Risk of malignancy in small pancreatic cysts decreases over time.

BACKGROUND: Pancreatic cysts <15 mm without worrisome features have practically no risk of malignancy at the time of diagnosis but this can change over time. Optimal duration of follow-up is a matter of debate. We evaluated predictors of malignancy and attempted to identify a time to safely discontinue surveillance. METHODS: Bi-centric study utilizing prospectively collected databases of patients with pancreatic cysts measuring <15 mm and without worrisome features who underwent surveillance at the Massachusetts General Hospital (1988-2017) and at the University of Verona Hospital Trust (2000-2016). The risk of malignant transformation was assessed using the Kaplan-Meier method and parametric survival models, and predictors of malignancy were evaluated using Cox regression. RESULTS: 806 patients were identified. Median follow-up was 58 months (6-347). Over time, 58 (7.2%) cysts were resected and of those, 11 had high grade dysplasia (HGD) or invasive cancer. Three additional patients had unresectable cancer for a total rate of malignancy of 1.7%. Predictors of development of malignancy included an increase in size ≥2.5 mm/year (HR = 29.54, 95% CI: 9.39-92.91, P < 0.001) and the development of worrisome features (HR = 9.17, 95% CI: 2.99-28.10, P = 0.001). Comparison of parametric survival models suggested that the risk of malignancy decreased after three years of surveillance and was lower than 0.2% after five years. CONCLUSIONS: Pancreatic cysts <15  mm at the time of diagnosis have a very low risk of malignant transformation. Our findings indicate the risk decreases over time. Size increase of ≥2.5 mm/year is the strongest predictor of malignancy.

Effect of anaesthesia type on postoperative mortality and morbidities: a matched analysis of the NSQIP database.

BACKGROUND: The anaesthetic technique may influence clinical outcomes, but inherent confounding and small effect sizes makes this challenging to study. We hypothesized that regional anaesthesia (RA) is associated with higher survival and fewer postoperative organ dysfunctions when compared with general anaesthesia (GA). METHODS: We matched surgical procedures and type of anaesthesia using the US National Surgical Quality Improvement database, in which 264,421 received GA and 64,119 received RA. Procedures were matched according to Current Procedural Terminology (CPT) and ASA physical status classification. Our primary outcome was 30-day postoperative mortality and secondary outcomes were hospital length of stay, and postoperative organ system dysfunction. After matching, multiple regression analysis was used to examine associations between anaesthetic type and outcomes, adjusting for covariates. RESULTS: After matching and adjusting for covariates, type of anaesthesia did not significantly impact 30-day mortality. RA was significantly associated with increased likelihood of early discharge (HR 1.09; P< 0.001), 47% lower odds of intraoperative complications, and 24% lower odds of respiratory complications. RA was also associated with 16% lower odds of developing deep vein thrombosis and 15% lower odds of developing any one postoperative complication (OR 0.85; P < 0.001). There was no evidence of an effect of anaesthesia technique on postoperative MI, stroke, renal complications, pulmonary embolism or peripheral nerve injury. CONCLUSIONS: After adjusting for clinical and patient characteristic confounders, RA was associated with significantly lower odds of several postoperative complications, decreased hospital length of stay, but not mortality when compared with GA.

Long-term cognitive impairment after critical illness.

BACKGROUND: Survivors of critical illness often have a prolonged and disabling form of cognitive impairment that remains inadequately characterized. METHODS: We enrolled adults with respiratory failure or shock in the medical or surgical intensive care unit (ICU), evaluated them for in-hospital delirium, and assessed global cognition and executive function 3 and 12 months after discharge with the use of the Repeatable Battery for the Assessment of Neuropsychological Status (population age-adjusted mean [±SD] score, 100±15, with lower values indicating worse global cognition) and the Trail Making Test, Part B (population age-, sex-, and education-adjusted mean score, 50±10, with lower scores indicating worse executive function). Associations of the duration of delirium and the use of sedative or analgesic agents with the outcomes were assessed with the use of linear regression, with adjustment for potential confounders. RESULTS: Of the 821 patients enrolled, 6% had cognitive impairment at baseline, and delirium developed in 74% during the hospital stay. At 3 months, 40% of the patients had global cognition scores that were 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury), and 26% had scores 2 SD below the population means (similar to scores for patients with mild Alzheimer's disease). Deficits occurred in both older and younger patients and persisted, with 34% and 24% of all patients with assessments at 12 months that were similar to scores for patients with moderate traumatic brain injury and scores for patients with mild Alzheimer's disease, respectively. A longer duration of delirium was independently associated with worse global cognition at 3 and 12 months (P=0.001 and P=0.04, respectively) and worse executive function at 3 and 12 months (P=0.004 and P=0.007, respectively). Use of sedative or analgesic medications was not consistently associated with cognitive impairment at 3 and 12 months. CONCLUSIONS: Patients in medical and surgical ICUs are at high risk for long-term cognitive impairment. A longer duration of delirium in the hospital was associated with worse global cognition and executive function scores at 3 and 12 months. (Funded by the National Institutes of Health and others; BRAIN-ICU ClinicalTrials.gov number, NCT00392795.).

