Diego Orbegozo Cortes

Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock

Multiple experimental and human trials have shown that microcirculatory alterations are frequent in sepsis. In this review, we discuss the various mechanisms that are potentially involved in their development and the implications of these alterations. Endothelial dysfunction, impaired inter-cell communication, altered glycocalyx, adhesion and rolling of white blood cells and platelets, and altered red blood cell deformability are the main mechanisms involved in the development of these alterations. Microcirculatory alterations increase the diffusion distance for oxygen and, due to the heterogeneity of microcirculatory perfusion in sepsis, may promote development of areas of tissue hypoxia in close vicinity to well-oxygenated zones. The severity of microvascular alterations is associated with organ dysfunction and mortality. At this stage, therapies to specifically target the microcirculation are still being investigated.

Monitoring the microcirculation

One of the main goals of hemodynamic support is to preserve tissue perfusion. However issue perfusion is related more to microvascular perfusion than aortic blood flow. Monitoring the microcirculation has long been difficult. Recent technologic advances have made feasible monitoring of the microcirculation at bedside of critically ill patients. In this review, we will discuss the relevance of the various tools available to monitor the microcirculation. Videomicroscopic devices such as sidestream darkfield imaging are the most appropriate techniques to evaluate the microcirculation, taking into account the heterogeneous aspect of diseased microcirculation, as in sepsis. The microcirculation can also be indirectly assessed by measuring tissue PCO2. Transcutaneous PCO2 measurement at ear lobe is particularly promising. Finally, near infrared spectroscopy can also provide interesting information, especially using vascular occlusion tests which reactivity of the microcirculation to a transient hypoxic insult. These different devices have provided important data helping us to better understand the pathophysiology of sepsis and multiple organ failure.

Soluble urokinase-type plasminogen activator receptor as a prognostic biomarker in critically ill patients.

PURPOSE The aim of this study was to assess the role of blood soluble urokinase-type plasminogen activator receptor (suPAR) levels in the diagnosis and prognostication of sepsis in critically ill patients. METHODS Serum suPAR levels were measured prospectively in adult intensive care unit (ICU) patients on admission and then daily until ICU discharge (maximum of 14 days) using an enzyme-linked immunosorbent assay kit. Normal levels were established in 31 healthy controls. RESULTS We included 258 patients (161 men); median admission Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 17 (9-23) and 6 (3-9), respectively. The mortality rate was 13.6%. Sepsis was diagnosed on admission in 94 patients (36%), of whom 23 had severe sepsis and 49 had septic shock. On admission, septic patients had higher suPAR levels than did nonseptic patients (8.9 [5.9-12.7] vs 3.7 [2.7-5.4] ng/mL), but the predictive value of suPAR for diagnosing sepsis was weaker than that of C-reactive protein. During the week after ICU admission, serum suPAR concentrations correlated with Sequential Organ Failure Assessment scores over time. High suPAR levels on admission were a strong independent predictor for ICU and 28-day mortality. In the global population, a suPAR level higher than 6.15 ng/mL had 66% sensitivity and 64% specificity for prediction of ICU mortality, with a receiver operating characteristic area under the curve of 0.726 (95% confidence interval, 0.645-0.808). CONCLUSIONS In ICU patients, serum suPAR concentrations have limited use for identifying sepsis, but their time course correlated with the degree of organ dysfunction, and they have prognostic value in septic and nonseptic populations.

Normobaric hyperoxia alters the microcirculation in healthy volunteers

The use of high concentrations of inhaled oxygen has been associated with adverse effects but recent data suggest a potential therapeutic role of normobaric hyperoxia (NH) in sepsis and cerebral ischemia. Hyperoxia may induce vasoconstriction and alter endothelial function, so we evaluated its effects on the microcirculation in 40 healthy adult volunteers using side-stream dark field (SDF) video-microscopy on the sublingual area and near-infrared spectroscopy (NIRS) on the thenar eminence. In a first group of volunteers (n=18), measurements were taken every 30 min: at baseline in air, during NH (close to 100% oxygen via a non-rebreathing mask) and during recovery in air. In a second group (n=22), NIRS measurements were taken in NH or ambient air on two separate days to prevent any potential influence of repeated NIRS measurements. NH significantly decreased the proportion of perfused vessels (PPV) from 92% to 66%, perfused vessel density (PVD) from 11.0 to 7.3 vessels/mm, perfused small vessel density (PSVD) from 9.0 to 5.8 vessels/mm and microvascular flow index (MFI) from 2.8 to 2.0, and increased PPV heterogeneity from 7.5% to 30.4%. Thirty minutes after return to air, PPV, PVD, PSVD and MFI remained partially altered. During NH, NIRS descending slope and NIRS muscle oxygen consumption (VO2) decreased from 8.5 to 7.9%/s and 127 to 103 units, respectively, in the first group and from 10.7 to 9.4%/s and 150 to 115 units in the second group. NH, therefore, alters the microcirculation in healthy subjects, decreasing capillary perfusion and VO2 and increasing the heterogeneity of the perfusion.

