ABSTRACT
PURPOSE: The aim of this study is to investigate the distribution of spherical equivalent and axial length in the general population and to analyze the influence of education on spherical equivalent with a focus on ocular biometric parameters. METHODS: The Gutenberg Health Study is a population-based cohort study in Mainz, Germany. Participants underwent comprehensive ophthalmologic examinations as part of the 5-year follow-up examination in 2012-2017 including genotyping. The spherical equivalent and axial length distributions were modeled with gaussian mixture models. Regression analysis (on person-individual level) was performed to analyze associations between biometric parameters and educational factors. Mendelian randomization analysis explored the causal effect between spherical equivalent, axial length, and education. Additionally, effect mediation analysis examined the link between spherical equivalent and education. RESULTS: A total of 8532 study participants were included (median age: 57 years, 49% female). The distribution of spherical equivalent and axial length follows a bi-Gaussian function, partially explained by the length of education (i.e., < 11 years education vs. 11-20 years). Mendelian randomization indicated an effect of education on refractive error using a genetic risk score of education as an instrument variable (- 0.35 diopters per SD increase in the instrument, 95% CI, - 0.64-0.05, p = 0.02) and an effect of education on axial length (0.63 mm per SD increase in the instrument, 95% CI, 0.22-1.04, p = 0.003). Spherical equivalent, axial length and anterior chamber depth were associated with length of education in regression analyses. Mediation analysis revealed that the association between spherical equivalent and education is mainly driven (70%) by alteration in axial length. CONCLUSIONS: The distribution of axial length and spherical equivalent is represented by subgroups of the population (bi-Gaussian). This distribution can be partially explained by length of education. The impact of education on spherical equivalent is mainly driven by alteration in axial length.
Subject(s)
Axial Length, Eye , Educational Status , Humans , Female , Male , Middle Aged , Germany/epidemiology , Axial Length, Eye/pathology , Normal Distribution , Biometry/methods , Refraction, Ocular/physiology , Follow-Up Studies , Refractive Errors/physiopathology , Refractive Errors/diagnosis , Refractive Errors/genetics , Aged , AdultABSTRACT
Primary open-angle glaucoma is a neurodegenerative disease with progressive chronic optic neuropathy and corresponding visual field defects. In this literature review, we discuss systemic diseases and their mechanism for developing glaucoma, including systemic hypertension and hypotension, diabetes, dyslipidemia, obstructive sleep apnoea syndrome, chronic kidney disease, migraine, and polypharmacy.
Subject(s)
Glaucoma, Open-Angle , Glaucoma , Neurodegenerative Diseases , Optic Nerve Diseases , Humans , Glaucoma, Open-Angle/complications , Glaucoma, Open-Angle/diagnosis , Glaucoma, Open-Angle/therapy , Optic Nerve , Intraocular PressureABSTRACT
OBJECTIVE: The objective of this study was to identify undertreated subgroups of patients with heart failure who would benefit from better perioperative optimization. SUMMARY OF BACKGROUND DATA: Patients with heart failure have increased risks of postoperative cardiac complications after noncardiac surgery. METHODS: In this analysis of hospital registry data of 130,677 patients undergoing noncardiac surgery, the exposure was preoperative history of heart failure. The outcome, cardiac complications, was defined as a composite of myocardial infarction, cardiac arrest, acute heart failure, and mortality within 30 postoperative days. RESULTS: History of heart failure (n = 10,256; 7.9%) was associated with increased risk of cardiac complications [8.1% vs 1.1%; adjusted odds ratio, 2.28 (95% CI, 2.02-2.56); P < 0.001). Patients with heart failure and who carried a lower risk profile had increased risks of postoperative cardiac complications secondary to heart failure [adjusted absolute risk difference, 1.7% (95% CI, 1.4%-2.0%, lower risk); P < 0.001 vs 0.5% (95% CI, -0.6% to 1.6%, higher risk); P = 0.38]. Patients with heart failure and lower risk received a lower level of health care utilization preoperatively, and less frequently received anti-heart failure medications (59% vs 72% and 61% vs 82%; both P < 0.001). These preventive therapies significantly decreased the risk of cardiac complications in patients with heart failure. CONCLUSIONS: In patients with heart failure who have a lower preoperative risk profile, clinicians often make insufficient attempts to optimize their clinical condition preoperatively. Preoperative preventive treatment reduces the risk of postoperative cardiac complications in these lower-risk patients with heart failure.
Subject(s)
Heart Diseases , Heart Failure , Myocardial Infarction , Humans , Retrospective Studies , Postoperative Complications , Risk FactorsABSTRACT
OBJECTIVES: Two previously published trials (ARDS et Curarisation Systematique [ACURASYS] and Reevaluation of Systemic Early Neuromuscular Blockade [ROSE]) presented equivocal evidence on the effect of neuromuscular blocking agent infusions in patients with acute respiratory distress syndrome (acute respiratory distress syndrome). The sedation regimen differed between these trials and also within the ROSE trial between treatment and control groups. We hypothesized that the proportion of deeper sedation is a mediator of the effect of neuromuscular blocking agent infusions on mortality. DESIGN: Retrospective cohort study. SETTING: Seven ICUs in an academic hospital network, Beth Israel Deaconess Medical Center (Boston, MA). PATIENTS: Intubated and mechanically ventilated ICU patients with acute respiratory distress syndrome (Berlin definition) admitted between January 2008 until June 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The proportion of deeper sedation was defined as days with nonlight sedation as a fraction of mechanical ventilation days in the ICU after acute respiratory distress syndrome diagnosis. Using clinical data obtained from a hospital network registry, 3,419 patients with acute respiratory distress syndrome were included, of whom 577 (16.9%) were treated with neuromuscular blocking agent infusions, for a mean (sd) duration of 1.8 (±1.9) days. The duration of deeper sedation was prolonged in patients receiving neuromuscular blocking agent infusions (4.6 ± 2.2 d) compared with patients without neuromuscular blocking agent infusions (2.4 ± 2.2 d; p < 0.001). The proportion of deeper sedation completely mediated the negative effect of neuromuscular blocking agent infusions on in-hospital mortality (p < 0.001). Exploratory analysis in patients who received deeper sedation revealed a beneficial effect of neuromuscular blocking agent infusions on mortality (49% vs 51%; adjusted odds ratio, 0.80; 95% CI, 0.63-0.99, adjusted absolute risk difference, -0.05; p = 0.048). CONCLUSIONS: In acute respiratory distress syndrome patients who receive neuromuscular blocking agent infusions, a prolonged, high proportion of deeper sedation is associated with increased mortality. Our data support the view that clinicians should minimize the duration of deeper sedation after recovery from neuromuscular blocking agent infusion.
