Norepinephrine Requirements Research Articles

Hemodynamic Impact of Cardiovascular Antihypertensive Medications in Patients With Sepsis-Related Acute Circulatory Failure.

Impact of prior cardiovascular antihypertensive medication during the initial phase of septic shock in terms of catecholamine requirements and mortality has been poorly investigated and remains unclear. To investigate the association between chronic prescription of cardiovascular antihypertensive medication prior to intensive care unit (ICU) admission, catecholamine requirement, and mortality in patients with septic shock. We included all consecutive patients diagnosed with septic shock within the first 24 h of ICU admission, defined as a microbiologically proven or clinically suspected infection, associated with acute circulatory failure requiring vasopressors despite adequate fluid filling. Prior cardiovascular antihypertensive medication was defined as the chronic use of betablockers (BB), calcium channel blockers (CCB), angiotensin converting enzyme inhibitor (ACEi)/angiotensin receptor blockers (ARB). ICU mortality was investigated using multivariate competitive risk analysis. Among 735 patients admitted for septic shock between 2008 and 2016, 46.9% received prior cardiovascular antihypertensive medication. Prior cardiovascular antihypertensive therapy was not associated with increased norepinephrine requirements during the first 24 h (median = 0.28 μg/kg/min in patients previously treated vs. 0.26 μg/kg/min). Prior cardiovascular antihypertensive medication was not associated with a higher risk of ICU mortality after adjustment (cause-specific hazard = 1.28, 95% confidence interval [0.98-1.66], P = 0.06). Subgroups analyses for BB, CCB, and ACEi/ARB using propensity score analyses retrieved similar results. In patients admitted with septic shock, prior cardiovascular antihypertensive medication seems to have limited impact on initial hemodynamic failure and catecholamine requirement.

Angiotensin I and angiotensin II concentrations and their ratio in catecholamine-resistant vasodilatory shock

BackgroundIn patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study.MethodsWe measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes.ResultsMedian baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30–676.00 pg/mL] vs 42 pg/mL [IQR 30.46–87.34 pg/mL] in controls; P < 0.0001) and median ANG I/II ratio (1.63 [IQR 0.98–5.25] vs 0.4 [IQR 0.28–0.64] in controls; P < 0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85–299.50 pg/mL] vs 97 pg/mL [IQR 35.27–181.01 pg/mL] in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P < 0.0001), lower ANG II levels (P < 0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P < 0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36–0.88; P = 0.01) on unadjusted analyses.ConclusionsPatients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction.Trial registrationClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.

Regulation of histamine and diamine oxidase in patients undergoing orthotopic liver transplantation

Increased concentrations of the vasodilator histamine have been observed in patients undergoing abdominal surgery. The role of histamine during orthotopic liver transplantation (OLT) has only been studied in animals. The aim of this study was to measure plasma concentrations of histamine and its degrading enzyme diamine oxidase (DAO) in patients undergoing orthotopic liver transplantation, and assess whether histamine or DAO correlate with intraoperative noradrenaline requirements. Histamine and DAO concentrations were measured in 22 adults undergoing liver transplantation and 22 healthy adults. Furthermore, norepinephrine requirements during liver transplantation were recorded. Baseline concentrations of histamine and DAO were greater in patients, who underwent liver transplantation, than in healthy individuals (Histamine: 6.4 nM, IQR[2.9–11.7] versus 4.3 nM, IQR[3.7–7.1], p = 0.029; DAO: 2.0 ng/mL, IQR[1.5–4.1] versus <0,5 ng/mL, IQR[<0.5–1.1], p < 0.001). During liver transplantation, histamine concentrations decreased to 1.8 nM, IQR[0.5–4.9] in the anhepatic phase (p < 0.0001 versus baseline), and to 1.5 nM, IQR[0.5–2.9] after reperfusion (p < 0.0001 versus baseline). In contrast, DAO concentrations increased to 35.5 ng/ml, IQR[20–50] in the anhepatic phase (p = 0.001 versus baseline) and to 39.5 ng/ml, IQR[23–64] after reperfusion (p = 0.001 versus baseline), correlating inversely with histamine. Norepinephrine requirements during human liver transplantation correlated significantly with DAO concentrations in the anhepatic phase (r = 0.58, p = 0.011) and after reperfusion (r = 0.56; p = 0.022). In patients undergoing orthotopic liver transplantation, histamine concentrations decrease whereas DAO concentrations increase manifold. Diamine oxidase correlates with intraoperative norepinephrine requirements in patients undergoing OLT.

