J. Trent Magruder

Diabetes and pancreatic cancer: chicken or egg?

Objectives: Although half of all patients with pancreatic cancer are diabetic at the time of diagnosis, it remains unclear whether the diabetes associated with pancreatic cancer is a cause or an effect of the malignancy. Methods: Epidemiologic studies were reviewed, the geographic prevalence of diabetes and the incidence of pancreatic cancer were examined, and clinical and laboratory studies were reviewed. Results: Long-standing diabetes increases the risk of pancreatic cancer by 40% to 100%, and recent-onset diabetes is associated with a 4- to 7-fold increase in risk, such that 1% to 2% of patients with recent-onset diabetes will develop pancreatic cancer within 3 years. Treatment of diabetes or morbid obesity decreases the risk of pancreatic cancer, and metformin therapy decreases the risk due to both its antidiabetic and antineoplastic effects. Recent-onset diabetes associated with pancreatic cancer likely represents secondary or type 3 diabetes. The discrimination of type 3 diabetes from the more prevalent type 2 diabetes may identify the high-risk subgroup of diabetic patients in whom potentially curable pancreatic cancer may be found. Conclusions: Type 2 and type 1 diabetes mellitus increase the risk of pancreatic cancer with a latency period of more than 5 years. Type 3 diabetes mellitus is an effect, and therefore a harbinger, of pancreatic cancer in at least 30% of patients.

Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: Unraveling the role of gut hormonal and pancreatic endocrine dysfunction

BACKGROUND Profound hypoglycemia occurs rarely as a late complication after Roux-en-Y gastric bypass (RYGB). We investigated the role of glucagon-like-peptide-1 (GLP-1) in four subjects who developed recurrent neuro-glycopenia 2 to 3 y after RYGB. METHODS A standardized test meal (STM) was administered to all four subjects. A 2 h hyperglycemic clamp with GLP-1 infusion during the second hour was performed in one subject, before, during a 4 wk trial of octreotide (Oc), and after 85% distal pancreatectomy. After cessation of both glucose and GLP-1 infusion at the end of the 2 h clamp, blood glucose levels were monitored for 30 min. Responses were compared with a control group (five subjects 12 mo status post-RYGB without hypoglycemic symptoms). RESULTS During STM, both GLP-1 and insulin levels were elevated 3- to 4-fold in all subjects, and plasma glucose-dependent insulinotropic peptide (GIP) levels were elevated 2-fold. Insulin responses to hyperglycemia ± GLP-1 infusion in one subject were comparable to controls, but after cessation of glucose infusion, glucose levels fell to 40 mg/dL. During Oc, the GLP-1 and insulin responses to STM were reduced (>50%). During the clamp, insulin response to hyperglycemia alone was reduced, but remained unchanged during GLP-1. Glucagon levels during hyperglycemia alone were suppressed and further suppressed after the addition of GLP-1. With the substantial drop in glucose during the 30 min follow-up, glucagon levels failed to rise. Due to persistent symptoms, one subject underwent 85% distal pancreatectomy; postoperatively, the subject remained asymptomatic (blood glucose: 119-220 mg/dL), but a repeat STM showed persistence of elevated levels of GLP-1. Histologically enlarged islets, and β-cell clusters scattered throughout the acinar parenchyma were seen, as well as β-cells present within pancreatic duct epithelium. An increase in pancreatic and duodenal homeobox-1 protein (PDX-1) expression was observed in the subject compared with control pancreatic tissue. CONCLUSIONS A persistent exaggerated hypersecretion of GLP-1, which has been shown to be insulinotropic, insulinomimetic, and glucagonostatic, is the likely cause of post-RYGB hypoglycemia. The hypertrophy and ectopic location of β-cells is likely due to overexpression of the islet cell transcription factor, PDX-1, caused by prolonged hypersecretion of GLP-1.

