Maximiliano Rovegno

Severe abnormalities in microvascular perfused vessel density are associated to organ dysfunctions and mortality and can be predicted by hyperlactatemia and norepinephrine requirements in septic shock patients

PURPOSE The aims of this study are to determine the general relationship of perfused vessel density (PVD) to mortality and organ dysfunctions and to explore if patients in the lowest quartile of distribution for this parameter present a higher risk of bad outcome and to identify systemic hemodynamic and perfusion variables that enhances the probability of finding a severe underlying microvascular dysfunction. MATERIALS AND METHODS This is a retrospective multicenter study including 122 septic shock patients participating in 7 prospective clinical trials on which at least 1 sublingual microcirculatory assessment was performed during early resuscitation. RESULTS Perfused vessel density was significantly related to organ dysfunctions and mortality, but this effect was largely explained by patients in the lowest quartile of distribution for PVD (P = .037 [odds ratio {OR}, 8.7; 95% confidence interval {CI}, 1.14-66.78] for mortality). Hyperlactatemia (P < .026 [OR, 1.23; 95% CI, 1.03-1.47]) and high norepinephrine requirements (P < .019 [OR, 7.04; 95% CI, 1.38-35.89]) increased the odds of finding a severe microvascular dysfunction. CONCLUSIONS Perfused vessel density is significantly related to organ dysfunctions and mortality in septic shock patients, particularly in patients exhibiting more severe abnormalities as represented by the lowest quartile of distribution for this parameter. The presence of hyperlactatemia and high norepinephrine requirements increases the odds of finding a severe underlying microvascular dysfunction during a sublingual microcirculatory assessment.

Impact of emergency intubation on central venous oxygen saturation in critically ill patients: a multicenter observational study

IntroductionCentral venous oxygen saturation (ScvO2) has emerged as an important resuscitation goal for critically ill patients. Nevertheless, growing concerns about its limitations as a perfusion parameter have been expressed recently, including the uncommon finding of low ScvO2 values in patients in the intensive care unit (ICU). Emergency intubation may induce strong and eventually divergent effects on the physiologic determinants of oxygen transport (DO2) and oxygen consumption (VO2) and, thus, on ScvO2. Therefore, we conducted a study to determine the impact of emergency intubation on ScvO2.MethodsIn this prospective multicenter observational study, we included 103 septic and non-septic patients with a central venous catheter in place and in whom emergency intubation was required. A common intubation protocol was used and we evaluated several parameters including ScvO2 before and 15 minutes after emergency intubation. Statistical analysis included chi-square test and t test.ResultsScvO2 increased from 61.8 ± 12.6% to 68.9 ± 12.2%, with no difference between septic and non-septic patients. ScvO2 increased in 84 patients (81.6%) without correlation to changes in arterial oxygen saturation (SaO2). Seventy eight (75.7%) patients were intubated with ScvO2 less than 70% and 21 (26.9%) normalized the parameter after the intervention. Only patients with pre-intubation ScvO2 more than 70% failed to increase the parameter after intubation.ConclusionsScvO2 increases significantly in response to emergency intubation in the majority of septic and non-septic patients. When interpreting ScvO2 during early resuscitation, it is crucial to consider whether the patient has been recently intubated or is spontaneously breathing.

Evolution of peripheral vs metabolic perfusion parameters during septic shock resuscitation. A clinical-physiologic study

PURPOSE Perfusion assessment during septic shock resuscitation is difficult and usually complex determinations. Capillary refill time (CRT) and central-to-toe temperature difference (Tc-toe) have been proposed as objective reproducible parameters to evaluate peripheral perfusion. The comparative evolution of peripheral vs metabolic perfusion parameters in septic shock resuscitation has not been studied. We conducted a prospective observational clinical-physiologic study to address this subject. METHODS Patients with sepsis-related circulatory dysfunction were resuscitated according to a standard local algorithm. Perfusion assessment included serial determinations of metabolic (central venous O(2) saturation [Scvo(2)] and central venous to arterial Pco(2) gradient [P(cv-a)co(2)]) and peripheral perfusion parameters (CRT and Tc-toe, among others). Successful resuscitation was defined as a normal plasma lactate at 24 hours. RESULTS Forty-one patients were included. The presence of normal values for both CRT and Tc-toe considered together at 6 hours was independently associated with a successful resuscitation (P = .02), as compared with the behavior of metabolic parameters. Capillary refill time was the first parameter to be significantly normalized. CONCLUSION Early recovery of peripheral perfusion anticipates a successful resuscitation compared with traditional metabolic parameters in septic shock patients. Our findings support the inclusion of serial peripheral perfusion assessment in multimodal monitoring strategies for septic shock resuscitation.