Intermittent Hemodialysis for Managing Metabolic Acidosis During Resuscitation of Septic Shock: A Descriptive Study.

Objectives:Septic shock is often complicated by severe metabolic acidosis, for which renal replacement therapy may be considered. However, little is known about the use of intermittent hemodialysis to manage this condition. The aim of this study was to compare physiologic and biochemical variables and vasopressor requirements before and after intermittent hemodialysis among patients who received intermittent hemodialysis to manage metabolic acidosis during resuscitation of septic shock.Design:This retrospective, cross-sectional study was conducted between April 2014 and September 2015.Settings:The ICU of a non-university-affiliated teaching hospital.Patients:Patients who were admitted to the ICU with septic shock and underwent intermittent hemodialysis to manage metabolic acidosis within 48 hours after the diagnosis of septic shock.Measurements and Main Results:The main outcomes were mean arterial pressure, minute ventilator volume, norepinephrine requirement, bicarbonate and pH before and after intermittent hemodialysis. Of 1,190 patients screened, 34 were included, and 33 accomplished a planned session of intermittent hemodialysis. After intermittent hemodialysis, an increased mean arterial pressure (+9.0 mm Hg; 95% CI, 6–13; p < 0.001), decreased minute ventilatory volume (–2.0 L/min; 95% CI, –3.3 to 0.8; p = 0.002), decreased norepinephrine requirement (–0.07 µg/kg/min; 95% CI, –0.12 to –0.02; p = 0.009), increased bicarbonate level (+7.2 mmol/L; 95% CI, 6.1–8.3; p < 0.001), and increased pH (+0.17; 95% CI, 0.13–0.21; p < 0.001) were observed in comparison to those before intermittent hemodialysis.Conclusions:In conclusion, intermittent hemodialysis appeared to be feasible and to stabilize hemodynamic and respiratory conditions in patients with septic shock complicated by metabolic acidosis during resuscitation.

Modulation of Peroxynitrite Reduces Norepinephrine Requirements in Ovine MRSA Septic Shock.

Vascular hypo-responsiveness to vasopressors during septic shock is a challenging problem. This study is to test the hypothesis that reactive nitrogen species (RNS), such as peroxynitrite, are major contributing factors to vascular hypo-responsiveness in septic shock. We hypothesized that adjunct therapy with peroxynitrite decomposition catalyst (PDC) would reduce norepinephrine requirements in sepsis resuscitation. Fourteen female Merino sheep were subjected to a "two-hit" injury (smoke inhalation and endobronchial instillation of live methicillin-resistant Staphylococcus aureus [1.6-2.5 × 10 CFUs]). The animals were randomly allocated to control: injured, fluid resuscitated, and titrated norepinephrine, n = 7; or PDC: injured, fluid resuscitated, titrated norepinephrine, and treated with PDC, n = 7. One-hour postinjury, an intravenous injection of PDC (0.1 mg/kg) was followed by a continuous infusion (0.04 mg/kg/h). Titration of norepinephrine started at 0.05 mcg/kg/min based on their mean arterial pressure. All animals were mechanically ventilated and monitored in the conscious state for 24 h. The mean arterial pressure was well maintained in the PDC with significantly less norepinephrine requirement from 7 to 23 h after injury compared with control. Total norepinephrine dose, the highest norepinephrine rate, and time on norepinephrine support were also significantly lower in PDC. Modified sheep organ failure assessment scores at 6 to 18 h postinjury were significantly lower in PDC compared with control. PDC improved survival rate at 24 h (71.4% vs. 28.6%). PDC treatment had no adverse effects. In conclusion, the modulation of RNS may be considered an effective adjunct therapy for septic shock, in the case of hypo-responsiveness to norepinephrine.

