Evaluation of International Normalized Ratio and C-Reactive

Protein as Predictors for Complicated Appendicitis

AUTHOR - Dr.Barath.K

CO AUTHOR – Dr. Rajan Vaithianathan

AFFLIATION: Department of General Surgery,

Mahatma Gandhi Medical College and Research Institute,
Sri Balaji Vidyapeet,
Pillayarkuppam,
Pondicherry – 607402.

Corresponding Author –

Dr. Rajan Vaithianathan

Professor, Department of General Surgery
Mahatma Gandhi Medical College and Research Institute,
Sri Balaji Vidyapeeth,
Pillayarkuppam,
Pondicherry – 607402.
Email id –57sylvan@gmail.com
Phone - +91 9791353360
ABSTRACT:
BACKGROUND: Acute appendicitis is the most common general surgical cause for
abdomen pain, Complicated appendicitis (CA) can result in increased morbidity and
mortality. In this study we have aimed to identify whether if clinical and laboratory
parameters ae helpful in identifying CA earlier, thereby conservative approach can be
deferred and patient can be taken up for surgery earlier.
MATERIAL AND METHODS: This study was a prospective observational single centre
study wherein 116 patients undergoing emergency appendicectomy whose preoperative
clinical findings, laboratory reports and ultrasound findings were studied to reliably predict
complicated appendicitis.
RESULTS: Out of 116 patients, 37 patients had complicated appendicitis and 79 patients had
uncomplicated appendicitis. Preoperative INR and CRP was elevated in association with
complicated appendicitis. Area under curve from receiver operating curve analysis of INR
and CRP are 0.82 and 0.59 respectively.
CONCLUSION: Preoperative INR and CRP were raised significantly in patients with
complicated appendicitis which predicts complicated appendicitis. Therefore, surgeons can
plan early surgical intervention to prevent post-operative complications.

INTRODUCTION
Acute appendicitis is the most common diagnosis in the emergency department requiring
surgical intervention.1,2Appendicectomy is performed on an emergency basis but the
postoperative complications can occur in about 50% of patients ranging from surgical site
infection to intra-abdominal abscess.3–5
Complicated appendicitisis defined by the presence of perforation, gangrene or abscess
intraoperatively.6 Uncomplicated appendicitisincludes patients without the above findings.2,6

Any delay in the diagnosis of complicated appendicitis leads to an elevated mortality and
morbidity rate. Thus it is imperative to find reliable parameters to predict CA.7–9
When an appendicitis is diagnosed it is always a challenge to rule out complicated
appendicitis, hence the role of predictors came as an important tool in helping to overcome
this obstacle.Initially, single laboratory marker like WCC or bilirubin was used but and found
not reliable. Several studies followed employing a combination of White Cell Count (WCC),
C-Reactive Protein(CRP), bilirubin and International normalized ratio (INR) established the
reliability of these parameters in predicting complicated appendicitis.9–12Several scoring
systems using clinical, laboratory and ultrasound findings have been developedto achieve an
accurate diagnosis of CA.13
We aimed to establish the correlation between elevated levels of INR and CRP in
complicated appendicitis. Also our study investigated the role of these parameters in selecting
patients suitable for conservative management.
SUBJECTS AND METHODS
This prospective study was carried out in the Department of General Surgery, in a
tertiary care teaching hospital. Ethics approval obtained from the Institutional Human Ethics
Committee (IHEC/2017/02/13). In total, 116 patients above 14 years who had undergone
emergency appendicectomyfrom February 2017 to June 2018 were included in the study.
Patients were evaluated with laboratory investigations including WCC, CRP, INR and
ultrasound abdomen following which emergency appendicectomy was performed. Informed
consent was obtained from patients. We excluded patients below 14 years of age, the
 immunocompromised, presence of inflammatory diseases and also who underwent elective
appendicectomy. Normal and cut off values for the studied parameters were standardised by
the pathology laboratory services. Normal value for INR was defined as less than or equal
to 1. The CRP was taken as elevated if it was detectable in the serum sample.
Data collected was entered in Microsoft Excel spreadsheet. Continuous variables were
summarized as mean (SD) and categorical variables were presented as percentages. Statistical
analysis carried out using SPSS(Statistical Package for the Social Sciences) version
....Receiver Operating characteristics(ROC) and Area under the curve (AUC) was calculated
for different parameters for predicting the outcome. Association of baseline characteristics
with outcome was assessed using Chi square test and a p value less than 0.05 was considered
as statistically significant.

