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Received 10 October 2012Received in revised form 3 October 2013Accepted 4 October 2013

Key words:Acute perforated appendicitisInterval appendectomyNonoperative management

Journal of Pediatric Surgery 49 (2014) 447450

Contents lists available at ScienceDirect

Journal of Pedi

l seperforated appendicitis (SAPA), who are systematically treated on intraabdominal uid, enlarged appendix diameter greater than

7 mm and associated surrounding inammatory changes and/oran interval AP pathway. We conducted an observational study toOptimal management of children with perforated appendicitiscontinues to be a challenging problem [1,2]. In patients presentingwith long-standing symptoms, particularly with mass or abscess,interval appendectomy (interval AP)antibiotics at diagnosis withoperation delayed weeks or monthshas frequently been used. Theintroduction of powerful broad-spectrum antibiotics made theinterval pathway a more attractive option and has widened itsapplication to larger groups of patients, including children withclinically diagnosed recent rupture and/or diffuse peritonitis. Despitegrowing use of such management nationwide, there are few dataregarding the outcome of patients with presumed rupture withoutmass or abscess at diagnosis, what we label suspected acute

1. Methods

After institutional review board approval, a prospective obser-vational study was conducted of all children aged 1 to 18 yearspresenting to Miami Children's Hospital between February 2007and August 2008 with suspected acute perforated appendicitis(SAPA). For the purposes of this study, SAPA was dened byduration of symptoms less than 96 hours, generalized abdominaltenderness on physical exam, laboratory studies including anelevated white blood cell count (WBC), N12,000, and diagnosticimaging ndings on ultrasound (US) or computerized tomography(CT). One or more diagnostic imaging ndings included freedetermine the efcacy of initial antibiotics anconsecutive series of patients with SAPA.

Corresponding author. Tel.: +1 508 847 6906; fax:E-mail address: Pradeepp.nazarey@umassmemorial.o

0022-3468/$ see front matter 2014 Elsevier Inc. Alhttp://dx.doi.org/10.1016/j.jpedsurg.2013.10.001plus fecalith on imaging, and WBC N15,000 plus duration of symptoms N48 hours were all signicantlyassociated with higher rates of readmission (p = 0.01, p = 0.04, p = 0.02) and need for interval AP prior tothe planned 8 weeks (p = 0.003, p = 0.05, p = 0.03).Conclusions: Treatment of SAPA with antibiotics and planned interval AP is successful in the majority ofpatients; however, complications such as abscess formation and/or readmission prior to plannedinterval AP occur in up to one-third of patients. Certain clinical variables are associated with increasedtreatment complications.

2014 Elsevier Inc. All rights reserved.patients with complicated perforated appendicitis; however, little experience exists with this approach inchildren with suspected acute perforated appendicitis (SAPA). We sought to determine the outcome of initialantibiotics and interval AP in children with SAPA.Methods: Over an 18-month period, 751 consecutive patients underwent appendectomy including 105patients with SAPA who were treated with initial intravenous antibiotics and planned interval AP 8 weeksafter presentation. All SAPA patients had symptoms for 96 hours. Primary outcome variables were rates ofreadmission, abscess formation, and need for interval AP prior to the planned 8 weeks.Results: Intraabdominal abscess rate was 27%. Appendectomy prior to planned interval AP was 11% andreadmission occurred in 34%. All patients underwent eventual appendectomy with pathologic conrmationconrming the previous appendiceal inammation. White blood cell (WBC) count N15,000, WBC N15,000Article history: Background: Initial antibiotics with planned interval appendectomy (interval AP) have been used to treata b s t r a c ta r t i c l e i n f oTreatment of suspected acute perforatedinterval appendectomy

