control
Adults, N ¼ 84 (data provided only for 82 patients); Age: >50 years
Appendicitis
Perforated appendicitis
<136 mEq/L
Retrospective case-control
Adults, N ¼ 1550; Age:>18 y; _:980 (63.2%) \:570 (36.8%)
Appendicitis
Perforated or gangrenous appendicitis (intraoperative finding)
<135 mEq/L
Retrospective cohort
Adults on hemodialysis N ¼ 11 (data provided only for 10 patients); Age: 63 ± 20a _:6 (54.5%) \:5 (45.5%)
Appendicitis
Perforated appendicitis
<135 mEq/L
CA: complicated appendicitis. N (%) CA: number of patients (percent of total population) with complicated appendicitis. N (%) CA þ Hyponatremia: number of patients (percent of complicated appendicitis population) with complicated appendicitis and hyponatremia. NCA: noncomplicated appendicitis. N (%) NCA: number of patients (percent of total population) with noncomplicated appendicitis. N (%) NCA þ Hyponatremia: number of patients (percent of noncomplicated appendicitis population) with noncomplicated appendicitis and hyponatremia. Na level: Serum sodium level. a Corresponds to mean ± standard deviation; y: corresponds to median (interquartile range).
p ¼ 0.103).17 Cut-off level for basal serum Na 138 mEq/L provided a sensitivity of 82.5% and specificity of 31.1% with AUC ¼ 0.580 (standard error 0.03, p ¼ 0.005; 95% CI:0.581e0.672) in the diagnosis of complicated appendicitis.17 A recent prospective diagnostic accuracy study by Lindestam et al. included 80 children (15 with complicated and 65 with noncomplicated appendicitis) and identified significantly lower levels of serum sodium in patients with perforated versus patients with nonperforated appendicitis.16 Plasma sodium concentration cut-off was set at 136 mEq/L and the difference between groups was significant in both crude and univariate logistic regression analysis (Crude OR ¼ 31.9 (95% CI:6.3e161.9); Univariate logistic regression: OR ¼ 25.5 (95%CI: 5.0e128)). Cut-off level for basal serum Na 136 mEq/L provided a sensitivity of 87% (95% CI, 60%e98%) and specificity of 83% (95% CI, 72%e91%) with AUC ¼ 0.93. In addition, hyponatremia was associated with a 15-fold higher perforation risk compared to serum sodium levels >136 mEq (RR ¼ 15 (95% CI:3.7e62)).16 Pham et al., who retrospectively evaluated 392 children (179 with complicated and 213 with noncomplicated appendicitis), defined hyponatremia as serum Na 135 mEq/L and complicated appendicitis as the presence of perforated or gangrenous appendix, an intra-abdominal abscess, or fecal peritonitis (intraoperative finding). Hyponatremia was more frequently observed in the complicated appendicitis group
(Crude OR ¼ 3.34 (95%CI: 2.21e5.07); Multivariate logistic regression OR ¼ 3.1 (95%CI: 2.0e4.9)).13 In a retrospective case-control study by Serradilla et al., a total of 162 children with gangrenous appendicitis were evaluated and the development of intra-abdominal abscess (post appendectomy) was significantly associated with preoperative hyponatremia (<135 mEq/L) (Crude OR ¼ 10), (95%CI: 4.68e21.36), p < 0,001; Multivariate logistic regression OR 8.143 (95%CI:3.551e18.674), (p < 0,001).15 Hyponatremia was evaluated as a marker of complicated appendicitis in 3 adult population studies,12,14,18 but only 1 of them showed significant difference between complicated and noncomplicated appendicitis groups. € ser et al. investigated the diagnostic role of hyponaKa tremia in cases of perforated diverticulitis or appendicitis in a population of patients older than 50 years.12 Perforated appendicitis subgroup consisted of 84 patients (contact with authors through email provided data for 82 participants) and the association between hyponatremia (Na < 136 mEq/L) and perforated appendicitis was not significant (OR ¼ 1.74, 95% CI: 0.61e4.95); Chi-Square test (p ¼ 0.296).12 Another study by Kim et al., involving 1550 adult patients (409 with complicated vs 1141 with noncomplicated appendicitis), investigated the association between hyponatremia (Na < 135 mEq/L) and intraoperatively identified perforated or gangrenous appendicitis and reported significant results on
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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N (%) CA
N (%) CA þ Hyponatr emia
Na Level CA (range)
N (%) NCA
N (%) NCA þ Hyponatr emia
Na Level NCA (range)
Na Level p value between groups
Hyponatremia e CA association statistics
45 (55%)
13 (29%)
NA
37 (45%)
7 (19%)
NA
NA
Crude OR ¼ 1.74 (95%CI:0.61e4.95); Chi-Square test p ¼ 0.296
409 (26.4%)
173 (42.3%)
136 (134e137)
1141 (73.6%)
NA
137 (136e139) y
p < 0.001
5 (50%)
2 (40%)
NA
5 (50%)
1 (20%)
NA
NA
Multiple logistic regression OR ¼ 2.8 (95%CI:2.1e3.8), p < 0.001 Crude OR ¼ 2.67 (95%CI:0.16e45.1)
multiple logistic regression analysis (OR ¼ 2.8, 95% CI: 2.1e3.8, p < 0.001).14 Wu et al. retrospectively compared hemodialysis (HD) patients with acute appendicitis versus non-hemodialysis patients with acute appendicitis and they further performed a subgroup analysis in HD patients (n ¼ 11) in order to investigate the influence of hyponatremia in the prognosis of HD patients with appendicitis. Perforation and acute appendicitis were not significantly associated (Crude OR ¼ 2.67 (95%CI: 0.16e45.1)).18
Quality assessment of included studies Quality assessment of each case-control study according to NHLBI assessment scale is presented in Table 3 and of each cohort study is shown in Table 4. Totally, 3 studies had an overall rating of good and 4 studies were rated as fair. In general, studies lacked sample size justification, with only one study16 providing data concerning the sample size and associated study power. Two of the studies12,14 investigating the adult population did not statistically adjust for some of the key potential confounding variables and a few items of the quality assessment tools were not reported across studies, especially the presence or absence of researchers blinding on case/control status of participants. The mean NHLBI cumulative score for the 5 case-control studies was 7.2 (SD: 0.84) and for the 2 cohort studies was 8.5 (SD: 0.71).
