The Escherichia coli TolC efflux pump protein is immunogenic and elicits protective antibodies.

Antimicrobial resistance is an increasing worldwide public health burden that threatens to make existent antimicrobials obsolete. An important mechanism of antimicrobial resistance is the overexpression of efflux pumps, which reduce the intracellular concentration of antimicrobials. TolC is the outer membrane protein of an efflux pump that has gained attention as a therapeutic target. Little is known about the immune response against TolC. Here we evaluated the immune response against TolC from Escherichia coli. TolC in silico epitope prediction showed several residues that could bind to human antibodies, and we showed that human plasma presented higher titers of anti-TolC IgG and IgA, than IgM. E. coli recombinant TolC protein stimulated macrophages in vitro to produce nitric oxide, as well as IL-6 and TNF-α, assessed by Griess assay and ELISA, respectively. Immunization of mice with TolC intraperitoneally and an in vitro re-stimulation led to increased T cell proliferation and IFNγ production, evaluated by flow cytometry and ELISA, respectively. TolC mouse immunization stimulated anti-TolC IgM and IgG production, with higher levels of IgG1 and IgG2, amongst the IgG subclasses. Anti-TolC murine antibodies could bind to live E. coli and increase bacterial uptake and elimination by macrophages in vitro. Intraperitoneal or intranasal, but not oral, immunizations with inactivated E. coli also led to anti-TolC antibody production. Finally, TolC immunization increased mouse survival rates to antimicrobial-sensitive or resistant E. coli infection. Our results showed that TolC is immunogenic, leading to the production of protective antibodies against E. coli, reinforcing its value as a therapeutic target.

Oral clinical findings and intensive care unit prognostic scores.

OBJECTIVE: Hospitalisation in intensive care unit (ICU) may cause changes in oral environment, which may influence patients' health status. The aim of this study was to evaluate the frequency of intraoral and extraoral findings observed during ICU admission, and to verify if there is an association with clinical prognosis scores. METHODS: Data regarding clinical characteristics of patients hospitalised in an ICU were collected from medical records. The prognostic scores Sepsis Related Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score (SAPS 3) were estimated with data collected from admission and SOFA on the day of the oral examination as well. Data on oral mucosa lesions, saliva, dental condition and oral hygiene were evaluated during oral examinations. RESULTS: The association of oral findings with prognostic scores was statistically verified. The majority (92.2%) of the 170 evaluated patients showed extraoral or intraoral findings during ICU admission. The most frequent findings were chapped and crusted lips, coated tongue, pale mucosa, haemorrhagic lesions, candidiasis, depapillated tongue and traumatic lesions. There were significant higher prognostic scores in the presence of the following extraoral and intraoral findings: crusted and ulcerated lips, haemorrhagic lesions, jaundice, spontaneous oral bleeding, coated and depapillated tongue. Median SAPS 3 was higher in patients with poor oral hygiene. CONCLUSIONS: Oral findings were frequent in the population of patients hospitalised in the ICU and some of them were associated with worse prognostic scores. Routine oral examinations must be performed in hospitalised patients from ICUs for detection of oral markers of worse clinical prognosis.

Increased Use of Antibiotics in the Intensive Care Unit During Coronavirus Disease (COVID-19) Pandemic in a Brazilian Hospital.

Background: Microbial drug resistance is one of the biggest public health problems. Antibiotic consumption is an essential factor for the emergence and spread of multiresistant bacteria. Therefore, we aimed to analyze the antibiotics consumption in the Intensive Care Unit (ICU), identifying trends in the antibiotics use profile and microbiological isolates throughout the COVID-19 pandemic. Methods: We performed this retrospective observational study in intensive care units of a Brazilian tertiary hospital from January 2019 to December 2020. The primary outcome was antimicrobial consumption in the ICU, measured by defined daily doses (DDDs) per 100 bed-days. As a secondary outcome, bacterial infections (microbiological isolates) were calculated in the same fashion. Outcomes trends were analyzed using Joinpoint regression models, considering constant variance (homoscedasticity) and first-order autocorrelation assumptions. A monthly percent change (MPC) was estimated for each analyzed segment. Results: Seven thousand and nine hundred fifty-three patients had data available on prescribed and received medications and were included in the analyses. Overall, the use of antibiotics increased over time in the ICU. The reserve group (World Health Organization Classification) had an increasing trend (MPC = 7.24) from February to April 2020. The azithromycin consumption (J01FA) increased rapidly, with a MPC of 5.21 from January to April 2020. Polymyxin B showed a relevant increase from March to June 2020 (MPC = 6.93). The peak of the antibiotic consumption of Reserve group did not overlap with the peak of the pathogenic agents they are intended to treat. Conclusion: Overall antimicrobial consumption in ICU has increased in the context of the COVID-19 pandemic. The peaks in the antimicrobial's use were not associated with the rise of the pathogenic agents they intended to treat, indicating an empirical use, which is especially concerning in the context of treating multidrug-resistant (MDR) infections. This fact may contribute to the depletion of the therapeutic arsenal for MDR treatment.