Emergence from general anaesthesia and evolution of delirium signs in the post-anaesthesia care unit.

BACKGROUND: Emergence from anaesthesia is often accompanied by signs of delirium, including fluctuating mental status and inattention. The evolution of these signs of delirium requires investigation since delirium in the post-anaesthesia care unit (PACU) may be associated with worse outcomes. METHODS: Adult patients emerging from anaesthesia were assessed for agitated emergence in the operating room using the Richmond Agitation-Sedation Scale (RASS). The Confusion Assessment Method for the Intensive Care Unit was then used to evaluate delirium signs at PACU admission and during PACU stay at 30 min, 1 h, and discharge. Signs consistent with delirium were classified as hyperactive vs hypoactive based upon a positive CAM-ICU assessment and the concomitant RASS score. Multivariable logistic regression was utilized to assess potential risk factors for delirium during PACU stay including age, American Society of Anesthesiologists classification, and opioid and benzodiazepine exposure. RESULTS: Among 400 patients enrolled, 19% had agitated emergence. Delirium signs were present at PACU admission, 30 min, 1 h, and PACU discharge in 124 (31%), 59 (15%), 32 (8%), and 15 (4%) patients, respectively. In patients with delirium signs, hypoactive signs were present in 56% at PACU admission and in 92% during PACU stay. Perioperative opioids were associated with delirium signs during PACU stay (P=0.02). CONCLUSIONS: A significant proportion of patients develop delirium signs in the immediate postoperative period, primarily manifesting with a hypoactive subtype. These signs often persist to PACU discharge, suggesting the need for structured delirium monitoring in the PACU to identify patients potentially at risk for worse outcomes in the postoperative period.

Insulin-like growth factor-1 and delirium in critically ill mechanically ventilated patients: a preliminary investigation.

BACKGROUND: Delirium occurs frequently in the intensive care unit (ICU), but its pathophysiology is still unclear. Low levels of insulin-like growth factor 1 (IGF-1), a hormone with neuroprotective properties, have been associated with delirium in some non-ICU studies, but this relationship has not been examined in the ICU. We sought to test the hypothesis that low IGF-1 concentrations are associated with delirium during critical illness. METHODS: Mechanically ventilated medical ICU patients were prospectively enrolled, and blood was collected after enrollment for measurement of IGF-1 using radioimmunometric assay. Delirium and coma were identified daily using the Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation Scale, respectively. The association between IGF-1 and delirium was evaluated with logistic regression. In addition, the association between IGF-1 and duration of normal mental state, measured as days alive without delirium or coma, was assessed using multiple linear regression. RESULTS: Among 110 patients, the median age was 65 years (IQR, 52-75) and APACHE II was 27 (IQR, 22 -32). IGF-1 levels were not a risk factor for delirium on the day after IGF-1 measurement (p = 0.97), at which time 65% of the assessable patients were delirious. No significant association was found between IGF-1 levels and duration of normal mental state (p = 0.23). CONCLUSIONS: This pilot study, the first to investigate IGF-1 and delirium in critically ill patients, found no association between IGF-1 and delirium. Future studies including serial measurements of IGF-1 and IGF-1 binding proteins are needed to determine whether this hormone has a role in delirium during critical illness.

Understanding international differences in terminology for delirium and other types of acute brain dysfunction in critically ill patients.

