Improved outcomes with minimally invasive pancreaticoduodenectomy in patients with dilated pancreatic ducts: a prospective study.

BACKGROUND: Little is known about what factors predict better outcomes for patients who undergo minimally invasive pancreaticoduodenectomy (MIPD) versus open pancreaticoduodenectomy (OPD). We hypothesized that patients with dilated pancreatic ducts have improved postoperative outcomes with MIPD compared to OPD. METHODS: All patients undergoing pancreaticoduodenectomy were prospectively followed over a time period of 47 months, and perioperative and pathologic covariates and outcomes were compared. Ideal outcome after PD was defined as follows: (1) no complications, (2) postoperative length of stay < 7 days, and (3) negative (R0) margins on pathology. Patients with dilated pancreatic ducts (≥ 3 mm) who underwent MIPD were 1:3 propensity score-matched to patients with dilated ducts who underwent OPD and outcomes compared. Likewise, patients with non-dilated pancreatic ducts (< 3 mm) who underwent MIPD were 1:3 propensity score-matched to patients with non-dilated ducts who underwent OPD and outcomes were compared. RESULTS: 371 patients underwent PD-74 (19.9%) MIPD and 297 (80.1%) underwent OPD. Overall, patients who underwent MIPD had significantly less intraoperative blood loss. After 1:3 propensity score matching, patients with dilated pancreatic ducts who underwent MIPD (n = 45) had significantly lower overall complication and 90-day readmission rates compared to matched OPD patients (n = 135) with dilated ducts. Patients with dilated duct who underwent MIPD were more likely to have an ideal outcome than patients with OPD (29 vs 15%, p = 0.035). There were no significant differences in postoperative outcomes among propensity score-matched patients with non-dilated pancreatic ducts who underwent MIPD (n = 29) compared to matched patients undergoing OPD (n = 87) with non-dilated ducts. CONCLUSIONS: MIPD is safe with comparable perioperative outcomes to OPD. Patients with pancreatic ducts ≥ 3 mm appear to derive the most benefit from MIPD in terms of fewer complications, lower readmission rates, and higher likelihood of ideal outcome.

Inability to manage non-severe complications on an outpatient basis increases non-white patient readmission rates after pancreaticoduodenectomy: A large metropolitan tertiary care center experience.

BACKGROUND: Pancreaticoduodenectomy (PD) has a high rate of readmission, and racial disparities in care could be an important contributor. METHODS: Patients undergoing PD were prospectively followed, and their complications graded using the Modified Accordion Grading System (MAGS). Patient factors and perioperative outcomes for patients with and without postoperative readmission were compared in univariate and multivariate analysis by severity. RESULTS: 837 patients underwent PD, the overall 90-day readmission rate was 27.5%. Non-white race was independently associated with readmission (OR 1.83, p = 0.007). 51.3% of readmissions were for non-severe complications (MAGS <3). Non-white race was independently associated with MAGS non-severe readmission (OR 2.13, p = 0.006), but not MAGS severe readmission. CONCLUSIONS: Non-white patients are more likely to be readmitted, particularly for non-severe complications. Follow up protocols should be tailored to address race disparities in the rates of readmission as readmission for less severe complications could potentially be avoidable.

Prospective Evaluation of Pasireotide in Patients Undergoing Pancreaticoduodenectomy: The Washington University Experience.

BACKGROUND: Pasireotide is a newer generation somatostatin analogue that led to a significant reduction in pancreatic fistula after pancreatectomy in a single-center randomized controlled trial. We sought to determine if pasireotide reduces the incidence of pancreatic fistula and other complications after pancreaticoduodenectomy at our high volume center. STUDY DESIGN: All patients undergoing pancreaticoduodenectomy between April 2011 and January 2017 were prospectively followed, and their complications were graded using the Modified Accordion Grading System (MAGS) in our institutional complications database. For 18 months, 5 pancreatic surgeons used pasireotide routinely in patients undergoing pancreaticoduodenectomy. Patients receiving pasireotide were then propensity score-matched to patients who did not receive pasireotide, and their outcomes were compared. RESULTS: There were 459 patients who underwent pancreaticoduodenectomy, and 127 patients (28%) received pasireotide. Patients who received pasireotide were significantly more likely to have dilated pancreatic ducts and have a drain left at the time of surgery. Patients who received pasireotide had no difference in pancreatic fistula, overall complications, 90-day readmission, or 90-day mortality. However, patients who received pasireotide had a significantly reduced rate of postoperative bleeding/anemia (8.7% vs 16.9%, p = 0.03). Among 112 propensity score-matched pairs, patients who received pasireotide did not have significantly different rates of pancreatic fistula, and the rates of severe (MAGS grades 3 to 6) pancreatic fistula were identical between the 2 groups (7.1% vs 7.1%, p = 1.00). Matched patients who received pasireotide had significantly decreased postoperative bleeding/anemia (9.8% vs 19.6%, p = 0.04). CONCLUSIONS: Pasireotide did not reduce the incidence or severity of pancreatic fistulas after pancreaticoduodenectomy, but was associated with a decrease in postoperative bleeding/anemia. A multicenter randomized trial is needed to accurately define the role of pasireotide in the postoperative management of pancreaticoduodenectomy patients.