Crystalloids versus colloids: exploring differences in fluid requirements by systematic review and meta-regression.

BACKGROUND:Positive fluid balance has been associated with worse outcomes, and knowledge of differences in the amounts of different types of fluid needed to achieve the same end points may have important clinical implications. Large molecules persist longer in the blood vessels than smaller molecules, such that less IV colloid may be needed to achieve similar hemodynamic end points compared with crystalloid. Recent clinical data have, however, challenged this physiological concept, with investigators reporting lower-than-expected crystalloid/colloid ratios in various populations. METHODS:We performed a systematic search in MEDLINE, EMBASE, and CENTRAL up to December 18, 2013, to retrieve all studies comparing (any) crystalloid with (any) colloid in all types of patients. The crystalloid/colloid ratio was calculated for each study. Descriptive analysis was performed for all studies, and a meta-analysis was performed in those studies reporting full data (in terms of means and standard deviations) of infused fluid volumes. Studies were grouped according to study and population characteristics. A meta-regression analysis was then performed to evaluate some of the possible reasons for differences in crystalloid/colloid ratios across studies. RESULTS:From 976 studies, 48 were retained for the final analysis; 24 of the studies had sufficient data for meta-analysis. The crystalloid/colloid ratio across all the studies included in the meta-analysis was 1.5 (95% confidence interval, 1.36–1.65) with marked heterogeneity among studies (I2 = 94%). From the meta-regression analysis, decade of publication across all publications (P = 0.001) and concentration (tonicity) in the subgroup of albumin studies (P = 0.001) were associated with the administered crystalloid/colloid ratio. The reduction in heterogeneity among studies for all publications in the meta-regression was minimal, with the maximal decrease obtained when decade of publication was considered (R2 = 12%). CONCLUSIONS:Greater fluid volumes are required to meet the same targets with crystalloids than with colloids, with an estimated ratio of 1.5 (1.36–1.65), but there is marked heterogeneity among studies. The crystalloid/colloid ratio seems to have decreased over the years, and differences in ratios are correlated with the concentration of albumin solutions; however, the main reasons behind the high heterogeneity among studies remain unclear.

Near infrared spectroscopy (NIRS) to assess the effects of local ischemic preconditioning in the muscle of healthy volunteers and critically ill patients

Near-infrared spectroscopy (NIRS) permits non-invasive evaluation of tissue oxygen saturation (StO2). A vascular occlusion test (VOT) produces transient controlled ischemia similar to that used in ischemic preconditioning. We hypothesized that we could evaluate local responses to ischemic preconditioning by performing repeated VOTs and observing the changes in different NIRS VOT-derived variables. In healthy volunteers (n=20), four VOTs were performed at 30-min intervals on one day and, in a second group (n=21), two VOTs with time intervals of 5, 15 or 30min were performed on 3 separate days. Two cohorts of patients, one with circulatory shock (n=23) and a hemodynamically stable group (n=20), were also studied, repeating the VOT twice with a 5-min interval. In the 1-day volunteers, there was a median decrease of 15 (6-21)% in the Desc slope (StO2 decrease during VOT) after the second VOT, but no significant change in the Asc slope (StO2 increase after VOT). In the 3-day volunteers, the Desc slope also decreased, regardless of the time interval between VOTs. There was no overall decrease in the Desc slope in either patient cohort with repeated VOTs but there was marked individual patient variability. Patients in whom the Desc slope decreased had less organ dysfunction at admission, required less norepinephrine (0.00 vs 0.08mcg/kg/min, p=0.02), less frequently had sepsis (12 vs 50%, p=0.02) and had a lower mortality (6 vs 39%, p=0.03) compared to those in whom it did not decrease. Repeated NIRS VOT can non-invasively assess the local effects of ischemic preconditioning in the muscle.

Characteristics of fluids used for intravascular volume replacement

In this review, the relative merits of the different fluid solutions used for fluid replacement will be discussed. Differences in chemical composition may have important implications on volume expansion capacities but also on organ function. Among crystalloids, differences in electrolyte composition, and in particular chloride load, alter acid base status but may also affect other aspects of organ function. Large observational cohorts suggest that chloride load may be associated with a poor outcome. Colloids provide greater expansion capacities than crystalloids. When colloids are indicated, albumin should be preferred as it is the only one that has been proved to be safe in a large randomized trial. Cumulative evidence suggests that starches, even of the new generations, are associated with development of acute kidney injury. Hypertonic solutions may represent an interesting option in some groups of patients but more research is needed in this field.