The Effect of Xenon-Based Anesthesia on Somatosensory-Evoked Potentials in Patients Undergoing Carotid Endarterectomy

The aim of this study was to investigate the influence of xenon-based anesthesia on somatosensory-evoked potentials. Observational cohort study. University hospital. Twenty subsequent adult patients undergoing elective carotid endarterectomy. Xenon-based anesthesia. Cortical-evoked responses to median nerve stimulation were quantified by measurement of the amplitude and latency of the N20 wave, which are typically assessed during carotid surgery to detect intraoperative cerebral hypoperfusion and ischemia. Primary (N20 amplitude and latency) and secondary (mean arterial pressure, norepinephrine requirements and depth of anesthesia) were assessed during (1) propofol/remifentanil and (2) subsequent xenon/remifentanil anesthesia. Xenon at an inspiratory fraction of 62.5 ± 7% decreased norepinephrine requirement (0.067 ± 0.04 v 0.028 ± 0.02 µg/kg/min, p < 0.001), and mean arterial pressure was unchanged (90.6 ± 15.0 v 93.1 ± 9.6 mmHg, p = 0.40). Somatosensory-evoked potentials were available in all patients during xenon/remifentanil. Despite similar depth of anesthesia (Narcotrend index 38.4 ± 6.2 v 38.5 ± 5.8) during propofol and xenon, N20 amplitude was reduced after xenon wash-in from 3.7 ± 1.7 to 1.4 ± 2.8 µV, p < 0.001 on the surgical and 3.6 ± 1.6 to 1.4 ± 0.6 µV, p < 0.001 on the contralateral side. N20 latency remained unchanged during xenon (22.9 ± 2.1 v 22.5 ± 2.8 ms, p = 0.34 and 22.9 ± 2.0 v 22.9 ± 3.0, p = 0.97). Xenon influences somatosensory-evoked potentials measurement by reducing N20 wave amplitude but not latency. When xenon is considered as an anesthetic for carotid endarterectomy, wash-in needs to be completed before carotid surgery is commenced to provide stable baseline somatosensory-evoked potential measurement.

The Mitochondria-Targeted H2S-Donor AP39 in a Murine Model of Combined Hemorrhagic Shock and Blunt Chest Trauma.

After blast wave-induced TxT or sham procedure, anesthetized and instrumented mice underwent 1 h of hemorrhage followed by 4 h of resuscitation comprising an i.v. bolus injection of 100 or 10 nmol kg AP39 or vehicle, retransfusion of shed blood, fluid resuscitation, and norepinephrine. Lung mechanics and gas exchange were assessed together with hemodynamics, metabolism, and acid-base status. Blood and tissue samples were analyzed for cytokine and chemokine levels, western blot, immunohistochemistry, mitochondrial oxygen consumption (JO2), and histological changes. High dose AP39 attenuated systemic inflammation and reduced the expression of inducible nitric oxide synthase (iNOS) and IκBα expression in lung tissue. In the combined trauma group (TxT + HS), animals treated with high dose AP39 presented with the lowest mean arterial pressure and thus highest norepinephrine requirements and higher mortality. Low dose AP39 had no effects on hemodynamics, leading to unchanged norepinephrine requirements and mortality rates. AP39 is a systemic anti-inflammatory agent. In our model of trauma with HS, there may be a narrow dosing and timing window due to its potent vasodilatory properties, which might result in or contribute to aggravation of circulatory shock-related hypotension.

Dexmedetomidine reduces norepinephrine requirements and preserves renal oxygenation and function in ovine septic acute kidney injury

