Right Ventricular Pressure Waveform Analysis-Clinical Relevance and Future Directions.

Continuous measurement of pressure in the right atrium and pulmonary artery has commonly been used to monitor right ventricular function in critically ill and surgical patients. This approach is largely based upon the assumption that right atrial and pulmonary arterial pressures provide accurate surrogates for diastolic filling and peak right ventricular pressures, respectively. However, due to both technical and physiologic factors, this assumption is not always true. Accordingly, recent studies have begun to emphasize the potential clinical value of also measuring right ventricular pressure at the bedside. This has highlighted both past and emerging research demonstrating the utility of analyzing not only the amplitude of right ventricular pressure but also the shape of the pressure waveform. This brief review summarizes data demonstrating that combining conventional measurements of right ventricular pressure with variables derived from waveform shape allows for more comprehensive and ideally continuous bedside assessment of right ventricular function, particularly when combined with stroke volume measurement or 3D echocardiography, and discusses the potential use of right ventricular pressure analysis in computational models for evaluating cardiac function.

Right Heart Failure in the Intensive Care Unit: Etiology, Pathogenesis, Diagnosis, and Treatment.

Right heart (RH) failure carries a high rate of morbidity and mortality. Patients who present with RH failure often exhibit complex aberrant cardio-pulmonary physiology with varying presentations. The treatment of RH failure almost always requires care and management from an intensivist. Treatment options for RH failure patients continue to evolve rapidly with multiple options available, including different pharmacotherapies and mechanical circulatory support devices that target various components of the RH circulatory system. An understanding of the normal RH circulatory physiology, treatment, and support options for the RH failure patients is necessary for all intensivists to improve outcomes. The purpose of this review is to provide clinical guidance on the diagnosis and management of RH failure within the intensive care unit setting, and to highlight the different pathophysiological manifestations of RH failure, its hemodynamics, and treatment options available at the disposal of the intensivist.

Integrating Right Ventricular Pressure Waveform Analysis With Two-Point Volume Measurement for Quantification of Systolic and Diastolic Function: Experimental Validation and Clinical Application.

OBJECTIVE: To define in an experimental model the variance, accuracy, precision, and concordance of single-beat measures of right ventricular (RV) contractility and diastolic capacitance relative to conventional reference standards, and apply the methods to a clinical data set. DESIGN: A retrospective, observational analysis of recorded pressure waveforms and RV volume measurements. SETTING: At a university laboratory. PARTICIPANTS: Archived data from previous studies of anesthetized swine and awake patients undergoing clinically-indicated right-heart catheterization. INTERVENTIONS: Recording of RV pressure with simultaneous measurement of RV volume by conductance (swine) or 3-dimensional (3D) echocardiography (humans) during changes in contractility and/or loading conditions. MEASUREMENTS AND MAIN RESULTS: Using experimental data, single-beat measures of RV contractility quantified as end-systolic elastance, and diastolic capacitance quantified as the predicted volume at an end-diastolic pressure of 15 mmHg (V15), were compared to multi-beat, preload- variant, reference standards using correlation, Bland-Altman analysis, and 4-quadrant concordance testing. This analysis indicated that the methods were not directly interchangeable with reference standards, but were sufficiently robust to suggest potential clinical utility. Clinical application supported this potential by demonstrating enhanced assessment of the response to inhaled nitric oxide in patients undergoing diagnostic right-heart catheterization. CONCLUSIONS: Study results supported the possibility of integrating automated RV pressure analysis with RV volume measured by 3D echocardiography to create a comprehensive assessment of RV systolic and diastolic function at the bedside.

Characterizing the Spatiotemporal Transcriptomic Response of the Right Ventricle to Acute Pressure Overload.