Subject(s)
Deep Sedation/mortality , Neuromuscular Blocking Agents/therapeutic use , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/therapy , Adult , Aged , Deep Sedation/methods , Female , Hospital Mortality , Humans , Infusions, Intravenous , Male , Middle Aged , Neuromuscular Blocking Agents/administration & dosage , New England/epidemiology , Registries , Respiration, Artificial , Retrospective StudiesABSTRACT
BACKGROUND: There is an under-recognised patient cohort at elevated risk of postoperative ischaemic stroke. We aimed to develop and validate a prognostic model for the identification of such patients at high risk of ischaemic stroke within 1 yr after noncardiac surgery. METHODS: This was a hospital registry study of adult patients undergoing noncardiac surgery between 2005 and 2017 at two independent healthcare networks in Massachusetts, USA without a preoperative indication for therapeutic anticoagulation. Logistic regression was used to fit a model from a priori defined candidate predictors for the outcome 1 yr postoperative ischaemic stroke. To enhance clinical applicability, the model was simplified to a scoring system and externally validated. RESULTS: In the development (n=107 756) and validation (n=141 724) cohorts, 1.4% and 0.5% of patients had an ischaemic stroke up to 1 yr postoperatively. The final model included 13 variables (patient characteristics, comorbidities, procedural factors), considering sub-models conditional on a previous history of ischaemic stroke. Areas under the curve were 0.89 (95% confidence interval 0.89-0.90) and 0.88 (95% confidence interval 0.86-0.89) in the development and validation cohorts. Decision curve analysis indicated positive net benefits superior to other prediction instruments. CONCLUSIONS: Stroke after surgery (STRAS) screening can reliably identify patients with a high risk for ischaemic stroke during the first year after surgery. A STRAS-guided risk stratification may inform the recruitment to future randomised trials testing the efficacy of treatments for the prevention of postoperative ischaemic stroke.
Subject(s)
Ischemic Stroke/epidemiology , Models, Statistical , Postoperative Complications/epidemiology , Surgical Procedures, Operative/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Follow-Up Studies , Humans , Ischemic Stroke/etiology , Logistic Models , Male , Massachusetts , Middle Aged , Prognosis , Risk Assessment/methods , Surgical Procedures, Operative/methods , Young AdultABSTRACT
BACKGROUND: We tested the primary hypothesis that use of general anaesthesia vs sedation increases vulnerability to adverse discharge (in-hospital mortality or new discharge to a nursing facility) after endoscopic retrograde cholangiopancreatography (ERCP). METHODS: In this retrospective cohort study, adult patients undergoing ERCP with general anaesthesia or sedation at a tertiary care hospital were included. We calculated adjusted absolute risk differences between patients receiving general anaesthesia vs sedation using provider preference-based instrumental variable analysis. We also used mediation analysis to determine whether intraoperative hypotension during general anaesthesia mediated its effect on adverse discharge. RESULTS: Among 17 538 patients undergoing ERCP from 2007 through 2018, 16 238 received sedation and 1300 received GA. Rates of adverse discharge were 5.8% (n=938) after sedation and 16.2% (n=210) after general anaesthesia. Providers' adjusted mean predicted probabilities of using general anaesthesia for ERCP ranged from 0.2% to 63.2% of individual caseloads. Utilising provider-related variability in the use of general anaesthesia for instrumental variable analysis resulted in an 8.6% risk increase (95% confidence interval, 4.5-12.6%; P<0.001) in adverse discharge among patients receiving general anaesthesia vs sedation. Intraoperative hypotensive events occurred more often during general anaesthesia and mediated 23.8% (95% confidence interval, 3.9-43.7%: P=0.019) of the primary association. CONCLUSIONS: These results suggest that use of sedation during ERCP facilitates reduced adverse discharge for patients for whom general anaesthesia is not clearly indicated. Intraoperative hypotension during general anaesthesia for ERCP partly mediates the increased vulnerability to adverse discharge.