Discussion Acute appendicitis affects approximately 100 per 100.000 of the general population per year and the lifetime risk is estimated to be 7e8%.1,2 Patients are usually in their second or third decade of life and a slightly increased incidence is observed in males compared to females.2 Despite being one of the most common surgical emergencies, acute appendicitis diagnosis is still a cause of diagnostic dilemma and frequently presents with atypical symptoms and as a mimicker of other conditions with overlapping clinical features.24 Clinical and laboratory findings have been combined in the form of appendicitis clinical risk evaluation scores (Alvarado score, appendicitis inflammatory response score eAIR, RIPASA score) in order to adequately stratify risk and guide further investigation and interventions.2,25 The appendicitis clinical risk scores provide good overall sensitivity, but specificity and thus the ability of confirming the presence of acute appendicitis is considered unreliable.2,24,25 Improved diagnostic accuracy has been achieved with the establishment of imaging tests, such as ultrasound (US), CT and magnetic resonance imaging (MRI).2,24 CT widespread use is associated with increased exposure to ionizing radiation, which increases the long-term risk of malignant neoplasms occurrence.24,26 An alternative approach, in order to avoid
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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Table 3 e Quality assessment of case-control studies with NHLBI quality assessment tool. NHLBI Quality Assessment of Case-Control Studies
Kaser Kim (2015) Pham (2016) Serradilla Besli (2019) (2013) (2018)
1. Was the research question or objective in this paper clearly stated and appropriate? 2. Was the study population clearly specified and defined? 3. Did the authors include a sample size justification? 4. Were controls selected or recruited from the same or similar population that gave rise to the cases (including the same timeframe)? 5. Were the definitions, inclusion and exclusion criteria, algorithms or processes used to identify or select cases and controls valid, reliable, and implemented consistently across all study participants? 6. Were the cases clearly defined and differentiated from controls? 7. If less than 100 percent of eligible cases and/or controls were selected for the study, were the cases and/or controls randomly selected from those eligible? 8. Was there use of concurrent controls? 9. Were the investigators able to confirm that the exposure/risk occurred prior to the development of the condition or event that defined a participant as a case? 10. Were the measures of exposure/risk clearly defined, valid, reliable, and implemented consistently (including the same time period) across all study participants? 11. Were the assessors of exposure/risk blinded to the case or control status of participants? 12. Were key potential confounding variables measured and adjusted statistically in the analyses? If matching was used, did the investigators account for matching during study analysis? Total score % Rating
Yes
Yes
Yes
Yes
Yes
Yes No Yes
Yes No Yes
Yes No Yes
No No Yes
Yes No Yes
Yes
Yes
Yes
NR
Yes
Yes No
Yes NA
Yes No
Yes NR
Yes NA
Yes No
Yes No
Yes No
Yes No
Yes No
Yes
Yes
Yes
Yes
Yes
NR
NR
NR
NR
NR
No
No
Yes
Yes
Yes
7 (58%) Fair
7 (58%) Fair
8 (67%) Good
6 (50%) Fair
8 (67%) Good
NR: not reported. NA: not applicable.
unnecessary radiation exposure, is to perform US initially and only in cases of negative or uncertain results to proceed to CT.24 Leeuwenburgh et al. compared MRI versus US combined with conditional use of CT and reported similar results between the two approaches in the detection of perforated appendicitis.27 Nevertheless, both diagnostic methods misdiagnosed almost half (43% for MRI and 52% for US þ conditional CT) of the patients with perforated appendicitis.27 The aforementioned disadvantages and limitations of currently established diagnostic tests mandate the need of newer diagnostic modalities, especially in the case of complicated appendicitis suspicion. Hyponatremia has been previously associated with increased mortality in necrotizing soft-tissue infections,28 gangrenous cholecystitis29 as well as ischemic bowel in patients presenting with a mechanical small bowel obstruction.30 Alsaleh et al. in their systematic review identified hyponatremia as a significant and potential clinically relevant indicator of anastomotic leakage in patients undergoing colorectal surgery.31 In addition, preoperative hyponatremia has been found to be a predictor of 30-day perioperative morbidity and mortality.19 Swart R.M. et al. suggest the nonosmotic release of antidiuretic hormone, mediated by the production of proinflammatory cytokines such as interleukins IL-1b and IL-6, being involved in the development of hyponatremia in severe inflammatory reactions.21 Circulating
cytokines crossing the blood-brain barrier act on neurons originating in the supraoptic and paraventricular nucleus and transduce their signal through activation of Janus tyrosine kinases (JAK) and their associated transcription factors, the so-called signal transducer and activator of transcription (STAT) family.21,31,32 Subsequently, cytokine mediated nonosmotic ADH secretion results in increased free water reabsorption in the kidney tubules and dilutional hyponatremia.21,31,32 Our review identified in total 7 studies associating hyponatremia and complicated appendicitis, but only 4 of them had statistically significant results (Table 1). Despite being retrospective, the adult population study by Kim et al. had the largest sample size (1550 patients) and reported a significant association in multiple logistic regression analysis (OR ¼ 2.8, 95% CI: 2.1e3.8, p < 0.001).14 The diagnostic accuracy study in a children population by Lindestam et al., rated as good in quality assessment by the NHLBI tool (Table 4), reported a strong association and was the only study to prospectively evaluate the relative risk of perforation in children patients with hyponatremia (RR ¼ 15 (95%CI:3.7e62)).16 The presence of hyponatremia at admission may act as an accessory marker helping surgeons and emergency medicine physicians in the earlier diagnosis and clinical management of complicated appendicitis. Based on these data, in a patient with suspected appendicitis and a serum sodium level equal to or less than
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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Table 4 e Quality Assessment of cohort studies with NHLBI Quality Assessment Tool. NHLBI Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies
Wu (2013)
1. 2. 3. 4.
Was the research question or objective in this paper clearly stated? Was the study population clearly specified and defined? Was the participation rate of eligible persons at least 50%? Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? 5. Was a sample size justification, power description, or variance and effect estimates provided? 6. For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? 7. Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? 8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)? 9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 10. Was the exposure(s) assessed more than once over time? 11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 12. Were the outcome assessors blinded to the exposure status of participants? 13. Was loss to follow-up after baseline 20% or less? 14. Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? Total score % Rating
Lindestam (2019)
Yes Yes NR Yes
Yes Yes No Yes
No
Yes
NR
Yes
Yes
Yes
NA
NA
Yes
Yes
NA Yes
NA YES
NR Yes Yes
NR NA Yes
8 (57%) Fair
9 (64%) Good
NR: not reported. NA: not applicable.
