Levosimendan in intensive care and emergency medicine: literature update and expert recommendations for optimal efficacy and safety.

The inodilator levosimendan, in clinical use for over two decades, has been the subject of extensive clinical and experimental evaluation in various clinical settings beyond its principal indication in the management of acutely decompensated chronic heart failure. Critical care and emergency medicine applications for levosimendan have included postoperative settings, septic shock, and cardiogenic shock. As the experience in these areas continues to expand, an international task force of experts from 15 countries (Austria, Belgium, China, Croatia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Spain, Sweden, Switzerland, and the USA) reviewed and appraised the latest additions to the database of levosimendan use in critical care, considering all the clinical studies, meta-analyses, and guidelines published from September 2019 to November 2021. Overall, the authors of this opinion paper give levosimendan a "should be considered" recommendation in critical care and emergency medicine settings, with different levels of evidence in postoperative settings, septic shock, weaning from mechanical ventilation, weaning from veno-arterial extracorporeal membrane oxygenation, cardiogenic shock, and Takotsubo syndrome, in all cases when an inodilator is needed to restore acute severely reduced left or right ventricular ejection fraction and overall haemodynamic balance, and also in the presence of renal dysfunction/failure.

D-dimer levels for Risk Stratification in Patients with Suspected COVID-19 - A Prospective Observational Study.

BACKGROUND: Elevated D-dimer levels have been observed in COVID-19 and are of prognostic value, but have not been compared to an appropriate control group. METHODS: Observational cohort study including emergency patients with suspected or confirmed COVID-19. Logistic regression defined the association of D-dimer levels, COVID-19 positivity, age, and gender with 30-day-mortality. RESULTS: 953 consecutive patients (median age 58, 43% women) presented with suspected COVID-19: 12 (7.4%) patients with confirmed SARS-CoV-2-infection died, compared with 28 (3.5%) patients without SARS-CoV-2-infection. Overall, most (56%) patients had elevated D-dimer levels (≥0.5mg/l). Age (OR 1.07, CI 1.05-1.10), D-dimer levels ≥0.5mg/l (OR 2.44, CI 0.98-7.39), and COVID-19 (OR 2.79, CI 1.28-5.80) were associated with 30-day-mortality. CONCLUSION: D-dimer levels are effective prognosticators in both patient groups.

Effect of n-3 fatty acids on markers of brain injury and incidence of sepsis-associated delirium in septic patients.

BACKGROUND: Data regarding immunomodulatory effects of parenteral n-3 fatty acids in sepsis are conflicting. In this study, the effect of administration of parenteral n-3 fatty acids on markers of brain injury, incidence of sepsis-associated delirium, and inflammatory mediators in septic patients was investigated. METHODS: Fifty patients with sepsis were randomized to receive either 2 ml/kg/day of a lipid emulsion containing highly refined fish oil (equivalent to n-3 fatty acids 0.12 mg/kg/day) during 7 days after admission to the intensive care unit or standard treatment. Markers of brain injury and inflammatory mediators were measured on days 1, 2, 3 and 7. Assessment for sepsis-associated delirium was performed daily. The primary outcome was the difference in S-100ß from baseline to peak level between both the intervention and the control group, compared by t-test. Changes of all markers over time were explored in both groups, fitting a generalized estimating equations model. RESULTS: Mean difference in change of S-100ß from baseline to peak level was 0.34 (95% CI: -0.18-0.85) between the intervention and control group, respectively (P = 0.19). We found no difference in plasma levels of S-100ß, neuron-specific enolase, interleukin (IL)-6, IL-8, IL-10, and C-reactive protein between groups over time. Incidence of sepsis-associated delirium was 75% in the intervention and 71% in the control groups (risk difference 4%, 95% CI -24-31%, P = 0.796). CONCLUSION: Administration of n-3 fatty acids did not affect markers of brain injury, incidence of sepsis-associated delirium, and inflammatory mediators in septic patients.

Prospective comparison of noninvasive, bedside ultrasound methods for assessing central venous pressure.

