Diagnostic value of an initial C-reactive protein level in acute

surgical patientsans_5668 52..55

Keith Wong,* Yasin Shahab* and P. Grantley Gill†*University of Adelaide, South Australia†Breast Endocrine and Surgical Oncology Unit, Royal Adelaide Hospital, and Department of Surgery, University of Adelaide, South Australia, Australia

Key words

CRP, diagnostic, emergency, surgical, outcomes.

Correspondence

Dr Keith Wong, 14A Saturn Crescent, Modbury North,SA 5092, Australia. Email: keithywong@gmail.com

K. Wong MB BS; Y. Shahab MB BS; P. G. Gill MD,FRACS.

Keith Wong is not a scholarship recipient.

This paper is not based on a previous communication toa society or meeting.

Accepted for publication 29 December 2010.

doi: 10.1111/j.1445-2197.2011.05668.x

Abstract

Background: In surgical patients, C-reactive protein (CRP) levels are often measuredas a marker of inflammation and infection. However, the diagnostic and prognosticvalue of a single initial CRP measurement in the acute presentation has not been wellestablished. This study was performed to investigate the usefulness of measuring CRPin such a setting.Methods: CRP levels were measured retrospectively in 473 surgical patients whopresented to the Royal Adelaide Hospital emergency department. This was correlatedwith patient outcomes, defined by the need for imaging tests and/or surgical interven-tions, the length of hospital stay and 30-day mortality. Spearman’s rank correlationand one-way analysis of variance were used for statistical analysis.Results: Of 473 patients, 42% had a CRP test in the emergency department within24 h of admission. Approximately 80% of patients required imaging for diagnosis and40% required surgery, regardless of the initial CRP level. No correlation was evidentbetween initial CRP level and length of hospital stay (r = 0.06). One-way analysis ofvariance revealed no variation in levels between patients who required imaging or hadsurgery compared to those who did not, with P-values of 0.76 and 0.85, respectively.Two patients died within 30 days of presentation.Conclusions: CRP has poor diagnostic and prognostic capabilities as a single initialmeasurement in acute surgical patients. The statistical analyses imply that CRP levelsare unable to accurately predict outcomes of such patients. Therefore, we suggest thatCRP should not be used as a routine screening tool.

Introduction

C-reactive protein (CRP) is a plasma protein that plays a role ininflammation and the acute-phase innate immune response. Anelevated serum level indicates active inflammation or infection.1

Since the mid-1990s, the measurement of serum CRP levels hasbeen used increasingly in clinical practice. Its use as an inflamma-tory marker, albeit not diagnostic, has been known to assist in man-agement when used in conjunction with clinical findings and otherinvestigations.1 As such, it is regularly used in hospitals around theworld as a routine test to evaluate patients with acute presentations.

Many studies have shown that serum CRP levels correspond to thedegree of inflammation and, in turn, the severity of the illness. CRPis useful as a prognostic indicator or an index of diseaseprogression.1–5 This is valuable in monitoring patients with known

inflammatory diseases, for example, measuring the disease activityin a patient with Crohn’s disease.6 However, the diagnostic andprognostic capabilities of serum CRP levels have been lessadequately studied in an acute setting, and its use in such situationsis not established.

In the acute presentation with acute illness, appropriate imaging isthe standard diagnostic investigation for the majority of surgicaldiseases. Consequently, using a single initial serum CRP measure-ment as part of the routine screening test in the work-up of acutesurgical patients could place an unnecessary financial burden onhospitals, whose resources could be better channelled into utilizingother diagnostic instruments. This study is a retrospective review ofthe use of a single initial serum CRP measurement in undiagnosedsurgical patients who presented acutely to a teaching hospital, and ofits value as a diagnostic and prognostic tool in these patients.

ORIGINAL ARTICLEANZJSurg.com

© 2011 The AuthorsANZ Journal of Surgery © 2011 Royal Australasian College of SurgeonsANZ J Surg 82 (2012) 52–55

Methods

Study design

A retrospective study was conducted in the Royal Adelaide Hospital,a major metropolitan hospital in South Australia. Data were col-lected with the approval of the local ethics committee.