BACKGROUND: Delirium (acute brain dysfunction) is a potentially life threatening disturbance in brain function that frequently occurs in critically ill patients. While this area of brain dysfunction in critical care is rapidly advancing, striking limitations in use of terminology related to delirium internationally are hindering cross-talk and collaborative research. In the English literature, synonyms of delirium such as the Intensive Care Unit syndrome, acute brain dysfunction, acute brain failure, psychosis, confusion, and encephalopathy are widely used. This often leads to scientific "confusion" regarding published data and methodology within studies, which is further exacerbated by organizational, cultural and language barriers. OBJECTIVE: We undertook this multinational effort to identify conflicts in terminology and phenomenology of delirium to facilitate communication across medical disciplines and languages. METHODS: The evaluation of the terminology used for acute brain dysfunction was determined conducting communications with 24 authors from academic communities throughout countries/regions that speak the 13 variants of the Romanic languages included into this manuscript. RESULTS: In the 13 languages utilizing Romanic characters, included in this report, we identified the following terms used to define major types of acute brain dysfunction: coma, delirium, delirio, delirium tremens, délire, confusion mentale, delir, delier, Durchgangs-Syndrom, acute verwardheid, intensiv-psykose, IVA-psykos, IVA-syndrom, akutt konfusion/forvirring. Interestingly two terms are very consistent: 100 % of the selected languages use the term coma or koma to describe patients unresponsive to verbal and/or physical stimuli, and 100% use delirium tremens to define delirium due to alcohol withdrawal. Conversely, only 54% use the term delirium to indicate the disorder as defined by the DSM-IV as an acute change in mental status, inattention, disorganized thinking and altered level of consciousness. CONCLUSIONS: Attempts towards standardization in terminology, or at least awareness of differences across languages and specialties, will help cross-talk among clinicians and researchers.

Alpha-2 agonists: can they modify the outcomes in the Postanesthesia Care Unit?

While most patients recover uneventfully from the effects of anesthesia and surgery, for a small percentage of patients the immediate postoperative period can be a period of significant physiological stress. Hence the goal for a Post Anesthesia Care Unit (PACU) is to provide a safe environment for a patient to recover, while avoiding the undesirable side effects of pain, nausea, vomiting and shivering, and to monitor for potentially life threatening hemodynamic and respiratory complications that may require admission into the intensive care unit (ICU). Anesthetic techniques in the operating room are extremely important as these may have significant bearing on the post-operative course. The type of surgery, the patients' co morbid conditions, anticipated extubation and recovery of the patient, as well as the sophistication of the PACU and the expertise of its staff, all influence the choice of anesthetic technique. These agents, however, may themselves contribute to some of the complications and unpleasant events encountered in the PACU. Therefore, evaluation of newer and safer agents, which promote a smoother PACU transition, are warranted. Alpha 2 agonists are increasingly being used as adjuvant therapeutic agents in the perioperative period because of their ability to block the sympathetic stress response, complete with their anesthetic and analgesic sparing properties, lack of respiratory depression and low and predictable side effect profile.

Feasibility and safety of early combined cognitive and physical therapy for critically ill medical and surgical patients: the Activity and Cognitive Therapy in ICU (ACT-ICU) trial.

PURPOSE: Cognitive impairment after critical illness is common and debilitating. We developed a cognitive therapy program for critically ill patients and assessed the feasibility and safety of administering combined cognitive and physical therapy early during a critical illness. METHODS: We randomized 87 medical and surgical ICU patients with respiratory failure and/or shock in a 1:1:2 manner to three groups: usual care, early once-daily physical therapy, or early once-daily physical therapy plus a novel, progressive, twice-daily cognitive therapy protocol. Cognitive therapy included orientation, memory, attention, and problem-solving exercises, and other activities. We assessed feasibility outcomes of the early cognitive plus physical therapy intervention. At 3 months, we also assessed cognitive, functional, and health-related quality of life outcomes. Data are presented as median (interquartile range) or frequency (%). RESULTS: Early cognitive therapy was a delivered to 41/43 (95%) of cognitive plus physical therapy patients on 100% (92-100%) of study days beginning 1.0 (1.0-1.0) day following enrollment. Physical therapy was received by 17/22 (77%) of usual care patients, by 21/22 (95%) of physical therapy only patients, and 42/43 (98%) of cognitive plus physical therapy patients on 17% (10-26%), 67% (46-87%), and 75% (59-88%) of study days, respectively. Cognitive, functional, and health-related quality of life outcomes did not differ between groups at 3-month follow-up. CONCLUSIONS: This pilot study demonstrates that early rehabilitation can be extended beyond physical therapy to include cognitive therapy. Future work to determine optimal patient selection, intensity of treatment, and benefits of cognitive therapy in the critically ill is needed.