PURPOSE: To prospectively evaluate the accuracy of noninvasive central venous pressure (CVP) assessment by compression ultrasound of a forearm vein (CUS), inferior vena cava (IVC-C) and internal jugular vein collapsibility (IJV-C) compared to invasive CVP measurement (invCVP) as the gold standard. MATERIALS AND METHODS: CUS, IVC-C and IJV-C were performed in a random sequence in 81 consecutive intensive care patients with simultaneous invCVP monitoring. Examiners were blinded to invCVP and previous examinations. RESULTS: Median invCVP was 12.0 mmHg (range 1 - 23). CUS, IVC-C and IJV-C could be obtained in 89 %, 95 % and 100 % of cases, respectively, within a median time of 188 sec [IQR 125; 270], 133 sec [IQR 100; 211] and 60 sec [IQR 50; 109], respectively. The Spearman correlation coefficient between invCVP and CUS, IVC-C, and IJV-C was 0.485 95 %-CI [0.25; 0.65], -0.186 [-0.42; 0.07], and -0.408 [-0.59; -0.18], respectively. The median absolute difference between CUS and invCVP was 3 mmHg [IQR 2; 6.75]. CVP was categorized as low (< 7 mmHg; collapsibility > 0.6), normal (7 - 12 mmHg; collapsibility 0.6 - 0.2) and high (> 12 mmHg; collapsibility < 0.2) as prespecified. The proportions of identical CVP classifications compared to invCVP were 61.4% 95%-CI [49.3%; 72.4%] with CUS, 48.7% [37.4%; 60%] with IVC-C and 51.3% [40.3%; 62.3%] with IJV-C (p > 0.10 for all pair-wise comparisons). CONCLUSION: The overall ability of CUS, IVC-C and IJV-C to assess invCVP was only moderate. CUS seems to be the preferable method if absolute CVP values are needed. IJV-C seems to be the fastest and most easily acquirable method, and thus may be especially valuable in emergency rooms.

Superior antitumoral activity of dimerized targeted single-chain TRAIL fusion proteins under retention of tumor selectivity.

Although targeting of the death receptors (DRs) DR4 and DR5 still appears a suitable antitumoral strategy, the limited clinical responses to recombinant soluble TNF-related apoptosis inducing ligand (TRAIL) necessitate novel reagents with improved apoptotic activity/tumor selectivity. Apoptosis induction by a single-chain TRAIL (scTRAIL) molecule could be enhanced >10-fold by generation of epidermal growth factor receptor (EGFR)-specific scFv-scTRAIL fusion proteins. By forcing dimerization of scFv-scTRAIL based on scFv linker modification, we obtained a targeted scTRAIL composed predominantly of dimers (Db-scTRAIL), exceeding the activity of nontargeted scTRAIL ∼100-fold on Huh-7 hepatocellular and Colo205 colon carcinoma cells. Increased activity of Db-scTRAIL was also demonstrated on target-negative cells, suggesting that, in addition to targeting, oligomerization equivalent to an at least dimeric assembly of standard TRAIL per se enhances apoptosis signaling. In the presence of apoptosis sensitizers, such as the proteasomal inhibitor bortezomib, Db-scTRAIL was effective at picomolar concentrations in vitro (EC(50) ∼2 × 10(-12) M). Importantly, in vivo, Db-scTRAIL was well tolerated and displayed superior antitumoral activity in mouse xenograft (Colo205) tumor models. Our results show that both targeting and controlled dimerization of scTRAIL fusion proteins provides a strategy to enforce apoptosis induction, together with retained tumor selectivity and good in vivo tolerance.

Effect of age on intraoperative cerebrovascular autoregulation and near-infrared spectroscopy-derived cerebral oxygenation.