Patient selection

A consecutive series of 473 adults (�18 years of age) who presentedbetween May 2010 and September 2010 to the emergency depart-ment (ED) of the Royal Adelaide Hospital, were initially triaged bythe ED medical officers and subsequently transferred to the AcuteSurgical Unit were selected. The Acute Surgical Unit functions as aspecialized referral service for all patients who present with anactive surgical problem. These patients were then assessed again bythe on-call surgical team and then transferred to the appropriatesurgical specialty unit for further management (such as colorectal orhepatobiliary). Thus, our study population included patients withactive surgical problems in the acute setting.

Data

Data collected from the medical records of the patients were asfollows: age, gender, serum CRP levels and white cell counts (WCC)performed within 24 h of presentation, any imaging test performedwithin 72 h of presentation, any surgical intervention performedduring admission, a past history of chronic inflammatory conditions,diagnosis made during the current admission, length of hospital stayand 30-day mortality. Imaging tests referred to X-rays, ultrasoundscans, computed tomography scans, magnetic resonance imagingscans, positron-emission tomography scans, radioactive isotopescans, endoscopies and colonoscopies. Patient outcomes were mea-sured on the basis of whether they had an imaging test performedwithin 72 h of presentation, whether they had a surgical intervention,their length of hospital stay and 30-day mortality.

Laboratory tests

All serum CRP levels and WCC were measured at the Institute ofMedical and Veterinarian Sciences, South Australia, using immuno-turbidimetry. The measurements were performed within 3 h ofobtaining the blood samples.

Statistical analysis

CRP was analysed as a continuous parameter and binary variable. ACRP level of �8 mg/L and a WCC of �11 ¥ 106/L were identified asbeing elevated. The association between CRP and patient outcomeswas analysed either through direct comparison using bar graphs orutilizing the Spearman’s rank correlation test and one-way analysisof variance.

Not all patients had CRP tested on admission. The decision toperform a serum CRP test was at the discretion of the ED doctor or thesurgical team who admitted the patient. The criteria that the medicalofficers used to decide which patients required a CRP test is unknownto us. It was likely to involve multiple factors, which included clinicalsigns and symptoms of active infection or inflammation, and/or asuspected differential diagnosis of an inflammatory condition. Thus,

the distribution of CRP levels plotted from our data may not accu-rately represent the actual distribution in the community.

Ethics

Low-level ethics clearance was granted by the local ethics commit-tee (SA Health Research Ethics Committee). All patient data werede-identified, and strict confidentiality was maintained on the datacollected.

Results

A total of 473 patients were included in the study. Two hundred andthree patients had CRP levels measured within the first 24 h ofpresentation, which represented 42.9% of all patients. One hundredand forty-four of them were found to have an elevated CRP (71%),while 59 of them had normal CRP (29%). Interestingly, only 52% ofpatients with a raised CRP had a raised WCC concurrently. Figure 1shows the distribution of CRP levels from the data collected, with amean of 52.5 mg/L and a standard deviation of 73.0 mg/L.

In total, 382 patients had further imaging tests performed within72 h of presentation. Of this group of patients, 117 had an elevatedCRP, 49 had a normal CRP, and 216 did not have CRP tested.Furthermore, 189 patients, which represented 40.0% of the patientpopulation, underwent a surgical intervention during their admis-sion. Of these, 77 had CRP tested, of which 54 had elevated CRPlevels, and 112 did not have CRP measured. Moreover, when using50 mg/L as criteria for defining an elevated CRP level, 64 patientsmet these criteria of having an elevated CRP level, of which 54 hadimaging tests and 25 had surgery. Table 1 shows the percentages ofpatients from each category (i.e. whether they had CRP tested or not,and whether it was elevated or not), who then proceeded to haveimaging tests and/or surgery.

Among all patients who had CRP levels tested, the median CRPlevel was 52.4 mg/L. The median level for patients who did not havefurther imaging was 55.5 mg/L, while it was 52.0 mg/L for thosewho did. The median level for patients who had surgery was52.8 mg/L, while it was 51.8 mg/L for patients who did not havesurgery. Analysing variance in the distribution of CRP levels inpatients who required imaging and/or surgical intervention com-pared to those who did not was accomplished with a one-way analy-sis of variance test. The F-statistic was 0.91 and P-value was 0.76when comparing CRP levels between patients who did and did notrequire imaging. The F-statistic was 0.36 and P-value was 0.85when comparing CRP levels between patients who did and did notrequire surgery. These analyses revealed no differences in CRPlevels in the patients regardless of whether or not they requiredfurther imaging and/or surgery.