Surgeon Variation in Intraoperative Supply Cost for Pancreaticoduodenectomy: Is Intraoperative Supply Cost Associated with Outcomes?

BACKGROUND: With increased scrutiny on the quality and cost of health care, surgeons must be mindful of their outcomes and resource use. We evaluated surgeon-specific intraoperative supply cost (ISC) for pancreaticoduodenectomy and examined whether ISC was associated with patient outcomes. STUDY DESIGN: Patients undergoing open pancreaticoduodenectomy between January 2012 and March 2015 were included. Outcomes were tracked prospectively through postoperative day 90, and ISC was defined as the facility cost of single-use surgical items and instruments, plus facility charges for multiuse equipment. Multivariate logistic regression was used to test associations between ISC and patient outcomes using repeated measures at the surgeon level. RESULTS: There were 249 patients who met inclusion criteria. Median ISC was $1,882 (interquartile range [IQR] $1,497 to $2,281). Case volume for 6 surgeons ranged from 18 to 66. Median surgeon-specific ISC ranged from $1,496 to $2,371. Greater case volume was associated with decreased ISC (p < 0.001). Overall, ISC was not predictive of postoperative complications (p = 0.702) or total hospitalization expenditures (p = 0.195). At the surgeon level, surgeon-specific ISC was not associated with the surgeon-specific incidence of severe complication or any wound infection (p > 0.227 for both), but was associated with delayed gastric emptying (p = 0.004) and postoperative pancreatic fistula (p < 0.001). CONCLUSIONS: In a single-institution cohort of 249 pancreaticoduodenectomies, high-volume surgeons tended to be low-cost surgeons. Across the cohort, ISC was not associated with outcomes. At the surgeon level, associations were noted between ISC and complications, but these may be attributable to unmeasured differences in the postoperative management of patients. These findings suggest that quality improvement efforts to restructure resource use toward more cost-effective practice may not affect patient outcomes, although prospective monitoring of safety and effectiveness must be of the utmost concern.

Whipple-specific complications result in prolonged length of stay not accounted for in ACS-NSQIP Surgical Risk Calculator.

BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Surgical Risk Calculator was developed to help counsel patients regarding estimated postoperative risk for a variety of surgical complications. This retrospective single institutional study examined the calculator's ability to accurately predict complications and length of hospital stay (LOS) in patients who had undergone a Pancreaticoduodenectomy (PD) at our institution. METHODS: 165 patients at Washington University School of Medicine who underwent a PD from 8/2011 to 7/2013 were included. Surgical complication risk as determined by the ACS-NSQIP Surgical Risk Calculator were compared to actual 30 day complications. PD complications not accounted for by the calculator were compared to those without PD-specific complications. RESULTS: Overall predicted LOS was significantly shorter than actual duration of hospitalization (median 8.5 vs. 8.0 days; p < 0.001). 38% patients (n = 62) with Whipple-specific complication demonstrated a significant increase in LOS (8.0 vs. 12.2 days; p < 0.0001). DISCUSSION: A large proportion of complications experienced after PD are pancreas-specific, accounting for the difference in predicted vs. actual LOS and providing rationale for future development of PD specific risk models.

Variations in definition and method of retrieval of complications influence outcomes statistics after pancreatoduodenectomy: comparison of NSQIP with non-NSQIP methods.