RESULTS

Out of the 116 patients included in analysis, 63(54%) were females and 53(46%) were
males. The mean age of the study group was 26.2 years. Most of the patients(80.2%) in our
study were febrile on presentation how many had complic. Among ....patients with tachy,
71(90%) had uncomplicated appendicitis.
Emergency appendicectomy was done in all the included patients and operative findings
confirmed complicated appendicitis in 37(31.9%) patients and uncomplicated appendicitis in
the remaining 79(78.1%) patients(Table1). The sensitivity and specificity of the parameters
are listed in Table 2.

Table 1: Characteristics and analysis of patients according to intraoperative findings

Complicated appendicitis (n=37) Uncomplicated Appendicitis (n=79) p value

Gender 21 (56.8) 42 (53.2)

Male
0.71
16 (43.2) 37 (46.9)
Female
Afebrile 12 (32.2) 68 (86.1)
Temperature 0.02
Febrile 25 (67.8) 11 (13.9)

Heart Rate <100 14 (37.8) 71 (89.9)

(beats/minute) <0.001
>100 23 (62.2) 8 (10.1)

WCC (cell/cumm) <11000 11 (29.7%) 36 (45.6%)

0.068
>11000 26 (70.3%) 43 (54.4%)

INR <1.2 8 (21.6) 52 (65.8)

<0.001
>1.2 29 (78.4) 27 (34.2)

CRP (mg/L)
Negative 12 (32.4) 41 (51.9)
0.05
Positive 25 (67.6) 38 (48.1)
 Table 2: Sensitivity, Specificity for parameters in complicated appendicitis

Parameter Sensitivity (%) Specificity (%)

C-reactive protein (>2.6 mg/L) 54.1 79.8

INR (>1.2) 67.6 74.7
Prothrombin (>16.2 seconds) 64.9 74.7
Heart rate (≥100 beats/minute) 37.8 91.1

ROC curve analysis was done as in Figure 1 with AUC maximum for INR with a value of
0.82, for heart rate 0.7 followed by CRP (0.67) and temperature (0.58) at presentation. These
parameters were useful in reliably predicting complicated appendicitis preoperatively.

Figure 1: Area under curve from receiver operating curve analysis of each parameter

DISCUSSION
Acute appendicitis is the most common medical emergency needing urgent surgical
intervention in the form of appendicectomy .The incidence of appendicitis is 22.71 per 1000
population per year, appendicectomy is 13.56 per 1000 population per year, of which
perforated appendicitis is 2.91 per 1000 population per year.14 However, recently many
studies have created a debate regarding conservative approach versus operative intervention
in acute appendicitis.15
 Management of uncomplicated appendicitis involves conservative treatment with
antibiotics whereas patients with complicated type as in perforation or gangrenous
appendicitis will definitely require a lifesaving surgical intervention.4,15 Timely operative
intervention in such cases is of paramount importance to improve post-operative outcomes
and reduction in morbidities. Heart rate was an important parameter studied in our group and
tachycardia was a significant finding noted in those diagnosed with complicated appendicitis.
However, multiple studies have established tachycardia as a common finding among patients
with acute appendicitis.16,19

