The harm of prophylactic octreotide in pancreatoduodenectomy: more artefact than fact?

We were surprised that McMillan et al.¹ concluded that octreotide may increase the risk for postoperative pancreatic fistula (POPF). This supposition is counter to findings in multiple prospective randomized controlled trials (RCTs) and meta-analyses, which find octreotide to reduce POPF. Other RCTs, however, have failed to show benefit. Given that, as the authors¹ point out, none of the RCTs controlled well for risk of fistula, their study controlling for fistula risk factors is laudable and long overdue. We congratulate the authors on making another important addition to the literature.

However, we must highlight several points regarding physiology, published evidence and study design. Does it make physiologic sense that decreasing pancreatic exocrine secretion should increase risk for POPF? Positing an anastomosis-threatening decrease in splanchnic blood flow, the authors cite the effect of SMS 201-995 on flow.² However, is a decrease of 20–25% clinically relevant, given the rich blood supply of the pancreas and jejunum? Elsewhere, research has found flow in the pancreatic and superior mesenteric arteries to be relatively preserved compared with hepatic flow,³ and that decreases in flow are mitigated post-prandially.⁴ Additionally, the authors¹ cite purportedly harmful octreotide-related increases in pancreatic enzyme concentration, associated with a beneficial decrease in volume, as possibly also impeding anastomotic healing, but their supporting evidence derives from a study with a sample size of one⁵ and, like the argument for decreased splanchnic flow, this claim is difficult to understand: given that the amylase concentration of pancreatic fluid is 10⁵–10⁶ U/l, is the tiny (1.5-fold) increase in protein output relevant? From a physiological perspective, it seems premature to conclude that octreotide prevents anastomotic healing.

Apropos of the published Level I evidence, including a Cochrane review which found the incidence of POPF to be 34% lower in the somatostatin analogue group,⁶ it is difficult to reconcile the conclusions drawn by McMillan et al.¹ with the fact that few to none of the many RCTs found significantly increased rates of POPF in association with octreotide. Although some fault can be found in most studies, we are nevertheless faced with multiple prospective RCTs (most with some risk for bias), all of which show either a significant decrease in POPF with octreotide or no improvement, which stand in opposition to McMillan et al.'s¹ single, retrospective and non-randomized, albeit beautifully fistula-risk-score-controlled, study, also of course at some risk for bias.

Bias, as McMillan et al.¹ point out, may exist in their study insofar that octreotide usage was not normally distributed among surgeons, suggesting at least the possibility of an important confounding bias. Similarly, drains and stents were used at the surgeon's discretion, introducing even more heterogeneity.

We agree that the observed increase in POPF ‘is almost certainly multifactorial’,¹ but respectfully suggest, in light of the above considerations, that a factor that must also be more seriously considered is ‘artefactor’.