This study analyzed microarray data of right ventricular (RV) tissue from rats exposed to pulmonary embolism to understand the initial dynamic transcriptional response to mechanical stress and compare it with experimental pulmonary hypertension (PH) models. The dataset included samples harvested from 55 rats at 11 different time points or RV locations. We performed principal component analysis (PCA) to explore clusters based on spatiotemporal gene expression. Relevant pathways were identified from fast gene set enrichment analysis using PCA coefficients. The RV transcriptomic signature was measured over several time points, ranging from hours to weeks after an acute increase in mechanical stress, and was found to be highly dependent on the severity of the initial insult. Pathways enriched in the RV outflow tracts of rats at 6 weeks after severe PE share many commonalities with experimental PH models, but the transcriptomic signature at the RV apex resembles control tissue. The severity of the initial pressure overload determines the trajectory of the transcriptomic response independent of the final afterload, but this depends on the location where the tissue is biopsied. Chronic RV pressure overload due to PH appears to progress toward similar transcriptomic endpoints.

Pressure-Regulated Ventilator Splitting for Disaster Relief: Design, Testing, and Clinical Experience.

The coronavirus disease 2019 (COVID-19) pandemic has revealed that even the best-resourced hospitals may lack sufficient ventilators to support patients under surge conditions. During a pandemic or mass trauma, an affordable, low-maintenance, off-the-shelf device that would allow health care teams to rapidly expand their ventilator capacity could prove lifesaving, but only if it can be safely integrated into a complex and rapidly changing clinical environment. Here, we define an approach to safe ventilator sharing that prioritizes predictable and independent care of patients sharing a ventilator. Subsequently, we detail the design and testing of a ventilator-splitting circuit that follows this approach and describe our clinical experience with this circuit during the COVID-19 pandemic. This circuit was able to provide individualized and titratable ventilatory support with individualized positive end-expiratory pressure (PEEP) to 2 critically ill patients at the same time, while insulating each patient from changes in the other's condition. We share insights from our experience using this technology in the intensive care unit and outline recommendations for future clinical applications.

Heart rate variability measures for prediction of severity of illness and poor outcome in ED patients with sepsis.

INTRODUCTION: This study evaluates the utility of heart rate variability (HRV) for assessment of severity of illness and poor outcome in Emergency Department (ED) patients with sepsis. HRV measures evaluated included low frequency (LF) signal, high frequency (HF) signal, and deviations in LF and HF signal from age-adjusted reference values. METHODS: This was a prospective, observational study. Seventy-two adult ED patients were assessed within 6 h of arrival. RESULTS: Severity of illness as defined by sepsis subtype correlated with decreased LF signal (sepsis: 70.68 ± 22.95, severe sepsis: 54.00 ± 28.41, septic shock: 45.54 ± 23.31, p = 0.02), increased HF signal (sepsis: 27.87 ± 19.42, severe sepsis: 44.63 ± 27.29, septic shock: 47.66 ± 20.98, p = 0.01), increasingly negative deviations in LF signal (sepsis: 0.41 ± 24.53, severe sepsis: -21.43 ± 30.09, septic shock -30.39 ± 26.09, p = 0.005) and increasingly positive deviations in HF signal (sepsis: -1.86 ± 21.09, severe sepsis: 20.07 ± 29.03, septic shock: 23.6 ± 24.17, p = 0.004). Composite poor outcome correlated with decreased LF signal (p = 0.008), increased HF signal (p = 0.03), large negative deviations in LF signal (p = 0.004) and large positive deviations in HF signal (p = 0.02). Deviations in LF and HF signal from age-adjusted reference values correlated with individual measures of poor outcome with greater consistency than LF or HF signal. DISCUSSION: Accounting for the influence of age on baseline HRV signal improves the predictive value of HRV measures in ED patients with sepsis.

Glymphatic System Function in Relation to Anesthesia and Sleep States.

