Prognosis of patients with severe left ventricular dysfunction after transvenous lead extraction and the need for additional hemodynamic support in the perioperative period.

BACKGROUND: Transvenous lead extraction (TLE) is necessary because of system infection, lead malfunction, or system upgrade. Patients with severe left ventricular dysfunction (SLVD) undergoing TLE may be at a higher risk because hemodynamic parameters may change unfavorably during or after TLE; however, this has not yet been clarified. OBJECTIVE: The purpose of this study was to examine whether patients with SLVD undergoing TLE have higher mortality. METHODS: All patients who underwent TLE were stratified as follows: patients with ejection fraction ≤ 35% (SLVD group) and those with ejection fraction > 35% (non-SLVD group). RESULTS: We assessed the data of 200 patients [SLVD group, 36 (18%); non-SLVD group, 164 (82%)]). Brain natriuretic peptide level and cardiac resynchronization therapy rate were higher in the SLVD group than in the non-SLVD group. There were no significant between-group differences in major complications and clinical success rates. Patients with SLVD were more likely to require additional hemodynamic support, such as catecholamine infusion, temporary atrium-ventricle sequential pacing, and temporary cardiac resynchronization therapy pacing (27.8% vs 1.2%; P < .001). The survival rate was not significantly different between the groups at 30 days and 1 year after TLE (SLVD vs non-SLVD: 30 days: 97.2% vs 99.4%; P = .215; 1 year: 80.6% vs 91.5%; P = .053). Multivariate Cox regression analysis revealed log brain natriuretic peptide and serum hemoglobin levels as predictors for 1-year mortality. CONCLUSION: The prognosis after TLE was comparable between patients with and without SLVD. However, additional hemodynamic support was often necessary for patients with SLVD.

Factor analysis of acute kidney injury in patients administered liposomal amphotericin B in a real-world clinical setting in Japan.

Liposomal amphotericin B (L-AMB) is a broad-spectrum antifungal drug that is used to treat fungal infections. However, clinical evidence of its use in patients with renal failure is limited. Here, we aimed to identify factors associated with acute kidney injury (AKI) in patients administered L-AMB. We retrospectively utilized a combination of Diagnosis Procedure Combination data and laboratory data obtained from hospitals throughout Japan between April 2008 and January 2018. In total, 507 patients administered L-AMB were identified. After L-AMB treatment initiation, AKI, which was defined as a ≥ 1.5-fold increase within 7 days or ≥ 0.3 mg/dL increase within 2 days in serum creatinine according to the KDIGO criteria, was recognized in 37% of the total patients (189/507). The stages of AKI were stage 1 in 20%, stage 2 in 11%, and stage 3 in 7%. Five factors were associated with AKI of all stages: prior treatment with angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers or carbapenem; concomitant administration of catecholamines or immunosuppressants; and ≥ 3.52 mg/kg/day of L-AMB dosing. Serum potassium < 3.5 mEq/L before L-AMB therapy was associated with severe AKI of stage 2 and 3. Altogether, these factors should be carefully considered to reduce the occurrence of AKI in patients administered L-AMB.

[The Role of Pharmacists in Home Medical Care of Patients with Heart Failure].

In recent years, home medical care has been strongly promoted. As a consequence, the conditions managed in home medical care have become increasingly diverse. Heart failure is one of the most common disorders after malignant diseases. Patients with chronic heart failure (CHF) are often forced into hospitalization because of the inability to control symptoms with oral medications, even though they hope to stay at home. Recently, we have experienced a case where the patient required continuous administration of dobutamine at home. In order to carry out CHF care at home successfully, it is necessary to adjust the doses of catecholamine and furosemide swiftly in response to changes in patients' conditions. In this case, the patient was able to spend four months at home thanks to the cooperation of a team of a physician, nurses, and pharmacists. Catecholamine-dependent patients with terminal CHF require expensive medical infusion pumps for precise administration. However, the economic assistance to such patients remains insufficient. Furthermore, dobutamine and furosemide injections are not dispensed extramurally, and therefore might become an impediment to the cooperation of the team. In this symposium, I consider and discuss the role of pharmacists in a home medical care team for patients with terminal CHF.

