Diamantino Salgado

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

PurposeTo discuss the techniques currently available to evaluate the microcirculation in critically ill patients. In addition, the most clinically relevant microcirculatory alterations will be discussed.MethodsReview of the literature on methods used to evaluate the microcirculation in humans and on microcirculatory alterations in critically ill patients.ResultsIn 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 O2 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.ConclusionsThe 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 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.m2, 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 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.

Coupling microcirculation to systemic hemodynamics

Purpose of reviewTo discuss the role of microcirculatory abnormalities in critically ill patients and the link between systemic hemodynamics and microvascular perfusion. Recent findingsMicrocirculatory 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. SummaryMicrovascular 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.

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

IntroductionSeptic 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.MethodsThis 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.ResultsIncreasing 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).ConclusionsIn 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.

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 20mg/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.

Modulation of the renin–angiotensin–aldosterone system in sepsis: a new therapeutic approach?

Importance of the field: Severe sepsis is characterized by relative hypotension associated with a high cardiac output, peripheral vasodilation, and organ dysfunction. The renin–angiotensin–aldosterone system (RAAS) is primarily activated to increase blood pressure, but recently potential pro-inflammatory effects of angiotensin II have attracted interest because of the reported association between angiotensin II levels and organ failure and mortality in sepsis. RAAS antagonists could represent a new therapeutic option in this setting. Areas covered in this review: The role of RAAS activation in severe sepsis and septic shock, and the potential benefits (and risks) of using RAAS antagonists. What the reader will gain: Insight into RAAS function in severe sepsis and the potential for RAAS inhibitors to be used as an adjunctive therapy in patients with severe sepsis, with discussion of promising results from animal models of sepsis. Take home message: Use of RAAS antagonists is an emerging therapeutic option in severe sepsis because these agents may reduce endothelial damage, organ failure, and mortality. However, timing of administration of RAAS antagonists is important because reduced RAAS function may contribute to refractive hypotension later on in septic shock and benefits of RAAS antagonists seem to be restricted to the early phases of sepsis.

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.

Adrenal function testing in patients with septic shock

IntroductionAdrenal failure (AF) is associated with increased mortality in septic patients. Nonetheless, there is no agreement regarding the best diagnostic criteria for AF. We compared the diagnosis of AF considering different baseline total cortisol cutoff values and Δmax values after low (1 μg) and high (249 μg) doses of corticotropin, we analyzed the impact of serum albumin on AF identification and we correlated laboratorial AF with norepinephrine removal.MethodsA prospective noninterventional study was performed in an intensive care unit from May 2002 to May 2005, including septic shock patients over 18 years old without previous steroid usage. After measurement of serum albumin and baseline total cortisol, the patients were sequentially submitted to 1 μg and 249 μg corticotropin tests with a 60-minute interval between doses. Post-stimuli cortisol levels were drawn 60 minutes after each test (cortisol 60 and cortisol 120). The cortisol 60 and cortisol 120 values minus baseline were called Δmax1 and Δmax249, respectively. Adrenal failure was defined as Δmax249 ≤ 9 μg/dl or baseline cortisol ≤ 10 μg/dl. Other baseline cortisol cutoff values referred to as AF in other studies (≤15, ≤20, ≤25 and ≤34 μg/dl) were compared with Δmax249 ≤ 9 μg/dl and serum albumin influence. Norepinephrine removal was compared with the baseline cortisol values and Δmax249 values.ResultsWe enrolled 102 patients (43 male). AF was diagnosed in 22.5% (23/102). Patients with albumin ≤2.5 g/dl presented a lower baseline total cortisol level (15.5 μg/dl vs 22.4 μg/dl, P = 0.04) and a higher frequency of baseline cortisol ≤25 μg/dl (84% vs 58.3%, P = 0.05) than those with albumin > 2.5 g/dl. The Δmax249 levels and Δmax249 ≤ 9, however, were not affected by serum albumin (14.5 μg/dl vs 18.8 μg/dl, P = 0.48 and 24% vs 25%, P = 1.0). Baseline cortisol ≤ 23.6 μg/dl was the most accurate diagnostic threshold to determine norepinephrine removal according to the receiver operating characteristic curve.ConclusionAF was identified in 22.5% of the studied population. Since Δmax249 ≤ 9 μg/dl results were not affected by serum albumin and since the baseline serum total cortisol varied directly with albumin levels, we propose that Δmax249 ≤ 9 μg/dl, which means Δmax after high corticotropin dose may be a better option for AF diagnosis whenever measurement of free cortisol is not available. Baseline cortisol ≤23.6 μg/dl was the best value for predicting norepinephrine removal in patients without corticosteroid treatment.

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 &mgr;g·kg−1·min−1. The sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy. A cutoff of 20 &mgr;m was used to differentiate small and large vessels. Experiments were pursued until the sheeps 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.