Understanding the complexity of cardiogenic shock management: the added value of advanced computational modeling.

PURPOSE OF REVIEW: The purpose of this review is to explain the value of computational physiological modeling for in-depth understanding of the complex derangements of cardiopulmonary pathophysiology during cardiogenic shock, particularly when treated with temporary mechanical circulatory support (tMCS) devices. RECENT FINDINGS: Computational physiological models have evolved in recent years and can provide a high degree of clinical realism in the simulation of cardiogenic shock and related conservative and interventional therapies. These models feature a large spectrum of practically relevant hemodynamic and respiratory parameters tunable to patient-specific disease states as well as adjustable to medical therapies and support device settings. Current applications work in real-time and can operate on an ordinary computer, laptop or mobile device. SUMMARY: The use of computational physiological models is increasingly appreciated for educational purposes as they help to understand the complexity of cardiogenic shock, especially when sophisticated management of tMCS is involved in addition to multimodal critical care support. Practical implementation of computational models as clinical decision support tools at the bedside is at the horizon but awaits rigorous clinical validation.

Early Restrictive Fluid Strategy Impairs the Diaphragm Force in Lambs with Acute Respiratory Distress Syndrome.

BACKGROUND: The effect of fluid management strategies in critical illness-associated diaphragm weakness are unknown. This study hypothesized that a liberal fluid strategy induces diaphragm muscle fiber edema, leading to reduction in diaphragmatic force generation in the early phase of experimental pediatric acute respiratory distress syndrome in lambs. METHODS: Nineteen mechanically ventilated female lambs (2 to 6 weeks old) with experimental pediatric acute respiratory distress syndrome were randomized to either a strict restrictive fluid strategy with norepinephrine or a liberal fluid strategy. The fluid strategies were maintained throughout a 6-h period of mechanical ventilation. Transdiaphragmatic pressure was measured under different levels of positive end-expiratory pressure (between 5 and 20 cm H2O). Furthermore, diaphragmatic microcirculation, histology, inflammation, and oxidative stress were studied. RESULTS: Transdiaphragmatic pressures decreased more in the restrictive group (-9.6 cm H2O [95% CI, -14.4 to -4.8]) compared to the liberal group (-0.8 cm H2O [95% CI, -5.8 to 4.3]) during the application of 5 cm H2O positive end-expiratory pressure (P = 0.016) and during the application of 10 cm H2O positive end-expiratory pressure (-10.3 cm H2O [95% CI, -15.2 to -5.4] vs. -2.8 cm H2O [95% CI, -8.0 to 2.3]; P = 0.041). In addition, diaphragmatic microvessel density was decreased in the restrictive group compared to the liberal group (34.0 crossings [25th to 75th percentile, 22.0 to 42.0] vs. 46.0 [25th to 75th percentile, 43.5 to 54.0]; P = 0.015). The application of positive end-expiratory pressure itself decreased the diaphragmatic force generation in a dose-related way; increasing positive end-expiratory pressure from 5 to 20 cm H2O reduced transdiaphragmatic pressures with 27.3% (17.3 cm H2O [95% CI, 14.0 to 20.5] at positive end-expiratory pressure 5 cm H2O vs. 12.6 cm H2O [95% CI, 9.2 to 15.9] at positive end-expiratory pressure 20 cm H2O; P < 0.0001). The diaphragmatic histology, markers for inflammation, and oxidative stress were similar between the groups. CONCLUSIONS: Early fluid restriction decreases the force-generating capacity of the diaphragm and diaphragmatic microcirculation in the acute phase of pediatric acute respiratory distress syndrome. In addition, the application of positive end-expiratory pressure decreases the force-generating capacity of the diaphragm in a dose-related way. These observations provide new insights into the mechanisms of critical illness-associated diaphragm weakness.

Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT): Protocol and statistical analysis plan for an investigator-initiated international meta-trial of prospective randomised clinical studies.

