t h e s u r g e o n 1 8 ( 2 0 2 0 ) 2 9 5 e3 0 4

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
b
Medical School, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece
c
Duke Surgery, Duke University Medical Center, Durham, 27710, NC, USA

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 5 February 2020 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, low-
cost 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.

pathophysiological process involves appendiceal luminal

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 asso-
ciated with significant morbidity (10%) and mortality (1e5%).3
Acute appendicitis severity ranges between mild inflam-
mation to severe gangrene with perforation and local or
widespread intra-abdominal contamination.4 The underlying
obstruction, mainly due to appendicoliths, foreign bodies or
lymphoid hyperplasia, and mucus accumulation-induced
luminal distention and bacterial overgrowth.4,5 Subse-
quently, 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: dimitrisgiannhs@gmail.com (D. Giannis), eva.matenoglou@gmail.com (E. Matenoglou), dimmoris@yahoo.com
(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.

Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en abril 25, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
296 t h e s u r g e o n 1 8 ( 2 0 2 0 ) 2 9 5 e3 0 4
By definition, complicated appendicitis includes perfora-
tion 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, intra-
abdominal abscess) rate and fewer unscheduled read-
missions 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), tachy-
cardia (>100 bpm), markedly elevated CRP (>50 mg/L), leuko-
cytosis (>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 prospec-
tive study in 247 children, including 53 patients with
ruptured appendicitis, reported African American race,
duration of symptoms > 48 h, presence of fecal on comput-
erized 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 (compli-
cated) appendicitis.12e18 Preoperative hyponatremia, a com-
mon 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 in-
volves proinflammatory cytokines such as interleukins IL-1b
and IL-6, milestone mediators of severe inflammatory
response, in the development of hyponatremia through an-
tidiuretic 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.
Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en abril 25, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
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 compre-
hensive literature search was performed independently by
two authors (DG and EM) in Pubmed (Medline), Cochrane Li-
brary, 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 EBS-
COHost, all of the databases were searched by using the
following search algorithm: (hyponatremia OR hypona-
traemia 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'’, “Hypona-
traemia 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 re-
views and articles in PubMed to avoid missing any important
data.
Original human studies investigating the association be-
tween 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 over-
lapping 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 avail-
able 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 charac-
teristics (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
 t h e s u r g e o n 1 8 ( 2 0 2 0 ) 2 9 5 e3 0 4 297

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 e-
mail) are classified as “no data available (NA)”. Any incon-
gruence 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 cumu-
lative 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 con-
sulted 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 (uni-
variate 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

Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en abril 25, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
298 t h e s u r g e o n 1 8 ( 2 0 2 0 ) 2 9 5 e3 0 4

Table 1 e Summary of eligible studies associating hyponatremia and complicated appendicitis in children.
Study Country, Study Population, Age,Sex Condition CA definition Hyponatr
Setting design emia definition

Besli et al., 2019 Turkey; Retrospective Children, Appendicitis Perforated <135 mEq/L
Tertiary case-control N ¼ 403; or gangrenous
care hospital, Age: 11.39 ± 3.58a y; appendix,
Pediatric _:273 (67.7%) generalized
emergency \:130 (32.3) peritonitis,
department and
intra-abdominal
abscess

Lindestam et al., 2019 Sweden; Prospective Children, N ¼ 80; Appendicitis Perforated 136 mEq/L
Tertiary diagnostic Age:1e14 y, appendicitis
care hospital, accuracy study 9.2 (7.3e11.1) y
Pediatric _:53 (66%)
Surgery \:27 (34%)
department

Pham et al., 2016 USA; Retrospective Children, Appendicitis Perforated 135 mEq/L
Tertiary care case-control N ¼ 392; Age 12 or gangrenous
hospital, _:260 (66.3%) appendix,
Pediatric Surgery \:132 (33.7%) an intra-abdominal
department abscess,
or fecal
peritonitis
(intraoperative
finding)
Serradilla et al., 2018 Spain; Retrospective Children, N ¼ 162 Gangrenous Intraabdominal <135 mEq/L
Tertiary care case-control appendicitis abscess
Hospital, Pediatric (postappendectomy)
Surgery department

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 hypona-
tremia.
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

Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en abril 25, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
 t h e s u r g e o n 1 8 ( 2 0 2 0 ) 2 9 5 e3 0 4 299

