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Introduction: Interventional radiology procedures and endoscopies are performed commonly worldwide, often necessitating pharmacological sedation to optimise patient comfort. It is unclear to what extent non-anaesthetists should provide procedural sedation., Methods: We studied adult patients who previously lived independently and underwent a non-ambulatory interventional radiology or gastroenterology procedure under anaesthetist-directed or non-anaesthetist-directed sedation at a large healthcare network. The primary outcomes were postprocedural adverse discharge to a nursing home and postprocedural duration of hospital stay., Results: Among 22,868 patients included, 15,168 (66.3%) and 7700 (33.7%) underwent anaesthetist-directed sedation and non-anaesthetist-directed sedation, respectively. Of all patients receiving anaesthetist-directed sedation, 9.2% experienced adverse discharge to a nursing home compared with 21.3% undergoing non-anaesthetist-directed sedation. Anaesthetist-directed sedation was associated with reduced risk of adverse discharge to a nursing home (adjusted relative risk 0.54, 95%CI 0.45-0.63, p < 0.001, adjusted risk difference -4.6%, 95%CI -5.8 to -3.4, p < 0.001) and a shorter postprocedural duration of hospital stay (median (IQR [range]) 2 (1-6 [0-315]) days vs. 5 (2-12 [0-268]) days; adjusted model estimate 0.84, 95%CI 0.79-0.89, p < 0.001). The lower risk of adverse discharge to a nursing home and shorter duration of hospital stay in patients undergoing anaesthetist-directed sedation was reproduced in an instrumental variable analysis (adjusted risk difference -4.3%, 95%CI -8.4 to -0.1, p = 0.043; and -1.41 days, 95%CI -1.43 to -1.41 days, p < 0.001, respectively). Among patients undergoing anaesthetist-directed sedation the mean (SD) proportion of missing blood pressure measurements was lower (0.7 (4.9) % vs. 8.0 (14.6) %, p < 0.001), which mediated the effect of anaesthetist-directed sedation on adverse discharge., Discussion: Among patients undergoing a non-ambulatory interventional radiology procedure or a gastrointestinal endoscopy, anaesthetist-directed sedation is associated with a reduced risk of adverse discharge to a nursing home and a shorter duration of hospital stay., (© 2024 Association of Anaesthetists.)

The role of antithrombotic therapy in the prevention of ischemic stroke after non-cardiac surgery is unclear. In this study, we tested the hypothesis that the association of new-onset postoperative atrial fibrillation (POAF) on ischemic stroke can be mitigated by postoperative oral anticoagulation therapy. Of 251,837 adult patients (155,111 female (61.6%) and 96,726 male (38.4%)) who underwent non-cardiac surgical procedures at two sites, POAF was detected in 4,538 (1.8%) patients. The occurrence of POAF was associated with increased 1-year ischemic stroke risk (3.6% versus 2.3%; adjusted risk ratio (RRadj) = 1.60 (95% confidence interval (CI): 1.37-1.87), P < 0.001). In patients with POAF, the risk of developing stroke attributable to POAF was 1.81 (95% CI: 1.44-2.28; P < 0.001) without oral anticoagulation, whereas, in patients treated with anticoagulation, no significant association was observed between POAF and stroke (RRadj = 1.04 (95% CI: 0.71-1.51), P = 0.847, P for interaction = 0.013). Furthermore, we derived and validated a computational model for the prediction of POAF after non-cardiac surgery based on demographics, comorbidities and procedural risk. These findings suggest that POAF is predictable and associated with an increased risk of postoperative ischemic stroke in patients who do not receive postoperative anticoagulation., Competing Interests: Competing interests M.E. receives funding from the National Institutes of Health (NIH) (R01AG065554 and R01HL132887) that does not pertain to this manuscript. He holds two patents for acyclic curcubiturils for reversal of drugs of abuse and neuromuscular blocking agents (patent numbers 9956229 and 9469648). He is a member of the associated editorial board for the British Journal of Anaesthesia. D.L.B. discloses the following relationships. Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma and Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options) and High Enroll (stock); Consultant: Broadview Ventures, Hims, SFJ and Youngene; Data Monitoring Committee: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic, Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute and Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (ACC) (senior associate editor, Clinical Trials and News; chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee, funded by Boehringer Ingelheim; AEGIS-II executive committee, funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (American Heart Association lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor and associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee and steering committee and USA national co-leader, funded by Bayer), WebMD (CME steering committees) and Wiley (steering committee); Other: Clinical Cardiology (deputy editor); Patent: sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital, assigned to Lexicon; neither D.L.B. nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene and 89Bio; Royalties: Elsevier (editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte and Vascular Solutions; Trustee: ACC; Unfunded Research: FlowCo. M.S.S. received funding for investigator-initiated studies from Merck & Co., which does not pertain to this manuscript. He is an associate editor for BMC Anesthesiology. He received honoraria for lectures from Fisher & Paykel Healthcare and Mindray Medical International Limited. He received an unrestricted philanthropic grant from Jeff and Judy Buzen. All other authors have no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work and no other relationships or activities that could appear to have influenced the submitted work., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Study Objective: A low dynamic driving pressure during mechanical ventilation for general anesthesia has been associated with a lower risk of postoperative respiratory complications (PRC), a key driver of healthcare costs. It is, however, unclear whether maintaining low driving pressure is clinically relevant to measure and contain costs. We hypothesized that a lower dynamic driving pressure is associated with lower costs., Design: Multicenter retrospective cohort study., Setting: Two academic healthcare networks in New York and Massachusetts, USA., Patients: 46,715 adult surgical patients undergoing general anesthesia for non-ambulatory (inpatient and same-day admission) surgery between 2016 and 2021., Interventions: The primary exposure was the median intraoperative dynamic driving pressure., Measurements: The primary outcome was direct perioperative healthcare-associated costs, which were matched with data from the Healthcare Cost and Utilization Project-National Inpatient Sample (HCUP-NIS) to report absolute differences in total costs in United States Dollars (US$). We assessed effect modification by patients' baseline risk of PRC (score for prediction of postoperative respiratory complications [SPORC] ≥ 7) and effect mediation by rates of PRC (including post-extubation saturation < 90%, re-intubation or non-invasive ventilation within 7 days) and other major complications., Main Results: The median intraoperative dynamic driving pressure was 17.2cmH 2 O (IQR 14.0-21.3cmH 2 O). In adjusted analyses, every 5cmH 2 O reduction in dynamic driving pressure was associated with a decrease of -0.7% in direct perioperative healthcare-associated costs (95%CI -1.3 to -0.1%; p = 0.020). When a dynamic driving pressure below 15cmH 2 O was maintained, -US$340 lower total perioperative healthcare-associated costs were observed (95%CI -US$546 to -US$132; p = 0.001). This association was limited to patients at high baseline risk of PRC (n = 4059; -US$1755;97.5%CI -US$2495 to -US$986; p < 0.001), where lower risks of PRC and other major complications mediated 10.7% and 7.2% of this association (p < 0.001 and p = 0.015, respectively)., Conclusions: Intraoperative mechanical ventilation targeting low dynamic driving pressures could be a relevant measure to reduce perioperative healthcare-associated costs in high-risk patients., Competing Interests: Declaration of competing interest Daniel Talmor received speaking fees and grant funds from Hamilton Medical, Inc. and Mindray Medical, outside the submitted work. Matthias Eikermann received grants from Merck & Co and serves as an Associate Editor for the British Journal of Anaesthesia. Maximilian S. Schaefer received funding for investigator-initiated studies from Merck & Co., which do not pertain to this manuscript. He is an associate editor for BMC Anesthesiology. He received honoraria for lectures from Fisher & Paykel Healthcare and Mindray Medical International Limited. He received an unrestricted philanthropic grant from Dr. Jeffrey and Judith Buzen. All other authors have no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work. This work was supported by an unrestricted grant from Dr. Jeffrey and Judith Buzen to Maximilian S. Schaefer. Dr. Jeffrey and Judith Buzen had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication., (Copyright © 2024. Published by Elsevier Inc.)