There is significant interest in the potential for nebulised unfractionated heparin (UFH), as a novel therapy for patients with COVID-19 induced acute hypoxaemic respiratory failure requiring invasive ventilation. The scientific and biological rationale for nebulised heparin stems from the evidence for extensive activation of coagulation resulting in pulmonary microvascular thrombosis in COVID-19 pneumonia. Nebulised delivery of heparin to the lung may limit alveolar fibrin deposition and thereby limit progression of lung injury. Importantly, laboratory studies show that heparin can directly inactivate the SARS-CoV-2 virus, thereby prevent its entry into and infection of mammalian cells. UFH has additional anti-inflammatory and mucolytic properties that may be useful in this context. METHODS AND INTERVENTION: The Can nebulised HepArin Reduce morTality and time to Extubation in Patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT) is a collaborative prospective individual patient data analysis of on-going randomised controlled clinical trials across several countries in five continents, examining the effects of inhaled heparin in patients with COVID-19 requiring invasive ventilation on various endpoints. Each constituent study will randomise patients with COVID-19 induced respiratory failure requiring invasive ventilation. Patients are randomised to receive nebulised heparin or standard care (open label studies) or placebo (blinded placebo-controlled studies) while under invasive ventilation. Each participating study collect a pre-defined minimum dataset. The primary outcome for the meta-trial is the number of ventilator-free days up to day 28 day, defined as days alive and free from invasive ventilation.

Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID-19: A multicentre case series of 98 patients.

AIMS: To determine the safety and efficacy-potential of inhaled nebulised unfractionated heparin (UFH) in the treatment of hospitalised patients with COVID-19. METHODS: Retrospective, uncontrolled multicentre single-arm case series of hospitalised patients with laboratory-confirmed COVID-19, treated with inhaled nebulised UFH (5000 IU q8h, 10 000 IU q4h, or 25 000 IU q6h) for 6 ± 3 (mean ± standard deviation) days. Outcomes were activated partial thromboplastin time (APTT) before treatment (baseline) and highest-level during treatment (peak), and adverse events including bleeding. Exploratory efficacy outcomes were oxygenation, assessed by ratio of oxygen saturation to fraction of inspired oxygen (FiO2 ) and FiO2 , and the World Health Organisation modified ordinal clinical scale. RESULTS: There were 98 patients included. In patients on stable prophylactic or therapeutic systemic anticoagulant therapy but not receiving therapeutic UFH infusion, APTT levels increased from baseline of 34 ± 10 seconds to a peak of 38 ± 11 seconds (P < .0001). In 3 patients on therapeutic UFH infusion, APTT levels did not significantly increase from baseline of 72 ± 20 to a peak of 84 ± 28 seconds (P = .17). Two patients had serious adverse events: bleeding gastric ulcer requiring transfusion and thigh haematoma; both were on therapeutic anticoagulation. Minor bleeding occurred in 16 patients, 13 of whom were on therapeutic anticoagulation. The oxygen saturation/FiO2 ratio and the FiO2 worsened before and improved after commencement of inhaled UFH (change in slope, P < .001). CONCLUSION: Inhaled nebulised UFH in hospitalised patients with COVID-19 was safe. Although statistically significant, inhaled nebulised UFH did not produce a clinically relevant increase in APTT (peak values in the normal range). Urgent randomised evaluation of nebulised UFH in patients with COVID-19 is warranted and several studies are currently underway.

The Impact of Nursing Delirium Preventive Interventions in the ICU: A Multicenter Cluster-randomized Controlled Clinical Trial.