Long-term outcomes of aortic root operations for Marfan syndrome: A comparison of Bentall versus aortic valve-sparing procedures

OBJECTIVES Prophylactic aortic root replacement improves survival in patients with Marfan syndrome with aortic root aneurysms, but the optimal procedure remains undefined. METHODS Adult patients with Marfan syndrome who had Bentall or aortic valve-sparing root replacement (VSRR) procedures between 1997 and 2013 were identified. Comprehensive follow-up information was obtained from hospital charts and telephone contact. RESULTS One hundred sixty-five adult patients with Marfan syndrome (aged > 20 years) had either VSRR (n = 98; 69 reimplantation, 29 remodeling) or Bentall (n = 67) procedures. Patients undergoing Bentall procedure were older (median, 37 vs 36 years; P = .03), had larger median preoperative sinus diameter (5.5 cm vs 5.0 cm; P = .003), more aortic dissections (25.4% vs 4.1%; P < .001), higher incidence of moderate or severe aortic insufficiency (49.3% vs 14.4%; P < .001) and more urgent or emergent operations (24.6% vs 3.3%; P < .001). There were no hospital deaths and 9 late deaths in more than 17 years of follow-up (median, 7.8 deaths). Ten-year survival was 90.5% in patients undergoing Bentall procedure and 96.3% in patients undergoing VSRR (P = .10). Multivariable analysis revealed that VSRR was associated with fewer thromboembolic or hemorrhagic events (hazard ratio, 0.16; 95% confidence interval, 0.03-0.85; P = .03). There was no independent difference in long-term survival, freedom from reoperation, or freedom from endocarditis between the 2 procedures. CONCLUSIONS After prophylactic root replacement in patients with Marfan syndrome, patients undergoing Bentall and valve-sparing procedures have similar late survival, freedom from root reoperation, and freedom from endocarditis. However, valve-sparing procedures result in significantly fewer thromboembolic and hemorrhagic events.

Nadir Oxygen Delivery on Bypass and Hypotension Increase Acute Kidney Injury Risk After Cardiac Operations.

BACKGROUND Acute kidney injury (AKI) continues to complicate cardiac operations. We sought to determine whether nadir oxygen delivery (DO2) on cardiopulmonary bypass (CPB) was a risk factor for AKI while also accounting for other postoperative factors. METHODS Using propensity scoring, we matched 85 patients who developed AKI after cardiac operations on CPB with 85 control patients who did not. We analyzed the following variables through midnight on postoperative day 1 (POD1): DO2, antibiotics, blood products and vasopressors (intraoperatively and postoperatively), and hemodynamic variables. RESULTS Univariable analysis revealed AKI patients had lower nadir DO2 on CPB (208 vs 230 mL O2/min/m(2) body surface area, p = 0.03), lower intensive care unit admission blood pressure gradient across the kidney (mean arterial pressure minus central venous pressure; 60 vs 68 mm Hg; p < 0.001), a greater proportion of patients with mean arterial pressure of less than 60 mm Hg for more than 15 minutes in the postoperative period (70% vs 42%, p < 0.001), a greater chance of having a cardiac index of less than 2.2 (74% vs 49%, p = 0.02), and greater total vasopressor use through the end of POD1 (5.2 vs 2.3 mg, p = 0.002). On multivariable analysis, predictors of AKI were a DO2 on CPB of less than 225 mL O2/min/m(2) (odds ratio, 2.46; 95% confidence interval, 1.21 to 5.03; p = 0.01) and postoperative mean arterial pressure of less than 60 mm Hg for more than 15 minutes (odds ratio, 3.96; 95% confidence interval, 1.92 to 8.20; p < 0.001). An average postoperative pressor dose greater than 0.03 μg/kg/min did not reach significance (odds ratio, 1.98; 95% confidence interval, 0.95 to 4.11; p = 0.07). CONCLUSIONS Postoperative hypotension on POD0 or POD1 and low DO2 on CPB both independently increase the AKI risk in cardiac surgical patients.

MELD-XI Score Predicts Early Mortality in Patients After Heart Transplantation

BACKGROUND The aim of this study was to determine the utility of the Model for End-Stage Liver Disease Excluding INR (MELD-XI) in predicting early outcomes (30 days and 1 year) and late outcomes (5 years) in patients after orthotopic heart transplantation (OHT). METHODS The United Network for Organ Sharing database was queried for all adult patients (aged ≥ 18 years) undergoing OHT from 2000 to 2012. A MELD-XI was calculated and the population stratified into score quartiles. Early and late survivals were compared among the MELD-XI cohorts. Multivariable Cox proportional hazards models were constructed to determine the capacity of MELD-XI (when modeled both as a categoric and a continuous variable) to predict 30-day, 1-year, and 5-year mortality. Conditional models were also designed to determine the effect of early mortality on long-term survival. RESULTS A total of 22,597 patients were included for analysis. The MELD-XI cutoff scores were established as follows: low (≤ 10.5), low-intermediate (10.6 to 12.6), intermediate-high (12.7 to 16.4), and high (>16.4). The high MELD-XI cohort experienced statistically worse 30-day, 1-year, and 5-year unconditional survivals when compared with patients with low scores (p < 0.001). Similarly, a high MELD-XI score was also predictive of early and late mortality (p < 0.001) after risk adjustment. There was, however, no difference in 5-year survival between the high score and low score cohorts after accounting for 1-year deaths. Subanalysis of patients bridged to transplant with a continuous-flow left ventricular assist device demonstrated similar findings. CONCLUSIONS This is the first known study to examine the relationship between a high MELD-XI score and outcomes in patients after OHT. Patients with hepatic or renal dysfunction before OHT should be closely monitored and aggressively optimized as early mortality appears to drive long-term outcomes.

Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model

&NA; Hypothermic circulatory arrest (HCA) provides neuroprotection during cardiac surgery but entails an ischemic period that can lead to excitotoxicity, neuroinflammation, and subsequent neurologic injury. Hydroxyl polyamidoamine (PAMAM) dendrimers target activated microglia and damaged neurons in the injured brain, and deliver therapeutics in small and large animal models. We investigated the effect of dendrimer size on brain uptake and explored the pharmacokinetics in a clinically‐relevant canine model of HCA‐induced brain injury. Generation 6 (G6, ˜6.7 nm) dendrimers showed extended blood circulation times and increased accumulation in the injured brain compared to generation 4 dendrimers (G4, ˜4.3 nm), which were undetectable in the brain by 48 h after final administration. High levels of G6 dendrimers were found in cerebrospinal fluid (CSF) of injured animals with a CSF/serum ratio of ˜20% at peak, a ratio higher than that of many neurologic pharmacotherapies already in clinical use. Brain penetration (measured by drug CSF/serum level) of G6 dendrimers correlated with the severity of neuroinflammation observed. G6 dendrimers also showed decreased renal clearance rate, slightly increased liver and spleen uptake compared to G4 dendrimers. These results, in a large animal model, may offer insights into the potential clinical translation of dendrimers. Graphical abstract Figure. No caption available.

A novel risk score that incorporates recipient and donor variables to predict 1-year mortality in the current era of lung transplantation

BACKGROUND In this study we sought to construct a novel scoring system to pre-operatively stratify a patients risk of 1-year mortality after lung transplantation (LTx) based on recipient- and donor-specific characteristics. METHODS The UNOS database was queried for adult (≥18 years) patients undergoing LTx between May 1, 2005 and December 31, 2012. The population was randomly divided in a 4:1 fashion into derivation and validation cohorts. A multivariable logistic regression model for 1-year mortality was constructed within the derivation cohort. Points were then assigned to independent predictors (p < 0.05) based on relative odds ratios. Risk groups were established based on score ranges. RESULTS During the study period, 9,185 patients underwent LTx and the 1-year mortality was 18.0% (n = 1,654). There was a similar distribution of variables between the derivation (n = 7,336) and validation (n = 1,849) cohorts. Of the 14 covariates included in the final model, 9 were ultimately allotted point values (maximum score = 70). The model exhibited good predictive strength (c = 0.65) in the derivation cohort and demonstrated a strong correlation between the observed and expected rates of 1-year mortality in the validation cohort (r = 0.87). The low-risk (score 0 to 11), intermediate-risk (score 12 to 21) and high-risk (score ≥22) groups had a 10.8%, 17.1% and 32.0% risk of mortality (p < 0.001), respectively. CONCLUSIONS This is the first scoring system that incorporates both recipient- and donor-related factors to predict 1-year mortality after LTx. Its use could assist providers in the identification of patients at highest risk for poor post-transplant outcomes.

Accuracy and Reliability of the Nova StatStrip® Glucose Meter for Real-Time Blood Glucose Determinations during Glucose Clamp Studies