Objective: We estimated hospital costs associated with postoperative reintubation and tested the hypothesis that prolonged surveillance in the post-anesthesia care unit (PACU) modifies the hospital costs of reintubation., Design: Retrospective observational research study., Setting: Two tertiary care academic healthcare networks in the Bronx, New York and Boston, Massachusetts, USA., Patients: 68,125 adult non-cardiac surgical patients undergoing general anesthesia between 2016 and 2021., Interventions: The exposure variable was unplanned reintubation within 7 days of surgery., Measurements: The primary outcome was direct hospital costs associated with patient care related activities. We used a multivariable generalized linear model based on log-transformed costs data, adjusting for pre- and intraoperative confounders. We matched our data with data from the Healthcare Cost and Utilization Project-National Inpatient Sample (HCUP-NIS). In the key secondary analysis, we examined if prolonged postoperative surveillance, defined as PACU utilization (≥4 h) modifies the association between reintubation and costs of care., Main Results: 1759 (2.6%) of patients were re-intubated within 7 days after surgery. Reintubation was associated with higher direct hospital costs (adjusted model estimate 2.05; 95% CI: 2.00-2.10) relative to no reintubation. In the HCUP-NIS matched cohort, the adjusted absolute difference (AD adj ) in costs amounted to US$ 18,837 (95% CI: 17,921-19,777). The association was modified by the duration of PACU surveillance (p-for-interaction <0.001). In patients with a shorter PACU length of stay, reintubation occurred later (median of 2 days; IQR 1, 5) versus 1 days (IQR 0, 2; p < .001), and was associated with magnified effects on hospital costs compared to patients who stayed in the PACU longer (AD adj of US$ 23,444, 95% CI: 21,217-25,799 versus AD adj of US$ 17,615, 95% CI: 16,350-18,926; p < .001)., Conclusion: Postoperative reintubation is associated with 2-fold higher hospital costs. Prolonged surveillance in the recovery room mitigated this effect. The cost-saving effect of longer PACU length of stay was likely driven by earlier reintubation in patients who needed this intervention., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Study Objective: Postoperative respiratory failure is a major surgical complication and key quality metric. Existing prediction tools underperform, are limited to specific populations, and necessitate manual calculation. This limits their implementation. We aimed to create an improved, machine learning powered prediction tool with ideal characteristics for automated calculation., Design, Setting, and Patients: We retrospectively reviewed 101,455 anesthetic procedures from 1/2018 to 6/2021. The primary outcome was the Standardized Endpoints in Perioperative Medicine consensus definition for postoperative respiratory failure. Secondary outcomes were respiratory quality metrics from the National Surgery Quality Improvement Sample, Society of Thoracic Surgeons, and CMS. We abstracted from the electronic health record 26 procedural and physiologic variables previously identified as respiratory failure risk factors. We randomly split the cohort and used the Random Forest method to predict the composite outcome in the training cohort. We coined this the RESPIRE model and measured its accuracy in the validation cohort using area under the receiver operating curve (AUROC) analysis, among other measures, and compared this with ARISCAT and SPORC-1, two leading prediction tools. We compared performance in a validation cohort using score cut-offs determined in a separate test cohort., Main Results: The RESPIRE model exhibited superior accuracy with an AUROC of 0.93 (95% CI, 0.92-0.95) compared to 0.82 for both ARISCAT and SPORC-1 (P-for-difference < 0.0001 for both). At comparable 80-90% sensitivities, RESPIRE had higher positive predictive value (11%, 95% CI: 10-12%) and lower false positive rate (12%, 95% CI: 12-13%) compared to 4% and 37% for both ARISCAT and SPORC-1. The RESPIRE model also better predicted the established quality metrics for postoperative respiratory failure., Conclusions: We developed a general-purpose, machine learning powered prediction tool with superior performance for research and quality-based definitions of postoperative respiratory failure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Patient blood management (PBM) is a systematic, evidence-based approach to improve patient outcomes by managing and preserving a patient's own blood and minimizing allogenic transfusion need and risk. According to the PBM approach, the goals of perioperative anemia management include early diagnosis, targeted treatment, blood conservation, restrictive transfusion except in cases of acute and massive hemorrhage, and ongoing quality assurance and research efforts to advance overall blood health., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To evaluate whether different gamma-aminobutyric acidergic (GABAergic) sedatives such as propofol and benzodiazepines carry differential risks of post-extubation delirium in the ICU., Design: Retrospective cohort study., Setting: Seven ICUs in an academic hospital network, Beth Israel Deaconess Medical Center (Boston, MA)., Patients: Ten thousand five hundred and one adult patients mechanically ventilated for over 24 