The future of intensive care: the study of the microcirculation will help to guide our therapies.

The goal of hemodynamic resuscitation is to optimize the microcirculation of organs to meet their oxygen and metabolic needs. Clinicians are currently blind to what is happening in the microcirculation of organs, which prevents them from achieving an additional degree of individualization of the hemodynamic resuscitation at tissue level. Indeed, clinicians never know whether optimization of the microcirculation and tissue oxygenation is actually achieved after macrovascular hemodynamic optimization. The challenge for the future is to have noninvasive, easy-to-use equipment that allows reliable assessment and immediate quantitative analysis of the microcirculation at the bedside. There are different methods for assessing the microcirculation at the bedside; all have strengths and challenges. The use of automated analysis and the future possibility of introducing artificial intelligence into analysis software could eliminate observer bias and provide guidance on microvascular-targeted treatment options. In addition, to gain caregiver confidence and support for the need to monitor the microcirculation, it is necessary to demonstrate that incorporating microcirculation analysis into the reasoning guiding hemodynamic resuscitation prevents organ dysfunction and improves the outcome of critically ill patients.

Systematic review and literature appraisal on methodology of conducting and reporting critical-care echocardiography studies: a report from the European Society of Intensive Care Medicine PRICES expert panel.

BACKGROUND: The echocardiography working group of the European Society of Intensive Care Medicine recognized the need to provide structured guidance for future CCE research methodology and reporting based on a systematic appraisal of the current literature. Here is reported this systematic appraisal. METHODS: We conducted a systematic review, registered on the Prospero database. A total of 43 items of common interest to all echocardiography studies were initially listed by the experts, and other "topic-specific" items were separated into five main categories of interest (left ventricular systolic function, LVSF n = 15, right ventricular function, RVF n = 18, left ventricular diastolic function, LVDF n = 15, fluid management, FM n = 7, and advanced echocardiography techniques, AET n = 17). We evaluated the percentage of items reported per study and the fraction of studies reporting a single item. RESULTS: From January 2000 till December 2017 a total of 209 articles were included after systematic search and screening, 97 for LVSF, 48 for RVF, 51 for LVDF, 36 for FM and 24 for AET. Shock and ARDS were relatively common among LVSF articles (both around 15%) while ARDS comprised 25% of RVF articles. Transthoracic echocardiography was the main echocardiography mode, in 87% of the articles for AET topic, followed by 81% for FM, 78% for LVDF, 70% for LVSF and 63% for RVF. The percentage of items per study as well as the fraction of study reporting an item was low or very low, except for FM. As an illustration, the left ventricular size was only reported by 56% of studies in the LVSF topic, and half studies assessing RVF reported data on pulmonary artery systolic pressure. CONCLUSION: This analysis confirmed sub-optimal reporting of several items listed by an expert panel. The analysis will help the experts in the development of guidelines for CCE study design and reporting.

Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy wasdeveloped at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroupsand among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.(AU)

Assessment of microperfusion in sepsis.

Microcirculatory alterations are frequent in sepsis and different mechanisms can be implied and variously studied. The severity of microvascular alterations is associated with organ dysfunction and mortality. The aim of this review is to make an overview of the most actual and used techniques applied on septic humans. We aimed at focus on the impact of different techniques on the evaluation of patients' management and outcome.

Evaluation of cardiac output in intensive care using a non-invasive arterial pulse contour technique (Nexfin(®)) compared with echocardiography.

In this prospective study, cardiac output was measured in 38 intensive care unit patients before and after a fluid challenge, using both pulse contour analysis (Nexfin(®); BMEYE, Amsterdam, the Netherlands) and transthoracic echocardiography. The ability of the Nexfin device to detect significant changes in the velocity-time integral was evaluated. The pulse wave could not be detected by the Nexfin device in five patients (13%), leaving 33 patients for analysis. The Nexfin device adequately tracked changes in the velocity-time integral in 20 (61%) patients. Using a cut-off of a 10% increase in cardiac output estimated by the Nexfin or by echocardiography, the sensitivity of the Nexfin device to detect a response to fluid challenge was 47%, with specificity 81% and accuracy 64%. The percentage error between the Nexfin and echocardiography was 448%; lower limit of agreement -48% (95% CI -62 to -36%) and upper limit of agreement, 32% (95% CI 20-45%). We conclude that the Nexfin device does not adequately track changes in cardiac output in critically ill patients.