Pradeep P. Nazarey a,, Steven Stylianos a,b, Evelio VRaquel Pasaron a, Vanessa Stylianos a, Leopoldo Malva Department of Pediatric Surgery, Miami Children's Hospital, Miami, FL, USAb FIU College of Medicine, Miami, FL, USAc College of Health Sciences, Barry University, Miami, FL, USA

j ourna l homepage: www.ed delayed operation in a

+1 774 443 2043.rg (P.P. Nazarey).

l rights reserved.pendicitis with antibiotics and

s c, Jason Triana a, Jeannette Diana-Zerpa a,zi a, Colin Knight a, Cathy Burnweit a

atric Surgery

v ie r .com/ locate / jpedsurgpresence of an intraabdominal appendicolith. All criteria had tohave been met. Patients with symptoms greater than 96 hours,palpable mass on physical examination or images showing a well-formed abscess were excluded from the report. Final diagnosis ofSAPA was made by one of four attending pediatric surgeons. Oncepatients were identied, standardized data forms were used to

collect clinical information and recorded data were collated at theend of the study period.

All eligible patients were initially treated with intravenous (IV)uids, analgesics and the initiation of intravenous antibiotics, withoperation planned for approximately 8 weeks after diagnosis.Piperacillin/tazobactam (100 mg/kg/dose) dosed every 6 hours wasused primarily; gentamycin (7.5 mg/kg/day) and clindamycin(30 mg/kg/day) were used in combination if the patient had apenicillin allergy. A peripherally inserted central catheter (PICC) wasplaced for antibiotic administration, and patients were treated with aminimum 7-day course. Patients afebrile for 24 hours, tolerating aregular diet and having adequate pain control with oral analgesicswere eligible for home administration of intravenous antibiotics. They

regarding quantitative data. All tests of signicance were performedwith the use of a two-sided type I error rate of 5%.

2. Results

During the 18-month study period, 751 patients underwent AP atour institution. One hundred ve patients consecutively diagnosedwith SAPA formed the study group. There were 63 males and 42

448 P.P. Nazarey et al. / Journal of Pediatric Surgery 49 (2014) 447450were discharged with a PICC and home health care, undergoingreevaluation on an outpatient basis. Criteria for discontinuingantibiotics were absence of tenderness on physical exam, notemperature above 100 F for 48 hours and a normal WBC.

About 2 weeks after the cessation of antibiotic treatment, patientswere seen in the clinic for reevaluation and scheduling of surgery. Theinterval AP was planned as an outpatient procedure using a single-incision, single-instrument technique [3]. In instances where thesingle-port technique was not feasible, a standard three-porttechnique was used. Patients were discharged home from theambulatory surgery suite unless their operative ndings necessitatedadmission for additional antibiotic therapy (e.g., for residual abscesscavity or exposed fecalith), for pain control or if the operation endedtoo late in the day for same-day discharge.

Patients seen for problems prior to the time of their scheduledinterval APwhether during antibiotic treatment or after termina-tionwere reevaluated using US and/or CT imaging where necessary.Patients with abscess formation underwent aspiration by interven-tional radiology (IR) with or without drain placement when feasible.If readmission was required for a clinical picture of recurrentappendicitis after the cessation of antibiotics, the initial nonoperativeprotocol with antibiotics was restarted, and a period of observationwas undertaken. Responders to the secondary therapy were takenoff antibiotic therapy when the previously outlined criteria weremet. Patients then returned at the scheduled time to have theirinterval AP. Nonresponders with persistent or worsening pain andfever despite the resumption of antibiotic therapyas determined bythe attending pediatric surgeonunderwent early AP and wereconsidered treatment failures. All specimens were examined by apediatric pathologist.

Primary outcome variables were rates of readmission prior toplanned interval AP, development of intraabdominal and/or pelvicabscess, and AP prior to the planned interval AP. Clinical variablesstudied are listed in Table 1. Analyses were performed to determinewhether any measured clinical variables were associated withreadmission and the need for early AP. Statistical analysis wascompleted using SAS software. Associations between categoricalvariables were evaluated using the Pearson chi-square analysis. TheStudent's t-test was used to identify differences between groups

Table 1Clinical variables in interval appendicitis patients.