Norepinephrine exacerbates renal medullary hypoxia in experimental septic acute kidney injury. Here we examined whether dexmedetomidine, an α2-adrenergic agonist, can restore vasopressor responsiveness, decrease the requirement for norepinephrine and attenuate medullary hypoxia in ovine gram-negative sepsis. Sheep were instrumented with pulmonary and renal artery flow probes, and laser Doppler and oxygen-sensing probes in the renal cortex and medulla. Conscious sheep received an infusion of live Escherichia coli for 30 hours. Eight sheep in each group were randomized to receive norepinephrine, norepinephrine with dexmedetomidine, dexmedetomidine alone or saline vehicle, from 24-30 hours of sepsis. Sepsis significantly reduced the average mean arterial pressure (84 to 67 mmHg), average renal medullary perfusion (1250 to 730 perfusion units), average medullary tissue pO2 (40 to 21 mmHg) and creatinine clearance (2.50 to 0.78 mL/Kg/min). Norepinephrine restored baseline mean arterial pressure (to 83 mmHg) but worsened medullary hypoperfusion (to 330 perfusion units) and medullary hypoxia (to 9 mmHg). Dexmedetomidine (0.5 μg/kg/h) co-administration significantly reduced the norepinephrine dose (0.8 to 0.4 μg/kg/min) required to restore baseline mean arterial pressure, attenuated medullary hypoperfusion (to 606 perfusion units), decreased medullary tissue hypoxia (to 29 mmHg), and progressively increased creatinine clearance (to 1.8 mL/Kg/min). Compared with vehicle time-control, dexmedetomidine given alone significantly prevented the temporal reduction in mean arterial pressure, but had no significant effects on medullary perfusion and oxygenation or creatinine clearance. Thus, in experimental septic acute kidney injury, dexmedetomidine reduced norepinephrine requirements, attenuated its adverse effects on the renal medulla, and maintained renal function.

Manipulating the Microcirculation in Sepsis - the Impact of Vasoactive Medications on Microcirculatory Blood Flow: A Systematic Review.

Sepsis is life-threatening organ dysfunction because of a dysregulated host response to infection. Disturbed microvascular blood flow is associated with excess mortality and is a potential future target for interventions. This review addresses the evidence for pharmacological manipulation of the microcirculation in sepsis assessed by techniques that evaluate the sublingual microvasculature. Systematic review using a published protocol. Eligibility criteria were studies of septic patients published from January 2000 to February 2018. Interventions were drugs aimed at improving perfusion. Outcome was improvement in microvascular flow using orthogonal polarization spectral, sidestream dark field, or incident dark field imaging (Grades of Recommendation, Assessment, Development, and Evaluation criteria used). Two thousand six hundred and six articles were screened and 22 included. (6 randomized controlled trials, 12 interventional, 3 observational, and 1 pilot, n = 572 participants). Multiple measurement techniques were described, including: automated analyses, subjective, and composite scoring systems. Norepinephrine was not found to improve microvascular flow (low-grade evidence, n = 6 studies); except in chronic hypertension (low, n = 1 study). Addition of arginine vasopressin or terlipressin to norepinephrine maintained flow while decreasing norepinephrine requirements (high, n = 2 studies). Neither dobutamine nor glyceryl trinitrate consistently improved flow (low, n = 6 studies). A single study (n = 40 participants) demonstrated improved flow with levosimendan (high). In a risk of bias assessment 16/16 interventional, pilot and observational studies were found to be high risk. There is no robust evidence to date that any one agent can reproducibly lead to improved microvascular flow. Furthermore, no study demonstrated outcome benefit of one therapeutic agent over another. Updated consensus guidelines could improve comparable reporting of measurements and reduce bias, to enable meaningful comparisons around the effects of individual pharmacological agents.

Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials.

We performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups. Our pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed as well as one-stage regression models with single treatment covariate interactions for subgroup analyses. Four trials were included with a total of 1453 patients. For the primary outcomes, there was no effect of vasopressin on 28-day mortality [relative risk (RR) 0.98, 95% CI 0.86-1.12] or serious adverse events (RR 1.02, 95% CI 0.82-1.26). Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%-3.2%] but fewer arrhythmias (ARD - 2.8%, 95% CI - 0.2% to - 5.3%). Mesenteric ischaemia and acute coronary syndrome events were similar between groups. Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74-0.99), but this finding was not robust to sensitivity analyses. There were no statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion). Vasopressin therapy in septic shock had no effect on 28-day mortality although the confidence intervals are wide. It appears safe but with a different side effect profile from norepinephrine. The finding on reduced RRT should be interpreted cautiously. Future trials should focus on long-term outcomes in select patient groups as well as incorporating cost effectiveness analyses regarding possible reduced RRT use.

Traumatic brain injury may worsen clinical outcomes after prolonged partial resuscitative endovascular balloon occlusion of the aorta in severe hemorrhagic shock model.