Association between high dose catecholamine support and liver dysfunction following cardiac surgery.

BACKGROUND: Cardiac surgery using cardiopulmonary bypass is a well-established procedure. However, up to 20% to 30% of patients require high dose vasopressor or inotropic support following surgery, enhancing the risk of organ dysfunction and impacting mortality. Nonalcoholic fatty liver disease (NAFLD) is a frequent finding in these patients and may be involved in the pathophysiology of vasoplegia and cardiac failure. METHODS: Retrospective analysis of 463 patients undergoing elective cardiac surgery in 2014 at our institution. NAFLD was defined using the NAFLD fibrosis score and the vasoactive-inotropy score was used to determine postoperative vasopressor and inotropic dependency. RESULTS: Patients with NAFLD more often presented with high vasopressor or inotropic support compared to patients without NAFLD, resulting in significant differences after 6 hours (n = 20 [27.0%] of 74 patients), 12 hours (n = 20 [27.0%] of 74 patients), and on the first postoperative day (n = 12 [16.4%] of 73 patients) of intensive care unit (ICU) treatment. Multivariate analysis revealed time of catecholamine application (P = .001), preoperative left ventricular ejection fraction (P = .001), type of surgery (P = .001), model of endstage liver disease on hospital admission (P = .002), pre-existing pulmonary hypertension (P = .004) and NAFLD-time interaction (P = .05) as independent predictors of high vasopressor and inotropic support. Patients with NAFLD had higher degrees of extrahepatic organ dysfunction, were more dependent on hemodialysis, spent more days in the ICU and within the hospital. Patients with NAFLD and high catecholamine support had the highest mortality rates among the study population. CONCLUSIONS: NAFLD is a common finding in elective cardiac surgery patients. Anesthesiologists and intensivists should be sensitive for the specific risk profile of this population.

Clinical utility of midodrine and methylene blue as catecholamine-sparing agents in intensive care unit patients with shock.

Shock is common in the intensive care unit, affecting up to one third of patients. Treatment of shock is centered upon managing hypotension and ensuring adequate perfusion via administration of fluids and catecholamine vasopressors. Due to the risks associated with catecholamine vasopressors, interest has grown in using catecholamine-sparing agents such as midodrine and methylene blue. Midodrine is an orally administered alpha-1 adrenergic agonist while methylene blue is an intravenously administered blue dye used to restore vascular tone and increase blood pressure. Separate MEDLINE, Scopus, and Embase database searches were conducted to assess literature revolving around these agents. Examples of search terms included "midodrine", "methylene blue", "critically ill", "shock", and "catecholamine-sparing." Several studies have evaluated their use in patients with shock and found potential benefits in terms of causing significant elevations in blood pressure and hastening catecholamine vasopressor discontinuation with few adverse effects; however, robust evidence is lacking for these off-label indications. Because of the variety of dosing strategies used and the incongruences between patient populations, it is also challenging to define finite recommendations. This review aims to summarize current evidence for the use of midodrine and methylene blue as catecholamine-sparing agents in critically ill patients with resolving or refractory shock.

Early assessment of cardiac troponin I predicts the postoperative cardiac status and clinical course after congenital heart disease surgery.

Cardiac troponin I (cTnI) is a regulatory protein with a high sensitivity and specificity for cardiac injury. Preoperative and postoperative elevations of cTnI are usually considered predictors of the mortality and morbidity. However, little is known about the relationship between the cTnI and postoperative course after the congenital heart disease (CHD) operation. Sixty-five consecutive patients who underwent cardiac surgery for CHD at our institution between March 2016 and January 2017 were included. The cTnI was measured after the operation. Also, the association between the cTnI and duration of the catecholamine use, ICU stay, aortic cross clamp time, and other clinical parameters were assessed. The cTnI level on postoperative day 1 was positively correlated with the duration of the catecholamine use (p < 0.001) and ICU stay (p < 0.001). Also, a higher cTnI level was associated with a lower urine volume and higher lactate level 24 h after the ICU admission. In the multivariable regression analysis, the cTnI was a significant independent predictor of the catecholamine use (p = 0.002) and ICU stay (p = 0.003). The cTnI level on postoperative day 1 was a predictor of the duration of the catecholamine use and ICU stay.