Aims/Hypothesis: The Andres clamp technique, which requires accurate and timely determination of glucose, utilizes the Beckman or Yellow Springs Instruments (YSI) glucose analyzers. Both instruments require maintenance, a dedicated operator, preparation of a plasma sample, and a duplicate measurement that takes ≥2 minutes. The Nova StatStrip glucose meter was evaluated for accuracy, reliability, and near-real-time availability of glucose. Methods: Blood samples from 24 patients who underwent 6-hour clamp studies and 12 patients who had a standardized meal tolerance test (SMT) were measured. Specimens were analyzed simultaneously and immediately upon collection by Beckman, YSI, and Nova. Results: Of 1004 data pairs for the Nova device versus Beckman, the Nova data points ranged from 32 to 444, while Beckman ranged from 42 to 412. The coefficient for the slope of Beckman versus Nova was 1.009 (r = 0.978). Using error grid analysis, the number and percentage of values for Nova were 976 (97.2%) in the A zone and 28 (2.8%) in the B zone. Of 399 data pairs for the Nova device versus YSI, the Nova data points ranged from 46 to 255, whereas YSI ranged from 47 to 231. The coefficient for the slope of YSI versus Nova was 1.023 (r = 0.989). All Nova readings fell in the A zone. Time required for final reading, in duplicate, was 15 seconds for Nova and 120–180 seconds for Beckman and YSI. Conclusions: The simplicity of Nova and its reliability, accuracy, and speed make it an acceptable replacement device for Beckman and YSI in the conduct of clamps, especially when perturbations require rapid glucose determination.

A pilot goal-directed perfusion initiative is associated with less acute kidney injury after cardiac surgery.

Background: We sought to determine whether a pilot goal‐directed perfusion initiative could reduce the incidence of acute kidney injury after cardiac surgery. Methods: On the basis of the available literature, we identified goals to achieve during cardiopulmonary bypass (including maintenance of oxygen delivery >300 mL O2/min/m2 and reduction in vasopressor use) that were combined into a goal‐directed perfusion initiative and implemented as a quality improvement measure in patients undergoing cardiac surgery at Johns Hopkins during 2015. Goal‐directed perfusion initiative patients were matched to controls who underwent cardiac surgery between 2010 and 2015 using propensity scoring across 15 variables. The primary and secondary outcomes were the incidence of acute kidney injury and the mean increase in serum creatinine within the first 72 hours after cardiac surgery. Results: We used the goal‐directed perfusion initiative in 88 patients and matched these to 88 control patients who were similar across all variables, including mean age (61 years in controls vs 64 years in goal‐directed perfusion initiative patients, P = .12) and preoperative glomerular filtration rate (90 vs 83 mL/min, P = .34). Controls received more phenylephrine on cardiopulmonary bypass (mean 2.1 vs 1.4 mg, P < .001) and had lower nadir oxygen delivery (mean 241 vs 301 mL O2/min/m2, P < .001). Acute kidney injury incidence was 23.9% in controls and 9.1% in goal‐directed perfusion initiative patients (P = .008); incidences of acute kidney injury stage 1, 2, and 3 were 19.3%, 3.4%, and 1.1% in controls, and 5.7%, 3.4%, and 0% in goal‐directed perfusion initiative patients, respectively. Control patients exhibited a larger median percent increase in creatinine from baseline (27% vs 10%, P < .001). Conclusions: The goal‐directed perfusion initiative was associated with reduced acute kidney injury incidence after cardiac surgery in this pilot study.

Development of a Transplantation Risk Index in Patients With Mechanical Circulatory Support: A Decision Support Tool.

OBJECTIVES The aim of this study was to develop a risk index specific to patients on mechanical circulatory support that accurately predicts 1-year mortality after orthotopic heart transplantation using the United Network for Organ Sharing database. BACKGROUND Few clinical tools are available to aid in the decision between continuing long-term device support and performing transplantation in patients bridging with mechanical circulatory support. METHODS Using a prospectively collected, open cohort, 6,036 patients receiving mechanical circulatory support who underwent orthotopic heart transplantation between 2000 and 2013 were evaluated and randomly separated into derivation (80%) and validation (20%) groups. Multivariate logistic regression models were constructed using variables that improved the explanatory power of the model, which was determined using multiple methods. Points for a simple additive risk index were apportioned on the basis of relative effect on odds of 1-year mortality. RESULTS A 75-point scoring system was created from 9 recipient and 4 donor variables. The average score in the validation cohort was 14.4 ± 7.7, and scores ranged from 0 to 57; these values were similar to those in the derivation cohort. Each 1-point increase predicted an 8.3% increase in the odds of 1-year mortality (odds ratio: 1.08; 95% confidence interval: 1.06 to 1.11). Low (0 to 10), intermediate (11 to 20), and high (>20) risk score cohorts were created, with predicted average 1-year mortalities of 8.6%, 12.8%, and 31%, respectively, in the validation cohort. CONCLUSIONS The investigators present a novel, internally cross-validated risk index that accurately predicts mortality in bridge-to-transplantation patients.