The use of partial resuscitative endovascular balloon occlusion of the aorta (pREBOA) in combined hemorrhagic shock (HS) and traumatic brain injury (TBI) has not been well studied. We hypothesized that the use of pREBOA in the setting of TBI would be associated with worse clinical outcomes. Female Yorkshire swine were randomized to the following groups: HS-TBI, HS-TBI-pREBOA, and HS-pREBOA (n = 5/cohort). Animals in the HS-TBI group were left in shock for a total of 2 hours, whereas animals assigned to pREBOA groups were treated with supraceliac pREBOA deployment (60 minutes) 1 hour into the shock period. All animals were then resuscitated, and physiologic parameters were monitored for 6 hours. Further fluid resuscitation and vasopressors were administered as needed. At the end of the observation period, brain hemispheric swelling (%) and lesion size (mm) were assessed. Mortality was highest in the HS-TBI-pREBOA group (40% [2/5] vs. 0% [0/5] in the other groups, p = 0.1). Severity of shock was greatest in the HS-TBI-pREBOA group, as defined by peak lactate levels and pH nadir (p < 0.05). Fluid resuscitation and norepinephrine requirements were significantly higher in the HS-TBI-pREBOA group (p < 0.05). No significant differences were noted in brain hemispheric swelling and lesion size between the groups. Prolonged application of pREBOA in the setting of TBI does not contribute to early worsening of brain lesion size and edema. However, the addition of TBI to HS-pREBOA may worsen the severity of shock. Providers should be aware of the potential physiologic sequelae induced by TBI.

Intraoperative reduction of vasopressors using processed electroencephalographic monitoring in patients undergoing elective cardiac surgery: a randomized clinical trial.

Intraoperative vasopressor and fluid application are common strategies against hypotension. Use of processed electroencephalographic monitoring (pEEG) may reduce vasopressor application, a known risk factor for organ dysfunction, in elective cardiac surgery patients. Randomized single-centre clinical trial at Jena University Hospital. Adult patients operated on cardiopulmonary bypass or off-pump coronary artery bypass grafting were randomised to receive anesthesia with visible or blinded pEEG using Narcotrend™. In blinded-Narcotrend (NT) depth of anesthesia was extrapolated from clinical signs, hemodynamic response and anesthetic concentration, supplemented by target indices between 37 and 64 in the visible-NT group. Intraoperative norepinephrine requirement (primary endpoint), fluid balance, extubation time, delirium occurrence and adverse events were evaluated. Patients of the intent-to-treat population (visible-NT: n = 123, blinded-NT: n = 122) had similar patient and procedural characteristics. Adjusted for type of surgery intraoperative Norepinephrine application was significantly reduced in visible-NT (n = 120, robust mean of cumulative dose 4.71µg/kg bodyweight) compared to blinded-NT patients (n = 119, 6.14µg/kg bodyweight) (adjusted robust mean difference 1.71 (95% CI 0.33-3.10) µg/kg bodyweight). Although reduction in patients operated on cardiopulmonary bypass was higher the interaction was not significant in post-hoc subgroup analysis. Intraoperative fluid balance was similar among both groups and strata. Extubation time was non-significantly lower in visible than in blinded-NT group. Overall postoperative delirium risk was 16.4% without differences among the groups. Adverse events-sudden movement/coughing, perspiration or hypertension-occurred more often with visible-NT, while one blinded-NT patient experienced intraoperative awareness. Titration of depth of anesthesia in elective cardiac surgery patients using pEEG allows to reduce application of norepinephrine.

Extracorporeal cytokine adsorption in septic shock: A proof of concept randomized, controlled pilot study