Oral health status of patients in intensive care unit: a cross-sectional study

Introduction: Patients in intensive care unit (ICU) may present oral alterations asa result of patients' systemic conditions, the use of medications, intubation orpoor oral hygiene. Oral alterations should be detected and treated because theymay aggravate patients' condition. The objective of this study was to evaluate thetypes and frequencies of clinically detected oral alterations in inpatients of an ICU.Methods: This is a cross-sectional study in which an oral evaluation of patientshospitalized in an ICU of a public hospital was performed. Demographic, socialand clinical characteristics were collected from medical records. Oral examswere performed by two trained dentists, with reliability checked by intra-classcorrelation coefficient, while patients were lying in the hospital bed, using a frontalheadlamp, tongue depressor and sterile gauze. All data were recorded in studyprotocol forms and transferred to a data base for analysis. Results: Thirty-sevenpatients, with similar distribution between genders, withmedian age of 62 yearswere evaluated. The most frequent causes for hospitalization were postoperativecare (51.35%) and respiratory problems (29.72%). About 90% of the inpatientspresented some type of oral alterations during the hospitalization period. Themost common clinical alterations were dry lips (86.5%); coated tongue (61.1%);paleness of the oral mucosa (54.1%); oral foci of infection (37.8%) and candidiasis(13.5%). Conclusion: The majority of inpatients of the ICU presented some type oforal alteration, and the most frequent were dry lips and coated tongue. Dataobserved in this study reinforce the need of the dental team support during theperiod of hospitalization.

Introdução: Pacientes em unidade de terapia intensiva (UTI) podem apresentaralterações orais como resultado das condições sistêmicas dos pacientes, uso demedicamentos, intubação ou falta de higiene bucal. Alterações orais devem serdetectadas e tratadas, pois podem agravar a condição do paciente. O objetivodeste estudo foi avaliar os tipos e frequências de alterações orais clinicamentedetectadas em pacientes internados em uma UTI. Métodos: Estudo transversalem que foi realizada avaliação oral de pacientes internados em uma UTI de umhospital público. Características demográficas, sociais e clínicas foram coletadasdos prontuários médicos. Os exames orais foram realizados por dois dentistastreinados, com confiabilidade verificada pelo coeficiente de correlação intra-classe, enquanto os pacientes estavam deitados na cama do hospital, utilizandofrontal, abaixador de língua e gaze estéril. Todos os dados foram registrados emformulários de protocolo do estudo e transferidos para uma base de dados paraanálise. Resultados: Foram avaliados 37 pacientes, com distribuição semelhanteentre os sexos, com mediana de idade de 62 anos. As causas mais frequentes deinternação foram cuidados pós-operatórios (51,35%) e problemas respiratórios(29,72%). Cerca de 90% dos pacientes internados apresentaram algum tipo dealteração bucal durante o período de internação. As alterações clínicas maiscomuns foram lábios secos (86,5%); língua (61,1%); palidez da mucosa oral (54,1%);focos orais de infecção (37,8%) e candidíase (13,5%). Conclusão: A maioria dospacientes internados em UTI apresentou algum tipo de alteração oral, sendo osmais frequentes lábios secos e língua. Os dados observados neste estudo reforçama necessidade do apoio da equipe odontológica durante o período de internação.

Control of hypertension in the critically ill: a pathophysiological approach.