Persistent Sepsis-Induced Hypotension without Hyperlactatemia: A Distinct Clinical and Physiological Profile within the Spectrum of Septic Shock

Introduction. A subgroup of septic shock patients will never develop hyperlactatemia despite being subjected to a massive circulatory stress. Maintenance of normal lactate levels during septic shock is of great clinical and physiological interest. Our aim was to describe the clinical, hemodynamic, perfusion, and microcirculatory profiles associated to the absence of hyperlactatemia during septic shock resuscitation. Methods. We conducted an observational study in septic shock patients undergoing resuscitation. Serial clinical, hemodynamic, and perfusion parameters were registered. A single sublingual microcirculatory assessment was performed in a subgroup. Patients evolving with versus without hyperlactatemia were compared. Results. 124 septic shock patients were included. Patients without hyperlactatemia exhibited lower severity scores and mortality. They also presented higher platelet counts and required less intensive treatment. Microcirculation was assessed in 45 patients. Patients without hyperlactatemia presented higher PPV and MFI values. Lactate was correlated to several microcirculatory parameters. No difference in systemic flow parameters was observed. Conclusion. Persistent sepsis-induced hypotension without hyperlactatemia is associated with less organ dysfunctions and a very low mortality risk. Patients without hyperlactatemia exhibit less coagulation and microcirculatory derangements despite comparable macrohemodynamics. Our study supports the notion that persistent sepsis-induced hypotension without hyperlactatemia exhibits a distinctive clinical and physiological profile.

Relationship of systemic, hepatosplanchnic, and microcirculatory perfusion parameters with 6-hour lactate clearance in hyperdynamic septic shock patients: an acute, clinical-physiological, pilot study

BackgroundRecent clinical studies have confirmed the strong prognostic value of persistent hyperlactatemia and delayed lactate clearance in septic shock. Several potential hypoxic and nonhypoxic mechanisms have been associated with persistent hyperlactatemia, but the relative contribution of these factors has not been specifically addressed in comprehensive clinical physiological studies. Our goal was to determine potential hemodynamic and perfusion-related parameters associated with 6-hour lactate clearance in a cohort of hyperdynamic, hyperlactatemic, septic shock patients.MethodsWe conducted an acute clinical physiological pilot study that included 15 hyperdynamic, septic shock patients undergoing aggressive early resuscitation. Several hemodynamic and perfusion-related parameters were measured immediately after preload optimization and 6 hours thereafter, with 6-hour lactate clearance as the main outcome criterion. Evaluated parameters included cardiac index, mixed venous oxygen saturation, capillary refill time and central-to-peripheral temperature difference, thenar tissue oxygen saturation (StO2) and its recovery slope after a vascular occlusion test, sublingual microcirculatory assessment, gastric tonometry (pCO2 gap), and plasma disappearance rate of indocyanine green (ICG-PDR). Statistical analysis included Wilcoxon and Mann–Whitney tests.ResultsFive patients presented a 6-hour lactate clearance <10%. Compared with 10 patients with a 6-hour lactate clearance ≥10%, they presented a worse hepatosplanchnic perfusion as represented by significantly more severe derangements of ICG-PDR (9.7 (8–19) vs. 19.6 (9–32)%/min, p < 0.05) and pCO2 gap (33 (9.1-62) vs. 7.7 (3–58) mmHg, p < 0.05) at 6 hours. No other systemic, hemodynamic, metabolic, peripheral, or microcirculatory parameters differentiated these subgroups. We also found a significant correlation between ICG-PDR and pCO2 gap (p = 0.02).ConclusionsImpaired 6-hour lactate clearance could be associated with hepatosplanchnic hypoperfusion in some hyperdynamic septic shock patients. Improvement of systemic, metabolic, and peripheral perfusion parameters does not rule out the persistence of hepatosplanchnic hypoperfusion in this setting. Severe microcirculatory abnormalities can be detected in hyperdynamic septic shock patients, but their role on lactate clearance is unclear. ICG-PDR may be a useful tool to evaluate hepatosplanchnic perfusion in septic shock patients with persistent hyperlactatemia.Trial registrationClinicalTrials.gov Identifier: NCT01271153

Mecanismos biológicos involucrados en la propagación del daño en el traumatismo encéfalo craneano

