Sprouting of afferent and efferent inputs to pelvic organs after spinal cord injury.

Neural plasticity occurs within the central and peripheral nervous systems after spinal cord injury (SCI). Although central alterations have extensively been studied, it is largely unknown whether afferent and efferent fibers in pelvic viscera undergo similar morphological changes. Using a rat spinal cord transection model, we conducted immunohistochemistry to investigate afferent and efferent innervations to the kidney, colon, and bladder. Approximately 3-4 weeks after injury, immunostaining demonstrated that tyrosine hydroxylase (TH)-labeled postganglionic sympathetic fibers and calcitonin gene-related peptide (CGRP)-immunoreactive sensory terminals sprout in the renal pelvis and colon. Morphologically, sprouted afferent or efferent projections showed a disorganized structure. In the bladder, however, denser CGRP-positive primary sensory fibers emerged in rats with SCI, whereas TH-positive sympathetic efferent fibers did not change. Numerous CGRP-positive afferents were observed in the muscle layer and the lamina propria of the bladder following SCI. TH-positive efferent inputs displayed hypertrophy with large diameters, but their innervation patterns were sustained. Collectively, afferent or efferent inputs sprout widely in the pelvic organs after SCI, which may be one of the morphological bases underlying functional adaptation or maladaptation.

Changes in the epidemiology of ventilator-associated events over the course of the coronavirus disease 2019 (COVID-19) pandemic.

Management of critically ill coronavirus disease 2019 (COVID-19) patients has evolved considerably during the pandemic. We investigated rates and causes of ventilator-associated events (VAEs) in COVID-19 patients in the late versus early waves in 4 Massachusetts hospitals. VAE rates per episode decreased, rates per ventilator day were stable, and most cases were caused by acute respiratory distress syndrome (ARDS).

The susceptibility of cardiac arrhythmias after spinal cord crush injury in rats.

High-level spinal cord injury (SCI) often interrupts supraspinal regulation of sympathetic input to the heart. Although it is known that dysregulated autonomic control increases the risk for cardiac disorders, the mechanisms mediating SCI-induced arrhythmias are poorly understood. Here, we employed a rat model of complete spinal cord crush injury at the 2nd/3rd thoracic (T2/3) level to investigate cardiac rhythm disorders resulting from SCI. Rats with T9 injury and naïve animals served as two controls. Four weeks after SCI, rats were implanted with a radio-telemetric device for electrocardiogram and blood pressure monitoring. During 24-h recordings, heart rate variability in rats with T2/3 but not T9 injury exhibited a significant reduction in the time domain, and a decrease in power at low frequency but increased power at high frequency in the frequency domain which indicates reduced sympathetic and increased parasympathetic outflow to the heart. Pharmacological blockade of the sympathetic or parasympathetic branches confirmed the imbalance of cardiac autonomic control. Activation of sympatho-vagal input during the induction of autonomic dysreflexia by colorectal distention triggered various severe arrhythmic events in T2/3 injured rats. Meanwhile, intravenous infusion of the ß1-adrenergic receptor agonist, dobutamine, caused greater incidence of arrhythmias in rats with T2/3 injury than naïve and T9 injured controls. Together, the results indicate that high-level SCI increases the susceptibility to developing cardiac arrhythmias likely owing to compromised autonomic homeostasis. The T2/3 crush model is appropriate for studying abnormal cardiac electrophysiology resulting from SCI.

Incidence, Characteristics, and Outcomes of Ventilator-associated Events during the COVID-19 Pandemic.