Subject(s)
Anesthesia, General/adverse effects , Cholangiopancreatography, Endoscopic Retrograde/methods , Deep Sedation/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Anesthesia, General/methods , Cohort Studies , Deep Sedation/methods , Female , Hospital Mortality , Humans , Male , Middle Aged , Nursing Homes , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: Readmission to the Intensive Care Unit (ICU) is associated with a high risk of in-hospital mortality and higher health care costs. Previously published tools to predict ICU readmission in surgical ICU patients have important limitations that restrict their clinical implementation. We sought to develop a clinically intuitive score that can be implemented to predict readmission to the ICU after surgery or trauma. We designed the score to emphasize modifiable predictors. METHODS: In this retrospective cohort study, we included surgical patients requiring critical care between June 2015 and January 2019 at Beth Israel Deaconess Medical Center, Harvard Medical School, MA, USA. We used logistic regression to fit a prognostic model for ICU readmission from a priori defined, widely available candidate predictors. The score performance was compared with existing prediction instruments. RESULTS: Of 7,126 patients, 168 (2.4%) were readmitted to the ICU during the same hospitalization. The final score included 8 variables addressing demographical factors, surgical factors, physiological parameters, ICU treatment and the acuity of illness. The maximum score achievable was 13 points. Potentially modifiable predictors included the inability to ambulate at ICU discharge, substantial positive fluid balance (>5 liters), severe anemia (hemoglobin <7 mg/dl), hyperglycemia (>180 mg/dl), and long ICU length of stay (>5 days). The score yielded an area under the receiver operating characteristic curve of 0.78 (95% CI 0.74-0.82) and significantly outperformed previously published scores. The performance of the underlying model was confirmed by leave-one-out cross-validation. CONCLUSION: The RISC-score is a clinically intuitive prediction instrument that helps identify surgical ICU patients at high risk for ICU readmission. The simplicity of the score facilitates its clinical implementation across surgical divisions.
Subject(s)
Intensive Care Units , Patient Readmission , Critical Care , Hospital Mortality , Humans , Retrospective StudiesABSTRACT
BACKGROUND: Residual neuromuscular blockade is associated with an increased incidence of postoperative respiratory complications. The REsidual neuromuscular block Prediction Score (REPS) identifies patients at high risk for residual neuromuscular blockade after surgery. METHODS: A total of 101,510 adults undergoing noncardiac surgery under general anesthesia from October 2005 to December 2018 at a tertiary care center in Massachusetts were analyzed for the primary outcome of postoperative respiratory complications (invasive mechanical ventilation requirement within 7 postoperative days or immediate postextubation desaturation [oxygen saturation {Spo2} <90%] within 10 minutes). The primary objective was to assess the association between the REPS and respiratory complications. The secondary objective was to compare REPS and train-of-four (TOF) ratio <0.90 on the strength of their association with respiratory complications. RESULTS: A high REPS (≥4) was associated with an increase in odds of respiratory complications (adjusted odds ratio [OR], 1.13 [95% confidence interval {CI}, 1.06-1.21]; P < .001). In 6224 cases with available TOF ratio measurements, a low TOF ratio (<0.9) was associated with respiratory complications (adjusted OR, 1.43 [95% CI, 1.11-1.85]; P = .006), whereas a high REPS was not (adjusted OR, 0.96 [95% CI, 0.74-1.23]; P = .73) (P = .018 for comparison between ORs). CONCLUSIONS: The REPS may be implemented as a screening tool to encourage clinicians to use quantitative neuromuscular monitoring in patients at risk of residual neuromuscular blockade. A positive REPS should be followed by a quantitative assessment of the TOF ratio.
Subject(s)
Anesthesia, General , Clinical Decision Rules , Delayed Emergence from Anesthesia/etiology , Lung/innervation , Neuromuscular Blockade/adverse effects , Neuromuscular Monitoring , Respiration Disorders/etiology , Respiration , Adult , Aged , Anesthesia, General/adverse effects , Delayed Emergence from Anesthesia/diagnosis , Delayed Emergence from Anesthesia/physiopathology , Delayed Emergence from Anesthesia/therapy , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Respiration Disorders/diagnosis , Respiration Disorders/physiopathology , Respiration Disorders/therapy , Respiration, Artificial , Retrospective Studies , Risk Assessment , Risk Factors , Time FactorsABSTRACT
BACKGROUND: Intraoperative cerebral blood flow is mainly determined by cerebral perfusion pressure and cerebral autoregulation of vasomotor tone. About 1% of patients undergoing noncardiac surgery develop ischemic stroke. We hypothesized that intraoperative hypotension within a range frequently observed in clinical practice is associated with an increased risk of perioperative ischemic stroke within 7 days after surgery. METHODS: Adult noncardiac surgical patients undergoing general anesthesia at Beth Israel Deaconess Medical Center and Massachusetts General Hospital between 2005 and 2017 were included in this retrospective cohort study. The primary exposure was intraoperative hypotension, defined as a decrease in mean arterial pressure (MAP) below 55 mm Hg, categorized into no intraoperative hypotension, short (<15 minutes, median [interquartile range {IQR}], 2 minutes [1-5 minutes]) and prolonged (≥15 minutes, median [IQR], 21 minutes [17-31 minutes]) durations. The primary outcome was a new diagnosis of early perioperative ischemic stroke within 7 days after surgery. In secondary analyses, we assessed the effect of a MAP decrease by >30% from baseline on perioperative stroke. Analyses were adjusted for the preoperative STRoke After Surgery (STRAS) prediction score, work relative value units, and duration of surgery. RESULTS: Among 358,391 included patients, a total of 1553 (0.4%) experienced an early perioperative ischemic stroke. About 42% and 3% of patients had a MAP of below 55 mm Hg for a short and a prolonged duration, and 49% and 29% had a MAP decrease by >30% from baseline for a short and a prolonged duration, respectively. In an adjusted analysis, neither a MAP <55 mm Hg (short duration: adjusted odds ratio [ORadj], 0.95; 95% confidence interval [CI], 0.85-1.07; P = .417 and prolonged duration: ORadj, 1.18; 95% CI, 0.91-1.55; P = .220) nor a MAP decrease >30% (short duration: ORadj, 0.97; 95% CI, 0.67-1.42; P = .883 and prolonged duration: ORadj, 1.30; 95% CI, 0.89-1.90; P = .176) was associated with early perioperative stroke. A high a priori stroke risk quantified based on preoperatively available risk factors (STRAS prediction score) was associated with longer intraoperative hypotension (adjusted incidence rate ratio, 1.04; 95% CI, 1.04-1.05; P < .001 per 5 points of the STRAS prediction score). CONCLUSIONS: This study found no evidence to conclude that intraoperative hypotension within the range studied was associated with early perioperative stroke within 7 days after surgery. These findings emphasize the importance of perioperative cerebral blood flow autoregulation to prevent ischemic stroke.
