Pharmacokinetics of C1-inhibitor in patients with acute myocardial infarction

Nederlands Tijdschrift voor Klinische Chemie 27(2),69(2002) -- Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde --

Pharmacokinetics of C1-inhibitor protein in patients with acute myocardial infarction

OBJECTIVES: C1-inhibitor protein (C1-INH) purified from pooled human plasma is used for the treatment of patients with hereditary angioedema. Recently, the beneficial effects of high-dose C1-INH treatment on myocardial ischemia or reperfusion injury have been reported in various animal models and in humans. We investigated the pharmacokinetic behavior of C1-INH in patients with acute myocardial infarction to calculate the amount of C1-INH required for optimal efficacy. METHODS: Twenty-two patients received an intravenous loading dose, followed by 48 hours of continuous infusion of C1-INH. Changes in the endogenous production of C1-INH were evaluated in 16 control patients with acute myocardial infarction. A 2-compartment model was used to estimate the fractional catabolic rate constant (FCR), transcapillary escape rate constant (TER), and extravascular return rate constant (ERR) of C1-INH. Software designed to analyze and fit measured data to unknown parameters in a system of differential equations was used to fit the experimental data against the 3-parameter model. RESULTS: With fixed TER and ERR values (0.014 h(-1) and 0.018 h(-1), respectively), 20 of the 22 cases yielded well-determined FCR values, and simultaneous fitting resulted in a median FCR of 0.011 h(-1) (95% confidence interval, 0.010 to 0.012 h(-1)) versus 0.025 h(-1) as reported in healthy control patients. Simultaneous estimation of TER, ERR, and FCR demonstrated weakly defined TER and ERR values, whereas the median FCR value remained unchanged. The use of a 2-compartment model resulted in a significantly better fit compared with the 1-compartment model. Physiologic explanations are offered for discrepancies in the literature. CONCLUSIONS: Dose calculation of C1-INH in patients treated with massive doses of C1-INH requires turnover parameters that differ from those found in healthy subjects, possibly because of suppression of continuous C1-INH consumption by target protease

Low tidal volume ventilation ameliorates left ventricular dysfunction in mechanically ventilated rats following LPS-induced lung injury

Background: High tidal volume ventilation has shown to cause ventilator-induced lung injury (VILI), possibly contributing to concomitant extrapulmonary organ dysfunction. The present study examined whether left ventricular (LV) function is dependent on tidal volume size and whether this effect is augmented during lipopolysaccharide(LPS)-induced lung injury. Methods: Twenty male Wistar rats were sedated, paralyzed and then randomized in four groups receiving mechanical ventilation with tidal volumes of 6 ml/kg or 19 ml/kg with or without intrapulmonary administration of LPS. A conductance catheter was placed in the left ventricle to generate pressure-volume loops, which were also obtained within a few seconds of vena cava occlusion to obtain relatively load-independent LV systolic and diastolic function parameters. The end-systolic elastance / effective arterial elastance (Ees/Ea) ratio was used as the primary parameter of LV systolic function with the end-diastolic elastance (Eed) as primary LV diastolic function. Results: Ees/Ea decreased over time in rats receiving LPS (p = 0.045) and high tidal volume ventilation (p = 0.007), with a lower Ees/Ea in the rats with high tidal volume ventilation plus LPS compared to the other groups (p < 0.001). Eed increased over time in all groups except for the rats receiving low tidal volume ventilation without LPS (p = 0.223). A significant interaction (p < 0.001) was found between tidal ventilation and LPS for Ees/Ea and Eed, and all rats receiving high tidal volume ventilation plus LPS died before the end of the experiment. Conclusions: Low tidal volume ventilation ameliorated LV systolic and diastolic dysfunction while preventing death following LPS-induced lung injury in mechanically ventilated rats. Our data advocates the use of low tidal volumes, not only to avoid VILI, but to avert ventilator-induced myocardial dysfunction as well

Basic concepts of fluid responsiveness

Predicting fluid responsiveness, the response of stroke volume to fluid loading, is a relatively novel concept that aims to optimise circulation, and as such organ perfusion, while avoiding futile and potentially deleterious fluid administrations in critically ill patients. Dynamic parameters have shown to be superior in predicting the response to fluid loading compared with static cardiac filling pressures. However, in routine clinical practice the conditions necessary for dynamic parameters to predict fluid responsiveness are frequently not met. Passive leg raising as a means to alter biventricular preload in combination with subsequent measurement of the change in stroke volume can provide a fast and accurate way to guide fluid management in a broad population of critically ill patients

Vasopressors and Inotropes in Acute Myocardial Infarction Related Cardiogenic Shock: A Systematic Review and Meta-Analysis

Vasopressors and inotropes are routinely used in acute myocardial infarction (AMI) related cardiogenic shock (CS) to improve hemodynamics. We aimed to investigate the effect of routinely used vasopressor and inotropes on mortality in AMI related CS. A systematic search of MEDLINE, EMBASE and CENTRAL was performed up to 20 February 2019. Randomized and observational studies reporting mortality of AMI related CS patients were included. At least one group should have received the vasopressor/inotrope compared with a control group not exposed to the vasopressor/inotrope. Exclusion criteria were case reports, correspondence and studies including only post-cardiac surgery patients. In total, 19 studies (6 RCTs) were included, comprising 2478 CS patients. The overall quality of evidence was graded low. Treatment with adrenaline, noradrenaline, vasopressin, milrinone, levosimendan, dobutamine or dopamine was not associated with a difference in mortality between therapy and control group. We found a trend toward better outcome with levosimendan, compared with control (RR 0.69, 95% CI 0.47–1.00). In conclusion, we found insufficient evidence that routinely used vasopressors and inotropes are associated with reduced mortality in patients with AMI related CS. Considering the limited evidence, this study emphasizes the need for randomized trials with appropriate endpoints and methodology