N (%) N (%) CA Na level N (%) N (%) NCA Na Level Hyponatremia e

CA CA þ NCA NCA þ Na level comparison CA association
Hyponatremia Hyponatremia between statistics
groups
245 62 (25.3%) 136.11 158 (39.2%) 29 (18.4%) 136.96 p ¼ 0.004 Crude OR ¼ 1.51 (95% CI:0.92e2.47);
(60.8%) ±3.03 ±2.54a 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%.
15 13 (86.7%) 134 65 11 (16.9%) 139 p < 0.001 Crude OR ¼ 31.9
(18.8%) (132e136) y (81.2%) (137e140) y (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
179 112 (63%) 134 213 71 (33%) 137 p < 0.01 Crude
(46%) (132e136) y (54%) (135e138) OR ¼ 3.34 (95%CI: 2.21e5.07);
Multivariate logistic regression
OR ¼ 3.1 (95%CI: 2.0e4.9)

54 NA NA 108 NA NA NA Crude OR ¼ 10,

(33.3%) (95%CI: 4.68e21.36), p < 0,001;
Multivariate logistic regression
OR 8.143 (95%CI:
3.551e18.674), p < 0,001

studies with available gender data we observed a male pre-
dominance (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 investi-
gating the role of hyponatremia as a marker of the
presence13,16,17 or development of appendicitis complica-
tions15 in children. In total, 3 out of 4 eligible studies reported
statistically significant results.
In a retrospective case-control study (including 403 chil-
dren) by Besli et al., complicated appendicitis was defined as
the presence of perforation or gangrenous appendix, perito-
nitis 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:

Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en abril 25, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
300 t h e s u r g e o n 1 8 ( 2 0 2 0 ) 2 9 5 e3 0 4

Table 2 e Summary of eligible studies associating hyponatremia and complicated appendicitis in adults.
Study Country, Study Population, Condition Complicated Hyponatremia
Setting design Age,Sex Appendicitis definition
(CA) definition

€ ser et al., 2013

Ka Switzerland; Retrospective Adults, N ¼ 84 Appendicitis Perforated <136 mEq/L
Tertiary case-control (data provided appendicitis
care hospital, only for 82 patients);
Adult Age: >50 years
emergency
department
Kim et al., 2015 USA; Retrospective Adults, N ¼ 1550; Appendicitis Perforated <135 mEq/L
Tertiary case-control Age:>18 y; or gangrenous
care hospital _:980 (63.2%) appendicitis
\:570 (36.8%) (intraoperative finding)

Wu et al., 2013 Taiwan; Retrospective Adults on hemodialysis Appendicitis Perforated appendicitis <135 mEq/L
Tertiary care hospital cohort N ¼ 11 (data provided
only for 10 patients);
Age: 63 ± 20a
_:6 (54.5%)
\:5 (45.5%)

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 hypona-
tremia.
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 Lindes-
tam 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 pro-
vided a sensitivity of 87% (95% CI, 60%e98%) and specificity of
83% (95% CI, 72%e91%) with AUC ¼ 0.93. In addition, hypo-
natremia 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 appen-
dicitis), 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 pre-
operative 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.
Ka€ ser et al. investigated the diagnostic role of hypona-
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 appen-
dicitis), investigated the association between hyponatremia
(Na < 135 mEq/L) and intraoperatively identified perforated or
gangrenous appendicitis and reported significant results on

Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en abril 25, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
 t h e s u r g e o n 1 8 ( 2 0 2 0 ) 2 9 5 e3 0 4 301

N (%) N (%) Na Level N (%) N (%) Na Level Na Level Hyponatremia e

CA CA þ Hyponatr CA (range) NCA NCA þ NCA p value CA association
emia Hyponatr (range) between statistics
emia groups
45 (55%) 13 (29%) NA 37 7 (19%) NA NA Crude OR ¼ 1.74
(45%) (95%CI:0.61e4.95);
Chi-Square
test p ¼ 0.296

409 173 (42.3%) 136 1141 NA 137 p < 0.001 Multiple logistic
(26.4%) (134e137) (73.6%) (136e139) y regression
OR ¼ 2.8
(95%CI:2.1e3.8),
p < 0.001
5 (50%) 2 (40%) NA 5 (50%) 1 (20%) NA NA 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) pa-
tients with acute appendicitis versus non-hemodialysis pa-
tients 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 asso-
ciated 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 cumu-
lative 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 esti-
mated 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 spec-
ificity and thus the ability of confirming the presence of acute
appendicitis is considered unreliable.2,24,25 Improved diag-
nostic 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 in-
creases the long-term risk of malignant neoplasms occur-
rence.24,26 An alternative approach, in order to avoid

Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en abril 25, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
302 t h e s u r g e o n 1 8 ( 2 0 2 0 ) 2 9 5 e3 0 4

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 Yes Yes Yes Yes Yes
paper clearly stated and appropriate?
2. Was the study population clearly specified and defined? Yes Yes Yes No Yes
3. Did the authors include a sample size justification? No No No No No
4. Were controls selected or recruited from the same or similar Yes Yes Yes Yes Yes
population that gave rise to the cases
(including the same timeframe)?
5. Were the definitions, inclusion and exclusion criteria, algorithms Yes Yes Yes NR Yes
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? Yes Yes Yes Yes Yes
7. If less than 100 percent of eligible cases and/or controls were selected for No NA No NR NA
the study, were the cases and/or controls
randomly selected from those eligible?
8. Was there use of concurrent controls? Yes Yes Yes Yes Yes
9. Were the investigators able to confirm that the exposure/risk occurred No No No No No
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, Yes Yes Yes Yes Yes
and implemented consistently
(including the same time period) across all study participants?
11. Were the assessors of exposure/risk blinded to the NR NR NR NR NR
case or control status of participants?
12. Were key potential confounding variables No No Yes Yes Yes
measured and adjusted statistically
in the analyses? If matching was used, did the investigators
account for matching during study analysis?
Total score % 7 (58%) 7 (58%) 8 (67%) 6 (50%) 8 (67%)
Rating Fair Fair Good Fair 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 be-
tween the two approaches in the detection of perforated
appendicitis.27 Nevertheless, both diagnostic methods mis-
diagnosed almost half (43% for MRI and 52% for
US þ conditional CT) of the patients with perforated appen-
dicitis.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 pa-
tients presenting with a mechanical small bowel obstruc-
tion.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 non-
osmotic 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 hypona-
tremia 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 non-
osmotic ADH secretion results in increased free water reab-
sorption in the kidney tubules and dilutional
hyponatremia.21,31,32
Our review identified in total 7 studies associating hypo-
natremia 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

Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en abril 25, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
 t h e s u r g e o n 1 8 ( 2 0 2 0 ) 2 9 5 e3 0 4 303

Table 4 e Quality Assessment of cohort studies with NHLBI Quality Assessment Tool.
NHLBI Quality Assessment Tool for Observational Cohort and Cross-Sectional Wu (2013) Lindestam (2019)
Studies
1. Was the research question or objective in this paper clearly stated? Yes Yes
2. Was the study population clearly specified and defined? Yes Yes
3. Was the participation rate of eligible persons at least 50%? NR No
4. Were all the subjects selected or recruited from the same or similar populations Yes Yes
(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 No Yes
provided?
6. For the analyses in this paper, were the exposure(s) of interest measured prior to the NR Yes
outcome(s) being measured?
7. Was the timeframe sufficient so that one could reasonably expect to see an association Yes Yes
between exposure and outcome if it existed?
8. For exposures that can vary in amount or level, did the study examine different levels NA NA
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, Yes Yes
and implemented consistently across all study participants?
10. Was the exposure(s) assessed more than once over time? NA NA
11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and Yes YES
implemented consistently across all study participants?
12. Were the outcome assessors blinded to the exposure status of participants? NR NR
13. Was loss to follow-up after baseline 20% or less? Yes NA
14. Were key potential confounding variables measured and adjusted statistically for Yes Yes
their impact on the relationship between exposure(s) and outcome(s)?
Total score % 8 (57%) 9 (64%)
Rating Fair 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
population studies by Ka € ser et al.12 and Wu et al.18 should be
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 cut-
off 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 asso-
ciation of hyponatremia with macroscopic pathological
changes. No effort was made to further evaluate the associa-
tion 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 use-
fulness 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 estab-
lish 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.

Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en abril 25, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
304 t h e s u r g e o n 1 8 ( 2 0 2 0 ) 2 9 5 e3 0 4
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.
12. Ka€ ser SA, Furler R, Evequoz DC, Maurer CA. Hyponatremia is
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-apendicectomı́a gangrenada. Un estudio
caso-control. Cir Pediatr 2018;31:4.
16. Lindestam U, Almstro € m M, Jacks J, et al. Low plasma sodium
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/s-
0039-1687870.
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.
Descargado para Anonymous User (n/a) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en abril 25, 2024. Para uso
personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
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/s13304-
019-00627-2.
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.