Subject(s)
Arterial Pressure , Cerebrovascular Circulation , Hypotension/etiology , Ischemic Stroke/etiology , Surgical Procedures, Operative/adverse effects , Adult , Aged , Boston , Female , Homeostasis , Humans , Hypotension/diagnosis , Hypotension/physiopathology , Intraoperative Period , Ischemic Stroke/diagnosis , Ischemic Stroke/physiopathology , Male , Middle Aged , Registries , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVE: Inability of home discharge occurs in nearly a third of patients undergoing cardiac surgery and is associated with increased mortality. The authors aimed to evaluate the incidence and risk factors for adverse discharge disposition (ADD) after cardiac surgery and develop a prediction tool for preoperative risk assessment. DESIGN: This retrospective cohort study included adult patients undergoing cardiac surgery between 2010 and 2018. The primary outcome was ADD, defined as in-hospital mortality, discharge to a skilled nursing facility, or transfer to a long-term care hospital. The authors created a prediction tool using stepwise backward logistic regression and used 5-fold and leave-one-out cross-validation. SETTING: University hospital network. PARTICIPANTS: Adult patients living at home prior to surgery, who underwent coronary artery bypass grafting and/or valve procedures at the authors' institution. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 3,760 patients were included in the final study cohort. The observed rate of ADD was 33.3%. The prediction model showed good discrimination and accuracy, with C-statistic of 0.78 (95% confidence interval [CI] 0.76-0.79) and unmodified Brier score of 0.177 (reliability 0.001). The final model comprised 14 predictors. Patients who experienced ADD were more likely to be older, of female sex, to have had higher length of hospital stay prior to surgery, and to have undergone emergency surgery. CONCLUSIONS: The authors present an instrument for prediction of loss of the ability to live independently in patients undergoing cardiac surgery. The authors' score may be useful in identifying high-risk patients such that earlier coordination of care can be initiated in this vulnerable patient population.
Subject(s)
Cardiac Surgical Procedures , Patient Discharge , Adult , Cardiac Surgical Procedures/adverse effects , Female , Humans , Length of Stay , Reproducibility of Results , Retrospective Studies , Skilled Nursing FacilitiesABSTRACT
BACKGROUND: Adverse discharge disposition, which is discharge to a long-term nursing home or skilled nursing facility is frequent and devastating in older patients after lower-extremity orthopaedic surgery. Predicting individual patient risk allows for preventive interventions to address modifiable risk factors and helps managing expectations. Despite a variety of risk prediction tools for perioperative morbidity in older patients, there is no tool available to predict successful recovery of a patient's ability to live independently in this highly vulnerable population. QUESTIONS/PURPOSES: In this study, we asked: (1) What factors predict adverse discharge disposition in patients older than 60 years after lower-extremity surgery? (2) Can a prediction instrument incorporating these factors be applied to another patient population with reasonable accuracy? (3) How does the instrument compare with other predictions scores that account for frailty, comorbidities, or procedural risk alone? METHODS: In this retrospective study at two competing New England university hospitals and Level 1 trauma centers with 673 and 1017 beds, respectively; 83% (19,961 of 24,095) of patients 60 years or older undergoing lower-extremity orthopaedic surgery were included. In all, 5% (1316 of 24,095) patients not living at home and 12% (2797 of 24,095) patients with missing data were excluded. All patients were living at home before surgery. The mean age was 72 ± 9 years, 60% (11,981 of 19,961) patients were female, 21% (4155 of 19,961) underwent fracture care, and 34% (6882 of 19,961) underwent elective joint replacements. Candidate predictors were tested in a multivariable logistic regression model for adverse discharge disposition in a development cohort of all 14,123 patients from the first hospital, and then included in a prediction instrument that was validated in all 5838 patients from the second hospital by calculating the area under the receiver operating characteristics curve (ROC-AUC).Thirty-eight percent (5360 of 14,262) of patients in the development cohort and 37% (2184 of 5910) of patients in the validation cohort had adverse discharge disposition. Score performance in predicting adverse discharge disposition was then compared with prediction scores considering frailty (modified Frailty Index-5 or mFI-5), comorbidities (Charlson Comorbidity Index or CCI), and procedural risks (Procedural Severity Scores for Morbidity and Mortality or PSS). RESULTS: After controlling for potential confounders like BMI, cardiac, renal and pulmonary disease, we found that the most prominent factors were age older than 90 years (10 points), hip or knee surgery (7 or 8 points), fracture management (6 points), dementia (5 points), unmarried status (3 points), federally provided insurance (2 points), and low estimated household income based on ZIP code (1 point). Higher score values indicate a higher risk of adverse discharge disposition. The score comprised 19 variables, including socioeconomic characteristics, surgical management, and comorbidities with a cutoff value of ≥ 23 points. Score performance yielded an ROC-AUC of 0.85 (95% confidence interval 0.84 to 0.85) in the development and 0.72 (95% CI 0.71 to 0.73) in the independent validation cohort, indicating excellent and good discriminative ability. Performance of the instrument in predicting adverse discharge in the validation cohort was superior to the mFI-5, CCI, and PSS (ROC-AUC 0.72 versus 0.58, 0.57, and 0.57, respectively). CONCLUSION: The Adverse Discharge in Older Patients after Lower Extremity Surgery (ADELES) score predicts adverse discharge disposition after lower-extremity surgery, reflecting loss of the ability to live independently. Its discriminative ability is better than instruments that consider frailty, comorbidities, or procedural risk alone. The ADELES score identifies modifiable risk factors, including general anesthesia and prolonged preoperative hospitalization, and should be used to streamline patient and family expectation management and improve shared decision making. Future studies need to evaluate the score in community hospitals and in institutions with different rates of adverse discharge disposition and lower income. A non-commercial calculator can be accessed at www.adeles-score.org. LEVEL OF EVIDENCE: Level III, diagnostic study.