hours., Interventions: None., Measurements and Main Results: We tested the hypothesis that benzodiazepine versus propofol-based sedation is associated with fewer delirium-free days within 14 days after extubation. Further, we hypothesized that the measured sedation level evoked by GABAergic drugs is a better predictor of delirium than the drug dose administered. The proportion of GABAergic drug-induced deep sedation was defined as the ratio of days with a mean Richmond Agitation-Sedation Scale of less than or equal to -3 during mechanical ventilation. Multivariable regression and effect modification analyses were used. Delirium-free days were lower in patients who received a high proportion of deep sedation using benzodiazepine compared with propofol-based sedation (adjusted absolute difference, -1.17 d; 95% CI, -0.64 to -1.69; p < 0.001). This differential effect was magnified in elderly patients (age > 65) and in patients with liver or kidney failure (p-for-interaction < 0.001) but not observed in patients who received a low proportion of deep sedation (p = 0.95). GABAergic-induced deep sedation days during mechanical ventilation was a better predictor of post-extubation delirium than the GABAergic daily average effective dose (area under the curve 0.76 vs 0.69; p < 0.001)., Conclusions: Deep sedation during mechanical ventilation with benzodiazepines compared with propofol is associated with increased risk of post-extubation delirium. Our data do not support the view that benzodiazepine-based compared with propofol-based sedation in the ICU is an independent risk factor of delirium, as long as deep sedation can be avoided in these patients., Competing Interests: Dr. Sarge received funding from Christie & Young PC, Intermountain Medical Center, and Downs Rachlin Martin PLLC. Dr. Subramaniam’s institution received funding from the National Institutes of Health and Mallinckrodt Pharmaceuticals. Dr. Eikermann received funding from Jeffrey and Judy Buzen and Merck. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objective: While studies have reported increased post-operative pulmonary complications with SARS-CoV-2 infection, many are limited by use of historical controls or focus on less severe respiratory complications. We characterized the association between pre-operative SARS-CoV-2 infection and post-operative respiratory failure (PORF)., Design and Setting: This was a single center retrospective cohort study in New York City between March 14-June 14, 2020., Patients: Exclusion criteria were age < 18-years, obstetric procedures, absence of SARS-CoV-2 PCR testing, and pre-operative respiratory failure. A total of 778 patients met criteria, of which 87 had SARS-CoV-2., Measurements: The primary outcome, PORF, included inability to extubate for ≥24 h or unplanned re-intubation within 5 days. Multiple exposures were measured including SARS-CoV-2 infection 4 weeks before or 5 days after surgery. Multivariable logistic regression was performed to adjust for pre-operative hypoxemia, oxygen use, and pneumonia as well as tachycardia, gender, Charlson Comorbidity Index (CCI), Surgical Mortality Probability Model (S-MPM) index, and peri-operative blood transfusion., Main Results: SARS-CoV patients had higher CCI (P = 0.007) and S-MPM scores (P = 0.02). The incidence of PORF was 16% versus 7% in uninfected comparators (P = 0.001). Amongst infected individuals, 39% exhibited symptoms of COVID-19 and PORF was more common in these patients compared to asymptomatic individuals (26% vs. 9%, P = 0.04). Adjusted analysis revealed increased odds of PORF with infection (OR 2.8, 95% CI 1.2-6.2). This persisted even when adjusting for probable mediators such as pre-operative hypoxemia. Infected patients also demonstrated increased adjusted odds of 30-day mortality (OR 3.5, 95% CI 1.4-9.1)., Conclusions: Detection of SARS-CoV-2 infection within 4 weeks before or 5 days after surgery is associated with increased odds of 5-day PORF and 30-day mortality. This supports delaying elective surgery, but questions remain regarding the applicability of this recommendation for asymptomatic patients needing urgent or semi-urgent procedures such as oncologic surgery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The novel SARS-CoV-2 pandemic starting in 2019 profoundly changed the world, and thousands of residents of New York City were affected, leading to one of the most acute surges in regional hospital capacity. As the largest academic medical center in the Bronx, Montefiore Medical Center was immediately impacted, and the entire hospital was mobilized to address the needs of its community. In this article, we describe our experiences as a large academic anesthesiology department during this pandemic. Our goals were to maximize our staff's expertise, maintain our commitment to wellness and safety, and preserve the quality of patient care. Lessons learned include the importance of critical care training presence and leadership, the challenges of converting an ambulatory surgery center to an intensive care unit (ICU), and the management of effective communication. Lastly, we provide suggestions for institutions facing an acute surge, or subsequent waves of COVID-19, based on a single center's experiences., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Left ventricular assist devices (LVADs) are associated with major vascular complications