BACKGROUND: NSQIP and the Accordion Severity Grading System have recently been used to develop quantitative methods for measuring the burden of postoperative complications. However, other audit methods such as chart reviews and prospective institutional databases are commonly used to gather postoperative complications. The purpose of this study was to evaluate discordance between different audit methods in pancreatoduodenectomy--a common major surgical procedure. The chief aim was to determine how these different methods could affect quantitative evaluations of postoperative complications. STUDY DESIGN: Three common audit methods were compared with NSQIP in 84 patients who underwent pancreatoduodenectomy. The methods were use of a prospective database, a chart review based on discharge summaries only, and a detailed retrospective chart review. The methods were evaluated for discordance with NSQIP and among themselves. Severity grading was performed using the Modified Accordion System. RESULTS: Fifty-three complications were listed by NSQIP and 31 complications were identified that were not listed by NSQIP. There was poor agreement for NSQIP-type complications between NSQIP and the other audit methods for mild and moderate complications (kappa 0.381 to 0.744), but excellent agreement for severe complications (kappa 0.953 to 1.00). Discordance was usually due to variations in definition of the complications in non-NSQIP methods. There was good agreement among non-NSQIP methods for non-NSQIP complications for moderate and severe complications, but not for mild complications. CONCLUSIONS: There are important differences in perceived surgical outcomes based on the method of complication retrieval. The non-NSQIP methods used in this study could not be substituted for NSQIP in a quantitative analysis unless that analysis was limited to severe complications.

Effects of aging on the immunopathologic response to sepsis.

OBJECTIVE: Aging is associated with increased inflammation following sepsis. The purpose of this study was to determine whether this represents a fundamental age-based difference in the host response or is secondary to the increased mortality seen in aged hosts. DESIGN: Prospective, randomized controlled study. SETTING: Animal laboratory in a university medical center. SUBJECTS: Young (6-12 weeks) and aged (20-24 months) FVB/N mice. INTERVENTIONS: Mice were subjected to 2 x 25 or 1 x 30 cecal ligation and puncture (CLP). MEASUREMENTS AND MAIN RESULTS: Survival was similar in young mice subjected to 2 x 25 CLP and aged mice subjected to 1 x 30 CLP (p = 0.15). Young mice subjected to 1 x 30 CLP had improved survival compared with the other groups (p < 0.05). When injury was held constant but mortality was greater, both systemic and peritoneal levels of tumor necrosis factor-alpha, interleukin (IL)-6, IL-10, and monocyte chemotactic protein-1 were elevated 24 hours after CLP in aged animals compared with young animals (p < 0.05). When mortality was similar but injury severity was different, there were no significant differences in systemic cytokines between aged mice and young mice. In contrast, peritoneal levels of tumor necrosis factor-alpha, IL-6, and IL-10 were higher in aged mice subjected to 1 x 30 CLP than young mice subjected to 2 x 25 CLP despite their similar mortalities (p < 0.05). There were no significant differences in either bacteremia or peritoneal cultures when animals of different ages sustained similar injuries or had different injuries with similar mortalities. CONCLUSIONS: Aged mice are more likely to die of sepsis than young mice when subjected to an equivalent insult, and this is associated with increases in both systemic and local inflammation. There is an exaggerated local but not systemic inflammatory response in aged mice compared with young mice when mortality is similar. This suggests that systemic processes that culminate in death may be age independent, but the local inflammatory response may be greater with aging.

CD4+ lymphocytes control gut epithelial apoptosis and mediate survival in sepsis.

Lymphocytes help determine whether gut epithelial cells proliferate or differentiate but are not known to affect whether they live or die. Here, we report that lymphocytes play a controlling role in mediating gut epithelial apoptosis in sepsis but not under basal conditions. Gut epithelial apoptosis is similar in unmanipulated Rag-1(-/-) and wild-type (WT) mice. However, Rag-1(-/-) animals have a 5-fold augmentation in gut epithelial apoptosis following cecal ligation and puncture (CLP) compared to septic WT mice. Reconstitution of lymphocytes in Rag-1(-/-) mice via adoptive transfer decreases intestinal apoptosis to levels seen in WT animals. Subset analysis indicates that CD4(+) but not CD8(+), gammadelta, or B cells are responsible for the antiapoptotic effect of lymphocytes on the gut epithelium. Gut-specific overexpression of Bcl-2 in transgenic mice decreases mortality following CLP. This survival benefit is lymphocyte dependent since gut-specific overexpression of Bcl-2 fails to alter survival when the transgene is overexpressed in Rag-1(-/-) mice. Further, adoptively transferring lymphocytes to Rag-1(-/-) mice that simultaneously overexpress gut-specific Bcl-2 results in improved mortality following sepsis. Thus, sepsis unmasks CD4(+) lymphocyte control of gut apoptosis that is not present under homeostatic conditions, which acts as a key determinant of both cellular survival and host mortality.

Intestine-specific overexpression of IL-10 improves survival in polymicrobial sepsis.