BackgroundThe aim of this proof of concept, prospective, randomized pilot trial was to investigate the effects of extracorporeal cytokine removal (CytoSorb®) applied as a standalone treatment in patients with septic shock. Methods20 patients with early (<24 h) onset of septic shock of medical origin, on mechanical ventilation, norepinephrine>10 μg/min, procalcitonin (PCT) > 3 ng/mL without the need for renal replacement therapy were randomized into CytoSorb (n = 10) and Control groups (n = 10). CytoSorb therapy lasted for 24 h. Clinical and laboratory data were recorded at baseline (T0), T12, T24, and T48 hours. ResultsOverall SOFA scores did not differ between the groups. In the CytoSorb-group norepinephrine requirements and PCT concentration decreased significantly (norepinephrine: CytoSorb: T0 = 0.54[IQR:0.20–1.22], T48 = 0.16[IQR:0.07–0.48], p = .016; Controls: T0 = 0.43[IQR:0.19–0.64], T48 = 0.25[IQR:0.08–0.65] μg/kg/min; PCT: CytoSorb: T0 median = 20.6[IQR: 6.5–144.5], T48 = 5.6[1.9–54.4], p = .004; Control: T0 = 13.2[7.6–47.8], T48 = 9.2[3.8–44.2]ng/mL). Big-endothelin-1 concentrations were also significantly lower in the CytoSorb group (CytoSorb: T0 = 1.3 ± 0.6, *T24 = 1.0 ± 0.4, T48 = 1.4 ± 0.8, *p = .003; Control: T0 = 1.1 ± 0.7, T24 = 1.1 ± 0.6, T48 = 1.2 ± 0.6 pmol/L, p = .115). There were no CytoSorb therapy-related adverse events. ConclusionsThis is the first trial to investigate the effects of early extracorporeal cytokine adsorption treatment in septic shock applied without renal replacement therapy. It was found to be safe with significant effects on norepinephrine requirements, PCT and Big-endothelin-1 concentrations compared to controls.Trial registration: The study has been registered on ClinicalTrials.gov, under the registration number of NCT02288975, registered 13 November 2014.

Efeitos do sulfato de magnésio e da milrinona sobre o vasoespasmo cerebral após hemorragia subaracnoidea por aneurisma: estudo randômico

BackgroundAneurysmal subarachnoid hemorrhage is an important cause of premature death and disability worldwide. Magnesium sulphate is shown to have a neuroprotective effect and it reverses cerebral vasospasm. Milrinone is also used in the treatment of cerebral vasospasm. The aim of the present study was to compare the effect of prophylactic magnesium sulphate and milrinone on the incidence of cerebral vasospasm after subarachnoid hemorrhage. MethodsThe study included 90 patients with aneurysmal subarachnoid hemorrhage classified randomly (by simple randomization) into two groups: magnesium sulphate was given as an infusion of 500mg.day−1 without loading dose for 21 days. Group B: milrinone was given as an infusion of 0.5μg.kg−1.min−1 without loading dose for 21 days. The cerebral vasospasm was diagnosed by mean cerebral blood flow velocity in the involved cerebral artery (mean flow velocity≥120cm.s−1), neurological deterioration by Glasgow coma scale, or angiography (the decrease in diameter of the involved cerebral artery >25%). ResultsThe mean cerebral blood flow velocity decreased significantly in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p<0.001). The incidence of cerebral vasospasm decreased significantly with magnesium compared to milrinone (p=0.007). The Glasgow coma scale significantly improved in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p=0.036, p=0.012, p=0.016, respectively). The incidence of hypotension was higher with milrinone than magnesium (p=0.012). ConclusionsThe incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage was significantly lower and Glasgow coma scale significantly better with magnesium when compared to milrinone. Milrinone was associated with a higher incidence of hypotension and requirement for dopamine and norepinephrine when compared to magnesium.

Abstract 334: Cardioplegia Defibrillation of Circulatory Phase Ventricular Fibrillation in a Swine Model: Three Randomized Controlled Trials

Introduction: We previously found potassium cardioplegia followed by rapid calcium reversal (K plegia) can achieve defibrillation in a swine model of electrical phase ventricular fibrillation (VF) comparable to standard care. Hypothesis: Exploring 3 possible potassium (K) dose and timing protocols, we hypothesize K plegia may benefit resuscitation of circulatory phase VF. Methods: Three separate blinded randomized placebo-controlled trials were performed with electrically-induced VF untreated for durations of 6,9, and 12 minutes in a swine model. All experimental groups received infusion of 1 or 2 boluses of intravenous (IV) K followed by a single calcium reversal bolus. Only K was replaced by saline in the control groups. All other treatments were the same. Outcomes included: amplitude spectrum area (AMSA) during VF, resulting rhythms, number of defibrillations, return of spontaneous circulation (ROSC), and hemodynamics for 1 hour post ROSC. Single nominal and interval outcomes were compared with Fisher’s Exact test and Mann-Whitney U, respectively. Results: Twelve, 12, and 8 animals were included at 6, 9 , and 12 minute VF durations for a total of 32. ROSC, average number of shocks, and post-ROSC norepinephrine requirement are listed below. 4/6 K plegia and 2/6 control animals achieved ROSC in the 9 minute protocol, (p=0.24). Two of 8 animals that achieved ROSC with K plegia did so without electrical defibrillation. Conclusions: The majority of animals achieved ROSC after up to 9 minutes of untreated VF arrest using K plegia protocols. K plegia requires further optimization for both peripheral IV and intraosseous infusion, and to assess for superiority over standard care.

