Vasopressor therapy in septic shock.

Independent Clinical Criteria in Medicine: The Unusual Case of Septic Shock

Another Look at Steroid Therapy for Septic Shock

IntroductionThe aim of this study was to assess the efficacy of arginine-vasopressin (AVP) as a rescue therapy in catecholamine-refractory septic and non-septic shock in extremely low birth weight (ELBW) infants with acute renal injury.MethodsProspective assessment of AVP therapy in three ELBW infants with catecholamine-refractory septic shock and acute renal injury (mean birth weight 600 ± 30 g) and three ELBW infants with non-septic shock and acute renal injury (mean birth weight 770 ± 110 g) at a University hospital. The main outcome measures were restoration of blood pressure with adequate organ perfusion and survival at discharge.ResultsIn all three ELBW infants with catecholamine-resistant septic shock, systemic arterial blood pressure increased substantively with restoration of urine output after AVP administration (dosage, 0.035 to 0.36 U/kg/h; length, 70 ± 21 hours). In the three ELBW infants with non-septic shock, only a transient stabilization in mean arterial pressure with restoration of urine output was observed after AVP therapy (dosage, 0.01 to 0.36 U/kg/h; length, 30 ± 16 hours). The mortality rate was 1/3 in the sepsis group versus 3/3 in the non-septic group.ConclusionAVP may be a promising rescue therapy in catecholamine-resistant shock in ELBW infants with acute renal injury. Larger prospective clinical trials are warranted to assess the efficacy and safety of AVP as a pressor adjunct in septic versus non-septic shock in ELBW infants.

Despite significant efforts toward improving therapy for septic shock, mortality remains high. Applying veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) in this context remains controversial. Since the cannulation of the femoral artery for V-A ECMO return leads to lower body hyperoxia, this study investigated the impact of V-A ECMO therapy on the intestinal and hepatic microcirculation during septic shock in a rodent model. Thirty male Lewis rats were randomly assigned to receive V-A ECMO therapy with low (60 mL/kg/min) or high (90 mL/kg/min) blood flow or a sham procedure. Hemodynamic data were collected through a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by intravenous administration of lipopolysaccharide (1 mg/kg). The rats received lung-protective ventilation during V-A ECMO therapy. The hepatic and intestinal microcirculation was measured by micro-lightguide spectrophotometry after median laparotomy for two hours. Systemic and pulmonary inflammation was detected via enzyme-linked immunosorbent assays (ELISA) of the plasma and bronchoalveolar lavage (BAL), respectively, measuring tumor necrosis factor-alpha (TNF-α), interleukins 6 (IL-6) and 10 (IL-10), and C-X-C motif ligands 2 (CXCL2) and 5 (CXCL5). Oxygen saturation and relative hemoglobin concentration were reduced in the hepatic and intestinal microcirculation during V-A ECMO therapy, independent of the blood flow rate. Further, rats treated with V-A ECMO therapy also presented elevated systolic, diastolic, and mean arterial blood pressure and increased stroke volume, cardiac output, and left ventricular end-diastolic volume. However, left ventricular end-diastolic pressure was only elevated during high-flow V-A ECMO therapy. Blood gas analysis revealed a dilutional anemia during V-A ECMO therapy. ELISA analysis showed an elevated plasma CXCL2 concentration only during high-flow V-A ECMO therapy and elevated BAL CXCL2 and CXCL5 concentrations only during low-flow V-A ECMO therapy. Rats undergoing V-A ECMO therapy exhibited impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Increased pulmonary inflammation was detected only during low-flow V-A ECMO therapy in septic shock.

Background: Current guidelines for septic shock management recommend administration of appropriate, broad-spectrum antimicrobials within 1 hour of recognition. Objective: To evaluate the interventions pharmacists make as part of a sepsis response team and to determine if these interventions increase the proportion of patients with appropriate empiric antimicrobial therapy. Methods: A retrospective cohort study was undertaken reviewing adult patients in a large, academic medical center with confirmed septic shock who had an order for a “sepsis bundle,” which includes notification of a pharmacist to assess adequacy of empiric therapy. Pharmacist interventions with regard to selection of empiric antimicrobials were documented. The proportion of patients with initial successful selection of antimicrobial therapy (SSAT) before and after pharmacist intervention was assessed as well as the time to first antimicrobial administration and time to appropriate antimicrobial administration. Results: A total of 76 patients were included. Pharmacist intervention increased the proportion of patients with SSAT from 66% to 80% (P = .04). Median time to first antimicrobial administration was 43 minutes, and time to appropriate antimicrobial therapy was 1 hour, 34 minutes for the entire cohort, with pharmacist intervention decreasing the latter time significantly in patients without SSAT on initiation of the “sepsis bundle” (P < .001). Conclusion: Pharmacist assessment of patients in septic shock offers the opportunity to improve SSAT. Systems designed to use a pharmacist responder for the care of patients with septic shock maximize the selection of antimicrobials, facilitate rapid administration, and improve surrogate outcomes for mortality in septic shock.

We performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups. Our pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed as well as one-stage regression models with single treatment covariate interactions for subgroup analyses. Four trials were included with a total of 1453 patients. For the primary outcomes, there was no effect of vasopressin on 28-day mortality [relative risk (RR) 0.98, 95% CI 0.86-1.12] or serious adverse events (RR 1.02, 95% CI 0.82-1.26). Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%-3.2%] but fewer arrhythmias (ARD - 2.8%, 95% CI - 0.2% to - 5.3%). Mesenteric ischaemia and acute coronary syndrome events were similar between groups. Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74-0.99), but this finding was not robust to sensitivity analyses. There were no statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion). Vasopressin therapy in septic shock had no effect on 28-day mortality although the confidence intervals are wide. It appears safe but with a different side effect profile from norepinephrine. The finding on reduced RRT should be interpreted cautiously. Future trials should focus on long-term outcomes in select patient groups as well as incorporating cost effectiveness analyses regarding possible reduced RRT use.

The severe vascular decoupling induced by septic shock may dissociate the physiological relation between pressure and flow in the periphery and this may have important clinical implications. We hypothesize that arterial pulse wave analysis (PWA) can track these vascular alterations and we tested this hypothesis in a swine experiment of septic shock and resuscitation with different drugs that differently interact with the cardiovascular system. PWA was found to effectively detect the different arterial response to treatment, proving to be highly informative in the monitoring of therapy response in septic shock.

Sepsis and Septic Shock: Selection of Empiric Antimicrobial Therapy

Optimal fluid resuscitation guided by central venous pressure (CVP) in patients having septic shock with ARDS is a perplexed issue having risk of underfilling and worsening of shock versus fluid overload leading to pulmonary edema. Whether stroke volume variation (SVV) (Flotrac-Vigileo system) guided fluid resuscitation has an impact on improvement of shock, oxygenation and mortality were tested in this single-center prospective study [1,2].

In patients with septic shock, hypovolemia is a major factor contributing to circulatory instability. In the early phase, cardiac filling pressures are often lowered, due to a decrease in venous return, compromising cardiac output and tissue perfusion [1, 2]. A decline in effective circulating volume can be induced by a variety of sepsis-related mechanisms. First, generalized vasodilation increases total vascular capacitance with subsequent relative hypovolemia. A decline in systemic vascular resistance, mainly due to arteriolar vasodilation, is a constant feature in human septic shock [3]. Alterations in the venous capacitance system, by far the largest part of the intravascular compartment, are however difficult to assess. The concept of venous pooling as a major factor limiting effective venous return stems from animal experiments [4, 5]. Experimental studies in endotoxin and sepsis models have indicated that in several body areas venous capacitance increases. Although significant increases in venous capacitance in the forearm could not be demonstrated in the clinical study [6], it is likely that also in human septic shock venous pooling in vascular beds other than skeletal muscle (e.g. the splanchnic area) is an important mechanism. The evidence for this is, however, only circumstantial. The observation that large amounts of fluids are usually required for initial resuscitation supports such a concept. Secondly, absolute hypovolemia may contribute to a defect in effective circulating volume. This could be due to fever with perspiration and increased insensible loss, vomiting, diarrhea, volume loss by drains or sequestration (e.g. in the gut), and inadequate oral intake.

Introduction: Sepsis-associated acute kidney injury (SA-AKI) represents a relevant cause of mortality and morbidity in critically ill children. Since with the “inflammatory theory” the authors have been witnessed an important role of inflammatory mediators in the pathophysiology and in the prognosis of SA-AKI, making the need of adjunctive therapies in association with kidney replacement therapies mandatory. Hemoperfusion with CytoSorb is a safe and well-tolerated therapy in septic shock: the very high surface area of the absorber means it is able to efficiently remove cytokines and other medium size molecules involved in cytokine storm, thus playing a synergistic effect with Continuous Kidney Replacement Therapy (CKRT).Materials and Methods: We retrospectively analyzed data from a cohort of eight critically ill children treated from January 2018 to March 2020 describing the impact of CKRT plus hemoperfusion with CytoSorb on renal outcome in critically ill children with septic shock.Results: We evidenced a significant reduction in interleukin (IL)-6 an IL-10 after hemoperfusion with CytoSorb in our pediatric population. Furthermore, we were able to show a significant improvement of creatinine and blood urea nitrogen (BUN) after blood purification and at pediatric intensive care units (PICU) discharge. We have observed a median of 2.5 CKRT days after stop of hemoperfusion (Q1 0.25; Q3 18.75). None of our patients required CKRT 30 days after PICU discharge (PICU-D). None of them developed CKD.Conclusion: Hemoperfusion with CytoSorb is a valuable therapeutic option in combination with CKRT in SA-AKI. More studies are warranted to confirm our results and in particular to define the role of this adjuvant therapy as a preemptive strategy to protect renal function in pediatric septic shock.