Traumatic brain injury (TBI) is a worldwide health problem that is especially prevalent in young adults. It is characterized by one or more primary injury foci, with secondary spread to initially not compromised areas via cascades of inflammatory response, excitotoxicity, energy failure conditions, and amplification of the original tissue injury by glia. In theory, such progression of injury should be amenable to management. However, all neuroprotective drug trials have failed, and specific treatments remain lacking. These negative results can be explained by a neuron centered approach, excluding the participation of other cell types and pathogenic mechanisms. To change this situation, it is necessary to secure a better understanding of the biological mechanisms determining damage progression or spread. We discuss the biological mechanisms involved in the progression of post-trauma tissue damage, including the general physiopathology of TBI and cellular mechanisms of secondary damage such as inflammation, apoptosis, cell tumefaction, excitotoxicity, and the role of glia in damage propagation. We highlight the role of glia in each cellular mechanism discussed. Therapeutic approaches related to the described mechanisms have been included. The discussion is completed with a working model showing the convergence of the main topics.

Connexin43 hemichannels mediate secondary cellular damage spread from the trauma zone to distal zones in astrocyte monolayers.

The mechanism of secondary damage spread after brain trauma remains unsolved. In this work, we redirected the attention to astrocytic communication pathways. Using an in vitro trauma model that consists of a scratch injury applied to an astrocyte monolayer, we found a significant and transient induction of connexin43 (Cx43) hemichannel activity in regions distal from the injury, which was maximal ∼1 h after scratch. Two connexin hemichannel blockers, La3+ and the peptide Gap26, abolished the increased activity, which was also absent in Cx43 KO astrocytes. In addition, the scratch‐induced increase of hemichannel activity was prevented by inhibition of P2 purinergic receptors. Changes in hemichannel activity took place with a particular spatial distribution, with cells located at ∼17 mm away from the scratch presenting the highest activity (dye uptake). In contrast, the functional state of gap junction channels (dye coupling) was not significantly affected. Cx43 hemichannel activity was also enhanced by the acute extracellular application of 60 mM K+. The increase in hemichannel activity was associated with an increment in apoptotic cells at 24 h after scratch that was totally prevented by Gap26 peptide. These findings suggest that Cx43 hemichannels could be a new approach to prevent or reduce the secondary cell damage of brain trauma. GLIA 2015;63:1185–1199

Age-related NMDA signaling alterations in SOD2 deficient mice

Oxidative stress affects the survival and function of neurons. Hence, they have a complex and highly regulated machinery to handle oxidative changes. The dysregulation of this antioxidant machinery is associated with a wide range of neurodegenerative conditions. Therefore, we evaluated signaling alterations, synaptic properties and behavioral performance in 2 and 6-month-old heterozygous manganese superoxide dismutase knockout mice (SOD2+/- mice). We found that their low antioxidant capacity generated direct oxidative damage in proteins, lipids, and DNA. However, only 6-month-old heterozygous knockout mice presented behavioral impairments. On the other hand, synaptic plasticity, synaptic strength and NMDA receptor (NMDAR) dependent postsynaptic potentials were decreased in an age-dependent manner. We also analyzed the phosphorylation state of the NMDAR subunit GluN2B. We found that while the levels of GluN2B phosphorylated on tyrosine 1472 (synaptic form) remain unchanged, we detected increased levels of GluN2B phosphorylated on tyrosine 1336 (extrasynaptic form), establishing alterations in the synaptic/extrasynaptic ratio of GluN2B. Additionally, we found increased levels of two phosphatases associated with dephosphorylation of p-1472: striatal-enriched protein tyrosine phosphatase (STEP) and phosphatase and tensin homolog deleted on chromosome Ten (PTEN). Moreover, we found decreased levels of p-CREB, a master transcription factor activated by synaptic stimulation. In summary, we describe mechanisms by which glutamatergic synapses are altered under oxidative stress conditions. Our results uncovered new putative therapeutic targets for conditions where NMDAR downstream signaling is altered. This work also contributes to our understanding of processes such as synapse formation, learning, and memory in neuropathological conditions.

Hipotermia intravascular prolongada en un paciente con hipertensión endocraneana refractaria

The use of hypothermia after cardiac arrest caused by ventricular fibrillation is a standard clinical practice, however its use for neuroprotection has been extended to other conditions. We report a 23-year-old male with intracranial hypertension secondary to a parenchymal hematoma associated to acute hydrocephalus. An arterial malformation was found and embolized. Due to persistent intracranial hypertension, moderate hypothermia with a target temperature of 33°C was started. After 12 hours of hypothermia, intracranial pressure was controlled. After 13 days of hypothermia a definitive control of intracranial pressure was achieved. The patient was discharged 40 days after admission, remains with a mild hemiparesia and is reassuming his university studies.