Epidemiology and complications of late-onset sepsis: an Italian area-based study.

BACKGROUND: Most studies regarding late-onset sepsis (LOS) address selected populations (i.e., neonates with low birth weight or extremely preterm neonates). Studying all age groups is more suitable to assess the burden of single pathogens and their clinical relevance. METHODS: This is a retrospective regional study involving paediatric departments and NICUs in Emilia-Romagna (Italy). Regional laboratory databases were searched from 2009 to 2012. Records of infants (aged 4 to 90 days) with a positive blood or cerebrospinal fluid (CSF) culture were retrospectively reviewed and analysed according to acquisition mode (whether hospital- or community-acquired). RESULTS: During the study period, there were 146,682 live births (LBs), with 296 patients experiencing 331 episodes of LOS (incidence rate: 2.3/1000 LBs). Brain lesions upon discharge from the hospital were found in 12.3% (40/296) of cases, with death occurring in 7.1% (23/296; 0.14/1000 LBs). With respect to full-term neonates, extremely preterm or extremely low birth weight neonates had very high risk of LOS and related mortality (> 100- and > 800-fold higher respectively). Hospital-acquired LOS (n = 209) was significantly associated with very low birth weight, extremely preterm birth, pneumonia, mechanical ventilation, and death (p< 0.01). At multivariate logistic regression analysis, catecholamine support (OR = 3.2), central venous line before LOS (OR = 14.9), and meningitis (OR = 44.7) were associated with brain lesions or death in hospital-acquired LOS (area under the ROC curve 0.81, H-L p = 0.41). Commonly identified pathogens included coagulase-negative staphylococci (CoNS n = 71, 21.4%), Escherichia coli (n = 50, 15.1%), Staphylococcus aureus (n = 41, 12.4%) and Enterobacteriaceae (n = 41, 12.4%). Group B streptococcus was the predominant cause of meningitis (16 of 38 cases, 42%). Most pathogens were sensitive to first line antibiotics. CONCLUSIONS: This study provides the first Italian data regarding late-onset sepsis (LOS) in all gestational age groups. Compared to full-term neonates, very high rates of LOS and mortality occurred in neonates with a lower birth weight and gestational age. Group B streptococcus was the leading cause of meningitis. Excluding CoNS, the predominant pathogens were Escherichia coli and Staphylococcus aureus. Neonates with hospital-acquired LOS had a worse outcome. Antibiotic associations, recommended for empirical treatment of hospital- or community-acquired LOS, were adequate.

Pancreatitis cytosorbents (CytoSorb) inflammatory cytokine removal: A Prospective Study (PACIFIC).

BACKGROUND: Acute pancreatitis (AP) usually has a mild course with a mortality rate below 1%. However, around 10% of patients develop severe AP (SAP) involving extra-pancreatic tissues and other organ systems. The mortality of SAP is around 42%. The outcome of SAP is closely related to the development of systemic inflammation and consecutive organ failures. Most current therapies including fluid resuscitation, antimicrobial therapy, drainage procedures, and endoscopic management of complications are symptomatic rather than causative approaches, except sphincterotomy for gallstone pancreatitis. Regarding the high mortality of SAP and its close association with systemic inflammation, extracorporeal removal of inflammatory mediators is an appealing approach. Several recent studies have demonstrated that the CytoSorb adsorber effectively eliminates inflammatory cytokines, such as IL-1ß, IL-6, IL-8, IL-10, and TNF-alpha. Some of these trials suggested that therapy with CytoSorb might improve outcome, including a reduction in the vasopressor dosage and reversal of shock.Therefore, it is the objective of this study to evaluate the effectiveness of 2 consecutive 24 h-treatments with CytoSorb on hemodynamics in patients with early SAP. METHODS: This study includes patients with early SAP (APACHE-II ≥10) and transpulmonary thermodilution hemodynamic monitoring (PiCCO; EV-1000) within a maximum of seven days from the onset of pain. Eligible patients will be treated with 2 consecutive periods of CytoSorb. A 20%-improvement in the vasopressor dependency index (VDI) - which relates is derived from mean arterial pressure (MAP) and catecholamine dosage - is the primary outcome. In addition to this clinical outcome, there are several laboratory (cytokine levels) and translational endpoints (including multiplex-ELISAs of numerous anti- and pro-inflammatory cytokines/chemokines and DNA analyses). Primary outcome analysis will compare the incidence of the primary endpoint in 30 patients from the intervention group to 60 matched controls with advanced hemodynamic monitoring recruited from recent studies in SAP within the same setting and the same centers. DISCUSSION: A potential improvement in hemodynamics and/or other outcomes by CytoSorb would provide a new therapeutic option in the early treatment of SAP with a pathophysiological rationale. TRIAL REGISTRATION: This study was registered on March 17, 2017 (ClinicalTrials.gov Identifier: NCT03082469). URL: https://clinicaltrials.gov/ct2/show/NCT03082469. VERSION: V_PACIFIC_1.0 September 30, 2018.