BACKGROUND: Age is an important risk factor for perioperative cerebral complications such as stroke, postoperative cognitive dysfunction, and delirium. We explored the hypothesis that intraoperative cerebrovascular autoregulation is less efficient and brain tissue oxygenation lower in elderly patients, thus, increasing the vulnerability of elderly brains to systemic insults such as hypotension. METHODS: We monitored intraoperative cerebral perfusion in 50 patients aged 18-40 and 77 patients >65 yr at two Swiss university hospitals. Mean arterial pressure (MAP) was measured continuously using a plethysmographic method. An index of cerebrovascular autoregulation (Mx) was calculated based on changes in transcranial Doppler flow velocity due to changes in MAP. Cerebral oxygenation was assessed by the tissue oxygenation index (TOI) using near-infrared spectroscopy. End-tidal CO2, O2, and sevoflurane concentrations and peripheral oxygen saturation were recorded continuously. Standardized anaesthesia was administered in all patients (thiopental, sevoflurane, fentanyl, atracurium). RESULTS: Autoregulation was less efficient in patients aged >65 yr [by 0.10 (se 0.04; P=0.020)] in a multivariable linear regression analysis. This difference was not attributable to differences in MAP, end-tidal CO2, or higher doses of sevoflurane. TOI was not significantly associated with age, sevoflurane dose, or Mx but increased with increasing flow velocity [by 0.09 (se 0.04; P=0.028)] and increasing MAP [by 0.11 (se 0.05; P=0.043)]. CONCLUSIONS: Our results do not support the hypothesis that older patients' brains are more vulnerable to systemic insults. The difference of autoregulation between the two groups was small and most likely clinically insignificant.

[Thrombotic microangiopathy after extracorporeal circulation: important differential diagnosis]. / Thrombotische Mikroangiopathien nach extrakorporaler Zirkulation : Wichtige Differenzialdiagnose.

Thrombotic microangiopathies are characterized by platelet activation, endothelial damage, hemolysis and microvascular occlusion. This group of diseases is primary represented by thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Patients present with microangiopathic hemolytic anemia and thrombocytopenia as well as occlusion-related organ ischemia to a variable degree. A deficiency of the metalloprotease ADAMTS-13 is a major risk for acute disease manifestation as this is a regulator of unusually large von Willebrand factor (vWF) multimers, which are extremely adhesive and secreted by endothelial cells. In classical TTP an ADAMTS-13 activity below 5% is specific, whereas in other forms of thrombotic microangiopathies activity of ADAMTS-13 ranges from very low to normal. Symptoms of different forms of thrombotic microangiopathy are frequently overlapping and a clear classification according to clinical criteria is often difficult. Due to a high mortality, particularly of TTP, immediate diagnosis and therapy are essential. In this article two cases of thombotic microangiopathy after cardiac surgery are reported. After exclusion of TTP and HUS as well as other etiologies of thrombotic microangiopathy a relationship between the use of extracorporeal circulation and the pathogenesis of thrombotic microangiopathy is assumed.

Midregional pro-atrial natriuretic peptide and procalcitonin improve survival prediction in VAP.

Ventilator-associated pneumonia (VAP) affects mortality, morbidity and cost of critical care. Reliable risk estimation might improve end-of-life decisions, resource allocation and outcome. Several scoring systems for survival prediction have been established and optimised over the last decades. Recently, new biomarkers have gained interest in the prognostic field. We assessed whether midregional pro-atrial natriuretic peptide (MR-proANP) and procalcitonin (PCT) improve the predictive value of the Simplified Acute Physiologic Score (SAPS) II and Sequential Related Organ Failure Assessment (SOFA) in VAP. Specified end-points of a prospective multinational trial including 101 patients with VAP were analysed. Death <28 days after VAP onset was the primary end-point. MR-proANP and PCT were elevated at the onset of VAP in nonsurvivors compared with survivors (p = 0.003 and p = 0.017, respectively) and their slope of decline differed significantly (p = 0.018 and p = 0.039, respectively). Patients with the highest MR-proANP quartile at VAP onset were at increased risk for death (log rank p = 0.013). In a logistic regression model, MR-proANP was identified as the best predictor of survival. Adding MR-proANP and PCT to SAPS II and SOFA improved their predictive properties (area under the curve 0.895 and 0.880). We conclude that the combination of two biomarkers, MR-proANP and PCT, improve survival prediction of clinical severity scores in VAP.

[Seizure and non-cardiogenic pulmonary edema after intoxication]. / 35-jährige Patientin mit generalisiertem Krampfanfall und nicht-kardiogenem Lungenödem nach Intoxikation.