Subject(s)
Clinical Decision Rules , Disability Evaluation , Lower Extremity/surgery , Orthopedic Procedures/rehabilitation , Patient Discharge/statistics & numerical data , Aged , Aged, 80 and over , Area Under Curve , Female , Humans , Male , Middle Aged , Predictive Value of Tests , ROC Curve , Reproducibility of Results , Retrospective Studies , Risk Assessment/methods , Risk Factors , Severity of Illness IndexABSTRACT
BACKGROUND: Reexposure to methamphetamine with a single "priming dose" can trigger intense cravings and precipitate relapse in methamphetamine-dependent individuals. The acyclic cucurbit[n]uril "molecular container" calabadion-2 shows a high affinity to bind and sequester methamphetamine in vitro and attenuates its locomotor-stimulating effect in rats. The present study investigates whether pretreatment with calabadion-2 is sufficient to prevent the reinstatement of drug seeking by a priming dose of methamphetamine in rats. METHODS: Male Long-Evans rats were trained to self-administer i.v. methamphetamine (0.06 mg/kg/infusion). Following 10 days of stable self-administration, rats underwent extinction training and were subsequently tested on a multi-phase reinstatement procedure. Drug-primed reinstatement sessions (0.3 mg/kg methamphetamine, i.v.) were preceded by either saline or calabadion-2 (130 mg/kg). Additional reinstatement tests were conducted after administration of yohimbine (1.0 mg/kg, i.v.) to define the pharmacological specificity of calabadion-2. RESULTS: Pretreatment with calabadion-2 significantly attenuated methamphetamine-induced reinstatement of responding. Cal2 did not affect drug-seeking behavior stimulated by the pharmacological stressor yohimbine, indicating a mechanism of action specific to methamphetamine. CONCLUSIONS: These results demonstrate the effectiveness of calabadion-2 in a preclinical model relapse-like behavior. With further structural optimization, molecular containers may provide a novel and efficacious pharmacokinetic approach to relapse prevention for methamphetamine-dependent individuals.
Subject(s)
Amphetamine-Related Disorders/drug therapy , Behavior, Addictive/drug therapy , Behavior, Animal/drug effects , Drug-Seeking Behavior/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Methamphetamine , Sulfonic Acids/pharmacology , Amphetamine-Related Disorders/physiopathology , Amphetamine-Related Disorders/psychology , Animals , Behavior, Addictive/physiopathology , Behavior, Addictive/psychology , Disease Models, Animal , Extinction, Psychological , Male , Rats, Long-Evans , Recurrence , Self Administration , Time FactorsABSTRACT
BACKGROUND: Neuromuscular blocking agents (NMBAs) with a non-depolarising mechanism of action carry the risk of postoperative residual paralysis and are associated with postoperative pulmonary complications (POPC). Owing to the shorter duration of action, the depolarising NMBA succinylcholine may be associated with less postoperative residual paralysis, and hence fewer POPC. We tested the association of succinylcholine administration during anaesthesia and POPC. METHODS: In a retrospective cohort study of registry data from two large US academic medical centres, 244 850 adult noncardiac surgical patients undergoing general anaesthesia were included. The primary outcome was POPC, defined as post-extubation haemoglobin oxygen de-saturation to <90%, or re-intubation requiring intensive care unit admission within 7 days after surgery. The association between succinylcholine and POPC and its dose-dependency were tested in a hierarchical fashion using a multivariable logistic regression model. RESULTS: A total of 13 206 patients (5.4%) experienced POPC. Use of succinylcholine was associated with increased risk of POPC (adjusted odds ratio [ORAdj]=1.11; 95% confidence interval [CI], 1.06-1.16; P<0.001; adjusted risk=5.18%; 95% CI, 5.06-5.30 without and 5.69%; 95% CI, 5.53-5.85 with succinylcholine), with a dose-dependent relationship (ORAdj=1.08; 95% CI, 1.05-1.11 per mg kg-1; P<0.001). In patients receiving non-depolarising NMBAs, succinylcholine further increased the risk of POPC (ORAdj=1.08; 95% CI, 1.03-1.14; P=0.001). The association between succinylcholine and POPC was modified (P=0.03 for interaction) by the duration of surgery with higher odds of POPC in patients undergoing surgeries of <2 vs ≥2 h (ORAdj=1.24; 95% CI, 1.15-1.33 and 1.05; 95% CI, 1.00-1.10, respectively). CONCLUSIONS: In contrast to our prediction, succinylcholine administration was associated with an increased risk of POPC. This association was dose-dependent and magnified in surgeries of shorter duration.