Rationale: Ventilator-associated event (VAE) surveillance provides an objective means to measure and compare complications that develop during mechanical ventilation by identifying patients with sustained increases in ventilator settings after a period of stable or decreasing ventilator settings. The impact of the coronavirus disease (COVID-19) pandemic on VAE rates and characteristics is unknown. Objectives: To compare the incidence, causes, and outcomes of VAE during the COVID-19 pandemic year versus prepandemic years and among ventilated patients with and without COVID-19. Methods: In this retrospective cohort study of mechanically ventilated adults at four academic and community hospitals in Massachusetts, we compared VAE incidence rates between March 1 and August 31 for each year from 2017 to 2020 (corresponding to the time frame of the pandemic first wave in 2020) and among COVID-19-positive and COVID-19-negative patients in 2020. The medical records of 200 randomly selected patients with VAEs in 2020 (100 with COVID-19 and 100 without COVID-19) were analyzed to compare conditions precipitating VAEs in patients with versus without COVID-19. Results: VAEs per 100 episodes of mechanical ventilation were more common in 2020 than in prior years (11.2 vs. 6.7; P < 0.01) but the rate of VAEs per 1,000 ventilator-days was similar (14.2 vs. 12.7; P = 0.08). VAEs were more frequent in COVID-19-positive patients than in COVID-19-negative patients in 2020 (29.0 vs. 7.1 per 100 ventilator episodes [P < 0.01] and 17.2 vs. 12.2 per 1,000 ventilator-days [P < 0.01]). Compared with patients without COVID-19 with VAEs, patients with COVID-19 and VAEs had similar rates of infection-related ventilator-associated complications, longer median durations of mechanical ventilation (22 vs. 14 d; P < 0.01), and similar in-hospital mortality (30% vs. 38%; P = 0.15). Progressive acute respiratory distress syndrome (ARDS) accounted for 53% of VAEs in patients with COVID-19, whereas it accounted for 14% of VAEs among patients without COVID-19. Conclusions: VAE rates per 100 episodes of mechanical ventilation and per 1,000 ventilator-days were higher among COVID-19-positive patients than among COVID-19-negative patients. Over 50% of VAEs in patients with COVID-19 were caused by progressive ARDS, whereas less than 15% of VAEs in patients without COVID-19 were caused by progressive ARDS. These findings provide insight into the natural history of COVID-19 in ventilated patients and may inform targeted strategies to mitigate complications in this population.

Ventilator-Associated Events: Epidemiology, Risk Factors, and Prevention.

The Centers for Disease Control and Prevention shifted the focus of safety surveillance in mechanically ventilated patients from ventilator-associated pneumonia to ventilator-associated events in 2013 to increase the objectivity and reproducibility of surveillance and to encourage quality improvement programs to focus on preventing a broader array of complications. Ventilator-associated events are associated with a doubling of the risk of dying. Prospective studies have found that minimizing sedation, increasing spontaneous awakening and breathing trials, and conservative fluid management can decrease event rates and the duration of ventilation. Multifaceted interventions to enhance these practices can decrease ventilator-associated event rates.

What Is the Utility of Measuring Lactate Levels in Patients with Sepsis and Septic Shock?

Elevations in blood lactate concentrations have been studied in sepsis and other disease states for decades and are well known to be associated with increased mortality. Many studies have also demonstrated the prognostic accuracy of serial lactate levels, and some have suggested that lactate clearance may be a useful therapeutic target for resuscitation. Lactate measurements have therefore gained an increasingly prominent role in sepsis definitions, screening protocols, management guidelines, and quality measures over the past two decades. The heavy emphasis on lactate monitoring, however, has also generated controversy and concerns. Lactate is not specific to infection and its frequent use for sepsis screening and diagnosis may therefore trigger unnecessary broad-spectrum antibiotic use in some patients. Because hyperlactatemia does not always reflect fluid-responsive hypoperfusion, titrating resuscitation to lactate clearance can also lead to unnecessary fluid and volume overload. More broadly, there is a lack of high-quality evidence demonstrating that initial and serial lactate monitoring leads to better patient-centered outcomes. Indeed, a recent randomized controlled trial comparing resuscitation strategies based on lactate clearance versus normalizing capillary refill time showed no benefit and potential harm with lactate-guided therapy. In this article, we review the basic pathobiology of lactate metabolism and delineate why the traditional paradigm that hyperlactatemia reflects tissue hypoxia is overly simplistic and incomplete. We then review the evidence behind the diagnostic, prognostic, and therapeutic uses of lactate monitoring and place this in the context of evolving sepsis diagnosis and management guidelines.