including stroke and gastrointestinal bleeding (GIB). These adverse vascular events may be the result of widespread vascular dysfunction resulting from pre-LVAD abnormalities or continuous flow during LVAD therapy. We hypothesized that pre-existing large artery atherosclerosis and/or abnormal blood flow as measured in carotid arteries using ultrasonography are associated with a post-implantation composite adverse outcome including stroke, GIB, or death. We retrospectively studied 141 adult HeartMate II patients who had carotid ultrasound duplex exams performed before and/or after LVAD surgery. Structural parameters examined included plaque burden and stenosis. Hemodynamic parameters included peak-systolic, end-diastolic, and mean velocity as well as pulsatility index. We examined the association of these measures with the composite outcome as well as individual subcomponents such as stroke. After adjusting for established risk factors, the composite adverse outcome was associated with pre-operative moderate-to-severe carotid plaque (OR 5.08, 95% CI 1.67-15.52) as well as pre-operative internal carotid artery stenosis (OR 9.02, 95% CI 1.06-76.56). In contrast, altered hemodynamics during LVAD support were not associated with the composite outcome. Our findings suggest that pre-existing atherosclerosis possibly in combination with LVAD hemodynamics may be an important contributor to adverse vascular events during mechanical support. This encourages greater awareness of carotid morphology pre-operatively and further study of the interaction between hemodynamics, pulsatility, and structural arterial disease during LVAD support.

From March to June of 2020, Montefiore Medical Center faced one of the most acute surges in hospital admissions and critical illness ever experienced in the United States due to the severe acute respiratory syndrome coronavirus 2 pandemic. The pandemic had not yet spread to most of the country, and there was a relative deficit of knowledge regarding treatments, prognosis, and prevention of the virus, making this experience relatively unique and challenging. As part of a surge plan, our institution converted nonclinical spaces, such as conference rooms, to inpatient care settings and placed elective surgeries on hold to free up resources. A central deployment office suspended anesthesiology resident rotations and instead assigned them to intensive care settings based on need. For the Montefiore Medical Center Department of Anesthesiology, preserving its academic mission and commitment to Graduate Medical Education was essential. Adaptations included changing the residency rotation structure to biweekly, converting didactics online, ensuring adequate case numbers for graduating residents, actively pursuing wellness interventions, and prioritizing the safety of the residents caring for patients with coronavirus disease 2019 (COVID-19). In this brief report, the authors discuss solutions devised to maintain the quality of anesthesiology resident education and training as much as possible during the COVID-19 surge., Competing Interests: Conflicts of interests and financial disclosures: C.C. was a paid attendee of a consultant meeting for Merck in December 2019 to discuss Sugammadex and received renumeration by MedEdicus to develop a continuing medical education module for residual neuromuscular blockade in November 2019. N.S. is a consultant and was on the advisory board for Acel Rx Pharmaceuticals and Averitas Pharma. He has received research funding from Grunenthal and Heron therapeutics. For both authors, these funding activities are declared here; however, are not in conflict with their roles and opinions in this publication. There are no funding sources supporting the submitted work to declare., (© 2021 Society for Education in Anesthesia.)

Purpose of Review: A discussion of recent research exploring the feasibility of perfusion-guided resuscitation of acute circulatory failure with a focus on lactate and microcirculation., Recent Findings: Upon diagnosis of shock, hyperlactemia is associated with poor outcome and, under appropriate clinical circumstances, may reflect inadequate tissue perfusion. Persistent hyperlactemia despite resuscitation is even more strongly correlated with morbidity and mortality. Importantly, there is minimal coherence between lactate trends and static hemodynamic measures such as blood pressure, especially after the initial, hypovolemic phase of shock. During this early period, lactate guided-resuscitation is effective and possibly superior to hemodynamic-guided resuscitation. Similar to hyperlactemia, impaired microcirculation is ubiquitous in shock and is evident even in the setting of hemodynamic compensation (i.e., occult shock). Moreover, persistent microcirculatory derangement is associated with poor outcome and may reflect ongoing shock and/or long-lasting damage. Although the wait continues for a microcirculation-guided resuscitation trial, there is progress toward this goal., Summary: Although questions remain, a multimodal perfusion-based approach to resuscitation is emerging with lactate and microcirculation as core measures. In this model, hyperlactemia and microcirculatory derangement support the diagnosis of shock, may help guide resuscitation during the initial period, and may reflect resuscitation efficacy and iatrogenic harm (e.g., fluid overload).

