statistical underpinnings of an equivalency or noninfe-riority trial require that an initial difference in outcomesbetween groups be designated as a clinically relevantdifference. Adhering to a strict interpretation of the re-sults of the equivalency trial, one can only make conclu-sions with respect to the difference in outcomes initiallydesignated. For our study, we chose 6% as that desig-nated difference, to avoid a potentially meaningless dif-ference in infection rate between groups, which mightbe statistically different but not clinically relevant. Thiswas balanced with the sample size requirements for asmaller equivalence threshold. In Dr Lee’s example forcomparing 9% infection rate for paint-only versus 4% inpaint-plus-scrub, the sample size requirements would beapproximately 650 patients per group (1,300 patientstotal).

We have contributed to the literature a controlledclinical trial that was designed to test the idea that pre-operative scrubbing of skin with povidone-iodine soapadds no incremental protection against wound infec-tion. We do not agree with Dr Lee that our results havethe same interpretation as a hypothetical trial, where theactual infection frequency was 9% in the paint-only armand 4% in the paint-plus-scrub arm. Although Dr Lee’sworst-case outcomes would be within the tolerance ofour 6% equivalence threshold based on our current re-sults and the results of previous trials, that specific out-come would be unlikely given the data that has beenreported as of this writing. Admittedly, Dr Lee is correctthat the interpretation of our results has not added to thepossible knowledge-space: povidone-iodine scrubbingmight add benefit, might have no effect at all, or mightactually increase infection likelihood. Statistical rea-soning does not deal in perfect knowledge states. Itcan lead to conclusions that speak to the likelihood ofoutcomes. We would argue that our data have shownthat the advantage of povidone-iodine scrubbing overpaint-only is minimal at best because it is the mostlikely interpretation.

Despite the results of even the most rigorously de-signed single clinical trial, the thoughtful clinician willalways weigh the pros and cons of altering his or herclinical practice. Results of our single clinical trial mustbe interpreted in the context of the four earlier clinicaltrials available for review, all of which are cited in ourpublication. Each of these was a negative trial, and eachtrial compared the “gold standard” scrub-plus-paint tosomething different and often less than scrub-plus-

paint. In view of this body of literature and our clearlynegative clinical trial, an objective observer who is notlost in the vagaries of statistical minutiae, can concludethat a reasonable argument can be made for abandoningscrub-and-paint.

Delayed Massive Hemorrhage afterPancreaticoduodenectomy: A NewTherapeutic Approach

Giuseppe Navarra, MD

Marcello Bartolotta, MD

Adalberto Barbera, MD

Messina, Italy

We read with great interest the series of delayed massivehemorrhages after pancreaticoduodenectomy reportedby Tien and colleagues1 in your journal. They have con-firmed that delayed massive hemorrhage after pancreati-coduodenectomy, often associated with septic complica-tions secondary to leakage or intraabdominal abscess, isstill a frequent event carrying a high mortality rate. Afterthe failure of conservative management, final manage-ment can be either radiologic or surgical, as stated byTien and colleagues.1 Although radiologic managementis partly dependent on resuscitation facilities at the de-partment of radiology and the prompt availability ofexperienced interventional radiologists, surgical man-agement is much more invasive and brings with it highmorbidity and mortality, even if it succeeds in stoppingthe bleeding. But there is a pharmacologic agent that canbe used as rescue treatment in case of massive bleeding:recombinant activated factor VII (rFVIIa), which weused to treat a case of delayed massive hemorrhage afterpancreaticoduodenectomy.

Recombinant FVIIa is a major alternative for man-agement of hemophiliac patients with inhibitors.2 Morerecently, it has been used off-label to control bleeding inpatients with trauma or other massive life-threateninghemorrhage, and to reduce blood loss in surgical pa-tients with normal coagulation.3-5 Recombinant FVIIabinds to activated platelets independently of tissue fac-tor. The resulting stimulation of an exaggerated earlythrombin burst at sites of vascular injury makes it anattractive potential treatment for massive, uncontrolledbleeding.