The brain is one of the most metabolically active organs in the body. The brain's high energy demand associated with wakefulness persists during rapid eye movement sleep, and even during non-rapid eye movement sleep, cerebral oxygen consumption is only reduced by 20%. The active bioenergetic state parallels metabolic waste production at a higher rate than in other organs, and the lack of lymphatic vasculature in brain parenchyma is therefore a conundrum. A common assumption has been that with a tight blood-brain barrier restricting solute and fluid movements, a lymphatic system is superfluous in the central nervous system. Cerebrospinal fluid (CSF) flow has long been thought to facilitate central nervous system tissue "detoxification" in place of lymphatics. Nonetheless, while CSF production and transport have been studied for decades, the exact processes involved in toxic waste clearance remain poorly understood. Over the past 5 years, emerging data have begun to shed new light on these processes in the form of the "glymphatic system," a novel brain-wide perivascular transit passageway dedicated to CSF transport and metabolic waste drainage from the brain. Here, we review the key anatomical components and operational drivers of the brain's glymphatic system, with a focus on its unique functional dependence on the state of arousal and anesthetic regimens. We also discuss evidence for why clinical exploration of this novel system may in the future provide valuable insight into new strategies for preventing delirium and cognitive dysfunction in perioperative and critical care settings.

Preclinical Pharmacology in the Rhesus Monkey of CW 1759-50, a New Ultra-short Acting Nondepolarizing Neuromuscular Blocking Agent, Degraded and Antagonized by L-Cysteine.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Structure-activity studies were performed to identify a new neuromuscular blocking agent retaining the ultra-short acting characteristics of gantacurium, including degradation and reversal by L-cysteine, but lacking its histaminoid properties in man. CW 1759-50 has emerged from this program. METHODS: Adduction of CW 1759-50 with L-cysteine was studied by high-performance liquid chromatography and mass spectrometry. Institutional Animal Care and Use Committee-approved comparisons of CW 1759-50 to gantacurium were performed in rhesus monkeys. ED95 for neuromuscular blockade was established. Spontaneous recovery was compared to reversal by L-cysteine in paired studies of boluses or infusions. In addition, changes in mean arterial pressure and heart rate after very large doses of 15 to 60 × ED95 were compared. RESULTS: The half-time of adduction of L-cysteine to CW 1759-50 in vitro was 2.3 min. The ED95 of CW 1759-50 was 0.069 ± 0.02 mg/kg; ED95 of gantacurium was 0.081 ± 0.05 mg/kg (P = 0.006). Duration of action (recovery to 95% twitch height after 98 to 99% blockade) was as follows: CW 1759-50, 8.2 ± 1.5 min; and gantacurium, 7.4 ± 1.9 min; (n = 8 and 9, P = 0.355). Administration of L-cysteine (30 mg/kg) shortened recovery (i.e., induced reversal) from CW 1759-50 after boluses or infusions (P always less than 0.0001). Recovery intervals (5 to 95% twitch) ranged from 6.1 to 6.7 min (and did not differ significantly) after boluses of 0.10 to 0.50 mg/kg, as well as control infusions (P = 0.426 by analysis of variance). Dose ratios comparing changes of 30% in mean arterial pressure or heart rate to ED95 for neuromuscular blockade (ED 30% Δ [mean arterial pressure or heart rate]/ED95) were higher for CW 1759-50 than for gantacurium. CONCLUSIONS: CW 1759-50, similar to gantacurium, is an ultra-short acting neuromuscular blocking agent, antagonized by L-cysteine, in the monkey. The circulatory effects, however, are much reduced in comparison with gantacurium, suggesting a trial in humans.

Pharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers.

BACKGROUND: CW002 is an investigational nondepolarizing, neuromuscular blocking agent with a rapid onset and intermediate duration of action in animals. This is a single ascending dose, healthy subject study exploring tolerability, pharmacokinetics, and potency. METHODS: Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed using plasma drug concentration data from a previously published dose-response study in 28 healthy subjects receiving single doses of CW002 during sevoflurane anesthesia. Subjects included in the models were from five different dose cohorts (cohorts 3, 4, 5, 6, and 8 receiving 0.04, 0.06, 0.08, 0.10, and 0.14 mg/kg, respectively). Serial arterial plasma concentrations and muscle twitch heights were monitored. RESULTS: A four-compartment model was fit to the concentration-time data, whereas a transit compartment with a sigmoid Emax model was fit to the pharmacokinetic/pharmacodynamic data. The population pharmacokinetics of CW002 was linear with very low interindividual variability in clearance (10.8%). Simulations were conducted to predict the onset and offset of effect at 2×, 3×, and 4× ED95. The time to 80% block was predicted to be 1.5, 0.8, and 0.7 min for 2×, 3×, and 4× ED95 doses, respectively. The simulated 25 to 75% recovery index was independent of dose. CONCLUSIONS: CW002 has predictable pharmacokinetics and is likely to have a rapid onset with an intermediate duration of action at 3× ED95. This model provides information to inform critical decisions (e.g., dose, study design) for continued development of CW002.