Conventional hemodynamic resuscitation may fail to optimize tissue perfusion: An observational study on the effects of dobutamine, enoximone, and norepinephrine in patients with acute myocardial infarction complicated by cardiogenic shock

Aim: To investigate the effects of inotropic agents on parameters of tissue perfusion in patients with cardiogenic shock. Methods and Results: Thirty patients with cardiogenic shock were included. Patients received dobutamine, enoximone, or norepinephrine. We performed hemodynamic measurements at baseline and after titration of the inotropic agent until cardiac index (CI) ≥2.5 L.min-1.m-2 or mixed-venous oxygen saturation (SvO 2) ≥70% (dobutamine or enoximone), and mean arterial pressure (MAP) ≥70 mmHg (norepinephrine). As parameters of tissue perfusion, we measured central-peripheral temperature gradient (delta-T) and sublingual perfused capillary density (PCD). All patients reached predefined therapeutic targets. The inotropes did not significantly change delta-T. Dobutamine did not change PCD. Enoximone increased PCD (9.1 [8.9-10.2] vs. 11.4 [8.4-13.9] mm.mm-2; p10.3 mm.mm-2; mortality 72% vs. 17%, p = 0.003). Conclusion: This study demonstrates the effects of commonly used inotropic agents on parameters of tissue perfusion in patients with cardiogenic shock. Despite hemodynamic optimization, tissue perfusion was not sufficiently restored in most patients. In these patients, mortality was high. Interventions directed at improving microcirculation may eventually help bridging the gap between improved hemodynamics and dismal patient outcome in cardiogenic shock

Outcome and predictors for mortality in patients with cardiogenic shock: a Dutch nationwide registry-based study of 75,407 patients with acute coronary syndrome treated by PCI

It is important to gain more insight into the cardiogenic shock (CS) population, as currently, little is known on how to improve outcomes. Therefore, we assessed clinical outcome in acute coronary syndrome (ACS) patients treated by percutaneous coronary intervention (PCI) with and without CS at admission. Furthermore, the incidence of CS and predictors for mortality in CS patients were evaluated. The Netherlands Heart Registration (NHR) is a nationwide registry on all cardiac interventions. We used NHR data of ACS patients treated with PCI between 2015 and 2019. Among 75,407 ACS patients treated with PCI, 3028 patients (4.1%) were identified with CS, respectively 4.3%, 3.9%, 3.5%, and 4.3% per year. Factors associated with mortality in CS were age (HR 1.02, 95%CI 1.02-1.03), eGFR (HR 0.98, 95%CI 0.98-0.99), diabetes mellitus (DM) (HR 1.25, 95%CI 1.08-1.45), multivessel disease (HR 1.22, 95%CI 1.06-1.39), prior myocardial infarction (MI) (HR 1.24, 95%CI 1.06-1.45), and out-of-hospital cardiac arrest (OHCA) (HR 1.71, 95%CI 1.50-1.94). In conclusion, in this Dutch nationwide registry-based study of ACS patients treated by PCI, the incidence of CS was 4.1% over the 4-year study period. Predictors for mortality in CS were higher age, renal insufficiency, presence of DM, multivessel disease, prior MI, and OHCA.Cardiolog

Pre-PCI versus immediate post-PCI Impella initiation in acute myocardial infarction complicated by cardiogenic shock

BACKGROUND: In selected patients with an acute myocardial infarction (AMI) complicated by Cardiogenic shock (CS), mechanical circulatory support with Impella may be beneficial, although conclusive evidence is still lacking. Nevertheless, it has been suggested that Impella initiation prior to primary PCI might improve survival. OBJECTIVE: To investigate the effect pre-PCI versus immediate post-PCI Impella initiation on short term mortality. METHODS: A prospective, single center, observational study, was performed including all patients with STEMI complicated by CS, treated with primary PCI and Impella. Thirty day mortality was compared between patients with Impella initiation pre-PCI and immediately post-PCI. RESULTS: A total of 88 patients were included. In the pre-PCI group (n = 21), admission heart rate was lower (84 versus 94 bpm, p = 0.04) and no IABP was implanted before Impella initiation, versus 17.9% in post-PCI group (n = 67), p = 0.04. Total 30-day all-cause mortality was 58%, and was lower in pre-PCI group, 47.6% versus 61.2% in the post-PCI group, however not statistically significant (HR 0.7, 95% CI 0.3-1.3, p = 0.21). Thirty-day cardiac mortality was significantly lower in the pre-PCI group, 19% versus 44.7% in the post-PCI group (HR 0.3, 95% CI 0.09-0.96, p = 0.042). CONCLUSION: Pre-PCI Impella initiation in AMICS patients was not associated with a statistically significant difference in 30-day all-cause mortality, compared to post-PCI Impella initiation