136 mEq/L one should have the possibility of complicated appendicitis in their differential. Our findings should be considered carefully and the quality of the included studies should be taken in to account. Furthermore, additional limitations should be acknowledged during the interpretation of our study results. Missing data as well as relatively small sample sizes included in the adult € ser et al.12 and Wu et al.18 should be population studies by Ka considered as a factor affecting the power of the study and thus the identification of hyponatremia and complicated appendicitis association. In addition, discrepancies in the cutoff definition of hyponatremia between studies may affect the generalizability of findings (Table 1, Table 2). Hyponatremia was defined as plasma sodium concentration <135 mEq/L in 4 studies,14,15,17,18 whereas 3 studies defined hyponatremia at a level of 135 mEq/L,13 136 mEq/l16 or <136 mEq/L.12 We propose that any future studies should use the ‘cut-off’ of <135 mEq/L in accordance with the generally accepted lowest limit of normal serum sodium concentration of 135 mEq/L.33,34 In addition, the identified studies only investigated the association of hyponatremia with macroscopic pathological changes. No effort was made to further evaluate the association between hyponatremia severity and histopathological changes. Finally, by the time hyponatremia result is obtained, other blood or imaging diagnostic modalities could indicate the presence of severe appendicitis and thus limit the usefulness of this marker. An alternate approach would include hyponatremia as one of the parameters of models that utilize inflammation markers (WBC count and type) and clinical
signs in order to diagnose or predict the development of complicated appendicitis. In summary, future well-designed prospective diagnostic accuracy studies are required to further elucidate and establish the connection between hyponatremia and perforated appendicitis. Nevertheless, we propose that the admission serum sodium level measurement, an easily and routinely performed, low-cost test, should be taken into account in patients with clinical presentation compatible with acute appendicitis and suspicion of underlying complications.
Conflict of interest None.
Funding sources and support This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
references
1. Stewart B, Khanduri P, McCord C, et al. Global disease burden of conditions requiring emergency surgery. Br J Surg 2014;101(1):e9e22. https://doi.org/10.1002/bjs.9329.
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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2. Bhangu A, Søreide K, Di Saverio S, Assarsson JH, Drake FT. Acute appendicitis: modern understanding of pathogenesis, diagnosis, and management. Lancet 2015;386(10000):1278e87. https://doi.org/10.1016/S0140-6736(15)00275-5. 3. Gomes CA, Sartelli M, Di Saverio S, et al. Acute appendicitis: proposal of a new comprehensive grading system based on clinical, imaging and laparoscopic findings. World J Emerg Surg WJES 2015;10. https://doi.org/10.1186/s13017-015-0053-2. 4. Howell EC, Dubina ED, Lee SL. Perforation risk in pediatric appendicitis: assessment and management. Pediatr Health Med Therapeut 2018;9:135e45. https://doi.org/10.2147/PHMT.S155302. 5. Gosain A, Williams RF, Blakely ML. Distinguishing acute from ruptured appendicitis preoperatively in the pediatric patient. Adv Surg 2010;44:73e85. 6. Klempa I. [Current therapy of complicated appendicitis]. Chir Z Alle Geb Oper Medizen 2002;73(8):799e804. 7. Peng Y-S, Lee H-C, Yeung C-Y, Sheu J-C, Wang N-L, Tsai Y-H. Clinical criteria for diagnosing perforated appendix in pediatric patients. Pediatr Emerg Care 2006;22(7):475e9. https:// doi.org/10.1097/01.pec.0000226871.49427.ec. 8. Willis ZI, Duggan EM, Bucher BT, et al. Effect of a clinical practice guideline for pediatric complicated appendicitis. JAMA Surg 2016;151(5):e160194. https://doi.org/10.1001/ jamasurg.2016.0194. 9. Ponsky TA, Huang ZJ, Kittle K, et al. Hospital- and patient-level characteristics and the risk of appendiceal rupture and negative appendectomy in children. J Am Med Assoc 2004;292(16):1977e82. https://doi.org/10.1001/jama.292.16.1977. 10. Bickell NA, Aufses AH, Rojas M, Bodian C. How time affects the risk of rupture in appendicitis. J Am Coll Surg 2006;202(3):401e6. https://doi.org/10.1016/ j.jamcollsurg.2005.11.016. 11. Bonadio W, Rebillot K, Ukwuoma O, Saracino C, Iskhakov A. Management of pediatric perforated appendicitis: comparing outcomes using early appendectomy versus solely medical management. Pediatr Infect Dis J 2017;36(10):937e41. https:// doi.org/10.1097/INF.0000000000001025. € ser SA, Furler R, Evequoz DC, Maurer CA. Hyponatremia is 12. Ka a specific marker of perforation in sigmoid diverticulitis or appendicitis in patients older than 50 years. Gastroenterol Res Pract 2013;2013:1e4. https://doi.org/10.1155/2013/462891. 13. Pham X-BD, Sullins VF, Kim DY, et al. Factors predictive of complicated appendicitis in children. J Surg Res 2016;206(1):62e6. https://doi.org/10.1016/j.jss.2016.07.023. 14. Kim DY, Nassiri N, de Virgilio C, et al. Association between hyponatremia and complicated appendicitis. JAMA Surg 2015;150(9):911. https://doi.org/10.1001/jamasurg.2015.1258. 15. Serradilla J, Bueno A. Factores predictivos de absceso intraabdominal post-apendicectomı´a gangrenada. Un estudio caso-control. Cir Pediatr 2018;31:4. € m M, Jacks J, et al. Low plasma sodium 16. Lindestam U, Almstro concentration predicts perforated acute appendicitis in children: a prospective diagnostic accuracy study. Eur J Pediatr Surg April 2019:s-0039es1687870. https://doi.org/10.1055/s0039-1687870. 17. Besli GE, Cetin M, Ulukaya Durakbasa C, Ozkanli S. Predictive value of serum sodium level in determining complicated appendicitis risk in children. Haydarpasa Numune Train Res Hosp Med J 2019;59(1):35e40. https://doi.org/10.14744/ hnhj.2019.16013. 18. Wu H-C, Yan M-T, Lu K-C, et al. Clinical manifestations of acute appendicitis in hemodialysis patients. Surg Today 2013;43(9):977e83. https://doi.org/10.1007/s00595-012-0349-8.