Accuracy of a Simulation Algorithm for Modelling LV Contractility, Diastolic Capacitance, and Energetics Using Data Available From Common Hemodynamic Monitors and Echocardiography.

OBJECTIVE: To test the hypothesis that a simulation algorithm populated with data readily available from hemodynamic monitors and echocardiography can accurately model cardiac contractility, diastolic capacitance, and energetics. DESIGN: Bland-Altman analysis of paired data sets. SETTING: University laboratory. PARTICIPANTS: Archived data previously recorded from 7 anesthetized swine. MEASUREMENTS AND MAIN RESULTS: Left ventricular pressure and volume (LVV) data that had been continuously recorded over a range of inotropic conditions were used as reference data. One investigator performed conventional analysis of measured pressure/volume loops during preload reduction to derive reference values for end-systolic elastance (Ees-a measure of contractility), the predicted LVV at an end-diastolic pressure of 30 mmHg (V30-an index of diastolic capacitance and chamber dilation), and pressure-volume area (PVA-a correlate of myocardial oxygen consumption). Other investigators blinded to these results entered pressure, cardiac output, and ejection fraction measurements into a simulator that predicts Ees, V30, and PVA. Analysis of simulated data was performed before and after correction of the estimated LVV at which pressure would be 0 mmHg (V0), which was initially fixed in the model. Before V0 correction, accuracy and precision of Ees, V30, and PVA tended to fall outside predefined limits for method interchangeability, but utility for qualitative assessment of acute changes was evident. After V0 correction, the accuracy and precision of simulated data were within the defined limits for method interchangeability. CONCLUSIONS: These data support the potential for clinical utility of simulation models populated with data readily available at the bedside to characterize left ventricular mechanical performance and energetics.

Perioperative pulmonary thromboembolism: current concepts and treatment options.

PURPOSE OF REVIEW: Anesthesiologists are familiar with pulmonary emboli prophylaxis paradigms and many have witnessed acute intraoperative embolization. Clinicians must balance conservative anticoagulation and aggressive intervention in perioperative submassive pulmonary emboli, yet the bulk of the literature excludes surgery as a relative contraindication. This review will summarize the current treatment options for acute pulmonary emboli, drawing attention to special considerations in perioperative submassive pulmonary emboli, and discuss right ventricular monitoring to improve assessment of intervention efficacy. RECENT FINDINGS: Recent reviews have identified the elevated risk and inadequacy of treatment of pulmonary embolism in intra and postoperative patients, in part because of the risks of systemic anticoagulation. Early studies of catheter-directed therapies have shown promising efficacy with a reduction in bleeding risk, which is especially important for perioperative patients. Success relies on defining endpoints, yet the practice of measuring mean pulmonary artery pressure alone to assess intervention efficacy is flawed. SUMMARY: Identifying submassive pulmonary emboli that requires treatment and optimizing therapy remains difficult. Researchers must consider avoiding systemic anticoagulation and focus on designing trials that evaluate intervention efficacy in surgical patients. The success of catheter-directed therapy in early trials warrants further investigation into using these therapies in the treatment of perioperative submassive pulmonary emboli.

Agreement of Bioreactance Cardiac Output Monitoring With Thermodilution During Hemorrhagic Shock and Resuscitation in Adult Swine.