Targeted IL-10 therapy improves survival in preclinical models of critical illness, and intestine-specific IL-10 decreases inflammation in models of chronic Inflammatory disease. We therefore sought to determine whether intestine-specific overexpression of IL-10 would improve survival in sepsis. Transgenic mice that overexpress IL-10 in their gut epithelium (Fabpi-IL-10 mice) and wild-type (WT) littermates (n = 127) were subjected to cecal ligation and puncture with a 27-gauge needle. The 7-day survival rate was 45% in transgenic animals and 30% in WT animals (P < or = 0.05). Systemic levels of IL-10 were undetectable in both groups of animals under basal conditions and were elevated to a similar degree in septic animals regardless of whether they expressed the transgene. Local parameter of injury, including gut epithelial apoptosis, intestinal permeability, peritoneal lavage cytokines, and stimulated cytokines from intraepithelial lymphocytes, were similar between transgenic and WT mice. However, in stimulated splenocytes, proinflammatory cytokines monocyte chemoattractant protein 1 (189 +/- 43 vs. 40 +/- 8 pg/mL) and IL-6 (116 +/- 28 vs. 34 +/- 9 pg/mL) were lower in Fabpi-IL-10 mice than WT littermates despite the intestine-specific nature of the transgene (P < 0.05). Cytokine levels were similar in blood and bronchoalveolar lavage fluid between the 2 groups, as were circulating LPS levels. Transgenic mice also had lower white blood cell counts associated with lower absolute neutrophil counts (0.5 +/- 0.1 vs. 1.0 +/- 0.2 10(3)/mm3; P < 0.05). These results indicate that gut-specific overexpression of IL-10 improves survival in a murine model of sepsis, and interactions between the intestinal epithelium and the systemic immune system may play a role in conferring this survival advantage.

Vasoactive drugs and the gut: is there anything new?

PURPOSE OF REVIEW: Systemic changes in blood pressure and cardiac output induced by pressors and inotropes do not always correlate to improvements in regional perfusion. Since the gut is often referred to as the 'motor' of the systemic inflammatory response syndrome, the impact of vasoactive agents on splanchnic perfusion has theoretical importance. This review will highlight recent studies examining secondary effects of vasoactive agents on intestinal perfusion, metabolism, and barrier function. RECENT FINDINGS: Norepinephrine has minimal impact on mesenteric blood flow although the combination of norepinephrine and dobutamine increases splanchnic blood flow in sepsis. Dopamine also increases mesenteric blood flow although this may be associated with negative hepatic energy balance at high does. Vasopressin and epinephrine both have negative effects on splanchnic blood flow. Newer inodilators levosimendan and olprinone preferentially improve mesenteric perfusion in animal models. SUMMARY: Secondary effects of norepinephrine and dopamine on splanchnic perfusion are minor compared with their systemic effects. While vasopressin usage is increasing in the intensive care unit, caution should be used because of its adverse effects on gut perfusion. Experimental agents for the treatment of heart failure have beneficial gut-specific effects although the clinical significance of this is currently limited by their availability.

Mechanisms of decreased intestinal epithelial proliferation and increased apoptosis in murine acute lung injury.

OBJECTIVES: The aim of this study was to determine the effects of acute lung injury on the gut epithelium and examine mechanisms underlying changes in crypt proliferation and apoptosis. The relationship between severity and timing of lung injury to intestinal pathology was also examined. DESIGN: Randomized, controlled study. SETTING: University research laboratory. SUBJECTS: Genetically inbred mice. INTERVENTIONS: Following induction of acute lung injury, gut epithelial proliferation and apoptosis were assessed in a) C3H/HeN wild-type and C3H/HeJ mice, which lack functional Toll-like receptor 4 (n = 17); b) C57Bl/6 mice that received monoclonal anti-tumor necrosis factor-alpha or control antibody (n = 22); and c) C57Bl/6 wild-type and transgenic mice that overexpress Bcl-2 in their gut epithelium (n = 21). Intestinal epithelial proliferation and death were also examined in animals with differing degrees of lung inflammation (n = 24) as well as in a time course analysis following a fixed injury (n = 18). MEASUREMENTS AND MAIN RESULTS: Acute lung injury caused decreased proliferation and increased apoptosis in crypt epithelial cells in all animals studied. C3H/HeJ mice had higher levels of proliferation than C3H/HeN animals without additional changes in apoptosis. Anti-tumor necrosis factor-alpha antibody had no effect on gut epithelial proliferation or death. Overexpression of Bcl-2 did not change proliferation despite decreasing gut apoptosis. Proliferation and apoptosis were not correlated to severity of lung injury, as gut alterations were lost in mice with more severe acute lung injury. Changes in both gut epithelial proliferation and death were apparent within 12 hrs, but proliferation was decreased 36 hrs following acute lung injury while apoptosis returned to normal. CONCLUSIONS: Acute lung injury causes disparate effects on crypt proliferation and apoptosis, which occur, at least in part, through differing mechanisms involving Toll-like receptor 4 and Bcl-2. Severity of lung injury does not correlate with perturbations in proliferation or death in the gut epithelium, and acute lung injury-induced changes in intestinal epithelial proliferation persist longer than those in apoptosis.