The mean length of hospital stay was 5 days. Figure 2 shows ascatter plot comparing CRP levels and the length of hospital stay.When utilizing the Spearman’s rank correlation test to compare CRPlevels and the length of hospital stay, the Spearman correlationcoefficient was r = 0.06, implying that there is very little correlationbetween CRP levels and a patient’s length of hospital stay.

Two patients died within 30 days of presentation. One passedaway from multi-organ failure within 24 h of presentation, and theother one passed away shortly after admission from multiple trauma

Use of CRP in acute surgical patients 53

© 2011 The AuthorsANZ Journal of Surgery © 2011 Royal Australasian College of Surgeons

injuries sustained from a motor vehicle accident. The former had araised CRP level, and the latter did not have CRP performed. Analy-sis of 30-day mortality as an outcome did not yield significant resultsdue to too few events.

Discussion

From the data above, there appears to be very little correlationbetween a single initial serum CRP measurement for an acute sur-gical patient presenting to the ED, and the outcomes of thatpatient. As observed in Table 1, around 80% of patients requiredfurther imaging, regardless of whether they had a CRP measure-ment or if the result was elevated, and approximately 40% patientsrequired a surgical intervention during their admission, againregardless of CRP levels. Moreover, these proportions remainedthe same even when using a higher value of 50 mg/L to define anelevated CRP level. Therefore, this reflects the low diagnostic andprognostic value of an initial CRP level. Furthermore, amongpatients who had CRP testing, no variation was present betweenthe CRP levels of patients who required imaging and surgery as

compared to those who did not (P-values 0.76 and 0.85, respec-tively). This implied that the actual CRP value was a poor predic-tor of whether the person required further imaging or surgicalintervention. Moreover, the low correlation between an initial CRPlevel and the length of hospital stay (Spearman’s rank correlationcoefficient of 0.06) demonstrated that a single initial CRP mea-surement could not predict morbidity.

Measurement of serum CRP levels is a routine investigation that isoften used as a screening tool in many hospitals. The marker is oftenused in the emergency setting to aid in the diagnosis of certainsurgical conditions. It is especially useful in excluding appendicitisin patients presenting with acute abdominal pain, as studies havefound that CRP has extremely high negative predictive value for

Fig. 1. Distribution of C-reactiveprotein (CRP) levels, in mg/L. Line isline of best fit on a normal distribution.

Table 1 Percentages of patients from each category who had imagingtests and/or surgery

Patient category Had imagingtests (%)

Had surgicalintervention (%)

All patients (n = 473) 81 40CRP measured (n = 203) 81 38CRP not measured (n = 270) 80 41CRP elevated (n = 144) 81 38CRP normal (n = 59) 83 39CRP above 50 mg/L (n = 64) 84 39

CRP, C-reactive protein.

Fig. 2. Scatter plot showing correlation between length of hospital stay(days) and C-reactive protein (CRP) levels. Spearman’s rank correlationcoefficient r = 0.06. No line of best fit was acceptable.

54 Wong et al.

© 2011 The AuthorsANZ Journal of Surgery © 2011 Royal Australasian College of Surgeons

appendicitis when combined with a normal WCC measurement inthese patients.2,3 Actual CRP levels, however, cannot accuratelypredict whether these patients will be treated operatively or non-operatively.6

CRP measurement is also valuable as a prognostic indicator inpost-operative surgical patients. Significantly elevated CRP levelshave been found to be associated with severe bacterial infections,malignant disease and high 30-day mortality rates.7 A preoperativeelevated CRP level has been shown to indicate increased risk ofpost-operative complications associated with cardiac surgery, col-orectal surgery and major abdominal surgery.4,5,8 Another study byKeshet et al. found that higher levels of CRP were associated withmortality, the need for intubation and longer hospitalization.9 Fur-thermore, raised CRP levels were associated with the developmentof surgical complications after fracture surgery, such as thrombosis,re-fracture or deep-wound infection.10

However, CRP has been found to be useful only when conductedas part of a serial measurement.11 After major surgery, CRP levelsrise post-operatively and peak on day 2, reflecting the organ traumaand inflammation caused by the operation.5,10 As such, it is difficultto differentiate infection or surgical trauma as a cause for CRPelevation post-operatively. Thus, serial CRP measurements allow forthe monitoring of aberrant changes in the natural trend of CRP aftersurgery and, in turn, for early detection and aggressive managementof infections and complications after surgery.