OBJECTIVE: The study tests the hypothesis that noninvasive cardiac output monitoring based upon bioreactance (Cheetah Medical, Portland, OR) has acceptable agreement with intermittent bolus thermodilution over a wide range of cardiac output in an adult porcine model of hemorrhagic shock and resuscitation. DESIGN: Prospective laboratory animal investigation. SETTING: Preclinical university laboratory. SUBJECTS: Eight ~ 50 kg Yorkshire swine with a femoral artery catheter for blood pressure measurement and a pulmonary artery catheter for bolus thermodilution. INTERVENTIONS: With the pigs anesthetized and mechanically ventilated, 40 mL/kg of blood was removed yielding marked hypotension and a rise in plasma lactate. After 60 minutes, pigs were resuscitated with shed blood and crystalloid. Noninvasive cardiac output monitoring and intermittent thermodilution cardiac output were simultaneously measured at nine time points spanning baseline, hemorrhage, and resuscitation. MEASUREMENTS AND MAIN RESULTS: Simultaneous noninvasive cardiac output monitoring and thermodilution measurements of cardiac output were compared by Bland-Altman analysis. A plot was constructed using the difference of each paired measurement expressed as a percentage of the mean of the pair plotted against the mean of the pair. Percent bias was used to scale the differences in the measurements for the magnitude of the cardiac output. Method concordance was assessed from a four-quadrant plot with a 15% zone of exclusion. Overall, noninvasive cardiac output monitoring percent bias was 1.47% (95% CI, -2.5 to 5.4) with limits of agreement of upper equal to 33.4% (95% CI, 26.5-40.2) and lower equal to -30.4% (95% CI, -37.3 to -23.6). Trending analysis demonstrated a 97% concordance between noninvasive cardiac output monitoring and thermodilution cardiac output. CONCLUSIONS: Over the wide range of cardiac output produced by hemorrhage and resuscitation in large pigs, noninvasive cardiac output monitoring has acceptable agreement with thermodilution cardiac output.

Single-lung ventilation and oxidative stress: a different perspective on a common practice.

PURPOSE OF REVIEW: To summarize what is currently known about the relationship between single-lung ventilation (SLV), oxidative stress, and postoperative disruption of organ function. RECENT FINDINGS: SLV produces progressive alelectasis that is associated with hypoxic pulmonary vasoconstriction and redistribution of blood flow away from the nonventilated lung. This local tissue hypoxia induces the generation of reactive oxygen and reactive nitrogen species, an effect subsequently amplified by lung re-expansion consistent with well described hypoxia/reperfusion responses. Both experimental and clinical data indicate that the magnitude of oxidative and nitrosative stress is related to the duration of SLV and that these stresses affect not only the collapsed/re-expanded lung, but other organs as well. SUMMARY: SLV and subsequent re-expansion of atelectatic lung are associated with the generation of reactive oxygen and nitrogen species that may modulate persistent systemic effects.

Anesthesia for nonintubated video-assisted thoracic surgery.

PURPOSE OF REVIEW: This review focuses primarily on nonintubated video-assisted thoracic surgery (NIVATS), and discusses advantages, indications, anesthetic techniques, and approaches to intraoperative crisis management. RECENT FINDINGS: Advancements in endoscopic, endovascular, and robotic techniques have expanded the range of surgical procedures that can be performed in a minimally invasive fashion. For thoracic operations in particular, video-assisted thoracic surgery (VATS) has largely replaced traditional thoracotomy, and continued technical development has made surgical access into the pleural space even less disruptive. As a consequence, the need for general anesthesia and endotracheal intubation has been re-examined, such that regional or epidural analgesia may be sufficient for cases where lung collapse can be accomplished with spontaneous ventilation and an open hemithorax. This concept of NIVATS has gained popularity, and in some centers has now expanded to include procedures involving placement of multiple ports. Although still relatively uncommon at present, a small number of randomized trials and meta-analyses have indicated some advantages, suggesting that NIVATS may be a desirable alternative to general anesthesia with endotracheal intubation for specific indications. SUMMARY: Although anesthesia for NIVATS is associated with some of the same risks as general anesthesia with endotracheal intubation, NIVATS can be successfully performed in carefully selected patients.

Dose-response and Cardiopulmonary Side Effects of the Novel Neuromuscular-blocking Drug CW002 in Man.