Rationale: Delirium is common in critically ill patients and is associated with deleterious outcomes. Nonpharmacological interventions are recommended in current delirium guidelines, but their effects have not been unequivocally established. Objectives: To determine the effects of a multicomponent nursing intervention program on delirium in the ICU. Methods: A stepped-wedge cluster-randomized controlled trial was conducted in ICUs of 10 centers. Adult critically ill surgical, medical, or trauma patients at high risk of developing delirium were included. A multicomponent nursing intervention program focusing on modifiable risk factors was implemented as standard of care. The primary outcome was the number of delirium-free and coma-free days alive in 28 days after ICU admission. Measurements and Main Results: A total of 1,749 patients were included. Time spent on interventions per 8-hour shift was median (interquartile range) 38 (14-116) minutes in the intervention period and median 32 (13-73) minutes in the control period (P = 0.44). Patients in the intervention period had a median of 23 (4-27) delirium-free and coma-free days alive compared with a median of 23 (5-27) days for patients in the control group (mean difference, -1.21 days; 95% confidence interval, -2.84 to 0.42 d; P = 0.15). In addition, the number of delirium days was similar: median 2 (1-4) days (ratio of medians, 0.90; 95% confidence interval, 0.75 to 1.09; P = 0.27). Conclusions: In this large randomized controlled trial in adult ICU patients, a limited increase in the use of nursing interventions was achieved, and no change in the number of delirium-free and coma-free days alive in 28 days could be determined. Clinical trial registered with www.clinicaltrials.gov (NCT03002701).

Early restrictive fluid resuscitation has no clinical advantage in experimental severe pediatric acute respiratory distress syndrome.

Intravenous fluids are widely used to treat circulatory deterioration in pediatric acute respiratory distress syndrome (PARDS). However, the accumulation of fluids in the first days of PARDS is associated with adverse outcome. As such, early fluid restriction may prove beneficial, yet the effects of such a fluid strategy on the cardiopulmonary physiology in PARDS are unclear. In this study, we compared the effect of a restrictive with a liberal fluid strategy on a hemodynamic response and the formation of pulmonary edema in an animal model of PARDS. Sixteen mechanically ventilated lambs (2-6 wk) received oleic acid infusion to induce PARDS and were randomized to a restrictive or liberal fluid strategy during a 6-h period of mechanical ventilation. Transpulmonary thermodilution determined extravascular lung water (EVLW) and cardiac output (CO). Postmortem lung wet-to-dry weight ratios were obtained by gravimetry. Restricting fluids significantly reduced fluid intake but increased the use of vasopressors among animals with PARDS. Arterial blood pressure was similar between groups, yet CO declined significantly in animals receiving restrictive fluids (P = 0.005). There was no difference in EVLW over time (P = 0.111) and lung wet-to-dry weight ratio [6.1, interquartile range (IQR) = 6.0-7.3 vs. 7.1, IQR = 6.6-9.4, restrictive vs. liberal, P = 0.725] between fluid strategies. Both fluid strategies stabilized blood pressure in this model, yet early fluid restriction abated CO. Early fluid restriction did not limit the formation of pulmonary edema; therefore, this study suggests that in the early phase of PARDS, a restrictive fluid strategy is not beneficial in terms of immediate cardiopulmonary effects.

INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP): Protocol and statistical analysis plan for an investigator-initiated international metatrial of randomised studies.

AIMS: Inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale that warrants urgent investigation of its therapeutic potential in patients with COVID-19. UFH has antiviral effects and prevents the SARS-CoV-2 virus' entry into mammalian cells. In addition, UFH has significant anti-inflammatory and anticoagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis. METHODS: The INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP) metatrial is a prospective individual patient data analysis of on-going randomised controlled trials and early phase studies. Individual studies are being conducted in multiple countries. Participating studies randomise adult patients admitted to the hospital with confirmed SARS-CoV-2 infection, who do not require immediate mechanical ventilation, to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome for the metatrial is intubation (or death, for patients who died before intubation) at day 28. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time-to-event analyses. Individual studies may have additional outcomes. ANALYSIS: We use a Bayesian approach to monitoring, followed by analysing individual patient data, outcomes and adverse events. All analyses will follow the intention-to-treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn. TRIAL REGISTRATION, ETHICS AND DISSEMINATION: The metatrial is registered at ClinicalTrials.gov ID NCT04635241. Each contributing study is individually registered and has received approval of the relevant ethics committee or institutional review board. Results of this study will be shared with the World Health Organisation, published in scientific journals and presented at scientific meetings.

Computational modeling of heart failure in microgravity transitions.