Variable Interval AP (n = 105)

Age (years), mean 9.84Duration of symptoms (hours), mean 53.87Generalized tenderness, n 87 (83%)Temperature (F), mean 100.19White blood cell count (103), mean 17.46Appendicolith on imaging, n 44 (42%)Initial LOS (days), mean 6.41Cumulative LOS, mean 7.52Duration of antibiotics (days), mean 12.96

AP = appendectomy.females with a mean age of 9.8 years (range, 218 years). All werestarted on the nonoperative protocol. Ninety-three (89%) of patientsunderwent planned interval AP. Twelve children (11%) had earlyappendectomies. All patients had pathologic conrmation of previousappendiceal inammation.

SAPA patients had a mean duration of symptoms of 54 hours priorto presentation in the emergency department and none more than96 hours, and 87 patients (83%) had peritoneal signs (rigidity,involuntary guarding) outside the right lower quadrant on physicalexamination and all patients had generalized abdominal tenderness.Mean WBC count on admission was 17,500. All SAPA patientsunderwent diagnostic imaging by either US or CT, and 44 (42%) hadndings of an intraabdominal appendicolith.

All SAPA patients were admitted to the hospital for initiation of thenonoperative protocol. The initial length of stay (LOS) until dischargecriteria were met was a mean of 6.4 days. We recalculated total LOSfor the group, accounting for readmission and the need for admissionafter interval AP and found a cumulative LOS of 7.5 days. Childrenwere treated with antibiotic therapy for a mean duration of 12.9 days(range 529). Ninety-ve percent of patients were treated withpiperacillin/tazobactam. All clinical data and outcomes are summa-rized in Tables 1 and 2.

Readmission prior to planned interval AP occurred in 36 patients(34%). All readmitted patients underwent diagnostic imaging.Twenty-eight patients (27% of the study group) were found to havean intraabdominal/pelvic abscess with 12 patients (33% of 36 or 11%of the entire group) being amenable to an IR-guided drainageprocedure. All patients ultimately met the criteria for discontinuanceof antibiotics after initial or subsequent therapy.

Twelve patients (33% of 36 or 11% of the entire group) presentingfor retreatment of appendicitis symptoms after being off antibioticscontinued to have pain, fever or worsening clinical symptoms andunderwent early AP, a decision made by the attending pediatricsurgeon. The remaining 24 readmitted patients (67%) responded tothe second course of nonoperative therapy and were brought back atthe appropriate time for their interval AP.

Since a third of our SAPA patients were readmitted prior to theplanned operation, we looked to identify clinical variables that couldbe associated with untoward events during nonoperative therapy.We found no statistical difference in the rate of readmission basedon admission WBC, presence of an appendicolith on imaging orduration of symptoms longer than 48 hours. Three sets of clinicalvariables, WBC N15,000 at admission (23.7% vs 4.5%, p = 0.003),WBC N15,000 plus imaging study showing an appendicolith (27.2%vs 7.8%, p = 0.05), and WBC N15,000 plus duration of symptomsmore than 48 hours (28.6% vs 8.8%, p = 0.03) were foundsignicantly more frequently in the patients undergoing early AP(Table 3). Pathology specimens in all patients conrmed theprevious appendiceal inammation.

Table 2Adverse events in patients treated with antibiotics and interval appendectomy(n = 105).

Intraabdominal/pelvic abscess 28 (27%)Abscess amenable to aspiration or drainage 12 (11%)Readmission prior to planned interval AP 36 (34%)Appendectomy prior to planned interval AP 12 (11%)

During the study period, 37 (6%) of the 646 patients undergoingimmediate AP for presumed acute simple appendicitis were found tohave perforated appendicitis. These patients were not included in thestudy cohort but were compared to the SAPA patients. Signicantdifferences existed in duration of symptoms prior to presentation,54 hours vs 35 hours (p b 0.001), and generalized tenderness withperitoneal signs on exam, 87 (83%) vs 9 (24%) (p b 0.001). Three

Table 3Early appendectomy rate based on clinical characteristics.

