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the Characterization and Prediction of ISGPF Grade C Fistulas Following Pancreatoduodenectomy
Matthew T. McMillan*1, Charles M. Vollmer1, Jeffrey Drebin1, Michael H. Sprys1, Stephen W. Behrman2
1Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 2Surgery, University of Tennessee Health Science Center, Memphis, TN
Introduction: ISGPF Grade C postoperative pancreatic fistulas (POPF) are the greatest contributor to major morbidity and mortality following pancreatoduodenectomy (PD); however, their infrequent occurrence (~2% of all PD) has hindered deeper analysis. This study sought to develop a predictive algorithm, which could facilitate effective management of this challenging complication.
Methods: Data was accrued from 4,301 PDs, performed by 55 surgeons at 15 institutions worldwide (2003-2014). Demographics, postoperative management, and microbiological characteristics of Grade C POPFs were evaluated. ACS-NSQIP preoperative variables were compared between Grade C POPFs and a 427-case sample of non-Grade C POPFs (including no-POPF and Grade A/B POPF cases) drawn from the overall cohort. Risk factors for Grade C POPF formation were identified using regression analysis and subsequently validated using resampling methodology.
Results: Grade C POPFs developed in 79 patients (1.8%). Deaths (90 Day) occurred in 2.0% (N=88) of the overall series, with 35% (N=25) occurring in the presence of a Grade C POPF. A similar proportion of Grade C POPFs resulted in death (37%). Reoperations were necessary 73% of the time, with 30% of these requiring multiple reoperations. The rates of single and multi-system organ failure were 28% and 40%, respectively. Mortality rates escalated with certain types of organ failure, but they were unaffected by reoperation(s) (Table 1). The median number of complications incurred was four (IQR: 2-5), and the median duration of hospital stay was 32 days (IQR: 21-54). Grade C POPF treatment required extensive resources: antibiotics (96%), ICU use (82%), transfusions (82%), and TPN (76%). Warning signs for impending Grade C POPFs most often presented on POD 6. Surgeons indicated Grade C POPFs evolved from a Grade B POPF 56% of the time. The predominant genera derived from cultures of these fistulas were: Enterococcus (42%), Staphylococcus (35.8%), and Candida (35.8%). Positive Candida cultures were associated with a mortality rate of 50% (P=0.082). Adjuvant chemotherapy might have benefited 56% of Grade C POPF patients, yet it was delayed or never delivered in 26% and 67% of patients, respectively. Preoperative factors associated with Grade C POPF occurrence were identified (Table 2) and a predictive model yielded an area under the ROC curve of 0.78 (95% C.I.: 0.71-0.84; P < 0.00001).
Conclusion: This multinational study represents the largest analysis of Grade C POPFs following PD. It demonstrates that Grade C POPFs incur a severe burden on patients, with high rates of reoperation and infection, while also potentially worsening overall survival by causing delay or complete omission of adjuvant therapy. The preoperative identification of high-risk patients using the proposed risk algorithm may facilitate optimal management and improve outcomes.
Table 2. Predictors of Grade C fistula occurrence
| Predictor | Odds Ratio (95% C.I.) | P-value | | Gender | | | Female | REF | 0.005 | | Male | 2.3 (1.2-4.4) | | Alcohol (> 2 drinks per day) | | | No | REF | 0.003 | | Yes | 4.3 (1.5-12.6) | | Previous cardiac event (ever) | | | No | REF | 0.001 | | Yes | 3.7 (1.7-8.1) | | Neurologic event/disease | | | No | REF | 0.009 | | Yes | 11.1 (1.0-116.9) | | Steroid use (≤ 30 days preoperatively) | | | No | REF | 0.001 | | Yes | 36.7 (2.8-481.1) | | Dyspnea (≤ 30 days preoperatively) | | | No | REF | 0.001 | | Yes | 15.0 (1.1-207.7) | | Preoperative functional status | | | Independent | REF | 0.001 | | Partially/totally dependent | 9.6 (2.1-44.3) | | Alkaline phosphatase (U/L) | | | Normal (38-126) | REF | < 0.001 | | Low (< 38) | 24.5 (4.1-147.6) | 0.001 | | High (> 126) | 2.5 (1.3-4.6) | 0.008 | | High-risk disease pathology | | | No (PDAC or pancreatitis) | REF | 0.043 | | Yes (pathology other than PDAC or pancreatitis) | 2.1 (1.1-3.9) |
Table 1. Analysis of 90-day mortality in Grade C POPF patients | Variable, N (%) | Mortality | P-value | | No | Yes | | Percutaneous drainage | | | No | 28 (63.6) | 16 (36.4) | 0.783 | | Yes | 22 (66.7) | 11 (33.3) | | Reoperation required | | | No | 13 (61.9) | 8 (38.1) | 0.806 | | Yes | 37 (64.9) | 20 (35.1) | | Further reoperation required | | | No | 27 (67.5) | 13 (32.5) | 0.530 | | Yes | 10 (58.8) | 7 (41.2) | | Organ failure | | | None | 21 (84.0) | 4 (16.0) | < 0.0001 | | Single-system | 18 (81.8) | 4 (18.2) | | Multi-system | 10 (32.3) | 21 (67.7) | | Type of organ failure | | | Pulmonary failure | | | No | 33 (89.2) | 4 (10.8) | < 0.0001 | | Yes | 16 (39.0) | 25 (61.0) | | Renal failure | | | No | 40 (78.4) | 11 (21.6) | < 0.0001 | | Yes | 9 (33.3) | 18 (66.7) | | Cardiac failure | | | No | 38 (67.9) | 18 (32.1) | 0.142 | | Yes | 11 (50.0) | 11 (50.0) | | Neurologic failure | | | No | 44 (73.3) | 16 (26.7) | 0.004 | | Yes | 5 (27.8) | 13 (72.2) |
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