Severe acute arterial hypertension can be associated with significant morbidity and mortality. After excluding a reversible etiology, choice of therapeutic intervention should be based on evaluation of a number of factors, such as age, comorbidities, and other ongoing therapies. A rational pathophysiological approach should then be applied that integrates the effects of the drug on blood volume, vascular tone, and other determinants of cardiac output. Vasodilators, calcium channel blockers, and beta-blocking agents can all decrease arterial pressure but by totally different modes of action, which may be appropriate or contraindicated in individual patients. There is no preferred agent for all situations, although some drugs may have a more attractive profile than others, with rapid onset action, short half-life, and fewer adverse reactions. In this review, we focus on the main mechanisms underlying severe hypertension in the critically ill and how using a pathophysiological approach can help the intensivist decide on treatment options.

Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome.

OBJECTIVES: Sepsis induces microvascular alterations that may play an important role in the development of organ dysfunction. However, the relationship of these alterations to systemic variables and outcome is still not well defined. We investigated which factors may influence microcirculatory alterations in patients with severe sepsis and whether these are independently associated with mortality. DESIGN: Analysis of prospectively collected data from previously published studies by our group. SETTING: A 36-bed, medicosurgical university hospital Department of Intensive Care. PATIENTS: A total of 252 patients with severe sepsis in whom the sublingual microcirculation was visualized using orthogonal polarization spectral or sidestream darkfield imaging techniques. MEASUREMENTS AND MAIN RESULTS: Microcirculatory measurements were obtained either early, within 24h of the onset of severe sepsis (n = 204), or later, after 48h (n = 48). When multiple measurements were obtained, only the first was considered. Although global hemodynamic variables were relatively preserved (mean arterial pressure 70 [65-77] mm Hg, cardiac index 3.3 [2.7-4.0] L/min.m, and SvO2 68.3 [62.8-74.7]%), microvascular variables were markedly altered (proportion of perfused small vessels 65 [50-74]%, microvascular flow index 2.15 [1.80-2.60], and heterogeneity of proportion of perfused small vessels 35 [20-50]%). Among microcirculatory variables, proportion of perfused small vessels was the strongest predictor of outcome (receiver operating characteristic curve area 0.818 [0.766-0.871], p < 0.001). Survival rates decreased markedly with severity of alterations in the proportion of perfused small vessels (70% and 75% in the two upper proportion of perfused small vessel quartiles compared with 3% and 44% in the two lower quartiles, p < 0.0001). Multivariable analysis identified proportion of perfused small vessels and sequential organ failure assessment score as independent predictors of outcome. Microcirculatory alterations were less severe in the later than in the earlier (proportion of perfused small vessels, 74 [57-82]% vs. 63 [48-71]%, p = 0.004) phase of sepsis. In multivariable analysis focused on the early period of sepsis, proportion of perfused small vessels and lactate were independent predictors of outcome. CONCLUSIONS: Microcirculatory alterations are stronger predictors of outcome than global hemodynamic variables.

Microcirculatory effects of angiotensin II inhibitors in patients with severe heart failure.

CONTEXT: The renin-angiotensin system is activated in patients with acute severe heart failure, and increased levels of angiotensin II could contribute to microcirculatory defects in these patients. OBJECTIVE: To evaluate the microcirculatory effects of angiotensin II antagonists in critically ill patients with severe heart failure. METHODS: After Ethics Committee approval and signed consent, we conducted a prospective observational study using sidestream darkfield (SDF) imaging to evaluate changes in the sublingual microcirculation of 25 adult patients with severe heart failure (ejection fraction < 40% or cardiac index < 2.5 L/min.m2) who received angiotensin inhibitors during their ICU stay. SDF images and global hemodynamic data were obtained immediately before and 4 h, 24 h, and 48 h after the first administration of the drug. RESULTS: Already 4 h after administration, there was a significant improvement in the proportion of perfused small (<20 µm) vessels (PPV) (from 78 [72-84] to 89 [82-94]%, P < 0.05) and the microvascular flow index (MFI) (from 2.25 [1.95-2.50] to 2.80 [2.39-2.95] points, P < 0.05), which persisted over subsequent hours. Large vessel perfusion remained constant. There was no correlation between changes in the PPV and changes in the mean arterial pressure (R2 0.02, P = 0.50), cardiac output (R2 0.004, P = 0.85), or central or mixed venous oxygen saturation (R2 0.03, P = 0.53). CONCLUSIONS: In patients with severe heart failure, introduction of angiotensin antagonist therapy was associated with an early improvement in the microcirculation that persisted over subsequent hours. The microcirculatory effects were independent of global hemodynamic variables. The improvement in microcirculatory perfusion observed with angiotensin inhibitors in patients with severe heart failure may partially explain the beneficial clinical effects of this intervention in such patients.

Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock.

OBJECTIVE: Supplementation with tetrahydrobiopterin, a nitric oxide synthase cofactor, may reduce microvascular endothelial dysfunction in severe sepsis. We studied whether tetrahydrobiopterin administration exerts beneficial effects in an ovine septic shock model. DESIGN: Randomized animal study. SETTING: University hospital animal research laboratory. SUBJECTS: Fourteen adult female sheep. INTERVENTIONS: Fecal peritonitis was induced, and the sheep were randomized to receive tetrahydrobiopterin (n=7), given intravenously as 20 mg/kg boluses at 4 and 12 hrs after sepsis induction, or placebo (n=7). All animals were fluid resuscitated. The experiment was continued until death or for a maximum of 30 hrs. MEASUREMENTS AND MAIN RESULTS: In addition to standard hemodynamic assessment, the sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy. The first bolus of tetrahydrobiopterin blunted the increase in heart rate and cardiac index seen in the control group without affecting mean arterial pressure, and the second bolus of tetrahydrobiopterin prevented the decreases in cardiac index and mean arterial pressure. The reduction in mixed venous blood oxygen saturation and the increase in blood lactate seen in the control group were also delayed. Tetrahydrobiopterin significantly attenuated the deterioration in perfused small vessel proportion and density, microvascular flow index, and the increase in microvascular heterogeneity observed in the control group. Tetrahydrobiopterin was associated with better preserved lung compliance and PaO2/FIO2 ratio, which were associated with a lower lung wet/dry weight ratio at the end of the study. Median survival time was significantly prolonged in the tetrahydrobiopterin group (25.0 vs. 17.8 hrs, p<.01). CONCLUSION: In this clinically relevant model of sepsis, tetrahydrobiopterin supplementation attenuated the impairment in sublingual microvascular perfusion and permeability, which was accompanied by better preserved gas exchange, renal flow and urine output, and prolonged survival.

Correlação entre marcadores de injúria miocárdica, disfunção ventricular e mortalidade na sepsis / The correlation between markers for myocardial injury, ventricular dysfunction and mortality in sepsis

Introdução: O choque séptico é a principal causa de morte nas unidades de terapia intensiva, sendo a depressão miocárdica um importante fator causal nesse desfecho. Objetivo: Avaliar a função ventricular e o tipo de alteração contrátil (regional ou difusa) presentes em pacientes na fase aguda da sepsis e sua correlação com marcadores de injúrias miocárdica e mortalidade. Método: Foram estudados prospectiva e, consecutivamente, 45 pacientes sépticos, admitidos na unidade de terapia intensiva no período de 24 meses. Foi realizado um ecocardiograma transtorácico (ETT) na fase aguda da sepsis, junto com ecocardiograma (ECG) e dosagem sérica troponina I (TNI). Em um segundo momento, foram analisadas a frequência e a correlação das alterações funcionais ao ecocardiograma, da elevação da TNI e a taxa de mortalidade dos pacientes. O ETT foi repetido nos pacientes que sobreviveram após a resolução do quadro séptico. Resultados: Dos 45 pacientes estudados, o ECG mostrou alterações isquêmicas em 40% e o ecocardiograma apresentou alteração regional ou difusa em 44% dos pacientes estudados. A TNI esteve elevada em 53% dos pacientes, dos quais 77% apresentavam disfunção ventricular esquerda (DVE) na fase aguda da sepsis. O ETT evolutivo foi realizado em 24 pacientes (53%%), mostrando melhora parcial...

Effects of changes in arterial pressure on organ perfusion during septic shock.