Development of acute kidney injury during continuous infusion of vancomycin in septic patients.

PURPOSE: Few data are available on the occurrence of renal failure during continuous infusion of vancomycin in critically ill patients. METHODS: We reviewed the data of all patients admitted to the intensive care unit (ICU) between January 2008 and December 2009 in whom vancomycin was given as a continuous infusion for more than 48 h in the absence of renal replacement therapy. We collected data on the doses of vancomycin and blood concentrations during therapy. Acute kidney injury (AKI) was defined as a daily urine output <0.5 ml/kg/h and/or an increase in the serum creatinine of ≥0.3 mg/dl from baseline levels during vancomycin therapy or within 72 h after its discontinuation. Multivariable logistic regression analysis was performed to identify predictors of AKI. RESULTS: Of 207 patients who met the inclusion criteria, 50 (24 %) developed AKI. These patients were more severely ill, had lower creatinine clearance at admission, were more frequently exposed to other nephrotoxic agents, had a longer duration of therapy, and had higher concentrations of vancomycin during the first 3 days of treatment (C(mean)). The C(mean) was independently associated with early AKI (within 48 h from the onset of therapy) and the duration of vancomycin administration with late AKI. CONCLUSIONS: AKI occurred in almost 25 % of critically ill patients treated with a continuous infusion of vancomycin. Vancomycin concentrations and duration of therapy were the strongest variables associated with the development of early and late AKI during therapy, respectively.

Recommendations in the event of a suspected transfusion-related acute lung injury (TRALI).

The following recommendations, which aim at improving the clinical diagnosis ofTRALI and the laboratory investigations that can support it, were drawn up by a working group of the Superior Health Council. TRALI is a complication of blood transfusion that is both serious and underreported. Systematic reporting may help to develop preventive actions. Therefore, the Superior Health Council recommends that there should be a more stringent surveillance of patients who receive a blood component transfusion. The clinician should pay very close attention to any change in the patient's respiratory status (cf. dyspnoea and arterial desaturation), which should be notified systematically to the haemovigilance contact person in the hospital.

Lactate/pyruvate ratio as a marker of tissue hypoxia in circulatory and septic shock.

In this prospective, observational study, we measured arterial lactate and pyruvate concentrations within the first four hours of shock and at four hour intervals during the first 24 hours in 26 patients with septic and 13 with cardiogenic shock. We also studied 10 intensive care unit patients with normal lactate levels as controls. Seven patients (18%) died during the first 24 hours of shock, 12 (31%) patients died later in the intensive care unit and 21 (54%) were discharged alive from the intensive care unit. Blood lactate values were higher at shock onset in the non-survivors than in the survivors (P=0.02) and remained significantly elevated throughout the study. The lactate/pyruvate ratio at shock onset was significantly higher in the non-survivors (24 [17 to 34] vs 15 [10 to 19], P=0.01) than in the survivors. All patients with cardiogenic shock had hyperlactataemia at the onset of shock, and 69% had a high lactate/pyruvate ratio. Only 65% of patients with septic shock had hyperlactataemia at the onset of shock and 76% of these also had a high lactate/pyruvate ratio. In conclusion, the lactate/pyruvate ratio confirms that hyperlactataemia is frequently, but not solely, due to hypoxia, especially at the onset of shock.

Vasopressors in shock: too early to move away from catecholamines?

Adrenergic and non-adrenergic vasopressor agents can be used to correct hypotension in shock states. For a similar increase in arterial pressure, these agents may be associated with different haemodynamic, metabolic, endocrinological or immunological effects. But how relevant are these differences? Do these affect the outcome of patients with shock? Large-scale randomized trials comparing the effects of different vasopressor agents are scarce. Data on potential alternatives, and especially vasopressin, are even more scarce. Over-interpretation of the data, and especially of data obtained in subgroups, is common. Analysis of subgroups may be useful to address mechanisms and to raise hypotheses. However, subgroup analysis is often biased by confounding factors, especially when subgroup categorization is defined by response to therapy and not by intrinsic patient or disease characteristics. In this issue of the British Journal of Pharmacology, Bracht and colleagues present their interpretation of data from trials comparing vasopressin with noradrenaline in patients with septic shock. Here, we present an alternative interpretation.

Treatment of shock.