During septic shock, fluid therapy is aimed at increasing cardiac output and improving tissue oxygenation, but it poses two problems: it has inconsistent and transient efficacy, and it has many well-documented deleterious effects. We suggest that there is a place for its personalization according to the patient characteristics and the clinical situation, at all stages of circulatory failure. Regarding the choice of fluid for volume expansion, isotonic saline induces hyperchloremic acidosis, but only for very large volumes administered. We suggest that balanced solutions should be reserved for patients who have already received large volumes and in whom the chloremia is rising. The initial volume expansion, intended to compensate for the constant hypovolaemia in the initial phase of septic shock, cannot be adapted to the patient’s weight only, as suggested by the Surviving Sepsis Campaign, but should also consider potential absolute hypovolemia induced by fluid losses. After the initial fluid infusion, preload responsiveness may rapidly disappear, and it should be assessed. The choice between tests used for this purpose depends on the presence or absence of mechanical ventilation, the monitoring in place and the risk of fluid accumulation. In non-intubated patients, the passive leg raising test and the mini-fluid challenge are suitable. In patients without cardiac output monitoring, tests like the tidal volume challenge, the passive leg raising test and the mini-fluid challenge can be used as they can be performed by measuring changes in pulse pressure variation, assessed through an arterial line. The mini-fluid challenge should not be repeated in patients who already received large volumes of fluids. The variables to assess fluid accumulation depend on the clinical condition. In acute respiratory distress syndrome, pulmonary arterial occlusion pressure, extravascular lung water and pulmonary vascular permeability index assess the risk of worsening alveolar oedema better than arterial oxygenation. In case of abdominal problems, the intra-abdominal pressure should be taken into account. Finally, fluid depletion in the de-escalation phase is considered in patients with significant fluid accumulation. Fluid removal can be guided by preload responsiveness testing, since haemodynamic deterioration is likely to occur in patients with a preload dependent state.

Septic shock is a systemic response to severe bacterial infections, generally caused by Gram-negative bacterial endotoxins, with multiple manifestations such as hypotension, tissue injury, disseminated intravascular coagulation, and multi-organ failure. All these effects, are induced by the generation of pro-inflammatory and vasodilator mediators, cell adhesion molecules, coagulation factors, and acute-phase proteins. Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two immunopeptides with anti-inflammatory properties exerted through type 1 and 2 VIP receptors (VPAC1 and VPAC2, respectively), and PACAP receptor (PAC1). The present results recapitulate the protective role of PAC1 in an experimental model of lethal endotoxemia using a knockout for the PAC1 receptor. Our results demonstrate that VIP and PACAP decrease lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) production, neutrophil infiltration and intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and fibrinogen expression through PAC1 receptor, providing an advantage to design more specific drugs complementing standard intensive care therapy in septic shock.

A gene expression-based approach for the precision use of hydrocortisone in septic shock patients; a secondary analysis of the ADRENAL trial☆

HDL has been shown to be able to neutralize the toxicity of lipopolysaccharide (LPS). Our previous study (J. Lipid Res. 2005. 46: 1303-1311) characterized the properties of secondary structure and in vitro functions of different cysteine mutants of apolipoprotein A-I. Here, we reconstituted recombinant HDLs (named rHDLwt, rHDL52, rHDL74, rHDL107, rHDL129, rHDL173, rHDL195, and rHDL228) by mixing wild type or those mutants with dipalmitoyl phosphatidylcholine and examined their in vivo effects on LPS-induced endotoxemia in mice. Our results showed that 24 h after injection, mice receiving rHDL74 or rHDL52 had a significant decrease of plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta), compared with control mice receiving either saline or rHDLwt (P < 0.05). Administration of rHDL74 to mice injected with LPS also led to a decrease of plasma IL-6, protection of lung against acute injury, and attenuation of endotoxin-induced clinical symptoms in mice, compared with controls injected with LPS only. However, injection of rHDL228 significantly increased plasma concentration of TNF-alpha and exacerbated LPS-induced lung injury. In summary, compared with rHDLwt, rHDL74 and rHDL52 exhibit higher anti-inflammation capabilities, whereas rHDL228 shows hyper-proinflammation by exacerbating LPS-induced endotoxemia in mice.