19. Leung AA, McAlister FA, Rogers SO, Pazo V, Wright A, Bates DW. Preoperative hyponatremia and perioperative complications. Arch Intern Med 2012;172(19):1474e81. https:// doi.org/10.1001/archinternmed.2012.3992. 20. Park SJ, Shin JI. Inflammation and hyponatremia: an underrecognized condition? Kor J Pediatr 2013;56(12):519e22. https://doi.org/10.3345/kjp.2013.56.12.519. 21. Swart RM, Hoorn EJ, Betjes MG, Zietse R. Hyponatremia and inflammation: the emerging role of interleukin-6 in osmoregulation. Nephron Physiol 2011;118(2):45e51. https:// doi.org/10.1159/000322238. 22. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700. https://doi.org/10.1136/ bmj.b2700. 23. Study quality assessment tools national Heart, Lung, and blood Institute (NHLBI). https://www.nhlbi.nih.gov/health-topics/ study-quality-assessment-tools. [Accessed 29 July 2019]. 24. Shogilev D, Duus N, Odom S, Shapiro N. Diagnosing appendicitis: evidence-based review of the diagnostic approach in 2014. West J Emerg Med 2014;15(7):859e71. https:// doi.org/10.5811/westjem.2014.9.21568. 25. Frountzas M, Stergios K, Kopsini D, Schizas D, Kontzoglou K, Toutouzas K. Alvarado or RIPASA score for diagnosis of acute appendicitis? A meta-analysis of randomized trials. Int J Surg 2018 Aug;56:307e14. https:// doi.org/10.1016/j.ijsu.2018.07.003. 26. Armao D, Smith JK. The Health risks of ionizing radiation from computed tomography. N C Med J 2014;75(2):126e31. https://doi.org/10.18043/ncm.75.2.126. 27. Leeuwenburgh MMN, Wiezer MJ, Wiarda BM, et al. Accuracy of MRI compared with ultrasound imaging and selective use of CT to discriminate simple from perforated appendicitis. Br J Surg 2014;101(1):e147e55. https://doi.org/10.1002/bjs.9350. 28. Yaghoubian A, de Virgilio C, Dauphine C, Lewis RJ, Lin M. Use of admission serum lactate and sodium levels to predict mortality in necrotizing soft-tissue infections. Arch Surg Chic Ill 1960 2007;142(9):840e6. https://doi.org/10.1001/ archsurg.142.9.840. discussion 844-846. 29. Falor AE, Zobel M, Kaji A, Neville A, De Virgilio C. Admission variables predictive of gangrenous cholecystitis. Am Surg 2012;78(10):1075e8. 30. O'Leary MP, Neville AL, Keeley JA, Kim DY, de Virgilio C, Plurad DS. Predictors of ischemic bowel in patients with small bowel obstruction. Am Surg 2016 Oct;82(10):992e4. 31. Alsaleh A, Pellino G, Christodoulides N, Malietzis G, Kontovounisios C. Hyponatremia could identify patients with intrabdominal sepsis and anastomotic leak after colorectal surgery: a systematic review of the literature. Updat Surg 2019;71(1):17e20. https://doi.org/10.1007/s13304019-00627-2. 32. Sharshar T, Blanchard A, Paillard M, Raphael JC, Gajdos P, Annane D. Circulating vasopressin levels in septic shock. Crit Care Med 2003 Jun;31(6):1752e8. 33. Sterns RH. Disorders of plasma sodium d causes, consequences, and correctionIngelfinger JR, editor. N Engl J Med 2015;372(1):55e65. https://doi.org/10.1056/ NEJMra1404489. 34. Maesaka JK, Imbriano LJ, Miyawaki N. Application of established pathophysiologic processes brings greater clarity to diagnosis and treatment of hyponatremia. World J Nephrol 2017;6(2):59. https://doi.org/10.5527/wjn.v6.i2.59.
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
Hyponatremia as a marker of complicated appendicitis: A systematic review Dimitrios Giannis a, Evangelia Matenoglou b, Dimitrios Moris c,* a
Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, 41110, Greece Medical School, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece c Duke Surgery, Duke University Medical Center, Durham, 27710, NC, USA b
article info
abstract
Article history:
Background: Acute appendicitis, the most common cause of acute surgical abdomen, is
Received 6 August 2019
associated with intra-abdominal complications, such as perforation, that increase
Received in revised form
morbidity and mortality. Early and accurate preoperative diagnosis of complicated
30 December 2019
appendicitis mandates the identification of new diagnostic markers. This systematic re-
Accepted 6 January 2020
view summarizes current literature on the adoption of hyponatremia as an early diagnostic
Available online xxx
and predictive marker of complicated appendicitis. Methods: Pubmed, Cochrane Library, Scopus, Google Scholar, WHO Global Health Library,
Keywords:
System for Information on Grey Literature, ISI Web of Science, EBSCOHost and Virtual
Hyponatremia
Health Library were searched in accordance with the PRISMA guidelines in order to identify
Appendicitis
original human studies investigating the association between hyponatremia and the
Perforation
presence or development of complicated appendicitis.
Complication
Results: A total of 7 studies conducted in 6 different countries were identified. A prospective
Diagnostic marker
diagnostic accuracy study reported a strong association between hyponatremia and complicated appendicitis in children. The largest sample size study performed in adults reported a significant association between hyponatremia and perforated or gangrenous appendicitis. Conclusions: The admission serum sodium level measurement, a routinely performed, lowcost test, should be taken into account in patients with clinical presentation compatible with acute appendicitis and suspicion of underlying complications. Future well-designed prospective diagnostic accuracy studies are required to further establish the association between hyponatremia and perforated appendicitis. © 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Introduction Appendicitis is the most common cause of acute surgical abdomen, with an estimated lifetime prevalence of 7e8%.1,2 Despite advances in diagnosis and treatment, it is still associated with significant morbidity (10%) and mortality (1e5%).3 Acute appendicitis severity ranges between mild inflammation to severe gangrene with perforation and local or widespread intra-abdominal contamination.4 The underlying
pathophysiological process involves appendiceal luminal obstruction, mainly due to appendicoliths, foreign bodies or lymphoid hyperplasia, and mucus accumulation-induced luminal distention and bacterial overgrowth.4,5 Subsequently, venous and lymphatic vessels impaired drainage results in arterial supply impairment and ischemic tissue necrosis.4,5 Eventually, in some patients, necrotic tissue perforation occurs resulting in local (abscess) or extensive (peritonitis) complications.4,5
* Corresponding author. E-mail addresses: [email protected] (D. Giannis), [email protected] (E. Matenoglou), [email protected] (D. Moris). https://doi.org/10.1016/j.surge.2020.01.002 1479-666X/© 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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By definition, complicated appendicitis includes perforation of the appendix, empyema or abscess formation, and finally fecal peritonitis.6 Perforation is an important factor of patient morbidity and is associated with increased frequency of postsurgical complications.7e10 Appendiceal rupture is associated with increased risk of developing postoperative complications, such as ileus, intra-abdominal abscess or wound infection as well as prolonged hospitalization.7,9 Bonadio et al. reported significantly shorter length of stay, lower post-admission complications (wound infection, intraabdominal abscess) rate and fewer unscheduled readmissions in surgically treated perforated appendicitis patients versus those who received medical management.11 Thus, early preoperative identification and surgical intervention in patients with perforated appendicitis has important clinical implications. Previous studies have identified advanced age, male gender, presence of comorbidities, fever (>37.5 C), tachycardia (>100 bpm), markedly elevated CRP (>50 mg/L), leukocytosis (>10/nL), neutrophil count > 85%, symptom duration >24 h, duration of abdominal pain >48 h to be associated with complicated appendicitis.12e14 Gosain et al. in their prospective study in 247 children, including 53 patients with ruptured appendicitis, reported African American race, duration of symptoms > 48 h, presence of fecal on computerized tomography (CT) and WBC> 19,400 cells/ml to be significantly associated predictors of ruptured appendicitis.5 Utilization and combination of these diagnostic markers resulted in the development of scoring systems, but many of them appear unreliable when applied in the populations other than the initial study population.5 The accurate and early preoperative diagnosis of perforated appendicitis mandates the identification of new diagnostic modalities. Recently, hyponatremia has been investigated as a potential diagnostic marker of complicated appendicitis presence as well as a predictive marker of postoperative intra-abdominal complications after management of gangrenous (complicated) appendicitis.12e18 Preoperative hyponatremia, a common electrolyte disorder, is associated with increased 30-day morbidity and mortality and should be considered as a marker of prognostic value for perioperative complications in the surgical population.19 The underlying pathogenesis involves proinflammatory cytokines such as interleukins IL-1b and IL-6, milestone mediators of severe inflammatory response, in the development of hyponatremia through antidiuretic hormone (ADH) secretion.20,21 Despite the presence of previous literature investigating the association between hyponatremia and severe forms of inflammatory reactions, their exact pathophysiologic correlation remains to be elucidated. In order to identify and summarize all available data regarding to the importance of hyponatremia as an early diagnostic and predictive marker of complicated appendicitis, we performed a systematic literature search of the available bibliography. Our study provides additional information to emergency department physicians and surgeons who frequently are in diagnostic dilemma in cases of suspected complicated appendicitis.