INTRODUCTION: Septic shock is characterized by altered tissue perfusion associated with persistent arterial hypotension. Vasopressor therapy is generally required to restore organ perfusion but the optimal mean arterial pressure (MAP) that should be targeted is uncertain. The aim of this study was to assess the effects of increasing MAP using norepinephrine (NE) on hemodynamic and metabolic variables and on microvascular reactivity in patients with septic shock. METHODS: This was a single center, prospective, interventional study conducted in the medico-surgical intensive care unit of a university hospital. Thirteen patients in septic shock for less than 48 hours who required NE administration were included. NE doses were adjusted to obtain MAPs of 65, 75, 85 and (back to) 65 mmHg. In addition to hemodynamic and metabolic variables, we measured thenar muscle oxygen saturation (StO2), using near infrared spectroscopy (NIRS), with serial vaso-occlusive tests (VOTs) on the upper arm. We also evaluated the sublingual microcirculation using sidestream dark field (SDF) imaging in 6 of the patients. RESULTS: Increasing NE dose was associated with an increase in cardiac output (from 6.1 to 6.7 l/min, P<0.05) and mixed venous oxygen saturation (SvO2, from 70.6 to 75.9%, P<0.05). Oxygen consumption (VO2) remained stable, but blood lactate levels decreased. There was a significant increase in the ascending slope of StO2 (from 111 to 177%/min, P<0.05) after VOTs. SDF imaging showed an increase in perfused vessel density (PVD, from 11.0 to 13.2 n/mm, P<0.05) and in microvascular flow index (MFI, from 2.4 to 2.9, P<0.05). CONCLUSIONS: In this series of patients with septic shock, increasing MAP above 65 mmHg with NE was associated with increased cardiac output, improved microvascular function, and decreased blood lactate concentrations. The microvascular response varied among patients suggesting that individualization of blood pressure targets may be warranted.

Microcirculatory alterations: potential mechanisms and implications for therapy.

Multiple experimental and human trials have shown that microcirculatory alterations are frequent in sepsis. In this review, we discuss the characteristics of these alterations, the various mechanisms potentially involved, and the implications for therapy. Sepsis-induced microvascular alterations are characterized by a decrease in capillary density with an increased number of stopped-flow and intermittent-flow capillaries, in close vicinity to well-perfused capillaries. Accordingly, the surface available for exchange is decreased but also is highly heterogeneous. Multiple mechanisms may contribute to these alterations, including endothelial dysfunction, impaired inter-cell communication, altered glycocalyx, adhesion and rolling of white blood cells and platelets, and altered red blood cell deformability. Given the heterogeneous nature of these alterations and the mechanisms potentially involved, classical hemodynamic interventions, such as fluids, red blood cell transfusions, vasopressors, and inotropic agents, have only a limited impact, and the microcirculatory changes often persist after resuscitation. Nevertheless, fluids seem to improve the microcirculation in the early phase of sepsis and dobutamine also can improve the microcirculation, although the magnitude of this effect varies considerably among patients. Finally, maintaining a sufficient perfusion pressure seems to positively influence the microcirculation; however, which mean arterial pressure levels should be targeted remains controversial. Some trials using vasodilating agents, especially nitroglycerin, showed promising initial results but they were challenged in other trials, so it is difficult to recommend the use of these agents in current practice. Other agents can markedly improve the microcirculation, including activated protein C and antithrombin, vitamin C, or steroids. In conclusion, microcirculatory alterations may play an important role in the development of sepsis-related organ dysfunction. At this stage, therapies to target microcirculation specifically are still being investigated.

Avaliação da microcirculação: uma nova arma no manejo da sepse? / Microcirculatory assessment: a new weapon in the treatment of sepsis?

A evolução para disfunção de múltiplos órgãos ainda é comum na sepse e está relacionada diretamente com a disfunção microcirculatória. Através de pesquisa nas bases de dados PubMed, empregando-se os unitermos microcirculação e sepse, vinte e seis artigos foram selecionados para esta revisão, bem como citações consideradas relevantes extraídas de artigos de revisão. Com o advento da técnica de imagem obtida através de polarização ortogonal, que permite a observação à beira do leito da microcirculação em pacientes críticos, é possível estabelecer uma relação entre disfunção microvascular e prognóstico, além de observar diretamente o efeito de diferentes intervenções terapêuticas. No entanto, a relação causal entre disfunção microcirculatória e prognóstico adverso na sepse, bem como os efeitos de terapias dirigidas para correção destas anormalidades microcirculatórias ainda precisam ser melhor definidos.

