Bernardo Bollen Pinto

Effects of balanced crystalloid vs. 0.9% saline-based vs. balanced 6% tetrastarch infusion on renal function and tubular integrity in ovine endotoxemic shock

Objective:Conflicting data exist on the renal effects of hydroxyethyl starch preparations. The aim of the present study was to evaluate the impact of balanced crystalloids, as well as 0.9% saline-based and balanced 6% tetrastarch solutions, on renal function and ultrastructural morphologic correlates of acute kidney injury in an established model of ovine endotoxemic shock. Design:Randomized, controlled, experimental study. Setting:Animal research facility of a university hospital. Subjects:A total of 31 awake instrumented sheep. Interventions:The animals were subjected to continuous endotoxin infusion (Salmonella typhosa) at incremental doses until the mean arterial pressure was <65 mm Hg and arterial lactate was ≥2 mmol·L−1 or (if arterial hypotension was absent) arterial lactate was ≥4 mmol·L−1. The subjects were then randomized to receive no fluid resuscitation (control group, n = 5) or blinded infusion of a balanced crystalloid (n = 9), 0.9% saline-based (n = 8), or balanced 6% hydroxyethyl starch 130/0.4 (n = 9) up to a maximum dose of 50 mL·kg−1, followed by open-label infusion of balanced crystalloid. Animals surviving the 12-hr intervention period were deeply anesthetized and killed. Kidney samples were taken immediately for transmission electron microscopic analyses. Additional specific experiments were performed to take kidney samples ex vivo. Measurements and Main Results:Endotoxemia was associated with arterial hypotension and capillary leakage. Fluid resuscitation established a hypotensive-hyperdynamic circulation in all resuscitated animals without significant hemodynamic differences among groups. Plasma creatinine and urea concentrations were higher in both hydroxyethyl starch groups as compared to the crystalloid group (creatinine, 1.2 ± 0.1 and 1.4 ± 0.3 vs. 0.8 ± 0.1 mg·dL−1; urea, 21 ± 1 and 21 ± 2 vs. 17 ± 2 mg·dL−1; p < .05 for 0.9% saline-based and balanced tetrastarch vs. crystalloids at 8 hrs). In contrast, kidney function, as measured by creatinine clearance and cumulative creatinine excretion, was similar between the colloid and crystalloid treatment groups (creatinine clearance at 8 hrs, 122 ± 18 and 108 ± 31 vs. 107 ± 13 mL·min−1·m−2; creatinine excretion per hour alive, 283 ± 29 and 264 ± 19 vs. 291 ± 24 mg·hr−1; p > .05 for 0.9% saline-based and balanced tetrastarch vs. crystalloids), whereas kidney function deteriorated markedly in control animals. The electron microscopic tubular injury score was lower in hydroxyethyl starch-treated animals as compared to the crystalloid group. Vacuolar tubular cell alterations were present in all groups. The percentage of intact microvilli brush borders was significantly higher in sheep treated with either hydroxyethyl starch solution as compared to the other groups. Conclusions:The present study provides evidence that renal function, as measured by creatinine clearance and cumulative creatinine excretion as well as ultrastructural tubular integrity, is preserved with the use of 6% tetrastarch solutions despite increases in plasma levels of renal retention variables in ovine endotoxemic shock.

Short-term hypoxic vasodilation in vivo is mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin-mediated nitrite reduction

Hypoxia increases blood flow through vasodilation, an adaptive response that increases oxygen availability to tissues. This response is probably mediated by nitric oxide (NO); different mechanisms have been postulated (increased de novo synthesis, release from preformed stores, reduced inactivation), but precise mechanisms remain controversial. In a short‐term rodent model, hypoxaemia was associated with hypotension and lower plasma nitrite levels suggestive of nitrite bioactivation; this was only partially reversed by NO synthase inhibition. Administration of sodium nitrite produced marked vasodilation and increased nitrosylation. Scavenging of NO had little effect. Early hypoxic vasodilation is mediated by a complex interaction of multiple NO‐related species, rather than by NO from haemoglobin‐mediated reduction of nitrite per se. NO and its metabolites play a pivotal role in the bodys initial adaptation to an acute decrease in oxygen supply, probably offering protection against a supply–demand mismatch.

Characterization of a metabolomic profile associated with responsiveness to therapy in the acute phase of septic shock

The early metabolic signatures associated with the progression of septic shock and with responsiveness to therapy can be useful for developing target therapy. The Sequential Organ Failure Assessment (SOFA) score is used for stratifying risk and predicting mortality. This study aimed to verify whether different responses to therapy, assessed as changes in SOFA score at admission (T1, acute phase) and 48 h later (T2, post-resuscitation), are associated with different metabolite patterns. We examined the plasma metabolome of 21 septic shock patients (pts) enrolled in the Shockomics clinical trial (NCT02141607). Patients for which SOFAT2 was >8 and Δ = SOFAT1 − SOFAT2 < 5, were classified as not responsive to therapy (NR, 7 pts), the remaining 14 as responsive (R). We combined untargeted and targeted mass spectrometry-based metabolomics strategies to cover the plasma metabolites repertoire as far as possible. Metabolite concentration changes from T1 to T2 (Δ = T2 − T1) were used to build classification models. Our results support the emerging evidence that lipidome alterations play an important role in individual patients’ responses to infection. Furthermore, alanine indicates a possible alteration in the glucose-alanine cycle in the liver, providing a different picture of liver functionality from bilirubin. Understanding these metabolic disturbances is important for developing any effective tailored therapy for these patients.