Materials and methods Search strategy and articles selection process This systematic review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and in compliance with the protocol agreed and approved by all authors.22 A comprehensive literature search was performed independently by two authors (DG and EM) in Pubmed (Medline), Cochrane Library, Scopus, Google Scholar, WHO Global Health Library (GHL), System for Information on Grey Literature (SIGLE), ISI Web of Science, EBSCOHost and Virtual Health Library to identify relevant articles. Except for Google Scholar and EBSCOHost, all of the databases were searched by using the following search algorithm: (hyponatremia OR hyponatraemia OR sodium) AND (appendi*) AND (complic* OR sever* OR prognos* OR diagnosis OR diagnostic OR predict* OR marker). Google Scholar was searched by using the following conditions in the advanced search method: (‛‛Find articles with all the words: appendicitis, with at least one of the words: hyponatremia hyponatraemia, where my words appear: anywhere in the article’’). EBSCOhost was searched by using the algorithms “Hyponatremia AND appendicitis'’, “Hyponatraemia AND appendicitis”, “Appendicitis AND sodium’’ in title and abstract search mode. In addition, a manual search using snowball methodology was executed, by searching through the references of the included articles, relevant reviews and articles in PubMed to avoid missing any important data. Original human studies investigating the association between hyponatremia and the presence or development of complicated appendicitis were considered eligible. There was no restriction regarding to publication date, age, sex, ethnicity, sample size, race, country or language. Exclusion criteria were: (1) any study without full-text availability, (2) non-primary studies such as reviews, systematic reviews and meta-analyses, (3) non-peer reviewed publications (theses, book chapters, conference posters), (4) animal studies, (5) studies without extractable data and (6) duplicated or overlapping datasets.
Data extraction A standardized data extraction template was developed and modified according to an initial pilot testing. Two authors (DG and EM) independently extracted the appropriate and available data parameters in the corresponding extraction sheet columns. The following data were extracted for each included study: Basic information about the articles (names of authors, publication year, country of first author, journal, study design, inclusion and exclusion criteria), important patient characteristics (age, gender, sample size, condition), laboratory findings (serum sodium levels, definition of hyponatremia) and outcomes associated data (definition of complicated appendicitis by the study, cases and controls subgroups sample sizes and number of patients with hyponatremia for
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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Figure 1 e Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart process.
each subgroup). Studies for which we could not obtain missing information (after at least two contact attempts via email) are classified as “no data available (NA)”. Any incongruence in the results of extraction was discussed thoroughly until a consensus was achieved and a third reviewer (DM) was consulted if needed.
Quality assessment tools The National Heart, Lung and Blood Institute (NHLBI) quality assessment tools23 were used in order to evaluate the quality of included studies. The choice of appropriate tool, one for case control studies and one for observational cohort and cross-sectional studies, was based on each individual study and its corresponding design. Both tools measure the internal validity and quality of studies in a similar manner consisting of 12 and 14 criteria respectively and each criterion question is answered as “yes”, “no”, “cannot determine”, “not reported”, “not applicable”. Two authors (DG and EM) independently applied the aforementioned rules in order to guide a cumulative rating for each study defined as “poor”, “fair” or “good”.
Any differences or discrepancies throughout the process were discussed and if needed the senior reviewer (DM) was consulted in order to achieve consensus among the reviewers.
Statistical method Categorical data on outcome of interest were tabulated and statistical measures reported by the studies’ authors (univariate analysis odds ratio, multivariate analysis odds ratio with 95% confidence interval, diagnostic sensitivity and specificity) were extracted. In addition, crude odds ratios with 95% confidence interval were calculated for studies with available data.
Results Literature search and eligible studies The initially proposed electronic database search yielded 4379 potentially eligible articles, of which 2020 were removed as
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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Table 1 e Summary of eligible studies associating hyponatremia and complicated appendicitis in children. Study
Country, Setting
Study design
Population, Age,Sex
Condition
CA definition
Hyponatr emia definition
Retrospective case-control
Children, N ¼ 403; Age: 11.39 ± 3.58a y; _:273 (67.7%) \:130 (32.3)
Appendicitis Perforated or gangrenous appendix, generalized peritonitis, and intra-abdominal abscess
<135 mEq/L
Lindestam et al., 2019 Sweden; Tertiary care hospital, Pediatric Surgery department
Prospective diagnostic accuracy study
Children, N ¼ 80; Age:1e14 y, 9.2 (7.3e11.1) y _:53 (66%) \:27 (34%)
Appendicitis Perforated appendicitis
136 mEq/L
Pham et al., 2016
USA; Tertiary care hospital, Pediatric Surgery department
Retrospective case-control
Children, N ¼ 392; Age 12 _:260 (66.3%) \:132 (33.7%)
135 mEq/L
Serradilla et al., 2018
Spain; Retrospective Tertiary care case-control Hospital, Pediatric Surgery department
Children, N ¼ 162
Appendicitis Perforated or gangrenous appendix, an intra-abdominal abscess, or fecal peritonitis (intraoperative finding) Gangrenous Intraabdominal appendicitis abscess (postappendectomy)
Besli et al., 2019
Turkey; Tertiary care hospital, Pediatric emergency department
<135 mEq/L
CA: complicated appendicitis. N (%) CA: number of patients (percent of total population) with complicated appendicitis. N (%) CA þ Hyponatremia: number of patients (percent of complicated appendicitis population) with complicated appendicitis and hyponatremia. NCA: noncomplicated appendicitis. N (%) NCA: number of patients (percent of total population) with noncomplicated appendicitis. N (%) NCA þ Hyponatremia: number of patients (percent of noncomplicated appendicitis population) with noncomplicated appendicitis and hyponatremia. Na level: Serum sodium level. a Corresponds to mean ± standard deviation; y: corresponds to median (interquartile range).