The progression into multi-organ failure continues to be a common feature of sepsis and is directly related to microcirculatory dysfunction. Based on a PubMed database search using the key words microcirculation and sepsis, twenty-six articles were selected for this review. The relevant references from these articles were also selected and included in this analysis. Orthogonal polarization spectral imaging allows for the bedside assessment of the microcirculation of critically ill patients. Such imaging has established a correlation between microvascular dysfunction and patient outcomes, which allows practitioners to directly assess the effects of therapeutic interventions. However, the causal relationships between microcirculatory dysfunction, adverse outcomes, and the effects of therapies aimed at these microcirculatory changes in sepsis, are not clear.

Sublingual microcirculatory effects of enalaprilat in an ovine model of septic shock.

Severe sepsis is frequently associated with microcirculatory abnormalities despite seemingly adequate hemodynamic resuscitation. As increased serum angiotensin II levels may play a role in this dysfunction, we evaluated the microcirculatory effects of enalaprilat in an experimental model of septic shock. One hour after injection of 1.5 g/kg body weight of feces into the abdominal cavity, 16 adult female anesthetized, mechanically ventilated sheep were randomized to receive 2.5 mg enalaprilat or saline. When fluid-resistant hypotension (mean arterial pressure, <65 mmHg) developed, norepinephrine was given up to a maximal dose of 3 µg·kg(-1)·min(-1). The sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy. A cutoff of 20 µm was used to differentiate small and large vessels. Experiments were pursued until the sheep's spontaneous death or for a maximum of 30 h. There were progressive and significant reductions in the proportion of small perfused vessels and in the microvascular flow index for small vessels (both P < 0.01 for trend) during shock and the first 2 h of norepinephrine infusion in the placebo group, which were prevented by the administration of enalaprilat. There were no differences between treated and placebo groups in global hemodynamic variables, time to shock or median survival time (21.8 [18.6-28.8] vs. 22.9 [21.8-30.0] h; P = 0.45). However, oxygen exchange was worse (PaO2/FiO2 ratio, 224 [128-297] vs. 332 [187-450]; P < 0.05), and creatinine concentrations increased more in the treated group (from 0.51 [0.42-0.75] to 1.19 [0.64-1.50] mg·dL(-1); P = 0.04) than in the control group (from 0.55 [0.45-0.62] to 0.78 [0.46-1.78] mg·dL(-1); P = 0.12), Enalaprilat therefore prevented the worsening of sublingual microcirculatory variables in this fluid-resuscitated, hyperdynamic model of septic shock, without significant effect on arterial pressure, but with a possible deleterious effect on renal and lung function.

Toward less sedation in the intensive care unit: a prospective observational study.

PURPOSE: Excessive sedation is associated with prolonged mechanical ventilation and longer intensive care unit (ICU) and hospital stays. We evaluated the feasibility of using minimal sedation in the ICU. METHODS: Prospective observational study in a university hospital 34-bed medico-surgical department of intensive care. All adult patients who stayed in the ICU for more than 12 hours over a 2-month period were included. Intensive care unit admission diagnoses, severity scores, use of sedatives and/or opiates, duration of mechanical ventilation, length of ICU stay, and 28-day mortality were recorded for each patient. RESULTS: Of the 335 patients (median age, 61 years) admitted during the study period, 142 (42%) received some sedation, most commonly with midazolam and propofol. Sedative agents were administered predominantly for short periods of time (only 10% of patients received sedation for >24 hours). One hundred fifty-five patients (46%) received mechanical ventilation, generating 15,240 hours of mechanical ventilation, of these, only 2993 (20%) hours were accompanied by a continuous sedative infusion. Self-extubation occurred in 6 patients, but only 1 needed reintubation. CONCLUSIONS: In a mixed medical-surgical ICU, minimal use of continuous sedation seems feasible without apparent adverse effects.

Microcirculatory assessment: a new weapon in the treatment of sepsis? / Avaliação da microcirculação: uma nova arma no manejo da sepse?