The space tourism industry is growing due to advances in rocket technology. Privatised space travel exposes non-professional astronauts with health profiles comprising underlying conditions to microgravity. Prior research has typically focused on the effects of microgravity on human physiology in healthy astronauts, and little is known how the effects of microgravity may play out in the pathophysiology of underlying medical conditions, such as heart failure. This study used an established, controlled lumped mathematical model of the cardiopulmonary system to simulate the effects of entry into microgravity in the setting of heart failure with both, reduced and preserved ejection fraction. We find that exposure to microgravity eventuates an increased cardiac output, and in patients with heart failure there is an unwanted increase in left atrial pressure, indicating an elevated risk for development of pulmonary oedema. This model gives insight into the risks of space flight for people with heart failure, and the impact this may have on mission success in space tourism.

Non-invasive blood pressure and cardiac index measurements using the Finapres Portapres in an emergency department triage setting.

UNLABELLED: Emergency department (ED) patients are triaged to determine the urgency of care. The Finapres Portapres (FP) measures blood pressure (BP) and cardiac output (CO) non-invasively, and may be of added value in early detection of patients at risk for hemodynamic compromise. OBJECTIVES: Compare non-invasive BP measurements using FP and standard automated sphygmomanometry. Compare FP cardiac index (CI), CO corrected for body surface area, of normotensive patients, to chart-based physician estimate of shock, to discover if there is additional value in CI measurements in triage. METHODS: ED Patients requiring BP measurement in triage were included. Systolic (SBP) and diastolic (DBP) BP were measured using both devices during a two minutes measurement. Two physicians independently judged probability of shock, defined as estimated CI ≤2.5 L min(-1) m(-2), based on chart review, three weeks after ED visit. RESULTS: Of a total of 112 patients 97 patients were included. Pearson's correlation coefficient was 0.50 for SBP, 0.53 for DBP, with a Blant-Altman mean bias of 11.3 (upper limit 65.3, lower limit -42.8) and 7.7 (39.2, -23.7) for SBP and DBP respectively. In normotensive patients, the group with low FP CI measurements had significantly more cases with physician-estimated shock, compared to the normal to high measurements (P = .036). CONCLUSIONS: When used as a triage device in the emergency department setting, non-invasive BP measurements using FP do not correlate well with automated sphygmomanometry. However, this study does indicate that use of the FP device in triage may aid physicians to recognize patients in early phases of shock.

The Impact of Non-Pharmacological Interventions on Delirium in Neurological Intensive Care Unit Patients: A Single-Center Interrupted Time Series Trial.

Background: Delirium is a pathobiological brain process that is frequently observed in Intensive Care Unit (ICU) patients, and is associated with longer hospitalization as well as long-term cognitive impairment. In neurological ICU patients, delirium may be more treatment-resistant due to the initial brain injury. This study examined the effects of a multicomponent non-pharmacological nursing intervention program on delirium in neurological ICU patients. Methods: A single-center interrupted time series trial was conducted in adult neurological ICU patients at high risk for developing delirium who were non-delirious at admission. A multicomponent nursing intervention program focusing on modifiable risk factors for delirium, including the optimalization of vision, hearing, orientation and cognition, sleep and mobilization, was implemented as the standard of care, and its effects were studied. The primary outcome was the number of delirium-free and coma-free days alive at 28 days after ICU admission. The secondary outcomes included delirium incidence and duration, ICU and hospital length-of-stay and duration of mechanical ventilation. Results: Of 289 eligible patients admitted to the ICU, 130 patients were included, with a mean age of 68 ± 11 years, a mean APACHE-IV score of 79 ± 25 and a median predicted delirium risk (E-PRE-DELIRIC) score of 42 [IQR 38-50]). Of these, 73 were included in the intervention period and 57 in the control period. The median delirium- and coma-free days alive were 15 days [IQR 0-26] in the intervention group and 10 days [IQR 0-24] in the control group (level change -0.48 days, 95% confidence interval (95%CI) -7 to 6 days, p = 0.87; slope change -0.95 days, 95%CI -2.41 to 0.52 days, p = 0.18). Conclusions: In neurological ICU patients, our multicomponent non-pharmacological nursing intervention program did not change the number of delirium-free and coma-free days alive after 28 days.