The laboratory investigations that were used for analysis in our study were WCC, INR and
CRP. We noted that significant proportion(70%) of patients with complicated appendicitis
had elevated (>11000) leukocyte count similar to a study done by Sahbaz et al.22
Many studies have reported varying significance of different lab markers to predict
complicated appendicitis with conflicting results.23–26We have incorporated clinical
parameters like temperature, HR and lab markers like WCC, INR and CRP to enable accurate
prediction of complicated appendicitis. The rational for using INR and CRP in acute
inflammatory conditions have been established in existing literature.
The pathogenesis of raised INR in complicated appendicitis is due to a cascade of events
during severe systemic infection or inflammatory process.10
CRP is an acute phase pentraxin protein combines with the pathogens to activate the
complement system which in-turns initiates the destruction of the causative pathogen. When
there is such systemic inflammation, injury or apoptosis occurring in various aetiologies,
there is sudden 1000 fold increase in CRP.27
CRP has a half-life of about 19 hours and due its abundant increase it is used as an
indicator for acute inflammatory process. Many studies have quoted CRP as a useful adjunct
marker in assessing the severity of acute appendicitis.26,28–31 Out of the 37 patients with
complicated appendicitis, 29(78.4%) had raised INR value with a significant P- value of
<0.001 in association with high relative risk [ 95% confidence interval 0.82 (0.74 - 0.90)].

When CRP levels were used, we found that 25(67.6%) out of 37 patients with
complicated appendicitis had significantly raised CRP levels (P value – 0.05) .Similar results
have been reported in multiple studies.10,26,29 The confirmation of acute appendicitis was
established by ultrasound in 96 patients (82.8%) out of 116 patients. However, studies have
shown that ultrasound cannot reliably distinguish CA from uncomplicated appendicitis as it is
user defined modality 32. Hence there is a need for laboratory parameters like INR, CRP,
procalcitonin and mean platelet volume in predicting complicated appendicitis.10,24,26
In our study, intraoperative findings were considered as the defining standard in
differentiating CA from UCA. Hence, the prediction ability of INR and CRP were calculated
by ROC analysis using intraoperative findings. Out of 116 cases, 37 cases had features of
perforation, gangrene or abscess formation confirming complicated appendicitis.

ROC curve analysis was performed to evaluate the predictive ability of the clinical
and lab parameters included in our study. AUC of INR, HR, CRP was 0.82,0.70,0.67
respectively, clearly demonstrating their feasibility as predictors of complicated appendicitis.
However, AUCs for WCC (0.59) and temperature (0.58) were comparatively lesser than that
of INR and CRP, hence these parameters may not be useful in predicting CA. Sahbaz et al
had also identified that WCC lacked the ability to predict complicated appendicitis which is
similar to our observations.22 With regard to temperature as a predictor, Lietzén et al had
already shown that it may not be a significant parameter in identifying patients with CA.18
Data published in the available literature till date has revealed that parameters in isolation
may not be reliable predictors for CA. However, combination of these variables is more
likely to be significant in predicting CA.9,10,29
We have noted in this study that presence of tachycardia along with raised INR and
CRP may prove to be more effective markers for accurately identifying patients with CA,
thus facilitating immediate surgical intervention and better postoperative outcomes.
An early and accurate prediction of CA and the subsequent surgical intervention will create
an ideal environment for implementing an Enhanced Recovery after Surgery (ERAS)
protocol in the surgical care pathway. This may lead to a substantial improvement in both
health and economic benefits.33–35

There were few limitations in our study. Our sample size was relatively small.Few of
patients got operated on the following day due to logistic reasons which would have led to
mismatch in the intra-operative finding. Correlation of studied parameters and post-operative
complications was not part of our study.

CONCLUSIONS
INR and CRP were helpful predictors in predicting complicated appendicitis. Addition of
INR and CRP helps in diagnosing complicated appendicitis thus precluding unnecessary
CECT or MRI which leads to delay in initiation of treatment.Combination of parameters
INR, CRP, heart rate will help in implementing the ERAS protocol in managing complicated
appendicitis Early initiation of effective antibiotics can be made in patients with elevated
predictors for complicated appendicitis.

REFERENCES
1. Zinner M, Ashley SW, Maingot R. Maingot’s abdominal operations [Internet]. 2013
[cited 2018 Oct 21]. Available from:
http://www.accesssurgery.com/resourceToc.aspx?resourceID=802

2. Sabiston DC, Townsend CM, Beauchamp RD, Evers BM, Mattox KL, editors. Sabiston
textbook of surgery: the biological basis of modern surgical practic. 20th edition.
Philadelphia, PA: Elsevier; 2017. 2146 p.

3. Pieper R, Kager L, Näsman P. Acute appendicitis: a clinical study of 1018 cases of

emergency appendectomy. Acta Chir Scand. 1982;148(1):51–62.