Deciphering Spinal Endogenous Dopaminergic Mechanisms That Modulate Micturition Reflexes in Rats with Spinal Cord Injury.

Spinal neuronal mechanisms regulate recovered involuntary micturition after spinal cord injury (SCI). It was recently discovered that dopamine (DA) is synthesized in the rat injured spinal cord and is involved in lower urinary tract (LUT) activity. To fully understand the role of spinal DAergic machinery in micturition, we examined urodynamic responses in female rats during pharmacological modulation of the DA pathway. Three to four weeks after complete thoracic SCI, the DA precursor L-DOPA administered intravenously during bladder cystometrogram (CMG) and external urethral sphincter (EUS) electromyography (EMG) reduced bladder overactivity and increased the duration of EUS bursting, leading to remarkably improved voiding efficiency. Apomorphine (APO), a non-selective DA receptor (DR) agonist, or quinpirole, a selective DR2 agonist, induced similar responses, whereas a specific DR2 antagonist remoxipride alone had only minimal effects. Meanwhile, administration of SCH 23390, a DR1 antagonist, reduced voiding efficiency by increasing tonic EUS activity and shortening the EUS bursting period. Unexpectedly, SKF 38393, a selective DR1 agonist, increased EUS tonic activity, implying a complicated role of DR1 in LUT function. In metabolic cage assays, subcutaneous administration of quinpirole decreased spontaneous voiding frequency and increased voiding volume; L-DOPA and APO were inactive possibly because of slow entry into the CNS. Collectively, tonically active DR1 in SCI rats inhibit urine storage and enhance voiding by differentially modulating EUS tonic and bursting patterns, respectively, while pharmacologic activation of DR2, which are normally silent, improves voiding by enhancing EUS bursting. Thus, enhancing DA signaling achieves better detrusor-sphincter coordination to facilitate micturition function in SCI rats.

Conversion of the death inhibitor ARC to a killer activates pancreatic ß cell death in diabetes.

Loss of insulin-secreting pancreatic ß cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains ß cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce ß cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. ß cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by ß cells. Loss of the serpin α1-antitrypsin from the extracellular space unleashes elastase, triggering the disruption of ß cell anchorage and subsequent cell death. Administration of α1-antitrypsin to mice with diabetes prevents ß cell death and metabolic abnormalities. These data uncover a pathway for ß cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome.

Delivery of the 5-HT2A Receptor Agonist, DOI, Enhances Activity of the Sphincter Muscle during the Micturition Reflex in Rats after Spinal Cord Injury.

Traumatic spinal cord injury (SCI) interrupts spinobulbospinal micturition reflex pathways and results in urinary dysfunction. Over time, an involuntary bladder reflex is established due to the reorganization of spinal circuitry. Previous studies show that manipulation of serotonin 2A (5-HT2A) receptors affects recovered bladder function, but it remains unclear if this receptor regulates the activity of the external urethral sphincter (EUS) following SCI. To elucidate how central and peripheral serotonergic machinery acts on the lower urinary tract (LUT) system, we employed bladder cystometry and EUS electromyography recordings combined with intravenous or intrathecal pharmacological interventions of 5-HT2A receptors in female SCI rats. Three to four weeks after a T10 spinal transection, systemic and central blockage of 5-HT2A receptors with MDL only slightly influenced the micturition reflex. However, delivery of the 5-HT2A receptor agonist, DOI, increased EUS tonic activity and elicited bursting during voiding. Additionally, subcutaneous administration of DOI verified the enhancement of continence and voiding capability during spontaneous micturition in metabolic cage assays. Although spinal 5HT2A receptors may not be actively involved in the recovered micturition reflex, stimulating this receptor subtype enhances EUS function and the synergistic activity between the detrusor and sphincter to improve the micturition reflex in rats with SCI.