Cell death and barrier disruption by clinically used iodine concentrations.

Povidone-iodine (PVP-I) inactivates a broad range of pathogens. Despite its widespread use over decades, the safety of PVP-I remains controversial. Its extended use in the current SARS-CoV-2 virus pandemic urges the need to clarify safety features of PVP-I on a cellular level. Our investigation in epithelial, mesothelial, endothelial, and innate immune cells revealed that the toxicity of PVP-I is caused by diatomic iodine (I2), which is rapidly released from PVP-I to fuel organic halogenation with fast first-order kinetics. Eukaryotic toxicity manifests at below clinically used concentrations with a threshold of 0.1% PVP-I (wt/vol), equalling 1 mM of total available I2 Above this threshold, membrane disruption, loss of mitochondrial membrane potential, and abolition of oxidative phosphorylation induce a rapid form of cell death we propose to term iodoptosis. Furthermore, PVP-I attacks lipid rafts, leading to the failure of tight junctions and thereby compromising the barrier functions of surface-lining cells. Thus, the therapeutic window of PVP-I is considerably narrower than commonly believed. Our findings urge the reappraisal of PVP-I in clinical practice to avert unwarranted toxicity whilst safeguarding its benefits.

Computational modeling of orthostatic intolerance for travel to Mars.

Astronauts in a microgravity environment will experience significant changes in their cardiopulmonary system. Up until now, there has always been the reassurance that they have real-time contact with experts on Earth. Mars crew however will have gaps in their communication of 20 min or more. In silico experiments are therefore needed to assess fitness to fly for those on future space flights to Mars. In this study, we present an open-source controlled lumped mathematical model of the cardiopulmonary system that is able simulate the short-term adaptations of key hemodynamic parameters to an active stand test after being exposed to microgravity. The presented model is capable of adequately simulating key cardiovascular hemodynamic changes-over a short time frame-during a stand test after prolonged spaceflight under different gravitational conditions and fluid loading conditions. This model can form the basis for further exploration of the ability of the human cardiovascular system to withstand long-duration space flight and life on Mars.

The inspiration hold maneuver is a reliable method to assess mean systemic filling pressure but its clinical value remains unclear.

BACKGROUND: The upstream pressure for venous return (VR) is considered to be a combined conceptual blood pressure of the systemic vessels: the mean systemic filling pressure (MSFP). The relevance of estimating the MSFP during dynamic changes of the circulation at the bedside is controversial. Herein, we studied the effect of high ventilatory pressures on the relationship between VR and central venous pressure (CVP). METHODS: In 9 healthy pigs under anaesthesia and mechanically ventilated, MSFP was estimated from extrapolated VR versus CVP relationships during inspiratory hold maneuvers (IHMs) with different levels of ventilatory pressure (Pvent). MSFP was measure 3 times per animal during euvolemia and hypovolemia. Hypovolemia was induced by bleeding with 10 mL/kg. The estimated MSFP values were compared to the blood pressure recording after induced ventricle fibrillation (i.e., mean circulatory filling pressure). RESULTS: Our results revealed a strong linear correlation between VR and CVP [R2 of 0.92 (range, 0.67-0.99)], during IHMs with different levels of Pvent. Volume status significantly alters the resulting MSFP, 20±1 and 16±2 mmHg for euvolemia and hypovolemia respectively. This estimation of the MSFP was strongly correlated-but not interchangeable-to the blood pressure recording after induced ventricle fibrillation (R2=0.8 and P=0.045). CONCLUSIONS: In conclusion, we showed a strong linear correlation between VR and CVP-when applying IHMs with high levels of Pvent-however the clinical applicability of this method to guide volume therapy in its current form is improbable.

Contribution of alarm noise to average sound pressure levels in the ICU: An observational cross-sectional study.