At presentation Rate of early appendectomyvs if variable not present

p

WBC N15,000 23.7% vs 4.5% 0.003WBC N15,000 plus appendicolith 27.2% vs 7.8% 0.05WBC N15,000 plus symptoms N48 hours 28.6% vs 8.8% 0.03

449P.P. Nazarey et al. / Journal of Pediatric Surgery 49 (2014) 447450developed intraabdominal abscesses (8% vs 28% in the intervalmanagement group, p b 0.001); additionally, three who had beendischarged were readmitted (8% vs 34% on interval management,p = 0.01) (Table 4).

3. Discussion

Our institution performs approximately 500 appendectomies peryear. Over a 5-year period, one-quarter to one-third were intervalappendectomies for patients diagnosed with perforated appendicitisand treated up-front with intravenous antibiotics followed by APabout 2 months later. Most studies employing delayed operation incases of perforated appendicitis have been conducted in childrenpresenting with a mass on exam or an abscess on imaging studies. Wesought to prospectively identify patients with SAPAperforatedappendicitis without mass or abscessand determine their outcomeson a pathway of interval management. In identifying children withSAPA, all four criteria outlined in the Methods section had to havebeen met. Any patient with symptoms longer than 4 days or withmass or abscess was excluded from the study.

Multiple studies have identied the characteristics of childrenmore likely to present with ruptured appendicitis; these includeyounger age, pain longer than 2 to 3 days, generalized abdominaltenderness and fever over 38 C [47]. A prospective cohort studyconducted by Williams et al. [8] suggested WBC greater than 19 andfecalith as additional independent preoperative predictors. Impor-tantly, they also found that pediatric surgeons were able todiagnose perforated appendicitis preoperatively with an accuracyof 93.5% and sensitivity and specicity of 96.4% and 83% respec-tively. Using our denition of SAPA and historical predictors ofruptured appendicitis, we were able to identify 105 patients withSAPA, all of whom were ultimately conrmed to have appendicealchanges at pathology.

Table 4Comparison of clinical characteristics: patients undergoing interval AP vs thoseundergoing immediate AP for suspected simple appendicitis but found to haveperforation.

Variable Interval AP(n = 105)

Early AP(n = 37)

pAge (years), mean 9.84 11.52 nsDuration of symptoms (hours), mean 53.87 34.86 nsGeneralized tenderness, n 87 (83%) 9 (24%) b0.001Temperature (F), mean 100.19 99.86 b0.001White blood cell count (103), mean 17.46 17.69 nsAppendicolith on imaging, n 44 (42%) 15 (41%) nsInitial LOS (days), mean 6.41 5.22 nsDuration of antibiotics (days), mean 12.96 11.54 nsIntraabdominal/pelvic abscess, n 28 (27%) 2 (5.4%) b0.01Readmission prior to planned interval AP, n 36 (34%) 3 (8%) b0.001Appendectomy prior to planned Interval AP, n 2 (11%) n/aWhen nonoperative management of perforated appendicitis wasstudied using appropriately matched controls, lower complicationrates (19% vs 43%, p b 0.01), fewer abscesses (4% vs 24%, p b 0.01) anda trend for shorter length of hospital stay (6.5 vs 8.8 days, p = 0.08)were found in a subset of patients presenting with a 7-day duration ofpain [9]. Another study evaluated the safety and efcacy of initialnonoperative management for perforated appendicitis not accompa-nied by a palpable mass in 77 adult patients [10]. All had localizedabdominal tenderness and none had a palpable abdominal mass.Initial nonoperative management was successful in 95% of patients, agure similar to our 89% in this pediatric cohort. Complicationsoccurred in 12% of their patients, while 34% in our series had adverseevents while on the pathway. Other retrospective data also showlower complication rates and lower or similar LOS in nonoperativelytreated patients with interval AP for perforated appendicitis [1114].It is difcult to compare studies, however, because signicantvariability exists between the criteria for diagnosing perforation,making it impossible to ascertain optimal management strategy.