Effect of magnesium sulphate and milrinone on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a randomized study

BackgroundAneurysmal subarachnoid hemorrhage is an important cause of premature death and disability worldwide. Magnesium sulphate is shown to have a neuroprotective effect and it reverses cerebral vasospasm. Milrinone is also used in the treatment of cerebral vasospasm. The aim of the present study was to compare the effect of prophylactic magnesium sulphate and milrinone on the incidence of cerebral vasospasm after subarachnoid hemorrhage. MethodsThe study included 90 patients with aneurysmal subarachnoid hemorrhage classified randomly (by simple randomization) into two groups: magnesium sulphate was given as an infusion of 500mg.day−1 without loading dose for 21 days. Group B: milrinone was given as an infusion of 0.5μg.kg−1.min−1 without loading dose for 21 days. The cerebral vasospasm was diagnosed by mean cerebral blood flow velocity in the involved cerebral artery (mean flow velocity≥120cm.s−1), neurological deterioration by Glasgow coma scale, or angiography (the decrease in diameter of the involved cerebral artery >25%). ResultsThe mean cerebral blood flow velocity decreased significantly in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p<0.001). The incidence of cerebral vasospasm decreased significantly with magnesium compared to milrinone (p=0.007). The Glasgow coma scale significantly improved in the magnesium group compared to milrinone group through Day 7, Day 14 and Day 21 (p=0.036, p=0.012, p=0.016, respectively). The incidence of hypotension was higher with milrinone than magnesium (p=0.012). ConclusionsThe incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage was significantly lower and Glasgow coma scale significantly better with magnesium when compared to milrinone. Milrinone was associated with a higher incidence of hypotension and requirement for dopamine and norepinephrine when compared to magnesium.

Clinical-grade mesenchymal stem cells derived from umbilical cord improve septic shock in pigs

BackgroundSeptic shock is the leading cause of death in intensive care units. The pathophysiological complexity of this syndrome contributes to an absence of specific treatment. Several preclinical studies in murine models of septic shock have shown improvements to organ injury and survival after administration of mesenchymal stem cells (MSCs). To better mimic a clinical approach in humans, we investigated the impact of randomized controlled double-blind administration of clinical-grade umbilical cord-derived MSCs to a relevant pig model of septic shock.MethodsSeptic shock was induced by fecal peritonitis in 12 male domestic pigs. Animals were resuscitated by an experienced intensivist including fluid administration and vasopressors. Four hours after the induction of peritonitis, pigs were randomized to receive intravenous injection of thawed umbilical cord-derived MSCs (UCMSC) (1 × 106 UCMSCs/kg diluted in 75 mL hydroxyethyl starch (HES), (n = 6) or placebo (HES alone, n = 6). Researchers were double-blinded to the treatment administered. Hemodynamic parameters were continuously recorded. Gas exchange, acid-base status, organ function, and plasma cytokine concentrations were assessed at regular intervals until 24 h after the onset of peritonitis when animals were sacrificed under anesthesia.ResultsPeritonitis induced profound hypotension, hyperlactatemia, and multiple organ failure. These disorders were significantly attenuated when animals were treated with UCMSCs. In particular, cardiovascular failure was attenuated, as attested by a better mean arterial pressure and reduced lactatemia, despite lower norepinephrine requirements. As such, UCMSCs improved survival in this very severe model (60% survival vs. 0% at 24 h).ConclusionUCMSCs administration is beneficial in this pig model of polymicrobial septic shock.