OBJECTIVES: To explore sound levels, alarm frequencies and the association between alarms and sound levels. DESIGN: A single center observational cross-sectional study. SETTING: Four intensive care units. MAIN OUTCOME MEASURES: Contribution of alarms: red (life threatening), yellow (indicate excess of limits) and blue (technical) to sound pressure levels dB(A) at nursing stations. RESULTS: Mean sound pressure levels differed significantly between day (56.1 ± 5.5), evening (55.1 ± 5.7) and night periods 53.6 ± 5.6; p < 0.01. 175,996 alarms were recorded of which 149,764 (85%) were yellow, 18,080 (10%) were red and 8,152 (5%) were blue. The mean sound levels without alarms (background) is 56.8 dB(A), with only red: 56.0 dB(A), only yellow: 55.6 dB(A), only blue: 56.0 dB(A) and mixed alarms: 56.3 dB(A). Yellow alarms (b = -0.93; 95% CI: -1.26 to -0.6; p < 0.001) were weakly but significantly associated with mean sound levels and lead to a slight decrease in noise level (1 dB), Red alarms (b = -0.3; 95% CI: -1.237 to 0.63; p = 0.52). The R Square of the model with all alarms was 0.01 (standard error of estimate, 6.9; p < 0.001). CONCLUSIONS: Sound levels were high during all day-periods. Alarms exceeding limits occurred most frequently. However, the contribution of alarms to sound levels measured at the nursing station is clinically limited.

Effect of Vasopressors on the Macro- and Microcirculation During Systemic Inflammation in Humans In Vivo.

AIM: Comparing the effects of different vasopressors in septic shock patients is hampered by high heterogeneity and the fact that current guidelines dictate the use of norepinephrine. Herein, we studied the effects of three vasopressor agents, norepinephrine, phenylephrine, and vasopressin, on the macro- and microcirculation during experimental human endotoxemia, a standardized, controlled model of systemic inflammation in humans in vivo. METHODS: We performed a randomized controlled study in which 40 healthy male volunteers were assigned to a 5-h infusion of either 0.05 µg/kg/min norepinephrine (n = 10), 0.5 µg/kg/min phenylephrine (n = 10), 0.04 IU/min vasopressin (n = 10), or saline (n = 10), starting 1 h before intravenous administration of 2 ng/kg lipopolysaccharide (LPS). The macrocirculation was monitored using arterial catheter-derived parameters with additional blood pressure waveform contour analysis (PCA) until 4.5 h following LPS administration. Sublingual microcirculatory density and flow were assessed using a handheld video microscope until 6 h post-LPS. RESULTS: LPS administration affected all macrocirculatory and microcirculatory parameters. The LPS-induced decrease in blood pressure and systemic vascular resistance (SVR) was refractory to low-dose norepinephrine and phenylephrine, and to a lesser extent, to vasopressin. Only vasopressin exerted effects on PCA parameters compared with placebo, by mitigating the LPS-induced decrease in diastolic blood pressure by stabilizing SVR and cardiac output. The endotoxemia-induced decreased indices of microvascular flow and density were not influenced by vasopressor therapy. CONCLUSIONS: In a highly controlled model of systemic inflammation in humans in vivo, a 5-h infusion of various vasopressors revealed distinctive effects on macrohemodynamic variables without affecting the sublingual microcirculation.

Hemodynamic response to ß-blockers in severe sepsis and septic shock: A review of current literature.

The administration of ß-blockers in patients with sepsis is a trending topic in intensive care medicine since the landmark study by Morelli and colleagues, showing a striking decrease in 28-day mortality compared to standard care. While the available evidence suggests that the use of ß-blockers in septic shock is safe, the effects on hemodynamics are controversial. In this paper, we review the effect of ß-blockade in septic shock on hemodynamics from animal models to critically ill patients.

ß-Blockade attenuates renal blood flow in experimental endotoxic shock by reducing perfusion pressure.