Subject(s)
Lung Diseases/chemically induced , Neuromuscular Depolarizing Agents/adverse effects , Postoperative Complications/chemically induced , Succinylcholine/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Dose-Response Relationship, Drug , Female , Hospitals , Humans , Male , Middle Aged , Registries , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: We hypothesised that Calabadion 1, an acyclic cucurbit[n]uril molecular container, reverses fentanyl-induced respiratory depression and dysfunction of the CNS. METHODS: Experiments were conducted in male Sprague-Dawley rats. A constant-rate i.v. infusion of fentanyl (12.5 or 25 µg kg-1 over 15 min) was administered followed by an i.v. bolus of Calabadion 1 (0.5-200 mg kg-1) or placebo. The primary outcome was reversal of ventilatory and respiratory depression, assessed by pneumotachography and arterial blood gas analysis, respectively. Key secondary outcomes were effects on fentanyl-induced central nervous dysfunction quantified by righting reflex, balance beam test, and electromyography (EMG). RESULTS: Calabadion 1 reversed fentanyl-induced respiratory depression across the endpoints minute ventilation, pH, and Paco2 (P=0.001). Compared with placebo, Calabadion 1 dose dependently (P for trend <0.001) reversed fentanyl-induced hypoventilation {81.9 [5.1] (mean [standard error of the mean]) vs 45.5 [12.4] ml min-1; P<0.001}, acidosis (pH 7.43 [0.01] vs 7.28 [0.04]; P=0.005), and hypercarbia (Paco2 43.4 [1.6] vs 63.4 [8.1] mm Hg; P=0.018). The effective Calabadion 1 doses required to reverse respiratory depression by 50% and 90% (ED50Res and ED90Res) were 1.7 and 15.6 mg kg-1, respectively. Higher effective doses were needed for recovery of righting reflex (ED50CNS: 9.6 mg kg-1; ED90CNS: 86.1 mg kg-1), which was accelerated by Calabadion 1 (4.6 [0.3] vs 9.0 [0.7] min; P<0.001). Calabadion 1 also significantly accelerated recovery of full functional mobility and reversal of muscle rigidity. CONCLUSIONS: Calabadion 1 selectively and dose dependently reversed the respiratory system and CNS side-effects of fentanyl.
Subject(s)
Analgesics, Opioid/adverse effects , Fentanyl/adverse effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Nervous System Physiological Phenomena/drug effects , Respiratory Insufficiency/chemically induced , Respiratory Insufficiency/prevention & control , Sulfonic Acids/pharmacology , Animals , Disease Models, Animal , Male , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Preclinical data suggest suppression of cancer proliferation by propofol, and retrospective studies suggest improved survival after cancer surgery with propofol-based anaesthesia. METHODS: To determine whether propofol dose administered for anaesthesia is associated with 1-yr mortality in patients with and without a diagnosis of solid cancer, we analysed adult patients undergoing monitored anaesthesia care or general anaesthesia at two academic medical centres in Boston, MA, USA. Logistic regression with interaction term analysis was applied with propofol dose (mg kg-1) as primary and diagnosis of solid cancer as co-primary exposure, and 1-yr mortality as the primary outcome. RESULTS: Of 280 081 patient cases, 10 744 (3.8%) died within 1 yr. Increasing propofol dose was associated with reduced odds of 1-yr mortality (adjusted odds ratio [aOR] 0.93 per 10 mg kg-1; 95% confidence interval [CI]: 0.89-0.98; absolute risk reduction fifth vs first quintile 0.5%; 95% CI: 0.2-0.7). This association was modified by a diagnosis of solid cancer (P<0.001 for interaction). Increasing propofol dose was associated with reduced odds of 1-yr mortality in patients without solid cancer (aOR: 0.78; 95% CI: 0.71-0.85), but not in patients with solid cancer (0.99; 0.94-1.04), a finding that was replicated when examining 5-yr mortality. CONCLUSIONS: Increasing propofol dose is associated with lower 1-yr mortality in patients without, but not in patients with, a diagnosis of solid cancer. We found evidence for competing effects, modifying the association between propofol dose and mortality.
Subject(s)
Anesthesia, General/methods , Anesthetics, Intravenous/administration & dosage , Neoplasms/mortality , Postoperative Complications/prevention & control , Propofol/administration & dosage , Adult , Aged , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Male , Massachusetts/epidemiology , Middle Aged , Postoperative Complications/mortality , Retrospective Studies , Survival AnalysisABSTRACT
BACKGROUND: Postoperative residual neuromuscular blockade continues to be a frequent occurrence with a reported incidence rate of up to 64%. However, the effect of postoperative residual neuromuscular blockade on health care utilization remains unclear. We conducted a retrospective cohort study to investigate the effects of postoperative residual neuromuscular blockade on hospital costs (primary outcome), intensive care unit admission rate, and hospital length of stay (secondary outcomes). METHODS: We performed a prespecified secondary analysis of data obtained in 2233 adult patients undergoing surgery under general anesthesia. Postoperative residual neuromuscular blockade was defined as a train-of-four ratio <0.9 in the postanesthesia care unit (PACU). Our confounder model adjusted for a variety of patient, surgical, and anesthesia-related factors. We fitted truncated negative binomial regression models for hospital cost and hospital length of stay analyses and a logistic regression model for our intensive care unit admission analysis. RESULTS: Overall, 457 (20.5%) patients in our cohort had residual neuromuscular blockade on admission to the PACU. Postoperative residual neuromuscular blockade was not independently associated with increased hospital costs (adjusted incidence rate ratio, 1.04, CI, 0.98-1.11; P = .22). There were significantly higher odds of intensive care unit admission in those with postoperative residual neuromuscular blockade compared to those without (adjusted odds ratio, 3.03, CI, 1.33-6.87; P < .01). Further, we found a trend toward increased hospital length of stay in patients with postoperative residual neuromuscular blockade (adjusted incidence rate ratio, 1.09; P = .06). Sensitivity analysis using the same model in the day of surgery admissions and ambulatory surgery confirmed our findings. CONCLUSIONS: Postoperative residual neuromuscular blockade at PACU admission was not significantly associated with increased hospital costs, but was associated with higher rates of intensive care unit admission. These findings support the view that clinicians should continue to work to reduce the rate of postoperative residual neuromuscular blockade.