Critical Care Skill Triad for Tactical Evacuations.

OBJECTIVE: Providing medical support to French soldiers deployed on war theater everywhere around the world is the first mission of the French Military Medical Service (FMMS). En-route critical care is critical to maintain the continuum of care and safety during forward and tactical medical evacuation (MEDEVAC). The FMMS has developed specific training programs to ensure optimal en-route critical care air transport. These courses need to be continuously adjusted to the returns of experience and to the operational changes. The aim of our survey was to characterize the critical care skills required for tactical MEDEVAC on fixed wing aircraft. METHODS: A 10-items survey was sent to 22 flight surgeons previously deployed in the Sahel-Saharan Strip. Eight questions focused on basic critical care skills. The 2 last items assessed the flight surgeons' willingness to follow a pre deployment course in a critical care unit and in a transfusion center. RESULTS: Fourteen of the 22 flight surgeons responded to the survey. All but one responder had to deal with at least one critical care skill. The most frequent critical care skills required were the management of mechanical ventilation, catecholamine infusion and blood product transfusion. Five of the 14 responders reported on-board blood product transfusion, including red blood cells, lyophilized plasma and fresh whole blood. CONCLUSION: Our survey highlights the need for the MEDEVAC teams to be skilled in critical care medicine. We defined a triad of critical care skills required for the management of severe casualties, including the management of mechanical ventilation, catecholamine infusion and blood product transfusion.

High-dose catecholamine donor support and outcomes after heart transplantation.

BACKGROUND: Higher dose norepinephrine donor support is a frequent reason for donor heart decline, but its associations with outcomes after heart transplantation are unclear. METHODS: We retrospectively analyzed 965 patients transplanted between 1992 and 2015 in the Heart Transplant Program Vienna. Stratification was performed according to donor norepinephrine dose administered before organ procurement (Group 0: 0 µg/kg/min; Group 1: 0.01 to 0.1 µg/kg/min; Group 2: >0.1 µg/kg/min). Sub-stratification of Group 2 was performed for comparison of high-dose subgroups (Group HD 1: 0.11 to 0.4 µg/kg/min; Group HD 2: >0.4 µg/kg/min). Associations between groups and outcome variables were investigated using a multivariable Cox proportional hazards model and logistic regression analyses. RESULTS: Donor norepinephrine dose groups were not associated with overall mortality (Group 1 vs 0: hazard ratio [HR] 1.12, 95% confidence interval [CI] 0.87 to 1.43; Group 2 vs 0: HR 1.07, 95% CI 0.82 to 1.39; p = 0.669). No significant group differences were found for rates of 30-day mortality (p = 0.35), 1-year mortality (p = 0.897), primary graft dysfunction (p = 0.898), prolonged ventilation (p = 0.133) and renal replacement therapy (p = 0.324). Groups 1 and 2 showed higher rates of prolonged intensive care unit stay (18.9% vs 28.5% vs 27.5%, p = 0.005). High-dose subgroups did not differ significantly in 1-year mortality (Group HD 1: 14.3%; Group HD 2: 17.8%; p = 0.549). CONCLUSIONS: Acceptance of selected donor hearts supported by higher doses of norepinephrine may be a safe option to increase the donor organ pool.

Electronic Medication Regimen Complexity Index at admission and complications during hospitalization in medical wards: a tool to improve quality of care?