A Critical Analysis of the Literature on Time-to-Antibiotics in Suspected Sepsis.

The Surviving Sepsis Campaign recommends immediate antibiotics for all patients with suspected sepsis and septic shock, ideally within 1 hour of recognition. Immediate antibiotic treatment is lifesaving for some patients, but a substantial fraction of patients initially diagnosed with sepsis have noninfectious conditions. Aggressive time-to-antibiotic targets risk promoting antibiotic overuse and antibiotic-associated harms for this subset of the population. An accurate understanding of the precise relationship between time-to-antibiotics and mortality for patients with possible sepsis is therefore critical to finding the best balance between assuring immediate antibiotics for those patients who truly need them versus allowing clinicians some time for rapid investigation to minimize the risk of overtreatment and antibiotic-associated harms for patients who are not infected. More than 30 papers have been published assessing the relationship between time-to-antibiotics and outcomes, almost all of which are observational cohort studies. Most report significant associations but all have important limitations. Key limitations include focusing just on the sickest subset of patients (only patients requiring intensive care and/or patients with septic shock), blending together mortality estimates from patients with very long intervals until antibiotics with patients with shorter intervals and reporting a single blended (and thus inflated) estimate for the average increase in mortality associated with each hour until antibiotics, and failure to control for large potential confounders including patients' presenting signs and symptoms and granular measures of comorbidities and severity of illness. In this study, we elaborate on these potential sources of bias and try to distill a better understanding of what the true relationship between time-to-antibiotics and mortality may be for patients with suspected sepsis or septic shock.

Validation of clinical scores for right ventricular failure prediction after implantation of continuous-flow left ventricular assist devices.

BACKGROUND: Several clinical prediction schemes for right ventricular failure (RVF) risk after left ventricular assist device (LVAD) implantation have been developed in both the pulsatile- and continuous-flow LVAD eras. The performance of these models has not been evaluated systematically in a continuous-flow LVAD cohort. METHODS: We evaluated 6 clinical RVF prediction models (Michigan, Penn, Utah, Kormos et al, CRITT, Pittsburgh Decision Tree) in 116 patients (age 51 ± 13 years; 41.4% white and 56.0% black; 66.4% men; 56.0% bridge to transplant, 37.1% destination therapy, 17.4% bridge to decision) who received a continuous-flow LVAD (HeartMate II: 79 patients, HeartWare: 37 patients) between 2008 and 2013. RESULTS: Overall, 37 patients (31.9%) developed RVF, defined: as pulmonary vasodilator use for ≥48 hours or inotrope use for ≥14 days post-operatively; re-institution of inotropes; multi-organ failure due to RVF; or need for mechanical RV support. Median (Quartile 1 to Quartile 3) time to initial discontinuation of inotropes was 6 (range 4 to 8) days. Among scores, the Michigan score reached significance for RVF prediction but discrimination was modest (C = 0.62 [95% CI 0.52 to 0.72], p = 0.021; positive predictive value [PPV] 60.0%; negative predictive value [NPV] 75.8%), followed by CRITT (C = 0.60 [95% CI 0.50 to 0.71], p = 0.059; PPV 40.5%; NPV 72.2%). Other models did not significantly discriminate RVF. The newer, INTERMACS 3.0 definition for RVF, which includes inotropic support beyond 7 days, was reached by 57 patients (49.1%). The Kormos model performed best with this definition (C = 0.62 [95% CI 0.54 to 0.71], p = 0.005; PPV 64.3%; NPV 59.5%), followed by Penn (C = 0.61), Michigan (C = 0.60) and CRITT (C = 0.60), but overall score performance was modest. CONCLUSION: Current schemes for post-LVAD RVF risk prediction perform only modestly when applied to external populations.

Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation.