Age disproportionately increases sepsis-induced apoptosis in the spleen and gut epithelium.

Both aging and sepsis independently increase splenic and gut epithelial apoptosis. Sepsis-induced apoptosis in either cell type is also associated with increased mortality in young mice. We sought to determine whether age alters sepsis-induced splenic and gut epithelial cell death. Young (2 months) and aged (22 months) male ND4 mice were subjected to either single-puncture cecal ligation and puncture (CLP) with a 23-gauge needle or sham laparotomy. Apoptosis was assessed 24 hours later in the spleen and gut epithelium by active caspase 3 and hematoxylin and eosin staining. Aged septic mice had increased splenic apoptosis compared with either young septic animals or aged sham animals (15 vs. 7 vs. 5 apoptotic cells/high-powered field, P < 0.05). Similarly, aged septic animals had an elevation in gut epithelial cell death compared with either young septic or aged sham mice (33 vs. 16 vs. 6 apoptotic cells/100 contiguous crypts, P < 0.05). Elevated intestinal cell death was not associated with changes in either gut proliferation or cell division. To verify that the increase in splenic apoptosis seen in septic aged animals was not strain specific, double-puncture CLP with a 25-gauge needle or sham laparotomy was performed on young (4 months) or aged (24 months) C57BL/6 male mice. Similar to results seen in outbred animals, aged septic animals in this inbred strain had increased splenic apoptosis compared with either young septic animals or aged sham animals (23 vs. 7 vs. 4 apoptotic cells/ high powered field, P < 0.05). These results indicate that although infection and aging each independently cause an increase in splenic and gut epithelial apoptosis, their combination leads to a disproportionate increase in cell death in these rapidly dividing cell populations,and potentially plays a role in the marked increase in mortality seen with aging in sepsis.

High-dose exogenous iron following cecal ligation and puncture increases mortality rate in mice and is associated with an increase in gut epithelial and splenic apoptosis.

OBJECTIVES: Despite having dysregulated iron metabolism, critically ill patients may receive exogenous iron for the treatment of anemia. Iron is associated with increased tissue apoptosis and may facilitate bacterial growth. We hypothesized that exogenous iron administration given after the onset of sepsis would lead to increased mortality rate. To discriminate between elevated cell death and bacterial overgrowth as potential mediators of mortality, we examined gut epithelial and lymphocyte apoptosis and systemic bacterial counts in animals given iron supplementation after the onset of sepsis. DESIGN: Prospective, randomized, controlled study. SETTING: Animal laboratory in a university medical center. SUBJECTS: Male C57BL/6 mice, 6-10 wks old. INTERVENTIONS: C57BL/6 mice were subjected to cecal ligation and puncture (CLP), a well-accepted model of intra-abdominal sepsis, followed by daily subcutaneous injections of either 1 mL of iron dextran (5 mg/mL) or 0.9% NaCl for a total of five doses. Animals (n = 78) were followed for survival for 8 days. Separate cohorts (n = 76) were killed 24 or 48 hrs after cecal ligation and puncture or sham laparotomy and were assayed for gut epithelial and splenic apoptosis as well as for quantitative blood cultures. MEASUREMENTS AND MAIN RESULTS: Eight-day survival was 7% in animals that received iron and 26% in mice that received 0.9% NaCl (p < .005). Iron supplementation after cecal ligation and puncture increased apoptosis by both active caspase 3 and hematoxylin and eosin staining in both the intestinal epithelium and spleen at 24 hrs (p < .05). Iron supplementation after sham laparotomy did not cause mortality or elevated apoptosis. Quantitative blood cultures revealed no detectable differences between septic animals that received iron and those that received 0.9% NaCl. CONCLUSIONS: High-dose iron supplementation with iron dextran after the onset of sepsis significantly increases mortality rate in this animal model. Iron-induced mortality may be mediated by an increase in gut epithelial and splenic apoptosis, whereas severity of bacteremia does not appear to play a causative role.