The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined channel contributions to behavioral responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of mechanosensitive and -insensitive pelvic nerve afferent classes were not different in TPDKO mice. Responses of mucosal and serosal class afferents to mechanical probing were unaffected, whereas responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice; sensitization of both muscular and muscular/mucosal afferents by inflammatory soup was also significantly attenuated. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that 1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally, 2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than does antagonism of either channel alone, and 3) the relative importance of these channels appears to be enhanced in colorectal hypersensitivity.

Irritable bowel syndrome (IBS) is characterized by altered bowel habits, persistent pain and discomfort, and typically colorectal hypersensitivity. Linaclotide, a peripherally restricted 14 aa peptide approved for the treatment of IBS with constipation, relieves constipation and reduces IBS-associated pain in these patients presumably by activation of guanylate cyclase-C (GC-C), which stimulates production and release of cyclic guanosine monophosphate (cGMP) from intestinal epithelial cells. We investigated whether activation of GC-C by the endogenous agonist uroguanylin or the primary downstream effector of that activation, cGMP, directly modulates responses and sensitization of mechanosensitive colorectal primary afferents. The distal 2 cm of mouse colorectum with attached pelvic nerve was harvested and pinned flat mucosal side up for in vitro single-fiber recordings, and the encoding properties of mechanosensitive afferents (serosal, mucosal, muscular, and muscular-mucosal; M/M) to probing and circumferential stretch studied. Both cGMP (10-300 μM) and uroguanylin (1-1000 nM) applied directly to colorectal receptive endings significantly reduced responses of muscular and M/M afferents to stretch; serosal and mucosal afferents were not affected. Sensitized responses (i.e., increased responses to stretch) of muscular and M/M afferents were reversed by cGMP, returning responses to stretch to control. Blocking the transport of cGMP from colorectal epithelia by probenecid, a mechanism validated by studies in cultured intestinal T84 cells, abolished the inhibitory effect of uroguanylin on M/M afferents. These results suggest that GC-C agonists like linaclotide alleviate colorectal pain and hypersensitivity by dampening stretch-sensitive afferent mechanosensitivity and normalizing afferent sensitization.

Vesicular glutamate transporters (VGLUTs) have been extensively studied in various neuronal systems, but their expression in visceral sensory and autonomic neurons remains to be analyzed in detail. Here we studied VGLUTs type 1 and 2 (VGLUT(1) and VGLUT(2) , respectively) in neurons innervating the mouse colorectum. Lumbosacral and thoracolumbar dorsal root ganglion (DRG), lumbar sympathetic chain (LSC), and major pelvic ganglion (MPG) neurons innervating the colorectum of BALB/C mice were retrogradely traced with Fast Blue, dissected, and processed for immunohistochemistry. Tissue from additional naïve mice was included. Previously characterized antibodies against VGLUT(1) , VGLUT(2) , and calcitonin gene-related peptide (CGRP) were used. Riboprobe in situ hybridization, using probes against VGLUT(1) and VGLUT(2) , was also performed. Most colorectal DRG neurons expressed VGLUT(2) and often colocalized with CGRP. A smaller percentage of neurons expressed VGLUT(1) . VGLUT(2) -immunoreactive (IR) neurons in the MPG were rare. Abundant VGLUT(2) -IR nerves were detected in all layers of the colorectum; VGLUT(1) -IR nerves were sparse. A subpopulation of myenteric plexus neurons expressed VGLUT2 protein and mRNA, but VGLUT1 mRNA was undetectable. In conclusion, we show 1) that most colorectal DRG neurons express VGLUT(2) , and to a lesser extent, VGLUT(1) ; 2) abundance of VGLUT2-IR fibers innervating colorectum; and 3) a subpopulation of myenteric plexus neurons expressing VGLUT(2). Altogether, our data suggests a role for VGLUT(2) in colorectal glutamatergic neurotransmission, potentially influencing colorectal sensitivity and motility., (Copyright © 2011 Wiley-Liss, Inc.)