Almost 90% of our patients completed the protocol and underwentAP at about 8 weeks postoperatively, 74% of these (69 of 93)following the pathway without complication. Patients requiringoperationbecause of deteriorating clinical picture prior to thetime for interval AP (11% in our study) were considered treatmentfailures. Other published series have demonstrated similar successrates, from 62% to 95%, following interval AP protocols [9,10,15,16].About one-third (36 patients) of SAPA patients had untoward eventsduring treatment or the interval between stopping the antibiotics andoperation, of which 27% (28 patients) formed intraabdominal and/orpelvic abscesses. Only 11% (12 patients) of SAPA patients required anIR procedure for drainage.

Comparison of clinical characteristics of SAPA patients to pub-lished reports of ruptured appendicitis presenting with mass orabscess and treated on an interval management pathway reveals thatSAPA patients tended to have a shorter duration of symptoms andlower temperature on admission. SAPA patients otherwise weresimilar in terms of admission WBC, location of tenderness andpresence of appendicolith on initial imaging. Most patients with SAPArespond well to nonoperative management and interval AP with asmall number needing early AP.

The role of early AP in perforated appendicitis is evolving as seen intwo recent randomized prospective trials. St. Peter et al. [17]evaluated children who over a 2-year span presented with a well-dened abdominal abscess by CT scan. Forty patients were enrolledand randomized to either immediate AP or nonoperative medicalmanagement after abscess drainage followed by interval AP. Nosignicant differences existed between the groups at time ofadmission. While this study was small, 20% of patients in thenonoperative cohort required early AP. The two groups did not differsignicantly with regard to operative times (though slightly longer inearly AP), total LOS, recurrence of abscess (20% early AP vs 25% forinterval management) and total charges. A signicantly greaternumber of CT scans, however, were used in the interval group (2.1scans vs 1.5 for immediate operation). We routinely use US as theinitial imaging modality in all patients with suspected appendicitis.Recent data [18] reveal that sonography compares favorably with CTwith respect to sensitivity and specicity (98.7% and 95.4%) in thediagnosis of appendicitis and minimizes radiation exposure. Theauthors concluded that there was no clear benet to either pathway,but pointed out that technical laparoscopic expertise and IR resourcesmust be available.

A recent randomized clinical trial by Blakely et al. [19] looked atearly (64 patients) versus delayed AP (67 patients) in those patientswith acute perforated appendicitis who did not have a well-formedabscess or mass on exam. These patients were similar to our SAPApatients; however, 39% of their patients in each arm had an imagingdiagnosis of an intraabdominal abscess at initial presentation. While

there were no signicant differences in operative times or totalduration of antibiotic therapy, there was a 34% treatment failure ratein the interval AP group, with all these patients undergoing early AP.Our treatment failure rate was lower at 11%. The interval group also

In conclusion, we attempted to identify a group of patients withSAPA without mass or abscess and outline their outcomes as no dataexist for this subgroup of patients. We believe that the majority ofpatients with SAPA can be successfully treated on an intervalmanagement protocol; however, readmission rate is signicant.

450 P.P. Nazarey et al. / Journal of Pediatric Surgery 49 (2014) 447450group (p = 0.003). Patients on the interval management pathwaywere more likely to have intraabdominal abscess subsequent toadmission [37% vs 19% for the early surgery cohort (p = 0.02)], smallbowel obstruction during treatment [10% vs 0% (p = 0.01)],unplanned readmission [31% vs 8% (p = 0.01)] and recurrentappendicitis [9% vs 0% (p = 0.01)]. Their primary outcome, measureof time away from normal activity, was signicantly shorter in theearly AP group, 13.8 days vs 19.4 days (p b 0.001). Early AP wasshown to have lower adverse event rates overall, notably loweroccurrence of intraabdominal abscess. Hospital charges and costswere signicantly lower for early AP when compared with intervalAP [20].