The progression into multi-organ failure continues to be a common feature of sepsis and is directly related to microcirculatory dysfunction. Based on a PubMed database search using the key words microcirculation and sepsis, twenty-six articles were selected for this review. The relevant references from these articles were also selected and included in this analysis. Orthogonal polarization spectral imaging allows for the bedside assessment of the microcirculation of critically ill patients. Such imaging has established a correlation between microvascular dysfunction and patient outcomes, which allows practitioners to directly assess the effects of therapeutic interventions. However, the causal relationships between microcirculatory dysfunction, adverse outcomes, and the effects of therapies aimed at these microcirculatory changes in sepsis, are not clear.

Monitoring the microcirculation in the critically ill patient: current methods and future approaches.

PURPOSE: To discuss the techniques currently available to evaluate the microcirculation in critically ill patients. In addition, the most clinically relevant microcirculatory alterations will be discussed. METHODS: Review of the literature on methods used to evaluate the microcirculation in humans and on microcirculatory alterations in critically ill patients. RESULTS: In experimental conditions, shock states have been shown to be associated with a decrease in perfused capillary density and an increase in the heterogeneity of microcirculatory perfusion, with non-perfused capillaries in close vicinity to perfused capillaries. Techniques used to evaluate the microcirculation in humans should take into account the heterogeneity of microvascular perfusion. Microvideoscopic techniques, such as orthogonal polarization spectral (OPS) and sidestream dark field (SDF) imaging, directly evaluate microvascular networks covered by a thin epithelium, such as the sublingual microcirculation. Laser Doppler and tissue O(2) measurements satisfactorily detect global decreases in tissue perfusion but not heterogeneity of microvascular perfusion. These techniques, and in particular laser Doppler and near-infrared spectroscopy, may help to evaluate the dynamic response of the microcirculation to a stress test. In patients with severe sepsis and septic shock, the microcirculation is characterized by a decrease in capillary density and in the proportion of perfused capillaries, together with a blunted response to a vascular occlusion test. CONCLUSIONS: The microcirculation in humans can be evaluated directly by videomicroscopy (OPS/SDF) or indirectly by vascular occlusion tests. Of note, direct videomicroscopic visualization evaluates the actual state of the microcirculation, whereas the vascular occlusion test evaluates microvascular reserve.

Microcirculatory abnormalities in patients with severe influenza A (H1N1) infection.

PURPOSE: This study was designed to evaluate the degree of microcirculatory abnormalities in patients with severe influenza A (H1N1) infection. METHODS: We assessed the sublingual microcirculation in seven consecutive patients with acute lung injury related to influenza A (H1N1) infection. The evaluation was carried out using sidestream dark field (SDF) imaging within the first 96 hr after the patients were admitted to the intensive care unit. Thenar oxygen saturation (StO(2)) was also measured with near-infrared spectroscopy (NIRS) during a vascular occlusion test. In addition, the Lung Injury Score (LIS) and the APACHE II and SOFA scores were recorded. RESULTS: All patients received invasive mechanical ventilation and at least one of the following adjuvant therapies: inhaled nitric oxide (n = 4), extracorporeal membrane oxygenation (n = 1), prone position (n = 4), recruitment maneuver (n = 3), and hydrocortisone 50 mg·hr(-6) (n = 6). The median time from admission to microcirculatory assessment was 21 hr. Three patients had bacterial superinfection. The median LIS and PaO(2)/F(i)O(2) were 2.5 (2.25-3.25) and 178 (158-212), respectively. Three subjects were treated with norepinephrine. During a vascular occlusion test, the microcirculation was moderately to severely compromised with a NIRS ascending slope of 2.39%·sec(-1) (1.75-2.67%·sec(-1)), 66% (60-86%) of perfused small vessels in the sublingual microcirculation, and a microvascular flow index of 1.9 (1.3-2.6). The degree of microcirculatory abnormalities detected by the NIRS and SDF imaging techniques was correlated with the severity of the disease, as reflected by the SOFA and APACHE II scores. CONCLUSIONS: The microcirculation as assessed by SDF imaging and NIRS techniques was compromised in patients with acute respiratory distress syndrome (ARDS) and influenza A (H1N1) infection.