duplicates (by Endnote 7 (Thompson Reuter, USA) or manually) and 2359 were further screened for relevance. Among the 2359 papers, 2349 were removed after title and abstract screening according to the predefined inclusion and exclusion criteria. The remaining 10 studies were screened in full-text and 3 of them were excluded (1 conference poster without full text and 2 irrelevant articles). Finally, after manual searching and no additional study retrieval, 7 studies were included in the systematic review (Fig. 1).
Patient and included studies characteristics A total of 7 studies with 2682 patients were conducted in 6 different countries. All studies were designed and performed in tertiary care centers. The total number of adults (>18 years), included in 3 studies, was 1645 (61.3%) and the number of children (<18 years), included in 4 studies, was 1037 (38.7%). Case-control design was implemented in 5 studies, one study was prospective cohort and one was retrospective cohort. In
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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N (%) CA
N (%) CA þ Hyponatremia
245 (60.8%)
62 (25.3%)
15 (18.8%)
CA Na level
N (%) NCA
N (%) NCA þ Hyponatremia
136.11 ±3.03
158 (39.2%)
29 (18.4%)
13 (86.7%)
134 (132e136) y
65 (81.2%)
179 (46%)
112 (63%)
134 (132e136) y
54 (33.3%)
NA
NA
Na Level comparison between groups
Hyponatremia e CA association statistics
136.96 ±2.54a
p ¼ 0.004
11 (16.9%)
139 (137e140) y
p < 0.001
213 (54%)
71 (33%)
137 (135e138)
p < 0.01
Crude OR ¼ 1.51 (95% CI:0.92e2.47); Chi-Square test p ¼ 0.103; AUC: 0.580 (standard error 0.03, p ¼ 0.005; p < 0.05, 95% (CI:0.581e0.672). Cut-off value Na 138 mEq/L., Sensitivity 82.5%, Specificity 31.1%. Crude OR ¼ 31.9 (95%CI:6.3e161.9); Univariate logistic regression: OR ¼ 25.5 (95%CI:5.0e128); RR ¼ 15 (95%CI:3.7e62); Cutoff Na 136 mEq/L for diagnosing CA: Sensitivity 0.87 (95% CI, 0.60e0.98), Specificity 0.83 (95% CI, 0.72e0.91), AUC ¼ 0.93 Crude OR ¼ 3.34 (95%CI: 2.21e5.07); Multivariate logistic regression OR ¼ 3.1 (95%CI: 2.0e4.9)
108
NA
NA
NA
studies with available gender data we observed a male predominance (1572 out of 2436 patients of 5 studies, equal to 64.5%). Eligible studies patient characteristics are summarized in Table 1 (children) and Table 2 (adults).
Hyponatremia and complicated appendicitis association Our systematic search identified 4 eligible studies investigating the role of hyponatremia as a marker of the
NCA Na level
Crude OR ¼ 10, (95%CI: 4.68e21.36), p < 0,001; Multivariate logistic regression OR 8.143 (95%CI: 3.551e18.674), p < 0,001
presence13,16,17 or development of appendicitis complications15 in children. In total, 3 out of 4 eligible studies reported statistically significant results. In a retrospective case-control study (including 403 children) by Besli et al., complicated appendicitis was defined as the presence of perforation or gangrenous appendix, peritonitis or intra-abdominal abscess.17 Hyponatremia (Na <135 mEq/L) was nonsignificantly associated with complicated appendicitis (OR ¼ 1.51, 95% CI:0.92e2.47; Chi-Square test:
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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Table 2 e Summary of eligible studies associating hyponatremia and complicated appendicitis in adults. Study
€ ser et al., 2013 Ka
Kim et al., 2015
Wu et al., 2013
Country, Setting
Switzerland; Tertiary care hospital, Adult emergency department USA; Tertiary care hospital
Taiwan; Tertiary care hospital
Study design
Population, Age,Sex
Condition
Complicated Appendicitis (CA) definition
Hyponatremia definition
Retrospective case-control
Adults, N ¼ 84 (data provided only for 82 patients); Age: >50 years
Appendicitis
Perforated appendicitis
<136 mEq/L
Retrospective case-control
Adults, N ¼ 1550; Age:>18 y; _:980 (63.2%) \:570 (36.8%)
Appendicitis
Perforated or gangrenous appendicitis (intraoperative finding)
<135 mEq/L
Retrospective cohort
Adults on hemodialysis N ¼ 11 (data provided only for 10 patients); Age: 63 ± 20a _:6 (54.5%) \:5 (45.5%)
Appendicitis
Perforated appendicitis
<135 mEq/L
CA: complicated appendicitis. N (%) CA: number of patients (percent of total population) with complicated appendicitis. N (%) CA þ Hyponatremia: number of patients (percent of complicated appendicitis population) with complicated appendicitis and hyponatremia. NCA: noncomplicated appendicitis. N (%) NCA: number of patients (percent of total population) with noncomplicated appendicitis. N (%) NCA þ Hyponatremia: number of patients (percent of noncomplicated appendicitis population) with noncomplicated appendicitis and hyponatremia. Na level: Serum sodium level. a Corresponds to mean ± standard deviation; y: corresponds to median (interquartile range).
