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Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: meta-analysis of randomised controlled trials

BMJ 2012; 344 doi: (Published 05 April 2012) Cite this as: BMJ 2012;344:e2156

Re: Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: meta-analysis of randomised controlled trials

There is a greater tendency for surgeons to propose less invasive treatments. The meta-analysis published by Varadhan et al[1], provides more evidence to continue this trend for less invasive and more conservative surgical treatments. Varadhan et al[1] offers a detailed and selective meta-analysis, which have made a great effort to select and analyze aspects (e.g. quality and outcomes) than in previous meta-analysis was not performed. Unfortunately there are still many unclear points regarding the surgical versus conservative treatment for uncomplicated acute appendicitis.

The article by Varadhan et al[1] needs to be analyzed taking into account items such as the definition and classification of appendicitis, the applicability to clinical guidelines for diagnosis and treatment, the cost-benefit assessments and applicability to other socio-economic contexts (e.g. developing countries).

A key point in the conclusions of this meta-analysis is the accurate diagnosis of uncomplicated appendicitis. In large part the impact of this meta-analysis will be influenced by this aspect, how to make an accurate diagnosis in a case of uncomplicated acute appendicitis? And this is necessary in order to define the clinical stage of the disease and the possible implementation of antibiotic therapy instead surgery.

Unfortunately this is not easy to do and in this published study, Varadhan et al mentions that diagnostic tools such as computed tomography (CT) and diagnostic laparoscopy more and more will help to achieve better diagnosis, while this is true, perhaps this could not be applied in many cases. Based on a CT scan to confirm the diagnosis will imply the need to think about the risks with respect to generalize the use of this imaging study, which although this is not an invasive test, is not risks free (such studies have been reported the possible effects of CT scan radiation on cancer [2]) Generalizing CT scan, also bring another problem, the medical costs, more important if we consider that there are hospitals in developing countries where are not available CT scan. Vons et al [3] in their clinical trial presented as an inclusion criteria that all patients need to count with a diagnosis of uncomplicated acute appendicitis by CT scan, which becomes inapplicable in many hospitals worldwide. Another diagnostic tool that suggests Varadhan et al [1], is the diagnostic laparoscopy, in which case the antibiotic management option would be relegated to the laparoscopic appendicectomy if acute appendicitis was diagnosed during this procedure. Should be important to emphasize that the accurate diagnosis of uncomplicated acute appendicitis is the key to successful treatment with antibiotics, and that this diagnosis should be based primarily on clinical history, physical examination, and diagnostic tools (less costly and more available) like laboratory tests and ultrasound.

The belief that appendicitis is a unique progressive disease has also been an error in which we have relied to choose surgical treatment over conservative treatment. The reality is that appendicitis is not a single entity, which by its multiple causes, such as the fecalith, foreign bodies, the inflammation (infectious or neuroinflammatory) and neoplasm’s may have multiple clinical courses [4]. Some studies report that although it has been established clinically diagnosis of appendicitis, between 15 and 33 percent of the appendices removed show histological normal data [5]. It is noteworthy that has also been reported series of cases on spontaneous resolution of appendicitis [6;7], suggesting that we have not able to characterize correctly this disease.

Other impacts that this study should consider, would be the recurrence or onset of chronic appendicitis [8]. Although recurrences are considered in this meta-analysis, patient follow up was performed during one year, but may be important to assess the follow up of these patients a longer period of time to evaluate possible recurrences and also consider in some cases the progression to chronic appendicitis. This topic has great relevance for cost-benefit analysis, although the cost of an initial appendicectomy is higher than the conservative treatment (antibiotics), may be if we add the follow up costs, recurrences, and possible surgical treatment of the cases that require it in future (in Varadhan meta-analysis, 65 of the 345 patients who had successful initial treatment with antibiotics required appendicectomy [1]), these costs could equal or surpass the initial cost of the initial appendicectomy, unfortunately only few studies have been conducted with this type of analysis and the information is still insufficient.

An important point to mention is the publication bias. Since this is a problem that can not be avoided entirely by any meta-analysis, it is noteworthy that the authors mention that there is significant risk of publication bias and should be considered when interpreting the results.

Other aspects that this study does not cover are the cases of uncomplicated acute appendicitis in children and the elderly. It is in these specific age groups where there are more diagnostic difficulties, and requires more care in the therapeutic decisions. The study neither mention the effect it had preoperative prophylaxis among studies and their impact on complications (Hansson et al [9] include preoperative prophylaxis in the surgical treatment, and the other clinical trials not taken into account). This have particular importance given that there are meta-analyses which report the effectiveness of preoperative prophylaxis on postoperative complications of the appendicectomy [10].

I'm surprised that within the keywords in the search strategy the authors did not include "appendicitis", "laparoscopic" or "laparoscopic appendicectomy".

In conclusion I believe that this meta-analysis helps to highlight the need to improve the diagnosis of uncomplicated appendicitis, the need of improving the definition of the disease, the need to define the clinical guidelines for treatment, the need to improve the quality of clinical trials in surgery, the need to consider a longer period of follow up of our patients, the need to include cost-benefit analysis in surgical studies and finally that the policy of wait, watch and treat (as also mentioned in the paper), will be our best weapon as surgeons at the moment.

Reference List

1. Varadhan KK, Neal KR, Lobo DN. Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: meta-analysis of randomised controlled trials. BMJ 2012;344:e2156.

2. Brenner DJ,.Hall EJ. Computed tomography--an increasing source of radiation exposure. N.Engl.J.Med. 2007;357:2277-84.

3. 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;377:1573-9.

4. Lamps LW. Infectious causes of appendicitis. Infect.Dis.Clin.North Am. 2010;24:995-x.

5. Bittinger F, Brochhausen C, Kohler H, Lehr HA, Otto M, Skarke C et al. Differential expression of cell adhesion molecules in inflamed appendix: correlation with clinical stage. J.Pathol. 1998;186:422-8.

6. Migraine S, Atri M, Bret PM, Lough JO, Hinchey JE. Spontaneously resolving acute appendicitis: clinical and sonographic documentation. Radiology 1997;205:55-8.

7. Cobben LP, de Van Otterloo AM, Puylaert JB. Spontaneously resolving appendicitis: frequency and natural history in 60 patients. Radiology 2000;215:349-52.

8. Stevenson RJ. Chronic right-lower-quadrant abdominal pain: is there a role for elective appendectomy? J.Pediatr.Surg. 1999;34:950-4.

9. Hansson J, Korner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br.J.Surg. 2009;96:473-81.

10. Andersen BR, Kallehave FL, Andersen HK. Antibiotics versus placebo for prevention of postoperative infection after appendicectomy. Cochrane.Database.Syst.Rev. 2005;CD001439.

Competing interests: No competing interests

14 April 2012
David Rojas-Rueda
General Surgeon, Epidemiologist.
Center of Research in Environmental Epidemiology (CREAL)
Dr Aiguader 88, Barcelona, Spain