We report a case of severe intoxication with extended-release verapamil. In addition to cardiovascular toxicities with hypotension, atrioventricular block and bradycardia, the patient suffered from grand-mal seizure and pulmonary edema 13 and 48 hours respectively, after ingestion of 4.8 g of extended-release verapamil. Adverse reactions after intoxications with extended-release tablets appear delayed with prolonged manifestation of symptoms. Early and repetitive administration of activated charcoal and antegrade whole bowel lavage are crucial, even in primary asymptomatic patients.

Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study.

In patients with ventilator-associated pneumonia (VAP), guidelines recommend antibiotic therapy adjustment according to microbiology results after 72 h. Circulating procalcitonin levels may provide evidence that facilitates the reduction of antibiotic therapy. In a multicentre, randomised, controlled trial, 101 patients with VAP were assigned to an antibiotic discontinuation strategy according to guidelines (control group) or to serum procalcitonin concentrations (procalcitonin group) with an antibiotic regimen selected by the treating physician. The primary end-point was antibiotic-free days alive assessed 28 days after VAP onset and analysed on an intent-to-treat basis. Procalcitonin determination significantly increased the number of antibiotic free-days alive 28 days after VAP onset (13 (2-21) days versus 9.5 (1.5-17) days). This translated into a reduction in the overall duration of antibiotic therapy of 27% in the procalcitonin group (p = 0.038). After adjustment for age, microbiology and centre effect, the rate of antibiotic discontinuation on day 28 remained higher in the procalcitonin group compared with patients treated according to guidelines (hazard rate 1.6, 95% CI 1.02-2.71). The number of mechanical ventilation-free days alive, intensive care unit-free days alive, length of hospital stay and mortality rate on day 28 for the two groups were similar. Serum procalcitonin reduces antibiotic therapy exposure in patients with ventilator associated pneumonia.

Intracranial pressure in patients with sepsis.

INTRODUCTION: In sepsis the brain is frequently affected although there is no infection of the CNS (septic encephalopathy). One possible cause of septic encephalopathy is failure of the blood-brain barrier. Brain edema has been documented in animal models of sepsis. Aggressive fluid resuscitation in the early course of sepsis improves survival and is standard practice. We hypothesized that aggressive fluid administration will increase intracranial pressure (ICP) and may cause critical reductions in cerebral perfusion pressure (CPP). MATERIALS AND METHODS: Patients with sepsis were investigated daily on up to four consecutive days in the intensive care unit. Mean arterial blood pressure (MAP) and blood flow velocity in the middle cerebral artery were monitored for one hour each day. ICP was calculated non-invasively from MAP and flow velocity data. S-100beta was determined daily. FINDINGS: Fifty-two measurements were performed in 16 patients. ICP could be determined in 45 measurements in 15 patients. Seven patients had an ICP > 15 mmHg and 11 patients had a CPP < 60 mmHg on at least 1 day. We found no significant correlation between ICP and fluid administration, but low CPP was significantly correlated with elevated S-100beta (r = -0.47, p = 0.001). CONCLUSIONS: Further research is needed to determine the role of ICP/CPP monitoring in patients with sepsis.

The NO donor SIN-1 improves intestinal-arterial P(CO(2)) gap in experimental endotoxemia: an animal study.

BACKGROUND: Dysfunction of the microcirculation is a prominent feature of sepsis and endotoxemia. Recently, it has been shown that microcirculatory alterations are completely reversed by local or systemic application of vasodilators in severely septic patients. Therefore, we investigated the influence of vasodilator therapy on microcirculatory dysfunction of the ileum during endotoxic shock in a prospective, controlled animal study. METHODS: After baseline measurements, shock was induced in 12 domestic pigs by lipopolysaccharide via the mesenteric vein until the mean arterial pressure fell below 60 mmHg. After 30 min in shock, six animals were resuscitated with either fluid alone (control) or fluid and 2 microg/kg/min of the vasodilator 3-morpholino-sydnonimine (SIN-1). The systemic and regional hemodynamics and oxygenation parameters, tonometric ileal P(CO(2)) and microvascular oxygen pressures (muP(O(2))) (by oxygen-dependent Pd-porphyrin phosphorescence) were measured simultaneously. RESULTS: The ileal-arterial P(CO(2)) gap increased during shock and the ileal mucosal and serosal muP(O(2)) decreased concurrently. SIN-1 in addition to fluid resuscitation significantly improved the ileal-arterial P(CO(2)), whereas fluid alone failed to decrease the P(CO(2)) gap. The SIN-1-induced improvement in the P(CO(2)) gap was accompanied by an increase in serosal muP(O(2)) above shock levels. Mucosal muP(O(2)) was resuscitated to baseline levels in both groups. CONCLUSION: The application of the vasodilator SIN-1 in addition to fluid resuscitation improves the ileal-arterial P(CO(2)) gap and mucosal muP(O(2)), together with a moderate increase in serosal muP(O(2)), after endotoxic shock. This finding is consistent with the concept that vasodilators may correct pathologic flow distribution within the intestinal wall.