854 Navva J Am Coll Surg

An 82-year-old woman presented with a diagnosis ofadenocarcinoma of the head of the pancreas underwenta pylorus-preserving pancreaticoduodenectomy. Duringthe postoperative course, a benign pancreatic fistula de-veloped that was treated conservatively. On the 23rd

postoperative day, a delayed massive hemorrhage oc-curred without any previously evident “sentinel bleed.”Fresh blood appeared in the abdominal drainage locatedclose to the pancreaticojejunostomy followed by emis-sion of red blood with stools. A CT scan showed noactive abdominal bleeding, aneurysm, or pseudoaneu-rysm of visceral arteries. Despite administration of 4 Uof packed red cell concentrates and 4 U of fresh frozenplasma, the hemoglobin dropped, suggesting a persis-tent hemorrhage. NovoSeven (Novo Nordisk) was givenintravenously at a dose of 40 �g/kg body weight. Thehemoglobin continued to drop slowly during the next6 hours, suggesting a persistent hemorrhage. NovoSevenwas readministered intravenously at a dose of 90 �g/kgbody weight. This additional application of rFVIIa sta-bilized the hemoglobin level; no more transfusion wasneeded, and the patient left the hospital 15 days later.

Although indications for NovoSeven in acute delayedmassive bleedings have not yet been formally evaluated,this report suggests that rFVIIa could be used effectivelyin this setting, avoiding interventional radiology pro-cedures or surgery. The concern that rFVIIa mightcause thrombotic events is reasonable given that thisagent is administered at a concentration 1,000-foldhigher than normal, but clinical evidence publishedto date has shown that the incidence of adverse eventsis � 1%.4

This experience shows interesting findings, but addi-tional research is needed before the safety and effective-ness of rFVIIa in all such patients can be confirmed.

The authors of the article have no experience with recombi-nant activated factor VII, so declined to reply.

REFERENCES

1. Tien YW, Lee PH, Yang CY, et al. Risk factors of massive bleedingrelated to pancreatic leak after pancreaticoduodenectomy. J AmColl Surg 2005;201:554–559.

2. Hedner U. NovoSeven as a universal haemostatic agent. BloodCoagul Fibrinolysis 2000;11:107–111.

3. Martinowitz U, Kenet G, Lubetski A, et al. Possible role of re-combinant activated factor VII (rFVIIa) in the control of hemor-

rhage associated with massive trauma. Can J Anesth2002;49:S15–S20.

4. MacLaren R, Weber LA, Brake H, et al. A multicenter assessmentof recombinant factor VIIa off-label usage: clinical experiencesand associated outcomes. Transfusion 2005;45:1434–1442.

5. Laffan MA, Tait RC, Blatny J, et al. Use of recombinant activatedfactor VII for bleeding in pancreatitis: a case series. Pancreas2005;30:279–284.

Does the TNM Staging System forEsophageal Cancer Need Revision?

CS Pramesh, MS, FRCS

Rajesh C Mistry, MS

Nirmala A Jambhekar, MD

Sarbani G Laskar, MD

Mumbai, India

We commend Kunisaki and colleagues1 for theirthought-provoking article on the development of an ap-propriate staging system for esophageal cancer in a re-cent issue of the Journal. There have been numerousarticles2,3 in recent times on the issue that bring intofocus the pitfalls in the existing TNM staging system.There is a lack of data correlating pathology with overallsurvival, which looks beyond the present TNM system,and this article attempts to evaluate the ability of otherstaging systems to do so. Though the article does notclearly demonstrate the superiority of one system overthe other, it infuses new ideas into the debate and gives itsome direction. It is common experience that patientswith a lower third esophageal malignancy with metasta-sis to supracarinal lymph nodes fare worse than thosewith a lower paraesophageal nodal metastasis. Similarly,patients with fewer metastatic nodes do better thanthose with multiple metastatic nodes. Hence, logically,the location and the number of metastatic lymph nodesshould have an impact on survival. These theories havealso been backed up by some studies.4 There have alsobeen studies5 emphasizing the importance of the ratio ofmetastatic to total lymph nodes dissected. Whether thisratio will have a widespread, universal impact is difficultto ascertain because of the wide variability of lymphnode sampling and dissection by surgeons and, moreimportantly, pathologists.

The only drawback of this study is the paucity ofnumbers. We suggest a large multicentric international

855Vol. 202, No. 5, May 2006 Letters