As evident from our data, performing a single initial CRP mea-surement in surgical patients in the emergency setting does little toinfluence the clinical assessment, diagnosis and subsequent manage-ment of the patient. Being a non-specific marker of inflammation, itis raised in a plethora of disease states and, thus, has low diagnosticimportance as a single initial test.1 Consequently, regardless of theresults of the test, the majority of acute surgical patients undiag-nosed by clinical acumen will require further investigation in theform of imaging or others. Furthermore, CRP is a poor predictor forwhether or not the patient will require surgical intervention duringtheir admission. Therefore, despite common practice, we suggestthat CRP should not be used as a routine screening tool in surgicalpatients in the emergency setting.

At present, there is insufficient information in the literature aboutthe diagnostic use of CRP in acute surgical patients. This pilot studycan hopefully allow for further studies to investigate into this area inmore detail, further establishing the usefulness of CRP in the diag-nosis and prognosis of these patients. Studies can also explore

current practices regarding CRP use in surgical patients in the emer-gency setting, for example, among the emergency staff compared tothe surgical registrars, when dealing with such patients. Another areathat might require investigation is the comparison between CRP andWCC levels and their value in the diagnosis of acute surgicalpatients. Perhaps, with sufficient data, guidelines can be drawn up asto which patients are suitable for an initial CRP investigation duringan acute presentation, such as in cases of acute abdominal pain torule out appendicitis.

References1. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J. Clin.

Invest. 2003; 111: 1805–12.2. Sengupta A, Bax G, Paterson-Brown S. White cell count and C-reactive

protein measurement in patients with possible appendicitis. Ann. R. Coll.Surg. Engl. 2009; 91: 113–5.

3. Woeste G, Muller C, Bechstein WO, Wullstein C. Increased serum levelsof C-reactive protein precede anastomotic leakage in colorectal surgery.World J. Surg. 2010; 34: 140–6.

4. Gronroos JM, Gronroos P. Leucocyte count and C-reactive protein in thediagnosis of acute appendicitis. Br. J. Surg. 1999; 86: 501–4.

5. Cole DS, Watts A, Scott-Coombes D, Avades T. Clinical utility orperi-operative C-reactive protein testing in general surgery. Ann. R. Coll.Surg. Engl. 2008; 90: 317–21.

6. Salem TA, Molloy RG, O’Dwyer PJ. Prospective study on the role ofC-reactive protein (CRP) in patients with an acute abdomen. Ann. R.Coll. Surg. Engl. 2007; 89: 233–7.

7. Chundadze T, Steinvil A, Finn T et al. Significantly elevated C-reactiveprotein serum levels are associated with very high 30-day mortality ratesin hospitalized medical patients. Clin. Biochem. 2010; 43 (13–14):1060–3.

8. Fransen EJ, Maessen JG, Elenbaas TW, van Aarnhem EE, van Dieijen-Visser MP. Enhanced preoperative C-reactive protein plasma levels as arisk factor for postoperative infections after cardiac surgery. Ann.Thorac. Surg. 1999; 67: 134–8.

9. Keshet R, Boursi B, Maoz R, Shnell M, Guzner-Gur H. Diagnostic andprognostic significance of serum C-reactive protein levels in patientsadmitted to the department of medicine. Am. J. Med. Sci. 2009; 337:248–55.

10. Neumaier M, Scherer MA. C-reactive protein levels for early detectionof post-operative infection after fracture surgery in 787 patients. ActaOrthop. 2008; 79: 428–32.

11. Lindberg M, Hole A, Johnsen H et al. Reference intervals for procalci-tonin and C-reactive protein after major abdominal surgery. Scand. J.Clin. Lab. Invest. 2002; 62: 189–94.

Use of CRP in acute surgical patients 55

© 2011 The AuthorsANZ Journal of Surgery © 2011 Royal Australasian College of Surgeons