Microcirculatory recruitment maneuvers correct tissue CO2 abnormalities in sepsis.

The rises in tissue partial pressure of carbon dioxide have been observed in critically ill patients with shock and sepsis for a long time and have been proposed to be an earlier and more reliable marker of tissue hypoxia than traditional markers. However, the mechanisms leading to those increases, especially in sepsis and endotoxemia, are not well understood. Recent studies provided further data, supporting the idea that the origin of those increases in partial pressure of CO2 in sepsis as being caused by microcirculatory perfusion deficit resulting in mitochondrial depression by time. Previously, we have termed this condition where despite correction of systemic oxygen delivery variables, regional hypoxia and oxygen extraction deficit persist as microcirculatory and mitochondrial distress syndrome (MMDS). Recent findings support the idea that the progression from early to severe sepsis is accompanied or possibly even caused by microcirculatory dysfunction, which leads to mitochondrial dysfunction by time. Therefore early identification of microcirculatory dysfunction and correction with microcirculatory recruitment maneuvers are needed to ensure adequate microcirculatory perfusion and tissue oxygenation. Microcirculatory imaging, such as SDF imaging technique, appears to be a very useful tool for this task and its combination together with other systemic and regional tissue oxygenation measurements may provide more information regarding the tissue oxygenation and will be a very promising tool for microcirculatory researchers and the management of critically ill patients at the bedside.

Effects of dopexamine in a rat model of supracoeliac aortic cross-clamping and declamping.

This experimental study in rats was designed to demonstrate effects of dopexamine (3 microg kg(-1) min(-1), n = 6) or physiologic saline solution (n = 6) on systemic as well as regional perfusion during 30 min of supracoeliac aortic cross-clamping and during 180 min of reperfusion following declamping. Rats were surgically instrumented with arterial, right atrial and portal venous catheters, ultrasonic flow probes around the abdominal aorta, superior mesenteric and carotid artery, and a paediatric tonometer for intestinal mucosal PCO(2) measurement. During 120 min of reperfusion, fluid resuscitation was titrated to keep abdominal aortic blood flow above 80% of baseline values. We found that during cross-clamping, values of arterial lactate (p = 0.002) and intestinal tonometric PCO(2) (p = 0.018) were higher in the dopexamine group than in the control group.

Neuropsychiatric thalamocortical dysrhythmia: surgical implications.

Clearly, more clinical experience must be amassed to define in detail the possibilities of this surgical approach in disabling neuropsychiatric disorders. We propose, however, that the evidence for benign and efficient surgical intervention against the neuropsychiatric TCD syndrome is already compelling. The potential appearance of strong postoperative reactive manifestations requires a close association between surgery and psychotherapy, with the latter providing support for the integration of the new situation as well as the resolution of old unresolved issues.

[Obstetric analgesia and anesthesia in Switzerland in 1999]. / Analgesie und Anästhesie zur Geburtshilfe in der Schweiz 1999.