Clinical data suggests that heart rate (HR) control with selective ß1-blockers may improve cardiac function during septic shock. However, it seems counterintuitive to start ß-blocker infusion in a shock state when organ blood flow is already low or insufficient. Therefore, we studied the effects of HR control with esmolol, an ultrashort- acting ß1-selective adrenoceptor antagonist, on renal blood flow (RBF) and renal autoregulation during early septic shock. In 10 healthy sheep, sepsis was induced by continuous i.v. administration of lipopolysaccharide, while maintained under anesthesia and mechanically ventilated. After successful resuscitation of the septic shock with fluids and vasoactive drugs, esmolol was infused to reduce HR with 30% and was stopped 30-min after reaching this target. Arterial and venous pressures, and RBF were recorded continuously. Renal autoregulation was evaluated by the response in RBF to renal perfusion pressure (RPP) in both the time domain and frequency domain. During septic shock, ß-blockade with esmolol significantly increased the pressure dependency of RBF to RPP. Stopping esmolol showed the reversibility of the impaired renal autoregulation. Showing that clinical diligence and caution are necessary when treating septic shock with esmolol in the acute phase since esmolol reduced RPP to critical values thereby significantly reducing RBF.

The influence of esmolol on right ventricular function in early experimental endotoxic shock.

The mechanism by which heart rate (HR) control with esmolol improves hemodynamics during septic shock remains unclear. Improved right ventricular (RV) function, thereby reducing venous congestion, may play a role. We assessed the effect of HR control with esmolol during sepsis on RV function, macrocirculation, microcirculation, end-organ-perfusion, and ventricular-arterial coupling. Sepsis was induced in 10 healthy anesthetized and mechanically ventilated sheep by continuous IV administration of lipopolysaccharide (LPS). Esmolol was infused after successful resuscitation of the septic shock, to reduce HR and stopped 30-min after reaching targeted HR reduction of 30%. Venous and arterial blood gases were sampled and the small intestines' microcirculation was assessed by using a hand-held video microscope (CytoCam-IDF). Arterial and venous pressures, and cardiac output (CO) were recorded continuously. An intraventricular micromanometer was used to assess the RV function. Ventricular-arterial coupling ratio (VACR) was estimated by catheterization-derived single beat estimation. The targeted HR reduction of >30% by esmolol infusion, after controlled resuscitation of the LPS induced septic shock, led to a deteriorated RV-function and macrocirculation, while the microcirculation remained depressed. Esmolol improved VACR by decreasing the RV end-systolic pressure. Stopping esmolol showed the reversibility of these effects on the RV and the macrocirculation. In this animal model of acute severe endotoxic septic shock, early administration of esmolol decreased RV-function resulting in venous congestion and an unimproved poor microcirculation despite improved cardiac mechanical efficiency.

Middle cerebral artery flow, the critical closing pressure, and the optimal mean arterial pressure in comatose cardiac arrest survivors-An observational study.

AIM: This study estimated the critical closing pressure (CrCP) of the cerebrovascular circulation during the post-cardiac arrest syndrome and determined if CrCP differs between survivors and non-survivors. We also compared patients after cardiac arrest to normal controls. METHODS: A prospective observational study was performed at the ICU of a tertiary university hospital in Nijmegen, the Netherlands. We studied 11 comatose patients successfully resuscitated from a cardiac arrest and treated with mild therapeutic hypothermia and 10 normal control subjects. Mean flow velocity (MFV) in the middle cerebral artery was measured by transcranial Doppler at several time points after admission to the ICU. CrCP was determined by a cerebrovascular impedance model. RESULTS: MFV was similar in survivors and non-survivors upon admission to the ICU, but increased stronger in non-survivors compared to survivors throughout the observation period (P<0.001). MFV was significantly lower in survivors immediately after cardiac arrest compared to normal controls (P<0.001), with a gradual restoration toward normal values. CrCP decreased significantly from 61.4[51.0-77.1]mmHg to 41.7[39.9-51.0]mmHg in the first 48h, after which it remained stable (P<0.001). CrCP was significantly higher in survivors compared to non-survivors (P=0.002). CrCP immediately after cardiac arrest was significantly higher compared to the control group (P=0.02). CONCLUSIONS: CrCP is high after cardiac arrest with high cerebrovascular resistance and low MFV. This suggests that cerebral perfusion pressure should be maintained at a sufficient high level to avoid secondary brain injury. Failure to normalize the cerebrovascular profile may be a parameter of poor outcome.