Blockade of the inflammatory cytokine tumor necrosis factor (TNF) in depressed patients with increased inflammation has been associated with decreased depressive symptoms. Nevertheless, the impact of TNF blockade on sleep in depressed patients has not been examined. Accordingly, sleep parameters were measured using polysomnography in 36 patients with treatment resistant major depression at baseline and 2weeks after 3 infusions (week 8) of either the TNF antagonist infliximab (n=19) or placebo (n=17). Markers of inflammation including c-reactive protein (CRP) and TNF and its soluble receptors were also assessed along with depression measured by the 17-item Hamilton Depression Rating Scale. No differences in sleep parameters were found as a function of infliximab treatment over time. Nevertheless, wake after sleep onset (WASO), the spontaneous arousal index and sleep period time significantly decreased, and sleep efficiency significantly increased, from baseline to week 8 in infliximab-treated patients with high (CRP>5mg/L) (n=9) versus low inflammation (CRP⩽5mg/L) (n=10), controlling for changes in scores of depression. Stage 2 sleep also significantly decreased in infliximab-treated patients with high versus low inflammation. Decreases in soluble TNF receptor 1 (sTNFR1) significantly correlated with decreases in WASO and increases in sleep efficiency in infliximab-treated subjects with high inflammation. Placebo-treated subjects exhibited no sleep changes as a function of inflammation, and no correlations between inflammatory markers and sleep parameters in placebo-treated patients were found. These data suggest that inhibition of inflammation may be a viable strategy to improve sleep alterations in patients with depression and other disorders associated with increased inflammation.

The apoptosis inhibitor ARC alleviates the ER stress response to promote ß-cell survival.

Type 2 diabetes involves insulin resistance and ß-cell failure leading to inadequate insulin secretion. An important component of ß-cell failure is cell loss by apoptosis. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of apoptosis that is expressed in cardiac and skeletal myocytes and neurons. ARC possesses the unusual property of antagonizing both the extrinsic (death receptor) and intrinsic (mitochondria/endoplasmic reticulum [ER]) cell death pathways. Here we report that ARC protein is abundant in cells of the endocrine pancreas, including >99.5% of mouse and 73% of human ß-cells. Using genetic gain- and loss-of-function approaches, our data demonstrate that ARC inhibits ß-cell apoptosis elicited by multiple inducers of cell death, including ER stressors tunicamycin, thapsigargin, and physiological concentrations of palmitate. Unexpectedly, ARC diminishes the ER stress response, acting distal to protein kinase RNA-like ER kinase (PERK) and inositol-requiring protein 1α, to suppress C/EBP homologous protein (CHOP) induction. Depletion of ARC in isolated islets augments palmitate-induced apoptosis, which is dramatically rescued by deletion of CHOP. These data demonstrate that ARC is a previously unrecognized inhibitor of apoptosis in ß-cells and that its protective effects are mediated through suppression of the ER stress response pathway.

One hundred consecutive laparoscopic ventral hernia repairs.

BACKGROUND: Laparoscopic ventral hernia repair is becoming a promising alternative with many potential advantages, but this procedure is still under study. Our objective was to evaluate the efficacy of the laparoscopic approach to ventral hernia repair. METHODS: One hundred consecutive laparoscopic ventral hernia repairs between April 2000 and February 2003 were prospectively entered into a database and reviewed. RESULTS: Ninety-seven ventral hernia repairs were completed laparoscopically. The mean time in the operating room was 128 minutes (range 37 to 255). The average length of stay was 2 days (range 0 to 9). The mortality rate was 0%. A total of 23% of patients experienced postoperative complications. Over a mean follow-up period of 3 months (range 0 to 26), 6% (6 of 97) of patients experienced recurrences. CONCLUSIONS: Laparoscopic ventral hernia repair can be safely performed with a low conversion rate and acceptable recurrence rate, operative time, length of stay, and morbidity. Securing the mesh with full-thickness abdominal wall sutures in at least 4 quadrants remains a key factor in preventing early recurrence.