Shock is a life-threatening condition, resulting from different causes, and leading to tissue hypoperfusion. Symptomatic therapy associates fluids and vasoactive agents. Vasopressor and inotropic adrenergic agents remain the most commonly used to correct hypotension and/or to increase cardiac output. These agents have different haemodynamic and metabolic profiles, but the relevance of these differences on outcome has long been challenged. Recent randomized trials have shaded some light on this issue. Dopamine and norepinephrine have been the most extensively studied. These trials raised major concerns on the use of dopamine, which was associated with tachycardia and increased arrhythmic events, and may be associated with an increased risk of death especially in the subgroup of patients with cardiogenic shock. The place of epinephrine is not well defined, this agent is associated with tachycardia, increased incidence of arrhythmic events, and undesired metabolic effects.

Dopamine versus norepinephrine: is one better?

Dopamine and norepinephrine are widely used as first line agents to correct hypotension in patients with acute circulatory failure. There has been considerable debate in recent years as to whether one is better than the other. Both drugs can increase blood pressure in shock states, although norepinephrine is more powerful. Dopamine can increase cardiac output more than norepinephrine, and in addition to the increase in global blood flow, has the potential advantage of increasing renal and hepatosplanchnic blood flow. However, dopamine has potentially detrimental effects on the release of pituitary hormones and especially prolactin, although the clinical relevance of these effects is unclear. Observational studies have provided conflicting results regarding the effects of these two drugs on outcomes, and results from a recently completed randomized controlled trial are eagerly waited.

90-day follow-up of patients treated with Drotrecogin Alfa (activated) for severe sepsis: a Belgian open label study.

INTRODUCTION: Severe sepsis is the major cause of mortality in intensive care units (ICUs). The BOOST study (= B (Belgian) OO (Open Label) ST (Study)) is a Belgian open-label trial designed to pragmatically assess the safety and efficacy of Drotrecogin Alfa (activated) (DAA), the only registered treatment in this indication with favourable ratio benefit/risk. METHODOLOGY: Adult patients with severe sepsis and 2 or more sepsis-induced organ dysfunctions (OD) within the 48-hour period preceding the treatment (DAA at 24 microg/kg/h for 96 hours), were included between January 2003 and October 2003. Platelet count < 30 000/mm3 and increased risk for bleeding were exclusion criteria. Mortality and location were evaluated at 28 and 90 days. RESULTS: Of the 100 included patients, 97 (median age: 66 years; men/women: 57/40) were treated and completed the study. The predominant infection sites were lung (49%) and abdomen (29%) and 35% had had recent surgery. The mean and median numbers of OD were 3.4 and 3.0, respectively, and most patients (80 %; 77/97) had 3 or more organ failures at baseline, predominantly respiratory (95%) and cardiovascular (87%). The mean APACHE II score was 25.3 (range: 6-53). The 28-day mortality rate was 32.0% (90% CI: 24.2-39.7) and increased with the number of OD: from 15% (1.9-28.1) for2 ODs, to 71% (52.4-88.8) for 5 ODs. At day 28, the 66 surviving patients were located in general ward (35%), in the ICU (32%) or at home (30%). The 90-day mortality rate was 42% (90% CI: 34.0-50.5), with most of the survivors (73%) staying at home. Eight serious adverse events, including 4 bleedings, were reported between study days 2 and 5, in 5 patients (5.2%) and led to death in 2 patients (2.1%). CONCLUSION: Despite a higher severity of illness at baseline, this phase IV open-label long-term study in Belgian ICUs shows consistent results with previous studies with DAA. Importantly, most of the surviving patients at day 90 were staying at home.

Effects of propofol on human microcirculation.

BACKGROUND: It is increasingly believed that acute microvascular alterations may be involved in the development of organ dysfunction in critically ill patients. Propofol significantly decreases vascular tone and venous return, which can induce arterial hypotension. However, little is known about the microcirculatory effects of propofol in healthy humans. METHODS: We conducted a prospective, open-labelled trial in 15 patients anaesthetized by propofol for transvaginal oocyte retrieval. The sublingual microcirculatory network was studied before, during, and after propofol infusion using orthogonal polarization spectral imaging. RESULTS: Mean (SD) calculated propofol effect-site concentration was 6.5 (1.8) microg ml(-1). During propofol administration, systemic haemodynamic and oxygenation variables were unchanged, but total microvascular density decreased by 9.1% (P<0.05). The venular density remained unchanged, but the density of perfused capillaries was significantly reduced by 16.7% (P<0.05). Microcirculatory alterations resolved 3 h after discontinuation of the propofol infusion. CONCLUSIONS: Propofol infusion for anaesthesia in man reduces capillary blood flow.