Ammonium tetrathiomolybdate following ischemia/reperfusion injury: Chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models

Background Early revascularization of ischemic organs is key to improving outcomes, yet consequent reperfusion injury may be harmful. Reperfusion injury is largely attributed to excess mitochondrial production of reactive oxygen species (ROS). Sulfide inhibits mitochondria and reduces ROS production. Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility. Methods and findings In vitro, ATTM releases sulfide in a time-, pH-, temperature-, and thiol-dependent manner. Controlled sulfide release from ATTM reduces metabolism (measured as oxygen consumption) both in vivo in awake rats and ex vivo in skeletal muscle tissue, with a superior safety profile compared to standard sulfide generators. Given intravenously at reperfusion/resuscitation to rats, ATTM significantly reduced infarct size following either myocardial or cerebral ischemia, and conferred survival benefit following severe hemorrhage. Mechanistic studies (in vitro anoxia/reoxygenation) demonstrated a mitochondrial site of action (decreased MitoSOX fluorescence), where the majority of damaging ROS is produced. Conclusions The inorganic thiometallate ATTM represents a new class of sulfide-releasing drugs. Our findings provide impetus for further investigation of this compound as a novel adjunct therapy for reperfusion injury.

VV-ECMO and brave heart: A subtle competition?

To the editor:H1N1 influenza infection is associated with severe forms of acuterespiratory distress syndrome (ARDS) with high mortality ratesamong younger subjects [1]. Evidence suggests improved outcomeswith the use of veno-venous extracorporeal membrane oxygenation(VV-ECMO) in the treatment of refractory hypoxemia associated withsevere cases of ARDS [2–5]. However, despite correct positioning ofthe cannulas and maximal ECMO blood flow, refractory hypoxemiamay persist. We describe how we improved arterial oxygenation of ayoungpatientwithsevereARDSbyreducingthepatientsnativecardiacoutput (CO) with beta-blockers.A 34-year old male, obese (BMI: 34), presented to the emergencydepartment with a history of fever, dyspnoea, cough and productivesputumworseningovertwoweeks.Atarrivalhewastachypneic,hemo-dynamicallystableandhemoglobinoxygensaturationwas89%inroomair. Chest radiography revealed right pulmonary infiltrates and bloodtestsweresignificantforleucopoenia,elevatedCRPandhighcreatinine.After 24 h of empiric treatment including oseltamivir, clarithromycineand ceftriaxone, the patient was admittedto intensive care with severeARDS. He was then sedated; intubated, paralyzed and low tidal volumeprotective lung ventilation with optimal PEEP was initiated. Corticoste-roids and inhaled nitric oxidewere alsostarted. Nasopharyngeal swabsrevealed influenza A infection.Despite recruitment maneuvers, PEEP 18–20 cm H

Feature selection for the accurate prediction of septic and cardiogenic shock ICU mortality in the acute phase

Circulatory shock is a life-threatening disease that accounts for around one-third of all admissions to intensive care units (ICU). It requires immediate treatment, which is why the development of tools for planning therapeutic interventions is required to deal with shock in the critical care environment. In this study, the ShockOmics European project original database is used to extract attributes capable of predicting mortality due to shock at the ICU. Missing data imputation techniques and machine learning models were used, followed by feature selection from different data subsets. Selected features were later used to build Bayesian Networks, revealing causal relationships between features and ICU outcome. The main result is a subset of predictive features that includes well-known indicators such as SOFA and APACHE II, but also less commonly considered ones related to cardiovascular function such as Left Atrial Dilation, Inferior Vena Cava Distensibility Index, or shock treatment (Norepinephrine). Importantly, certain selected features are shown to be most predictive at certain time-steps. This means that, as shock progresses, different attributes could be prioritized. Clinical traits obtained at 24h. from ICU admission are shown to accurately predict cardiogenic and septic shock mortality, suggesting that relevant life-saving decisions could be made shortly after ICU admission.

Baroreflex Sensitivity and Blood Pressure Variability can Help in Understanding the Different Response to Therapy During Acute Phase of Septic Shock

Background: Mean values of hemodynamic variables are poorly effective in evaluating an actual recovery of the short-term autonomic mechanisms for blood pressure (BP) and heart rate (HR) regulation. The aim of this work is to analyze the response to therapy in the early phase of septic shock to verify possible associations between BP recovery and BP autonomic control. Methods: This is an ancillary study from the multicenter prospective observational trial Shockomics (NCT02141607). A total of 21 septic shock patients were studied at two time points during the acute phase of shock and were classified according to changes in SOFA score. Time series of BP components and HR were analyzed in time and frequency domain. Baroreflex sensitivity (BRS) was assessed, and a mathematical model for the decomposition of diastolic arterial pressure (DAP) oscillations was used to understand the different contributions of BRS and HR on peripheral vascular resistance control. Results: Only those patients, who significantly improved organ function (responders, R), showed an increase of mean value and low frequency (LF) power in BP time series. Fluid accumulation was higher in the non-responders (NR). BRS increased in NR and the model of DAP variability showed that the contribution of HR was highly reduced in NR. Conclusions: Although patients reached the mean BP target of 65 mmHg, our analyses highlighted important differences in terms of autonomic nervous system control. BP variability, HR variability and baroreflex trends can add information to individual vital sign measure such as mean BP, and can help in understanding the responsiveness to the combination of symphatomimetic drugs and fluid therapy.