p ¼ 0.103).17 Cut-off level for basal serum Na 138 mEq/L provided a sensitivity of 82.5% and specificity of 31.1% with AUC ¼ 0.580 (standard error 0.03, p ¼ 0.005; 95% CI:0.581e0.672) in the diagnosis of complicated appendicitis.17 A recent prospective diagnostic accuracy study by Lindestam et al. included 80 children (15 with complicated and 65 with noncomplicated appendicitis) and identified significantly lower levels of serum sodium in patients with perforated versus patients with nonperforated appendicitis.16 Plasma sodium concentration cut-off was set at 136 mEq/L and the difference between groups was significant in both crude and univariate logistic regression analysis (Crude OR ¼ 31.9 (95% CI:6.3e161.9); Univariate logistic regression: OR ¼ 25.5 (95%CI: 5.0e128)). Cut-off level for basal serum Na 136 mEq/L provided a sensitivity of 87% (95% CI, 60%e98%) and specificity of 83% (95% CI, 72%e91%) with AUC ¼ 0.93. In addition, hyponatremia was associated with a 15-fold higher perforation risk compared to serum sodium levels >136 mEq (RR ¼ 15 (95% CI:3.7e62)).16 Pham et al., who retrospectively evaluated 392 children (179 with complicated and 213 with noncomplicated appendicitis), defined hyponatremia as serum Na 135 mEq/L and complicated appendicitis as the presence of perforated or gangrenous appendix, an intra-abdominal abscess, or fecal peritonitis (intraoperative finding). Hyponatremia was more frequently observed in the complicated appendicitis group
(Crude OR ¼ 3.34 (95%CI: 2.21e5.07); Multivariate logistic regression OR ¼ 3.1 (95%CI: 2.0e4.9)).13 In a retrospective case-control study by Serradilla et al., a total of 162 children with gangrenous appendicitis were evaluated and the development of intra-abdominal abscess (post appendectomy) was significantly associated with preoperative hyponatremia (<135 mEq/L) (Crude OR ¼ 10), (95%CI: 4.68e21.36), p < 0,001; Multivariate logistic regression OR 8.143 (95%CI:3.551e18.674), (p < 0,001).15 Hyponatremia was evaluated as a marker of complicated appendicitis in 3 adult population studies,12,14,18 but only 1 of them showed significant difference between complicated and noncomplicated appendicitis groups. € ser et al. investigated the diagnostic role of hyponaKa tremia in cases of perforated diverticulitis or appendicitis in a population of patients older than 50 years.12 Perforated appendicitis subgroup consisted of 84 patients (contact with authors through email provided data for 82 participants) and the association between hyponatremia (Na < 136 mEq/L) and perforated appendicitis was not significant (OR ¼ 1.74, 95% CI: 0.61e4.95); Chi-Square test (p ¼ 0.296).12 Another study by Kim et al., involving 1550 adult patients (409 with complicated vs 1141 with noncomplicated appendicitis), investigated the association between hyponatremia (Na < 135 mEq/L) and intraoperatively identified perforated or gangrenous appendicitis and reported significant results on
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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N (%) CA
N (%) CA þ Hyponatr emia
Na Level CA (range)
N (%) NCA
N (%) NCA þ Hyponatr emia
Na Level NCA (range)
Na Level p value between groups
Hyponatremia e CA association statistics
45 (55%)
13 (29%)
NA
37 (45%)
7 (19%)
NA
NA
Crude OR ¼ 1.74 (95%CI:0.61e4.95); Chi-Square test p ¼ 0.296
409 (26.4%)
173 (42.3%)
136 (134e137)
1141 (73.6%)
NA
137 (136e139) y
p < 0.001
5 (50%)
2 (40%)
NA
5 (50%)
1 (20%)
NA
NA
Multiple logistic regression OR ¼ 2.8 (95%CI:2.1e3.8), p < 0.001 Crude OR ¼ 2.67 (95%CI:0.16e45.1)
multiple logistic regression analysis (OR ¼ 2.8, 95% CI: 2.1e3.8, p < 0.001).14 Wu et al. retrospectively compared hemodialysis (HD) patients with acute appendicitis versus non-hemodialysis patients with acute appendicitis and they further performed a subgroup analysis in HD patients (n ¼ 11) in order to investigate the influence of hyponatremia in the prognosis of HD patients with appendicitis. Perforation and acute appendicitis were not significantly associated (Crude OR ¼ 2.67 (95%CI: 0.16e45.1)).18
Quality assessment of included studies Quality assessment of each case-control study according to NHLBI assessment scale is presented in Table 3 and of each cohort study is shown in Table 4. Totally, 3 studies had an overall rating of good and 4 studies were rated as fair. In general, studies lacked sample size justification, with only one study16 providing data concerning the sample size and associated study power. Two of the studies12,14 investigating the adult population did not statistically adjust for some of the key potential confounding variables and a few items of the quality assessment tools were not reported across studies, especially the presence or absence of researchers blinding on case/control status of participants. The mean NHLBI cumulative score for the 5 case-control studies was 7.2 (SD: 0.84) and for the 2 cohort studies was 8.5 (SD: 0.71).
Discussion Acute appendicitis affects approximately 100 per 100.000 of the general population per year and the lifetime risk is estimated to be 7e8%.1,2 Patients are usually in their second or third decade of life and a slightly increased incidence is observed in males compared to females.2 Despite being one of the most common surgical emergencies, acute appendicitis diagnosis is still a cause of diagnostic dilemma and frequently presents with atypical symptoms and as a mimicker of other conditions with overlapping clinical features.24 Clinical and laboratory findings have been combined in the form of appendicitis clinical risk evaluation scores (Alvarado score, appendicitis inflammatory response score eAIR, RIPASA score) in order to adequately stratify risk and guide further investigation and interventions.2,25 The appendicitis clinical risk scores provide good overall sensitivity, but specificity and thus the ability of confirming the presence of acute appendicitis is considered unreliable.2,24,25 Improved diagnostic accuracy has been achieved with the establishment of imaging tests, such as ultrasound (US), CT and magnetic resonance imaging (MRI).2,24 CT widespread use is associated with increased exposure to ionizing radiation, which increases the long-term risk of malignant neoplasms occurrence.24,26 An alternative approach, in order to avoid
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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Table 3 e Quality assessment of case-control studies with NHLBI quality assessment tool. NHLBI Quality Assessment of Case-Control Studies
Kaser Kim (2015) Pham (2016) Serradilla Besli (2019) (2013) (2018)
1. Was the research question or objective in this paper clearly stated and appropriate? 2. Was the study population clearly specified and defined? 3. Did the authors include a sample size justification? 4. Were controls selected or recruited from the same or similar population that gave rise to the cases (including the same timeframe)? 5. Were the definitions, inclusion and exclusion criteria, algorithms or processes used to identify or select cases and controls valid, reliable, and implemented consistently across all study participants? 6. Were the cases clearly defined and differentiated from controls? 7. If less than 100 percent of eligible cases and/or controls were selected for the study, were the cases and/or controls randomly selected from those eligible? 8. Was there use of concurrent controls? 9. Were the investigators able to confirm that the exposure/risk occurred prior to the development of the condition or event that defined a participant as a case? 10. Were the measures of exposure/risk clearly defined, valid, reliable, and implemented consistently (including the same time period) across all study participants? 11. Were the assessors of exposure/risk blinded to the case or control status of participants? 12. Were key potential confounding variables measured and adjusted statistically in the analyses? If matching was used, did the investigators account for matching during study analysis? Total score % Rating
Yes
Yes
Yes
Yes
Yes
Yes No Yes
Yes No Yes
Yes No Yes
No No Yes
Yes No Yes
Yes
Yes
Yes
NR
Yes
Yes No
Yes NA
Yes No
Yes NR
Yes NA
Yes No
Yes No
Yes No
Yes No
Yes No
Yes
Yes
Yes
Yes
Yes
NR
NR
NR
NR
NR
No
No
Yes
Yes
Yes
7 (58%) Fair
7 (58%) Fair
8 (67%) Good
6 (50%) Fair
8 (67%) Good
NR: not reported. NA: not applicable.