ISCHEMIC CONDITIONING PROTECTS THE MICROCIRCULATION, PRESERVES ORGAN FUNCTION, AND PROLONGS SURVIVAL IN SEPSIS.

ABSTRACT Ischemic conditioning induces a series of cellular modifications that may prevent injury from further hypoxic episodes, but there are few data in sepsis. In this randomized controlled study, we evaluated the effects of ischemic conditioning on the microcirculation, organ function, and survival time in an ovine model of septic shock. Sepsis was induced in 14 anesthetized, mechanically ventilated adult sheep by injecting autologous feces into the abdominal cavity. Animals were then randomized to ischemic pre- and post-conditioning or no conditioning (both n = 7). Remote ischemic conditioning was performed by inflating the balloon of a catheter in the aortic bifurcation for 2 min, followed by a 4-min deflation period. The procedure was performed four times before sepsis induction and 4-hourly afterward. Animals were followed until death or for a maximum of 30 h. Hemodynamic, oxygenation, and microcirculatory variables were monitored. The conditioned group had higher mixed venous oxygen saturation from 8 h after randomization, higher cardiac index, and oxygen delivery from 16 h, and higher mean arterial pressure and lower lactate levels from 20 h. They also had greater renal blood flow, urine output, and creatinine clearance. Microcirculatory variables were better preserved in the conditioned than in the control group from 6 h after randomization: the median proportion of perfused vessels was 91 (89–93)% versus 89 (86–90)% (P = 0.024) and there was less heterogeneity. Oliguria, hypotension, and death occurred later in the conditioned than in the control group. In this sepsis model, remote ischemic pre- and post-conditioning therefore decreased organ dysfunction, preserved the microcirculation, and prolonged survival.

Carbon dioxide management after cardiac arrest: Quite a complex issue

We read with interest the article by Schneider et al.,1 which valuated the impact of arterial carbon dioxide (PaCO2) on neuological outcome in patients resuscitated after cardiac arrest CA). The main finding of this study was that more patients ere discharged home among those defined as “hypercapnic” PaCO2 > 45 mmHg) than among those who were normocapnic r hypocapnic (PaCO2 < 35 mmHg), after adjustment for several onfounders. Although we agree that hypocapnia can promote neuonal injury and should not be routinely used, except for the acute anagement of impending herniation,2 some important issues eed to be discussed. First, the authors classified patients into three categories on the asis of the PaCO2 values obtained from the arterial blood gas (ABG) nalysis associated with the worst oxygenation, which was used to alculate the APACHE II score on admission. The use of a single aCO2 value may not reliably estimate the exposure of a patient o low or high carbon dioxide levels. Indeed, when the correlation etween PaCO2 measurements of all ABGs available for a nested ohort of 570 patients and classification into different PaCO2 groups as considered, only 55% of samples were correctly associated with he initial sub-group. Moreover, most “hypercapnic” values were ecorded during the first hours after hospital admission and PaCO2 eturned to normal ranges thereafter, suggesting that this event as transient. Although the effects of even short exposure to low aCO2 after anoxic injury need to be better studied, a weighted verage of all PaCO2 values within the first 24 or 48 h of ICU stay ay have been a better reflection of the potential effects of carbon ioxide on brain function after CA. Second, nearly 40% of the patients were treated with therapeutic ypothermia (TH). In these conditions, blood pH increases, whereas aCO2 and PaO2 progressively decrease.3 Thus, if ABGs were conidered as having been measured at 37 ◦C and not corrected for core emperature, the occurrence of hypocapnia may have been signifcantly underestimated in most patients. Indeed, carbon dioxide evels should be corrected for patient temperature to avoid inapropriate estimation of brain exposure to different PaCO2 levels.4 Finally, the mechanisms underlying the potential neuroprotecive effects of hypercapnia in post-anoxic injury should be further tudied, essentially in terms of brain perfusion. In this setting,

Short-Acting β-Blocker Administration in Patients With Septic Shock

The study by Dr Morelli and colleagues1 evaluated the effect of short-acting β-blocker (esmolol) administration in patients with septic shock; however, we have some problems with their interpretation of the results. First, stroke volume and left ventricular stroke work index (without any difference in arterial pressure) moved in parallel in the 2 groups. Analysis of the area under the curve (AUC) is frequently used in studies of drug pharmacokinetics, but in this case, a simple visual exploration (Figure 3 in article) does not support the reported differences because the baseline values were quite different.