QUESTION: This survey investigated the common practice of obstetric analgesia and anaesthesia in Swiss hospitals and evaluated the influence of the Swiss interest group for obstetric anaesthesia. METHODS: In March 1999 we submitted 145 questionnaires to all Swiss hospitals providing an obstetric service. RESULTS: The rate of epidural analgesia (EA) was higher in large hospitals (> 1,000 births/year) than in small services. EA was maintained by continuous infusion techniques in 53% of the responding hospitals. For elective caesarean section, spinal anaesthesia (SA) and EA were performed in 77% and 16% of the patients, respectively. General anaesthesia (5%) was only used in small hospitals (< 500 births/year). Emergency caesarean section was performed under SA in 75% of all hospitals and only in 25% was a general anaesthesia used. An already existing EA for labour analgesia was continued for anaesthesia for caesarean section in 63% of Swiss hospitals. CONCLUSIONS: Regional anaesthesia was most commonly used for obstetric anaesthesia in Swiss hospitals. Epidemiological studies, recommendations of the Swiss interest group for obstetric anaesthesia, as well as the expectations of pregnant women, increased the numbers of regional anaesthesia compared with the first survey in 1992.

Critical hematocrit in intestinal tissue oxygenation during severe normovolemic hemodilution.

BACKGROUND: A critical point in oxygen supply for microvascular oxygenation during normovolemic hemodilution has not been identified. The relation between organ microvascular oxygen partial pressure (microPO2) and organ oxygen consumption (VO2) during a decreasing oxygen delivery (DO2) is not well understood. The present study was designed to determine the systemic hematocrit and organ DO2 values below which organ microPO2 and VO2 cannot be preserved by regulatory mechanisms during normovolemic hemodilution. METHODS: Eighteen male Wistar rats were randomized between an experimental group (n = 12), in which normovolemic hemodilution was performed with pasteurized protein solution (PPS), and a control group (n = 6). Systemic hemodynamic and intestinal oxygenation parameters were monitored. Intestinal microPO2 was measured using the oxygen-dependent quenching of palladium-porphyrin phosphorescence. RESULTS: Baseline values in hemodilution and control group were similar. Hemodilution decreased hematocrit to 6.2 +/- 0.8% (mean +/- SD). Constant central venous pressure measurements suggested maintenance of isovolemia. Despite an increasing mesenteric blood flow, intestinal DO2 decreased immediately. Initially, microPO2 was preserved, whereas mesenteric venous PO2 (P(mv)O2) decreased; below a hematocrit of 15%, microPO2 decreased significantly below P(mv)O2. Critical DO2 was 1.5 +/- 0.5 ml x kg(-1) x min(-1) for VO2, and 1.6 +/- 0.5 ml x kg(-1) x min(-1) for microPO2. Critical hematocrit values for VO2 and microPO2 were 15.8 +/- 4.6% and 16.0 +/- 3.5%, respectively. CONCLUSIONS: Intestinal microPO2 and VO2 were limited by a critical decrease in DO2 and hematocrit at the same time. Beyond these critical points not only shunting of oxygen from the microcirculation could be demonstrated, but also a significant correlation between intestinal microPO2 and VO2.

The effect of the transfusion of stored RBCs on intestinal microvascular oxygenation in the rat.

BACKGROUND: Although it is known that the transfusion of stored RBCs does not always improve tissue O(2) consumption under conditions of limited tissue oxygenation, the efficiency of O(2) delivery to the microcirculation by stored RBCs has never been determined. STUDY DESIGN AND METHODS: In a rat hemorrhagic shock model, the effects of resuscitation with fresh or 28-day-old RBCs stored in CPD plasma, saline-adenine-glucose-mannitol, and CPDA-1 plasma were investigated. Systemic hemodynamic and intestinal oxygenation measures were monitored. Intestinal microvascular PO(2) was determined with the O(2)-dependent quenching of palladium-porphyrin phosphorescence, and the RBC deformability was measured with a Laser-assisted optic rotational cell analyzer. RESULTS: Hemodynamic and oxygenation measures were significantly decreased during hemorrhagic shock. Intestinal oxygen consumption and mesenteric venous pO(2) were restored with the transfusion of both fresh and stored RBCs, except for CPD-stored RBCs. The intestinal microvascular pO(2) improved only with the transfusion of fresh RBCs. Deformability of the stored RBCs was significantly decreased. CONCLUSION: In contrast to that of fresh RBCs, the transfusion of stored RBCs did not restore the microcirculatory oxygenation, possibly because of impaired O(2) unloading, but, except for CPD-stored RBCs, the storage-induced changes were not enough to impair intestinal VO(2) and mesenteric venous pO(2).