Microcirculatory assessment in daily clinical practice - not yet ready but not too far! / Avaliação da microcirculação na prática clínica diária - ainda não disponível, mas não tão longe!

Shock is characterized by an alteration in tissue perfusion that may lead to tissue hypoxia. Recent guidelines recommend aggressive and early resuscitation therapy, but mortality rate is still unacceptably high. Unfortunately, traditional clinical surrogates used to guide resuscitation therapy poorly correlate with microcirculatory blood flow, a key determinant of tissue perfusion. New techniques that directly assess microcirculatory perfusion at the bedside have emerged as a complement to traditional macrohemodynamic parameters. These techniques have been supported by several studies showing microcirculatory alterations in different clinical settings. In addition, these microcirculatory alterations are related with outcome and persist regardless of arterial pressure normalization, being a better predictor of organ dysfunction and mortality than global hemodynamic and laboratory parameters. These findings allowed the concept of "microcirculatory-goal directed therapy", which is now in its preliminary phase, as the impact of many interventions still needs to be assessed. Finally, microcirculation assessment has also been explored in other medical s such as perioperative, systemic arterial hypertension, heart failure, and hyperviscosity syndromes. In this review, we shortly present the characteristics of microcirculation and the main determinants of capillary blood flow, and we discuss advantages and limitations of some recently available techniques to evaluate microcirculation at the bedside, and how they could be useful for the general clinician in daily practice.

O choque é caracterizado por uma alteração na perfusão tecidual que pode levar à hipóxia tecidual. Diretrizes recentes recomendam uma terapia de ressuscitação hemodinâmica precoce e agressiva nos estados de choque, mas a taxa de mortalidade ainda é inaceitavelmente alta. Os parâmetros clínicos habituais usados para orientar a terapia de reanimação correlacionam-se mal com o fluxo sanguíneo capilar, um determinante essencial da perfusão tecidual. Novas técnicas que avaliam diretamente a perfusão da microcirculação à beira do leito surgem como um complemento aos parâmetros macro-hemodinâmicos tradicionais. Estas técnicas foram testadas em vários estudos que mostraram alterações microcirculatórias em diferentes situações clínicas de choque. Além disso, estas alterações microcirculatórias estão relacionadas ao prognóstico, e persistem independentemente da normalização da pressão arterial, sendo um melhor preditor de disfunção orgânica e mortalidade do que os parâmetros hemodinâmicos globais e laboratoriais. Estes achados permitiram lançar o conceito de "terapia dirigida por parâmetros microcirculatórios", atualmente em fase preliminar, uma vez que o impacto de muitas intervenções ainda precisa ser avaliado. Finalmente, a avaliação da microcirculação também foi explorada em outras áreas que não o choque, como o período perioperatório, hipertensão arterial sistêmica, insuficiência cardíaca e síndromes de hiperviscosidade. Nesta revisão, apresentamos sucintamente as características da microcirculação e os principais determinantes do fluxo sanguíneo capilar e discutimos as vantagens e limitações de algumas tecnologias recentes disponíveis para avaliar a microcirculação à beira do leito e como podem ser úteis ao clínico geral na prática diária.

Coupling microcirculation to systemic hemodynamics.

PURPOSE OF REVIEW: To discuss the role of microcirculatory abnormalities in critically ill patients and the link between systemic hemodynamics and microvascular perfusion. RECENT FINDINGS: Microcirculatory alterations have been repeatedly observed in patients with severe sepsis, but recent findings show that these also occur in patients with severe heart failure and in those submitted to high-risk surgery. More severe and more persistent alterations are observed in patients with a poor outcome. Even though a minimal cardiac output and arterial pressure is mandatory to sustain the microcirculation, this level is not yet well defined and seems to be submitted to high individual variability. Above this level, microcirculation and systemic circulation are relatively dissociated, so that microcirculatory alterations can be observed even when systemic hemodynamics are within satisfactory goals. In addition, the response of the microcirculation to therapeutic interventions is often dissociated from systemic effects. However, microcirculatory perfusion can be affected by cardiac output and arterial pressure when these are critically altered. SUMMARY: Microvascular alterations frequently occur in critically ill patients and these may be implicated in the development of organ failure and are associated with outcome. The link between systemic hemodynamics and microcirculation is relatively loose.