BACKGROUND: CW002 is a benzylisoquinolinium nondepolarizing neuromuscular-blocking drug found to be inactivated by cysteine in preclinical studies. The current study represents a dose escalation clinical trial designed to describe CW002 potency, duration, cardiopulmonary side effects, and histamine release. METHODS: Healthy subjects anesthetized with sevoflurane/nitrous oxide were divided into five groups (n = 6), each receiving a fixed CW002 dose (0.02, 0.04, 0.06, 0.08, or 0.10 mg/kg), and one group (n = 4) receiving 0.14 mg/kg. Blood pressure and heart rate were continuously recorded along with airway dynamic compliance. Neuromuscular blockade was assessed with mechanomyography at the adductor pollicis. Arterial blood was obtained before and after CW002 injection for analysis of plasma histamine concentration. Potency was estimated from a baseline sigmoid Emax model. RESULTS: ED50 was found to be 0.036 mg/kg (95% CI, 0.020 to 0.053 mg/kg) and ED95 0.077 mg/kg (95% CI, 0.044 to 0.114 mg/kg). At 0.14 mg/kg (1.8 × ED95), 80% twitch depression occurred in 94 ± 18 s with complete block in 200 ± 87 s. Clinical recovery (25% of maximum twitch) occurred in 34 ± 3.4 min, with a 5 to 95% recovery interval of 35.0 ± 2.7 min. The time to a train-of-four ratio greater than 0.9 ranged from 59 to 86 min. CW002 did not elicit histamine release or significant (greater than 10%) changes in blood pressure, heart rate, or dynamic airway compliance. CONCLUSIONS: In healthy subjects receiving sevoflurane/nitrous oxide, CW002 at 1.8 × estimated ED95 produces a clinical duration less than 40 min, elicits no histamine release, and has minimal cardiopulmonary side effects.

Preclinical Pharmacology of CW002: A Nondepolarizing Neuromuscular Blocking Drug of Intermediate Duration, Degraded and Antagonized by l-cysteine-Additional Studies of Safety and Efficacy in the Anesthetized Rhesus Monkey and Cat.

BACKGROUND: CW002, a novel nondepolarizing neuromuscular blocking agent of intermediate duration, is degraded in vitro by L-cysteine; CW002-induced neuromuscular blockade (NMB) is antagonized in vivo by exogenous L-cysteine. Further, Institutional Animal Care and Use Committee-approved studies of safety and efficacy in eight anesthetized monkeys and six cats are described. METHODS: Mean arterial pressure, heart rate, twitch, and train-of-four were recorded; estimated dose producing 95% twitch inhibition (ED95) for NMB and twitch recovery intervals from 5 to 95% of baseline were derived. Antagonism of 99 to 100% block in monkeys by L-cysteine (50 mg/kg) was tested after bolus doses of approximately 3.75 to 20 × ED95 and after infusions. Vagal and sympathetic autonomic responses were recorded in cats. Dose ratios for [circulatory (ED20) or autonomic (ED50) changes/ED95 (NMB)] were calculated. RESULTS: ED95s of CW002 in monkeys and cats were 0.040 and 0.035 mg/kg; L-cysteine readily antagonized block in monkeys: 5 to 95% twitch recovery intervals were shortened to 1.8 to 3.6 min after 3.75 to 10 × ED95 or infusions versus 11.5 to 13.5 min during spontaneous recovery. ED for 20% decrease of mean arterial pressure (n = 27) was 1.06 mg/kg in monkeys; ED for 20% increase of HR (n = 27) was 2.16 mg/kg. ED50s for vagal and sympathetic inhibition in cats were 0.59 and >>0.80 mg/kg (n = 14 and 15). Dose ratios for [circulatory or autonomic changes/ED95 (NMB)] were all more than 15 × ED95. CONCLUSIONS: The data further verify the neuromuscular blocking properties of CW002, including rapid reversal by L-cysteine of 100% NMB under several circumstances. A notable lack of autonomic or circulatory effects provided added proof of safety and efficacy.