4. Deutsch AA, Shani N, Reiss R. Are some some appendectomies unnecessary? An

analysis of 319 white appendices. J R Coll Surg Edinb. 1983 Jan;28(1):35–40.

5. Noorit P, Siribumrungwong B, Thakkinstian A. Clinical prediction score for superficial

surgical site infection after appendectomy in adults with complicated appendicitis.
World J Emerg Surg. 2018;13:23.

6. Atema JJ, van Rossem CC, Leeuwenburgh MM, Stoker J, Boermeester MA. Scoring
system to distinguish uncomplicated from complicated acute appendicitis. British
Journal of Surgery. 2015 Jul;102(8):979–90.

7. Von Titte SN, McCabe CJ, Ottinger LW. Delayed appendectomy for appendicitis:
causes and consequences. Am J Emerg Med. 1996 Nov;14(7):620–2.
8. Williams RF, Blakely ML, Fischer PE, Streck CJ, Dassinger MS, Gupta H, et al.
Diagnosing Ruptured Appendicitis Preoperatively in Pediatric Patients. Journal of the
American College of Surgeons. 2009 May;208(5):819–25.

9. Jamaluddin M, Hussain SMA, Ahmad H. Hyperbilirubinaemia a predictive factor for

complicated acute appendicitis: a study in a tertiary care hospital. J Pak Med Assoc.
2013;63(11):5.

10. Kim M, Kim S-J, Cho HJ. International normalized ratio and serum C-reactive protein
are feasible markers to predict complicated appendicitis. World Journal of Emergency
Surgery [Internet]. 2016 Dec [cited 2018 Oct 20];11(1). Available from:
http://wjes.biomedcentral.com/articles/10.1186/s13017-016-0081-6

11. Kim TH, Cho BS, Jung JH, Lee MS, Jang JH, Kim CN. Predictive Factors to
Distinguish Between Patients With Noncomplicated Appendicitis and Those With
Complicated Appendicitis. Annals of Coloproctology. 2015;31(5):192.

12. Pham X-BD, Sullins VF, Kim DY, Range B, Kaji AH, de Virgilio CM, et al. Factors
predictive of complicated appendicitis in children. Journal of Surgical Research. 2016
Nov;206(1):62–6.

13. N N. A Comparative Study of RIPASA Score and ALVARADO Score in the Diagnosis
of Acute Appendicitis. JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH
[Internet]. 2014 [cited 2018 Oct 21]; Available from:
http://jcdr.net/article_fulltext.asp?issn=0973-
709x&year=2014&volume=8&issue=11&page=NC03&issn=0973-709x&id=5170

14. Lee JH, Park YS, Choi JS. The Epidemiology of Appendicitis and Appendectomy in
South Korea: National Registry Data. Journal of Epidemiology. 2010;20(2):97–105.

15. Vons C, Barry C, Maitre S, Pautrat K, Leconte M, Costaglioli B, et al. Amoxicillin plus
clavulanic acid versus appendicectomy for treatment of acute uncomplicated
appendicitis: an open-label, non-inferiority, randomised controlled trial. Lancet. 2011
May 7;377(9777):1573–9.

16. Humes DJ, Simpson J. Acute appendicitis. BMJ. 2006 Sep 9;333(7567):530–4.

17. Addiss DG, Shaffer N, Fowler BS, Tauxe RV. The epidemiology of appendicitis and
appendectomy in the United States. Am J Epidemiol. 1990 Nov;132(5):910–25.

18. Lietzén E, Mällinen J, Grönroos JM, Rautio T, Paajanen H, Nordström P, et al. Is

preoperative distinction between complicated and uncomplicated acute appendicitis
feasible without imaging? Surgery. 2016 Sep;160(3):789–95.

19. Thompson JP. Mimickers of Acute Appendicitis. 3(4):12.

20. Tzanakis NE, Efstathiou SP, Danulidis K, Rallis GE, Tsioulos DI, Chatzivasiliou A, et
al. A New Approach to Accurate Diagnosis of Acute Appendicitis. World Journal of
Surgery. 2005 Sep;29(9):1151–6.