Sedation in the intensive care unit.

Analgesics and sedatives are commonly prescribed in the ICU environment for patient comfort, however, recent studies have shown that these medications can themselves lead to adverse patient outcomes. Interventions that facilitate a total dose reduction in analgesic and sedative medications e.g. the use of nurse controlled protocol guided sedation, the combination of spontaneous awakening and breathing trials, and the use of short acting medications, are associated with improved outcomes such as decreased time of mechanical ventilation and ICU length of stay. This purpose of this review is to provide an overview of the pharmacology of commonly prescribed analgesics and sedatives, and to discuss the evidence regarding best prescribing practices of these medications, to facilitate early liberation from mechanical ventilation and to promote animation in critically ill patients.

Understanding terminology of delirium and long-term cognitive impairment in critically ill patients.

Delirium, an acute brain dysfunction, frequently affects intensive care unit (ICU) patients during the course of a critical illness. Besides the acute morbidities, ICU survivors often experience long-term sequelae in the form of cognitive impairment (LTCI-CI). Though delirium and LTCI-CI are associated with adverse outcomes, little is known on the terminology used to define these acute and chronic co-morbidities. The use of a correct terminology is a key factor to spread the knowledge on clinical conditions. Therefore, we first review the epidemiology, definition of delirium and its related terminology. Second, we report on the epidemiology of LTCI-CI and compare its definition to other forms of cognitive impairments. In particular, we define mild cognitive impairment, dementia and finally postoperative cognitive dysfunction. Future research is needed to interpret the trajectories of LTCI-CI, to differentiate it from neurodegenerative diseases and to provide a formal disease classification.

Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients.

AIM: The pathophysiology of delirium remains elusive though neurotransmitters and their precursor large neutral amino acids (LNAAs) may play a role. This pilot study investigated whether alterations of tryptophan (Trp), phenylalanine (Phe), and tyrosine (Tyr) plasma levels were associated with a higher risk of transitioning to delirium in critically ill patients. METHODS: Plasma LNAA concentrations were determined on days 1 and 3 in mechanically ventilated (MV) patients from the MENDS randomized controlled trial (dexmedetomidine vs. lorazepam sedation). Three independent variables were calculated by dividing plasma concentrations of Trp, Phe, and Tyr by the sum of all other LNAA concentrations. Delirium was assessed daily using the confusion assessment method for the intensive care unit (CAM-ICU). Markov regression models were used to analyze independent associations between plasma LNAA ratios and transition to delirium after adjusting for covariates. RESULTS: The 97 patients included in the analysis had a high severity of illness (median APACHE II, 28; IQR, 24-32). After adjusting for confounders, only high or very low tryptophan/LNAA ratios (p = 0.0003), and tyrosine/LNAA ratios (p = 0.02) were associated with increased risk of transitioning to delirium, while phenylalanine levels were not (p = 0.27). Older age, higher APACHE II scores and increasing fentanyl exposure were also associated with higher probabilities of transitioning to delirium. CONCLUSIONS: In this pilot study, plasma tryptophan/LNAA and tyrosine/LNAA ratios were associated with transition to delirium in MV patients, suggesting that alterations of amino acids may be important in the pathogenesis of ICU delirium. Future studies evaluating the role of amino acid precursors of neurotransmitters are warranted in critically ill patients.

Vascular and extravascular complications of liver transplantation: comprehensive evaluation with three-dimensional contrast-enhanced volumetric MR imaging and MR cholangiopancreatography.