Guidelines for the use of fresh frozen plasma.

Recommendations, which aim at standardising and rationalising clinical indications for the transfusion of fresh frozen plasma (FFP) in Belgium, were drawn up by a working group of the Superior Health Council. For this purpose the Superior Health Council organised an expert meeting devoted to "Transfusion Guidelines: Pathogen reduction, products and indications for the transfusion of plasma" in collaboration with the Belgian Haematological Society.The experts discussed the indications for the transfusion of FFP, pathogen reduction for FFP and the practical issues of administering FFP and plasma-derived concentrates. The recommendations formulated by the experts were validated by the working group with the purpose of harmonising FFP transfusion in Belgian hospitals.

The microcirculation in critically-ill patients.

The microcirculation plays a major role in oxygen delivery and organ perfusion, and is largely involved in the pathophysiological alterations of shock states. It has been a focus of research for a long time, but human clinical and physiological studies have been limited by a lack of reliable techniques available at the bedside. Intravital microscopy, although of interest in experimental studies, is not feasible in human studies. Laser Doppler techniques can measure blood flow, but do not take into account the heterogeneity of the microcirculation. Recently, the Orthogonal Polarized Spectral (OPS) imaging technique has enabled the study of the microcirculation in humans. This technique has allowed a better definition of microcirculatory alterations in disease states, defined the role of some medical interventions, and been used to predict outcome. In this text, we briefly describe the techniques available to study the microcirculation and review experimental and human studies in this domain.

Microcirculatory alterations in critically ill patients.

The recent onset of orthogonal polarization spectral (OPS) imaging techniques has allowed the direct visualization of the microcirculation at the bedside of critically ill patients. A systematic review with particular emphasis on recent findings and implications in pathophysiological processes is presented. Using OPS techniques various investigators have observed microcirculatory alterations in critically ill patients, and especially in patients with severe sepsis and septic shock. These alterations include a decrease in vessel density and an increased proportion of non perfused or intermittently perfused capillaries, and these alterations can be fully reversed by the topical application of acetylcholine. Similar alterations are observed in patients with septic and cardiogenic shock. Persistent microvascular alterations are associated with the development of organ failure and death. In addition, the reversal of these alterations during resuscitation procedures is highly predictive of outcome. Unfortunately, the effects of many therapeutic interventions usually performed in critically ill patients are still not well defined, even though evidence coming from animal experiments is sometimes available. In particular, the role of fluid resuscitation, red blood cell transfusions, inotropic, vasoactive and anesthetic agents should be investigated. Microcirculation plays an important role in the pathogenesis of shock and organ dysfunction, especially in sepsis. The microcirculatory effects of various therapeutic interventions have still to be reported. OPS technique may become a valuable tool to monitor patients with circulatory failure.

Successful treatment of septic shock due to pan-resistant Acinetobacter baumannii using combined antimicrobial therapy including tigecycline.

Reported here is the case of a patient with septic shock due to multidrug-resistant Acinetobacter baumannii, which developed after complicated acute pancreatitis with intra-abdominal abscess. Treatment with colistin methanesulphonate and high doses of meropenem were initiated, but since shock persisted, tigecycline was added to the regimen, resulting in successful resolution of the infection.

Acute eosinophilic pneumonia associated with intramuscular administration of progesterone as luteal phase support after IVF: case report.

We report two cases of acute eosinophilic pneumonia induced by i.m. administration of progesterone used as luteal phase support after IVF. For both patients, the symptoms began 3 weeks after the first injection of progesterone. Both patients were in respiratory distress, and one of them required ventilatory assistance for a week, with 5 days in the intensive care unit. Symptoms improved as the i.m. form was shifted to a vaginal form of progesterone together with the administration of corticosteroids. Sesame oil (used as excipient) and benzyl alcohol (used as preservative) could both be incriminated in the development of the hypersensitivity reaction. The need for luteal phase support is clearly established in IVF cycles with GnRH agonist protocols, and progesterone is the generally recommended compound. However, there is no definitive consensus regarding the optimal route of administration of progesterone. These two cases of acute drug-induced disease show that the use of i.m. progesterone can be associated with a severe morbidity in otherwise healthy young patients. This is an additional argument to advocate the use of vaginal progesterone as luteal support in IVF.