Subject(s)
Critical Care/economics , Critical Care/methods , Delayed Emergence from Anesthesia/economics , Intensive Care Units , Adult , Aged , Atracurium/adverse effects , Atracurium/analogs & derivatives , Data Interpretation, Statistical , Female , Humans , Incidence , Length of Stay/economics , Male , Middle Aged , Neuromuscular Blockade/adverse effects , Patient Admission , Postoperative Period , Prospective Studies , Retrospective Studies , Rocuronium/adverse effects , Treatment Outcome , Vecuronium Bromide/adverse effectsABSTRACT
BACKGROUND: In this prespecified cohort study, we investigated the influence of postoperative admission to the intensive care unit versus surgical ward on health care utilization among patients undergoing intermediate-risk surgery. METHODS: Of adult surgical patients who underwent general anesthesia without an absolute indication for postoperative intensive care unit admission, 3530 patients admitted postoperatively to an intensive care unit were matched to 3530 patients admitted postoperatively to a surgical ward using a propensity score based on 23 important preoperative and intraoperative predictor variables. Postoperative hospital length of stay and hospital costs were defined as primary and secondary end points, respectively. RESULTS: Among patients with low propensity for postoperative intensive care unit admission, initial triage to an intensive care unit was associated with increased postoperative length of stay (incidence rate ratio, 1.69 [95% CI, 1.59-1.79]; P < .001) and hospital costs (incidence rate ratio, 1.92 [95% CI, 1.81-2.03]; P < .001). By contrast, postoperative intensive care unit admission of patients with high propensity was associated with decreased postoperative length of stay (incidence rate ratio, 0.90 [95% CI, 0.85-0.95]; P < .001) and costs (incidence rate ratio, 0.92 [95% CI, 0.88-0.97]; P = .001). Decisions regarding postoperative intensive care unit resource utilization were influenced by individual preferences of anesthesiologists and surgeons. CONCLUSIONS: In patients with an unclear indication for postoperative critical care, intensive care unit admission may negatively impact postoperative hospital length of stay and costs. Postoperative discharge disposition varies substantially based on anesthesia and surgical provider preferences but should optimally be driven by an objective assessment of a patient's status at the end of surgery.
Subject(s)
Hospital Costs/trends , Intensive Care Units/trends , Length of Stay/trends , Patient Admission/trends , Postoperative Care/trends , Propensity Score , Adult , Aged , Cohort Studies , Female , Humans , Intensive Care Units/economics , Length of Stay/economics , Male , Middle Aged , Patient Admission/economics , Postoperative Care/economics , Postoperative Care/methodsABSTRACT
OBJECTIVE: Evaluate the dose-response relationship between intraoperative fluid administration and postoperative outcomes in a large cohort of surgical patients. BACKGROUND: Healthy humans may live in a state of fluid responsiveness without the need for fluid supplementation. Goal-directed protocols driven by such measures are limited in their ability to define the optimal fluid state during surgery. METHODS: This analysis of data on file included 92,094 adult patients undergoing noncardiac surgery with endotracheal intubation between 2007 and 2014 at an academic tertiary care hospital and two affiliated community hospitals. The primary exposure variable was total intraoperative volume of crystalloid and colloid administered. The primary outcome was 30-day survival. Secondary outcomes were respiratory complications within three postoperative days (pulmonary edema, reintubation, pneumonia, or respiratory failure) and acute kidney injury. Exploratory outcomes were postoperative length of stay and total cost of care. Our models were adjusted for patient-, procedure-, and anesthesia-related factors. RESULTS: A U-shaped association was observed between the volume of fluid administered intraoperatively and 30-day mortality, costs, and postoperative length of stay. Liberal fluid volumes (highest quintile of fluid administration practice) were significantly associated with respiratory complications whereas both liberal and restrictive (lowest quintile) volumes were significantly associated with acute kidney injury. Moderately restrictive volumes (second quintile) were consistently associated with optimal postoperative outcomes and were characterized by volumes approximately 40% less than traditional textbook estimates: infusion rates of approximately 6-7âmL/kg/hr or 1 L of fluid for a 3-hour case. CONCLUSIONS: Intraoperative fluid dosing at the liberal and restrictive margins of observed practice is associated with increased morbidity, mortality, cost, and length of stay.