OBJECTIVE: Our purpose was to evaluate a comprehensive MR imaging strategy for recipients of liver transplants that relies on dynamic interpolated three-dimensional (3D) MR imaging for simultaneous vascular, parenchymal, and extrahepatic imaging. MATERIALS AND METHODS: Twenty-three consecutive adult patients underwent 30 MR imaging examinations between 2 days and 99 months (mean, 15 months) after transplantation using a breath-hold 3D gradient-echo sequence (TR range/TE range, 3.7-4.7/1.8-1.9; flip angle, 12-30 degrees ) with an intermittent fat-saturation pulse and interpolation in the section-select direction to enable pixel size 3 mm or less in all dimensions. Unenhanced and triphasic contrast-enhanced 3D imaging (average dose, 0.13 mmol/kg of gadopentetate dimeglumine) was performed. A subset of patients (n = 13) also underwent MR cholangiopancreatography using half-Fourier single-shot turbo spin-echo imaging. MR imaging examinations were correlated with digital subtraction angiography (n = 8), contrast-enhanced cholangiography (n = 9), sonography (n = 13), and histopathology (n = 14). RESULTS: MR imaging revealed abnormal findings in 27 (90%) of 30 examinations, including vascular disease in nine, biliary complications in four, and evidence of intra- or extra-hepatic hepatocellular carcinoma recurrence in six. Digital subtraction angiography confirmed seven MR angiography examinations but suggested disease overestimation in one. Contrast-enhanced cholangiography confirmed findings of MR cholangiopancreatography in seven cases but suggested disease underestimation in two. CONCLUSION: Dynamic interpolated 3D MR imaging combined with dedicated MR cholangiopancreatography can provide a comprehensive assessment of vascular, biliary, parenchymal, and extrahepatic complications in most recipients of liver transplants.

FLT3 ligand induces the generation of functionally active dendritic cells in mice.

FLT3 ligand (FL) is a recently described hematopoietic growth factor that stimulates the proliferation and differentiation of hematopoietic progenitors. We have investigated the effect of FL on murine hematopoiesis and dendritic cell (DC) generation and accumulation in lymphoid tissues and liver in vivo and in vitro evaluating the morphologic, phenotypic, and functional characteristics of these DC. We have observed extramedullary hematopoiesis in the mouse spleen with all lineages of hematopoietic cells represented after the administration of FL. Injection of FL results in a time-dependent and reversible accumulation of DC in the spleen, bone marrow, lymph nodes, and liver. Both flow cytometry and immunohistochemistry revealed a significant accumulation of DC in these tissues. Results of mixed leukocyte reaction suggested that these cells, isolated from murine bone marrow or spleen, were active as antigen presenting cells. Furthermore, cultivation of splenic and marrow cells with GM-CSF and IL-4 gave rise to large numbers of functionally active mature DC. Thus, the results of this study suggest that FL is a promising growth factor that stimulates the generation of large number of DC and may be a useful cytokine for the immunotherapy of cancer.

MR imaging as the sole preoperative imaging modality for right hepatectomy: a prospective study of living adult-to-adult liver donor candidates.

OBJECTIVE: Our aim was to investigate the feasibility of MR imaging as a comprehensive preoperative imaging test for examination of liver donor candidates for adult-to-adult right lobe transplantation. SUBJECTS AND METHODS: Twenty-five consecutive donor candidates were examined at 1.5 T using a torso phased array coil with breath-hold T1- and T2-weighted imaging of the abdomen, MR cholangiography using T2-weighted turbo spin-echo imaging, and MR angiography and venography of the liver using two interpolated three-dimensional spoiled gradient-echo sequences (average dose of gadolinium contrast material, 0.17 mmol/kg). Images were interpreted for liver parenchymal and extrahepatic abnormalities; measurements of right and left lobe liver volumes; definition of hepatic arterial, portal venous, and hepatic venous anatomy; and definition of the biliary branching pattern. Findings were compared with those of conventional angiography in 13 patients, 11 of whom also had surgical findings for comparison. RESULTS: Nine patients were excluded as candidates for donation on the basis of MR imaging findings that included parenchymal or extrahepatic abnormalities in five patients, vascular anomalies in two, and biliary anomalies in three. Two patients who did not undergo surgery underwent conventional angiography that confirmed MR angiographic findings except for a small (<2 mm) accessory left hepatic artery missed on MR imaging. Of the nine patients who underwent successful right hepatectomy, all MR imaging findings were corroborated intraoperatively. In two patients, right hepatectomy was aborted at laparotomy because of intraoperative cholangiography findings; in one of them, the biliary finding was unsuspected on MR imaging. CONCLUSION: A comprehensive MR imaging examination has the potential to serve as the sole preoperative imaging modality for living adult-to-adult liver donor candidates provided improvements in definition of intrahepatic biliary anatomy can be achieved.