Since early AP has shown to have benets of lower recurrentabscess rate, we compared our SAPA patients on interval manage-ment with the 37 excluded patients who were initially operated onfor suspected acute simple appendicitis but who were found to haveperforation upon appendectomy. As expected, the early AP patientshad favorable clinical criteria compared to SAPA patients for allclinical characteristics but signicantly lower duration of symptomsand less generalized tenderness with peritoneal signs. Thesepatients with perforated appendicitis, who were treated with earlyAP, also showed a signicantly decreased intraabdominal abscessand readmission rates (Table 4) compared to our SAPA cohorttreated on the interval management pathway. Though the groupswere clinically different based on the examining surgeon's opinion,the role of early AP in patients relegated to the SAPA pathway mayprove to be benecial.

We analyzed our clinical and imaging data to see if any variablesidentied which patients would be delayed responders or treatmentfailures or return before scheduled operation with recurrent appen-dicitis. Nadler et al. [10] found no difference between patients whowent through the interval management pathway with no untowardevents and all others, when examining age, gender, initial WBC,percent bands, percent neutrophils or duration and type of presentingsymptoms. Event-free patients, however, were more likely to have aphlegmon without abscess on CT scan compared to all others. In thislatter group, patients were twice as likely to undergo drainage of anabscess by IR. The authors concluded that treatment could be directedappropriately to those patients who had pretreatment variables thatpredicted complication during nonoperative therapy.

Whyte et al. [16] determined that the admission band count,temperature response in the rst 24 hours and CT ndings were mosthelpful in predicting problemswith initial nonoperative therapy. As inour study, while the presence of a fecalith alone was not a signicantpredictor of adverse event on the delayed operation pathway, patientswith certain clinical factorshigher band count, prolonged fever, andCT nding of disease spread beyond the right lower quadranthadmore problems with interval management. We found that WBCgreater than 15,000, especially when accompanied by appendicolithor symptoms longer than 48 hours duration led to a signicantlygreater likelihood of an AP prior to planned interval AP. Ein et al. [21],on the other hand, showed in a retrospective review that if a therewasa fecalith in the ruptured appendix (with an associated inammatorymass or abscess) that was initially treated nonoperatively, there was a72% recurrence rate of appendicitis, usually within 3 months.While 89% of children did complete the pathway and underwentplanned interval AP, certain clinical features such as WBC over 15,000when accompanied by fecalith or symptoms longer than 2 days wereassociated with treatment failure. Our study adds to the growing bodyof complex and conicting literature on the application of intervalmanagement in the treatment of childhood appendicitis. Furtherwork needs to be done to identify patients who will benet from earlyintervention in the face of perforated appendicitis, whether withmassor diffuse perforation, separating them clinically from children bestsuited to early antibiotic treatment and delayed surgery. Though agreat body of literature exists supporting the use of intervalmanagement in perforated appendicitis, evidence may be swingingtoward the more frequent use of early AP.

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[19] Blakely ML, Williams R, Dassinger MS, et al. Early vs interval appendectomy forchildren with perforated appendicitis. Arch Surg 2011;146:6605.

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[21] Ein SH, Langer JC, Daneman A. Non-operative management of pediatric rupturedappendix with inammatory mass or abscess: presence of an appendicolithpredicts recurrent appendicitis. J Pediatr Surg 2005;40:16125.had an overall adverse event rate of 55% versus 30% in the early AP

Treatment of suspected acute perforated appendicitis with antibiotics and intervalappendectomy1. Methods2. Results3. DiscussionReferences