Subject(s)
Fluid Therapy/adverse effects , Intraoperative Care/adverse effects , Intraoperative Care/methods , Postoperative Complications , Rehydration Solutions/administration & dosage , Rehydration Solutions/adverse effects , Acute Kidney Injury/etiology , Acute Kidney Injury/prevention & control , Dose-Response Relationship, Drug , Hospital Costs , Hospital Mortality , Humans , Intubation, Intratracheal , Length of Stay , Pneumonia/etiology , Pneumonia/prevention & control , Postoperative Complications/prevention & control , Pulmonary Edema/etiology , Pulmonary Edema/prevention & control , Registries , Respiratory Insufficiency/etiology , Respiratory Insufficiency/prevention & control , Retrospective StudiesABSTRACT
BACKGROUND: Residual neuromuscular block (rNMB) after surgery is not difficult to identify if proper neuromuscular monitoring is used, but many clinicians do not use quantitative neuromuscular monitoring. OBJECTIVE: The aim of this study was to develop a REsidual neuromuscular block Prediction Score (REPS) to predict postoperative rNMB and compare the predictive accuracy of the prediction score with train-of-four count (TOFC) measurement at the end of a surgical case. DESIGN: Retrospective cohort study of data on file. DATA SOURCE: Electronic patient data and peri-operative data on vital signs, administered medications, and train-of-four ratio (TOFR) obtained in the postoperative recovery rooms [postanaesthesia care unit (PACU)] at Massachusetts General Hospital in Boston, Massachusetts, USA. PATIENTS: Quantitative TOFR measurements obtained on admission to the PACU were available from 2144 adult noncardiac surgical patients. MAIN OUTCOME MEASURE: Presence of rNMB at PACU admission, defined as a TOFR of less than 0.9. RESULTS: In the score development cohort (n=2144), rNMB occurred in 432 cases (20.2%). Ten independent predictors for residual paralysis were identified and used for the score development. The final model included: hepatic failure, neurological disease, high-neostigmine dose, metastatic tumour, female sex, short time between neuromuscular blocking agent administration and extubation, aminosteroidal neuromuscular blocking agent, BMI more than 35, absence of nurse anaesthetist and having an experienced surgeon. The model discrimination by C statistics was 0.63, 95% confidence interval (0.60 to 0.66), and risk categories derived from the REPS had a higher accuracy than the last documented intra-operative TOFC for predicting rNMB (net reclassification improvement score 0.26, standard error 0.03, Pâ<â0.001). CONCLUSION: The REPS can be used to identify patients at greater risk of rNMB. This tool may inform anaesthetists better than an intra-operative TOFC and thus enable peri-operative anaesthetic practices to be tailored to the patient and minimise the undesirable effects of rNMB. TRIAL REGISTRY NUMBER: Approved by Partners Human Research Committee (protocol number 2016P000940) at MGH in Boston, Massachusetts, USA on 25 April 2016.
Subject(s)
Delayed Emergence from Anesthesia/diagnosis , Neuromuscular Blockade/adverse effects , Neuromuscular Blocking Agents/adverse effects , Neuromuscular Monitoring/methods , Adult , Aged , Delayed Emergence from Anesthesia/etiology , Electronic Health Records/statistics & numerical data , Feasibility Studies , Female , Humans , Male , Middle Aged , Neuromuscular Blockade/methods , Neuromuscular Blocking Agents/administration & dosage , Predictive Value of Tests , Prognosis , Recovery Room/statistics & numerical data , Retrospective Studies , Time FactorsABSTRACT
BACKGROUND: Immobilisation predicts adverse outcomes in patients in the surgical intensive care unit (SICU). Attempts to mobilise critically ill patients early after surgery are frequently restricted, but we tested whether early mobilisation leads to improved mobility, decreased SICU length of stay, and increased functional independence of patients at hospital discharge. METHODS: We did a multicentre, international, parallel-group, assessor-blinded, randomised controlled trial in SICUs of five university hospitals in Austria (n=1), Germany (n=1), and the USA (n=3). Eligible patients (aged 18 years or older, who had been mechanically ventilated for <48 h, and were expected to require mechanical ventilation for ≥24 h) were randomly assigned (1:1) by use of a stratified block randomisation via restricted web platform to standard of care (control) or early, goal-directed mobilisation using an inter-professional approach of closed-loop communication and the SICU optimal mobilisation score (SOMS) algorithm (intervention), which describes patients' mobilisation capacity on a numerical rating scale ranging from 0 (no mobilisation) to 4 (ambulation). We had three main outcomes hierarchically tested in a prespecified order: the mean SOMS level patients achieved during their SICU stay (primary outcome), and patient's length of stay on SICU and the mini-modified functional independence measure score (mmFIM) at hospital discharge (both secondary outcomes). This trial is registered with ClinicalTrials.gov (NCT01363102). FINDINGS: Between July 1, 2011, and Nov 4, 2015, we randomly assigned 200 patients to receive standard treatment (control; n=96) or intervention (n=104). Intention-to-treat analysis showed that the intervention improved the mobilisation level (mean achieved SOMS 2·2 [SD 1·0] in intervention group vs 1·5 [0·8] in control group, p<0·0001), decreased SICU length of stay (mean 7 days [SD 5-12] in intervention group vs 10 days [6-15] in control group, p=0·0054), and improved functional mobility at hospital discharge (mmFIM score 8 [4-8] in intervention group vs 5 [2-8] in control group, p=0·0002). More adverse events were reported in the intervention group (25 cases [2·8%]) than in the control group (ten cases [0·8%]); no serious adverse events were observed. Before hospital discharge 25 patients died (17 [16%] in the intervention group, eight [8%] in the control group). 3 months after hospital discharge 36 patients died (21 [22%] in the intervention group, 15 [17%] in the control group). INTERPRETATION: Early, goal-directed mobilisation improved patient mobilisation throughout SICU admission, shortened patient length of stay in the SICU, and improved patients' functional mobility at hospital discharge. FUNDING: Jeffrey and Judy Buzen.