Comparison of first-line and second-line terlipressin versus sole norepinephrine in fulminant ovine septic shock

The Surviving Sepsis Guidelines suggest the use of vasopressin in case of catecholamine-refractory septic shock. Terlipressin (TP) as a V1-selective AVP analogue is a potential alternative, though data regarding the first-line administration in septic shock are scarce. The present study explored and compared the effects of first-line vs. second-line infusion of TP or sole norepinephrine regarding organ function, fluid and norepinephrine requirements and survival in fulminant ovine septic shock. Peritoneal sepsis was induced in 23 ewes after laparotomy and faecal withdrawal from the caecum. After onset of shock, causal and supportive sepsis therapy (antibiotics, peritoneal lavage, fluids and open-label norepinephrine) was performed in all animals. Concurrently, animals were randomized to receive 0.9% sodium chloride (control group) or TP (2 µg∙kg−1∙h−1, first-line group) after shock onset. In the second-line TP group, TP (2 µg∙kg−1∙h−1) was started once norepinephrine requirements exceeded 0.5 µg∙kg−1∙min−1. No significant differences were found between groups regarding survival, haemodynamics as well as fluid- and catecholamine-requirements. Kidney function and electron microscopic kidney injury were comparable between groups. In the present model of fulminant ovine septic shock, first-line TP infusion had no significant effect on fluid and norepinephrine requirements or organ dysfunction as compared to second-line TP infusion or placebo.

Comparison of Levosimendan and Milrinone for ECLS Weaning in Patients After Cardiac Surgery—A Retrospective Before-and-After Study

Pharmacodynamics suggests that levosimendan might be a valuable inotrope for weaning from extracorporeal life support (ECLS). As there is a paucity of evidence regarding the effectiveness and safety of such an approach, the aim was to report the authors' experiences in ECLS weaning before and after the implementation of levosimendan in clinical practice. Retrospective before-and-after study. Cardiac intensive care unit of a university hospital. A total of 64 patients under ECLS for postcardiotomy cardiac failure, who underwent an ECLS weaning trial. Group comparisons between patients treated with levosimendan and patients treated with milrinone were made with the Mann-Whitney U test or the Pearson chi-squared test. Results are given as median (interquartile range) or numbers (percentages). Of 64 patients, 26 (41%) received levosimendan. Successful ECLS weaning was achieved in 24 (92%) and 30 patients (79%) in the levosimendan and milrinone group, respectively (p = 0.18). In the levosimendan group, fewer patients had an intra-aortic balloon pump for weaning (2 [7.7%] v 15 [40%], p = 0.008). The support with norepinephrine was similar in the levosimendan and milrinone groups at the time of ECLS removal (0.06 [0.01-0.11] v 0.07 [0.01-0.16] µg/kg/min, p = 0.64) and 24 hours later (0.06 [0.04-0.09] v 0.04 [0.00-0.09] µg/kg/min, p = 0.15). Twenty-eight days (9/26 (35%) v 14/35 (40%), p = 0.28) and 180 days (13/26 [50%] v 15/34 [44%], p = 0.80) mortalities after ECLS removal were similar in the levosimendan and the milrinone groups. Levosimendan enabled ECLS weaning without increasing norepinephrine requirements when compared to a control group receiving milrinone.

Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.

The aim of this study was to assess the influence of intraoperative cytokine adsorption on the perioperative vasoplegia, inflammatory response and outcome during orthotopic heart transplantation (OHT). Eighty-four OHT patients were separated into the cytokine adsorption (CA)-treated group or controls. Vasopressor demand, inflammatory response described by procalcitonin and C-reactive protein, and postoperative outcome were assessed performing propensity score matching. In the 16 matched pairs, the median noradrenaline requirement was significantly less in the CA-treated patients than in the controls on the first and second postoperative days (0.14 vs 0.3μg*kg-1 *min-1 , P=.039 and 0.06 vs 0.32μg*kg-1 *min-1 , P=.047). The inflammatory responses were similar in the two groups. There was a trend toward shorter length of mechanical ventilation and intensive care unit (ICU) stay in the CA-treated group compared to the controls. No difference in adverse events was observed between the two groups. The frequency of renal replacement therapy was less in the CA‐treated patients than in the controls. Intraoperative CA treatment was associated with reduced vasopressor demand with a favorable tendency in length of mechanical ventilation, ICU stay and renal replacement therapy. CA treatment was not linked to higher rates of adverse events.