21. Kanumba ES, Mabula JB, Rambau P, Chalya PL. Modified Alvarado Scoring System as
a diagnostic tool for Acute Appendicitis at Bugando Medical Centre, Mwanza,
 Tanzania. BMC Surgery [Internet]. 2011 Dec [cited 2018 Oct 21];11(1). Available
from: http://bmcsurg.biomedcentral.com/articles/10.1186/1471-2482-11-4

22. Sahbaz NA, Bat O, Kaya B, Ulukent SC, Ilkgul O, Ozgun MY, et al. The clinical value
of leucocyte count and neutrophil percentage in diagnosing uncomplicated (simple)
appendicitis and predicting complicated appendicitis. Turkish Journal of Trauma and
Emergency Surgery. 2014;20(6):423–6.

23. de Carvalho BR, Diogo-Filho A, Fernandes C, Barra CB. [Leukocyte count, C reactive
protein, alpha-1 acid glycoprotein and erythrocyte sedimentation rate in acute
appendicitis]. Arq Gastroenterol. 2003 Mar;40(1):25–30.

24. Fan Z, Pan J, Zhang Y, Wang Z, Zhu M, Yang B, et al. Mean Platelet Volume and
Platelet Distribution Width as Markers in the Diagnosis of Acute Gangrenous
Appendicitis. Disease Markers. 2015;2015:1–4.

25. Estrada JJ, Petrosyan M, Barnhart J, Tao M, Sohn H, Towfigh S, et al.

Hyperbilirubinemia in Appendicitis: A New Predictor of Perforation. Journal of
Gastrointestinal Surgery. 2007 Jun 11;11(6):714–8.

26. Gavela T, Cabeza B, Serrano A, Casado-Flores J. C-reactive protein and procalcitonin

are predictors of the severity of acute appendicitis in children. Pediatr Emerg Care. 2012
May;28(5):416–9.

27. S C. C - reactive protein: An inflammatory marker with specific role in physiology,

pathology, and diagnosis. Internet Journal of Rheumatology and Clinical Immunology
[Internet]. 2014 Oct 30 [cited 2018 Oct 21];2(S1). Available from:
http://pp.chanrejournals.com/index.php/rheumatology/article/view/117

28. Black S, Kushner I, Samols D. C-reactive Protein. J Biol Chem. 2004 Nov
19;279(47):48487–90.

29. de Dios O, Gavela-Pérez T, Aguado-Roncero P, Pérez-Tejerizo G, Ricote M, González

N, et al. C-reactive protein expression in adipose tissue of children with acute
appendicitis. Pediatric Research [Internet]. 2018 Jul 10 [cited 2018 Oct 20]; Available
from: http://www.nature.com/articles/s41390-018-0091-z

30. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003
Jun;111(12):1805–12.

31. Tillett WS, Francis T, Jr. SEROLOGICAL REACTIONS IN PNEUMONIA WITH A

NON-PROTEIN SOMATIC FRACTION OF PNEUMOCOCCUS. The Journal of
Experimental Medicine. 1930 Sep 30;52(4):561.

32. Malia L, Sturm JJ, Smith SR, Brown RT, Campbell B, Chicaiza H. Diagnostic accuracy
of laboratory and ultrasound findings in patients with a non-visualized appendix. The
American Journal of Emergency Medicine [Internet]. 2018 Aug [cited 2018 Oct 20];
Available from: https://linkinghub.elsevier.com/retrieve/pii/S0735675718306508

33. Lichtner S, Pflanz M. Appendectomy in the Federal Republic of Germany:

Epidemiology and Medical Care Patterns. Medical Care. 1971;9(4):311–30.
34. Li X, Zhang J, Sang L, Zhang W, Chu Z, Li X, et al. Laparoscopic versus conventional
appendectomy - a meta-analysis of randomized controlled trials. BMC Gastroenterology
[Internet]. 2010 Dec [cited 2018 Oct 20];10(1). Available from:
http://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-10-129

35. Melnyk M, Casey RG, Black P, Koupparis AJ. Enhanced recovery after surgery (ERAS)
protocols: Time to change practice? Canadian Urological Association Journal. 2011 Oct
1;342–8.