OBJECTIVE: Adverse events during hospitalization are a major worry considering their frequency and their burden. Many could be avoided by immediate identification of at-risk patients at admission and adapted prevention. The complexity of a patient's medication regimen immediately available at admission is a good indicator of the complexity of the patient's condition. This study aims to determine whether the electronic Medication Regimen Complexity Index (MRCI) at admission is associated with complications during hospitalization. DESIGN: We performed a multilevel logistic regression model, adjusted for age and sex. SETTING: Premier Perspective™ database, a clinical and financial information system from 417 US hospitals. PARTICIPANTS: Adults hospitalized for more than 3 days in a medical ward and included in Premier's Perspective™ database for 2006. INTERVENTION(S): Multilevel logistic regression. MAIN OUTCOME MEASURE: Association of the MRCI and complications during hospitalization, defined as in-hospital death, hospital-acquired infection, pressure ulcers; and need for highly technical healthcare, identified as the secondary introduction of catecholamines. RESULTS: In total, 1 592 383 admissions were included. The median MRCI at admission was 13 [interquartile range: 9-19]. The higher the MRCI, the higher the adjusted odds ratio of the following: in-hospital mortality, hospital-acquired infections, pressure ulcers and the secondary introduction of catecholamines. CONCLUSIONS: Our results suggested that the MRCI at admission was correlated with patient complexity, independent of age. Considering that patients with complex conditions pose a heavier workload for staff, measuring MRCI at admission could be used to allocate resources in medical wards at an institutional level. The MRCI might be a useful tool to assess the management of care.

Effect of Levosimendan on Low Cardiac Output Syndrome in Patients With Low Ejection Fraction Undergoing Coronary Artery Bypass Grafting With Cardiopulmonary Bypass: The LICORN Randomized Clinical Trial.

Importance: Low cardiac output syndrome after cardiac surgery is associated with high morbidity and mortality in patients with impaired left ventricular function. Objective: To assess the ability of preoperative levosimendan to prevent postoperative low cardiac output syndrome. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled trial conducted in 13 French cardiac surgical centers. Patients with a left ventricular ejection fraction less than or equal to 40% and scheduled for isolated or combined coronary artery bypass grafting with cardiopulmonary bypass were enrolled from June 2013 until May 2015 and followed during 6 months (last follow-up, November 30, 2015). Interventions: Patients were assigned to a 24-hour infusion of levosimendan 0.1 µg/kg/min (n = 167) or placebo (n = 168) initiated after anesthetic induction. Main Outcomes and Measures: Composite end point reflecting low cardiac output syndrome with need for a catecholamine infusion 48 hours after study drug initiation, need for a left ventricular mechanical assist device or failure to wean from it at 96 hours after study drug initiation when the device was inserted preoperatively, or need for renal replacement therapy at any time postoperatively. It was hypothesized that levosimendan would reduce the incidence of this composite end point by 15% in comparison with placebo. Results: Among 336 randomized patients (mean age, 68 years; 16% women), 333 completed the trial. The primary end point occurred in 87 patients (52%) in the levosimendan group and 101 patients (61%) in the placebo group (absolute risk difference taking into account center effect, -7% [95% CI, -17% to 3%]; P = .15). Predefined subgroup analyses found no interaction with ejection fraction less than 30%, type of surgery, and preoperative use of ß-blockers, intra-aortic balloon pump, or catecholamines. The prevalence of hypotension (57% vs 48%), atrial fibrillation (50% vs 40%), and other adverse events did not significantly differ between levosimendan and placebo. Conclusions and Relevance: Among patients with low ejection fraction who were undergoing coronary artery bypass grafting with cardiopulmonary bypass, levosimendan compared with placebo did not result in a significant difference in the composite end point of prolonged catecholamine infusion, use of left ventricular mechanical assist device, or renal replacement therapy. These findings do not support the use of levosimendan for this indication. Trial Registration: EudraCT Number: 2012-000232-25; clinicaltrials.gov Identifier: NCT02184819.

Angiotensin II for the Treatment of Vasodilatory Shock.

BACKGROUND: Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODS: We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 µg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTS: A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). CONCLUSIONS: Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843 .).