unnecessary radiation exposure, is to perform US initially and only in cases of negative or uncertain results to proceed to CT.24 Leeuwenburgh et al. compared MRI versus US combined with conditional use of CT and reported similar results between the two approaches in the detection of perforated appendicitis.27 Nevertheless, both diagnostic methods misdiagnosed almost half (43% for MRI and 52% for US þ conditional CT) of the patients with perforated appendicitis.27 The aforementioned disadvantages and limitations of currently established diagnostic tests mandate the need of newer diagnostic modalities, especially in the case of complicated appendicitis suspicion. Hyponatremia has been previously associated with increased mortality in necrotizing soft-tissue infections,28 gangrenous cholecystitis29 as well as ischemic bowel in patients presenting with a mechanical small bowel obstruction.30 Alsaleh et al. in their systematic review identified hyponatremia as a significant and potential clinically relevant indicator of anastomotic leakage in patients undergoing colorectal surgery.31 In addition, preoperative hyponatremia has been found to be a predictor of 30-day perioperative morbidity and mortality.19 Swart R.M. et al. suggest the nonosmotic release of antidiuretic hormone, mediated by the production of proinflammatory cytokines such as interleukins IL-1b and IL-6, being involved in the development of hyponatremia in severe inflammatory reactions.21 Circulating
cytokines crossing the blood-brain barrier act on neurons originating in the supraoptic and paraventricular nucleus and transduce their signal through activation of Janus tyrosine kinases (JAK) and their associated transcription factors, the so-called signal transducer and activator of transcription (STAT) family.21,31,32 Subsequently, cytokine mediated nonosmotic ADH secretion results in increased free water reabsorption in the kidney tubules and dilutional hyponatremia.21,31,32 Our review identified in total 7 studies associating hyponatremia and complicated appendicitis, but only 4 of them had statistically significant results (Table 1). Despite being retrospective, the adult population study by Kim et al. had the largest sample size (1550 patients) and reported a significant association in multiple logistic regression analysis (OR ¼ 2.8, 95% CI: 2.1e3.8, p < 0.001).14 The diagnostic accuracy study in a children population by Lindestam et al., rated as good in quality assessment by the NHLBI tool (Table 4), reported a strong association and was the only study to prospectively evaluate the relative risk of perforation in children patients with hyponatremia (RR ¼ 15 (95%CI:3.7e62)).16 The presence of hyponatremia at admission may act as an accessory marker helping surgeons and emergency medicine physicians in the earlier diagnosis and clinical management of complicated appendicitis. Based on these data, in a patient with suspected appendicitis and a serum sodium level equal to or less than
Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002
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Table 4 e Quality Assessment of cohort studies with NHLBI Quality Assessment Tool. NHLBI Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies
Wu (2013)
1. 2. 3. 4.
Was the research question or objective in this paper clearly stated? Was the study population clearly specified and defined? Was the participation rate of eligible persons at least 50%? Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? 5. Was a sample size justification, power description, or variance and effect estimates provided? 6. For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? 7. Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? 8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)? 9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 10. Was the exposure(s) assessed more than once over time? 11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 12. Were the outcome assessors blinded to the exposure status of participants? 13. Was loss to follow-up after baseline 20% or less? 14. Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? Total score % Rating
Lindestam (2019)
Yes Yes NR Yes
Yes Yes No Yes
No
Yes
NR
Yes
Yes
Yes
NA
NA
Yes
Yes
NA Yes
NA YES
NR Yes Yes
NR NA Yes
8 (57%) Fair
9 (64%) Good
NR: not reported. NA: not applicable.
136 mEq/L one should have the possibility of complicated appendicitis in their differential. Our findings should be considered carefully and the quality of the included studies should be taken in to account. Furthermore, additional limitations should be acknowledged during the interpretation of our study results. Missing data as well as relatively small sample sizes included in the adult € ser et al.12 and Wu et al.18 should be population studies by Ka considered as a factor affecting the power of the study and thus the identification of hyponatremia and complicated appendicitis association. In addition, discrepancies in the cutoff definition of hyponatremia between studies may affect the generalizability of findings (Table 1, Table 2). Hyponatremia was defined as plasma sodium concentration <135 mEq/L in 4 studies,14,15,17,18 whereas 3 studies defined hyponatremia at a level of 135 mEq/L,13 136 mEq/l16 or <136 mEq/L.12 We propose that any future studies should use the ‘cut-off’ of <135 mEq/L in accordance with the generally accepted lowest limit of normal serum sodium concentration of 135 mEq/L.33,34 In addition, the identified studies only investigated the association of hyponatremia with macroscopic pathological changes. No effort was made to further evaluate the association between hyponatremia severity and histopathological changes. Finally, by the time hyponatremia result is obtained, other blood or imaging diagnostic modalities could indicate the presence of severe appendicitis and thus limit the usefulness of this marker. An alternate approach would include hyponatremia as one of the parameters of models that utilize inflammation markers (WBC count and type) and clinical
signs in order to diagnose or predict the development of complicated appendicitis. In summary, future well-designed prospective diagnostic accuracy studies are required to further elucidate and establish the connection between hyponatremia and perforated appendicitis. Nevertheless, we propose that the admission serum sodium level measurement, an easily and routinely performed, low-cost test, should be taken into account in patients with clinical presentation compatible with acute appendicitis and suspicion of underlying complications.
Conflict of interest None.
Funding sources and support This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Please cite this article as: Giannis D et al., Hyponatremia as a marker of complicated appendicitis: A systematic review, The Surgeon, https://doi.org/10.1016/j.surge.2020.01.002