Disparities in hemodynamic resuscitation of the obese critically ill septic shock patient.

BACKGROUND: With a growing obesity epidemic, the approach to care of this patient remains controversial and in many circumstances different than the general population. Appropriate hemodynamic support, although still controversial, remains a cornerstone of septic shock therapy. Catecholamines are currently recommended by guidelines without a preferred dosing strategy. However, the use of weight-based (µg kg-1 min-1) or nonweight-based (µg/min) vasopressor drip rates may impact patient care in these populations. METHODS: A multicenter retrospective chart review was conducted. Patients receiving nonweight-based catecholamine infusions for septic shock were grouped into nonobese (n = 112) or obese (n = 196), and evaluated based on hemodynamic resuscitation. For the primary outcome, groups were analyzed for the requirement of a secondary hemodynamic support agent to obtain a goal mean arterial pressure of greater than or equal to 65 mm Hg. Secondary outcomes included an evaluation of time to a secondary hemodynamic support agent, time to hemodynamic stability (HDS), ability to obtain HDS at 24 hours, and death due to cardiovascular collapse. RESULTS: With the exception of weight and sex, baseline characteristics were similar among groups. Early resuscitative fluids were given at a lower weight based, but not total volume dose in the obese group (nonobese, 34.8 mL/kg vs obese, 22.4 mL/kg; P < .0001). The primary end point of addition of any secondary hemodynamic support agent was significantly greater in obese patients when adjusted for institution (nonobese, 19% vs obese, 27%; adjusted odds ratio, 0.42; 95% confidence interval, 0.23-0.77). Time to HDS was also prolonged (nonobese, 3.5 hours vs obese, 5.3 hours; P = .006). CONCLUSION: This study calls into question the adequacy of a nonweight-based approach to hemodynamic support of critically ill obese patients. This strategy seems to result in less aggressive, lower weight-based vasopressor and fluid doses, and more diverse approach than their nonobese counterparts.

Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDO-RCA): safety and efficacy of low-dose prostacyclin administration and blood pressure target in addition to standard therapy, as compared to standard therapy alone, in post-cardiac arrest syndrome patients: study protocol for a randomized controlled trial.

BACKGROUND: Morbidity and mortality following initial survival of cardiac arrest remain high despite great efforts to improve resuscitation techniques and post-resuscitation care, in part due to the ischemia-reperfusion injury secondary to the restoration of the blood circulation. Patients resuscitated from cardiac arrest display evidence of endothelial injury and coagulopathy (hypocoagulability, hyperfibrinolysis), which in associated with poor outcome. Recent randomized controlled trials have revealed that treatment with infusion of prostacyclin reduces endothelial damage after major surgery and AMI. Thus, a study is pertinent to investigate if prostacyclin infusion as a therapeutic intervention reduces endothelial damage without compromising, or even improving, the hemostatic competence in resuscitated cardiac arrest patients. Post-cardiac arrest patients frequently have a need for vasopressor therapy (catecholamines) to achieve the guideline-supported blood pressure goals. To evaluate a possible catecholamine interaction with the primary endpoints of this study, included patients will be randomized into two different blood pressure goals within guideline-recommended targets. METHODS/DESIGN: A randomized, placebo-controlled, double-blind investigator-initiated pilot trial in 40 out-of-hospital-cardiac-arrest (OHCA) patients will be conducted. Patients will be randomly assigned to either the active treatment group (48 hours of active study drug (iloprost, 1 ng/kg/min) or to the control group [placebo (saline) infusion]. Target mean blood pressure levels will be allocated 1:1 to 65 mmHg or approximately 75 mmHg, which gives four different permutations, namely: (i) iloprost/65 mHg, (ii) iloprost/75 mmHg, (iii) placebo/65 mmHg, and (iv) placebo/75 mmHg. All randomized patients will be treated in accordance with state-of-the art therapy including targeted temperature management. The primary endpoint of this study is change in biomarkers indicative of endothelial activation and damage, [soluble thrombomodulin (sTM), sE-selectin, syndecan-1, soluble vascular endothelial growth factor (sVEGF), nucleosomes] and sympathoadrenal over activation (epinephrine/norepinephrine) from baseline to 48 hours post-randomization. The secondary endpoints of this trial will include: (1) the hemostatic profile [change in functional hemostatic blood test (thrombelastography (TEG) and whole blood platelet aggregometry (multiplate)) blood cell and endothelial cell-derived microparticles]; (2) feasibility of blood pressure target intervention (target 90 %); (3) interaction of primary endpoints and blood pressure target; (4) levels of neuron-specific enolase at 48 hours post-inclusion according to blood pressure targets. DISCUSSION: The ENDO-RCA study is a pilot study trial that investigates safety and efficacy of low-dose infusion of prostacyclin administration as compared to standard therapy in post-cardiac arrest syndrome patients. TRIAL REGISTRATION: Trial registration at ClinicalTrials.gov (identifier NCT02685618 ) on 18 February 2016.

Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration.

RATIONALE: Catecholamines increase cardiac contractility, but exposure to high concentrations or prolonged exposures can cause cardiac injury. A recent study demonstrated that a single subcutaneous injection of isoproterenol (ISO; 200 mg/kg) in mice causes acute myocyte death (8%-10%) with complete cardiac repair within a month. Cardiac regeneration was via endogenous cKit(+) cardiac stem cell-mediated new myocyte formation. OBJECTIVE: Our goal was to validate this simple injury/regeneration system and use it to study the biology of newly forming adult cardiac myocytes. METHODS AND RESULTS: C57BL/6 mice (n=173) were treated with single injections of vehicle, 200 or 300 mg/kg ISO, or 2 daily doses of 200 mg/kg ISO for 6 days. Echocardiography revealed transiently increased systolic function and unaltered diastolic function 1 day after single ISO injection. Single ISO injections also caused membrane injury in ≈10% of myocytes, but few of these myocytes appeared to be necrotic. Circulating troponin I levels after ISO were elevated, further documenting myocyte damage. However, myocyte apoptosis was not increased after ISO injury. Heart weight to body weight ratio and fibrosis were also not altered 28 days after ISO injection. Single- or multiple-dose ISO injury was not associated with an increase in the percentage of 5-ethynyl-2'-deoxyuridine-labeled myocytes. Furthermore, ISO injections did not increase new myocytes in cKit(+/Cre)×R-GFP transgenic mice. CONCLUSIONS: A single dose of ISO causes injury in ≈10% of the cardiomyocytes. However, most of these myocytes seem to recover and do not elicit cKit(+) cardiac stem cell-derived myocyte regeneration.

Clinical predictors of prolonged postresection hypotension after laparoscopic adrenalectomy for pheochromocytoma.

BACKGROUND: Although the perioperative management of patients with pheochromocytoma has been improving recently, severe hypotensive episodes can occur that require postoperative catecholamine support and are challenging to manage. Our aim was to identify the clinical factors that predict prolonged postresection hypotension in patients after laparoscopic adrenalectomy for pheochromocytoma. METHODS: The records of 73 Japanese patients who underwent unilateral laparoscopic adrenalectomy for pheochromocytoma were surveyed retrospectively. Patients were divided into 2 groups according to whether catecholamine support was needed after postoperatively. Clinical and biochemical data were evaluated at baseline and after operation. RESULTS: Thirty-four of 73 patients (47%) required continuous infusion of catecholamine to maintain systolic blood pressure >90 mm Hg at the end of the operation. The median duration of postoperative catecholamine support was 17 hours (range, 3-130) in these 34 patients. On multivariate analysis, tumor size >60 mm, urinary epinephrine levels >200 µg/day, and urinary norepinephrine levels >600 µg/day were independent predictors of prolonged hypotension requiring postoperative catecholamine support. Tumor size and urinary norepinephrine levels were significantly correlated with the duration of postoperative catecholamine support. CONCLUSION: Larger tumor size and greater values of urinary epinephrine and norepinephrine levels were significant predictors of prolonged hypotension requiring postoperative catecholamine support. Moreover, tumor size and urinary norepinephrine levels were positively correlated with the duration of postoperative catecholamine support. Clinicians can identify and manage patients more effectively with a greater risk of prolonged hypotension after tumor resection using these preoperative clinical variables.