Management of Refractory Anaphylaxis: An Overview of Current Guidelines.

In this review, we compare different refractory anaphylaxis (RA) management guidelines focusing on cardiovascular involvement and best practice recommendations, discuss postulated pathogenic mechanisms underlining RA and highlight knowledge gaps and research priorities. There is a paucity of data supporting existing management guidelines. Therapeutic recommendations include the need for the timely administration of appropriate doses of aggressive fluid resuscitation and intravenous (IV) adrenaline in RA. The preferred second-line vasopressor (noradrenaline, vasopressin, metaraminol and dopamine) is unknown. Most guidelines recommend IV glucagon for patients on beta-blockers, despite a lack of evidence. The use of methylene blue or extracorporeal life support (ECLS) is also suggested as rescue therapy. Despite recent advances in understanding the pathogenesis of anaphylaxis, the factors that lead to a lack of response to the initial adrenaline and thus RA are unclear. Genetic factors, such as deficiency in platelet activating factor-acetyl hydrolase or hereditary alpha-tryptasaemia, mastocytosis may modulate reaction severity or response to treatment. Further research into the underlying pathophysiology of RA may help define potential new therapeutic approaches and reduce the morbidity and mortality of anaphylaxis.

Evaluation of Oral Vasoactive Medications to Maintain Mean Arterial Pressure in Spinal Cord Injury.

INTRODUCTION: An acute spinal cord injury (SCI) results in significant morbidity worldwide. Guidelines recommend mean arterial pressure (MAP) augmentation to prevent hypoperfusion. Although there is no consensus on a single vasoactive agent for MAP augmentation, intravenous vasopressors are commonly utilized, requiring an intensive care unit (ICU). Beyond the financial burden for patients, ICU stays require significant hospital system resource utilization. Oral vasoactive agents, such as pseudoephedrine and midodrine, are also utilized for MAP augmentation, but little data on their efficacy are available. This study investigates the use and dosing of oral vasoactive agents as an alternative in MAP augmentation in SCI. MATERIALS AND METHODS: Adult SCI patients were retrospectively investigated. Total daily vasoactive dose, treatment efficacy, and ICU length of stay were evaluated. RESULTS: 141 patients were evaluated, with 7.1% receiving oral agents alone, and 80.9% receiving vasopressors who either transitioned to pseudoephedrine, pseudoephedrine plus midodrine, or no oral agent. Patients receiving oral agents trended toward decreased ICU stay, but there was no difference in vasopressor duration. Similar MAP goal success rates were found between groups. A variety of initial and maximum daily doses of PO agents were used. Median doses were 120 mg pseudoephedrine and 30 mg midodrine. Early initiation of pseudoephedrine resulted in shorter ICU stays. CONCLUSIONS: This study demonstrated shorter ICU length of stay and similar MAP goal success with PO agents as compared to vasopressors. This may indicate these medications could be utilized to decrease the financial burden placed on patients and the health care system from lengthy ICU courses. This study is limited by a small sample size and variable agent dosing.

Efficacy and Safety of Perioperative Angiotensin II Versus Phenylephrine as a First-Line Continuous Infusion Vasopressor in Kidney Transplant Recipients.

INTRODUCTION: Angiotensin II (ATII) maintains blood pressure via RAAS with a beneficial adverse effect profile versus catecholamines and phenylephrine. Head-to-head data comparing ATII to phenylephrine are lacking regarding renal allograft function, hemodynamic efficacy, and safety within the perioperative period of kidney transplantation. METHODS: This single-center, retrospective study included adult kidney transplant recipients who received continuous infusions of ATII or phenylephrine within a 24-h perioperative period as a first-line vasopressor according to an institutional algorithm. The primary endpoint was allograft function. Secondary endpoints were hemodynamic efficacy and adverse effects. RESULTS: Among 105 patients, there was no significant difference in IGF (p = 0.545), SGF (p = 0.557), or DGF (p = 0.878) between patient cohorts. In the 34 patients with cold ischemia time (CIT) > 14-h, IGF was higher (p = 0.013) and DGF (p = 0.045) was lower in the ATII cohort versus phenylephrine. In all patients, ATII was associated with a decreased need for additional vasopressor agents (p < 0.001). Adverse effect profiles were similar between cohorts (p > 0.05). CONCLUSION: Among kidney transplant recipients, ATII may be a suitable first-line alternative compared with phenylephrine in the perioperative period for hypotension management with a reduced need for additional vasopressor support. Allograft benefits were observed in patients with prolonged CIT.

Survival study of enteral and parenteral nutrition pathways in critically ill patients receiving vasopressors: an analysis of the Medical Information Mart for Intensive Care-IV database.

This study compared survival outcomes between intensive care unit (ICU) patients receiving enteral nutrition (EN) and parenteral nutrition (PN) with vasopressor support, explored risk factors affecting clinical outcomes and established an evaluation model. Data from 1046 ICU patients receiving vasopressor therapy within 24 h from 2008 to 2019 were collected. Patients receiving nutritional therapy within 3 d of ICU admission were divided into EN or PN (including PN+EN) groups. Cox analysis and regression were used to determine relevant factors and establish a nomogram for predicting survival. The 28-d survival rate was significantly better in the EN group compared with the PN/PN+EN group. Risk factors included age, peripheral capillary oxygen saturation, red cell distribution width, international normalised ratio, potassium level, mean corpuscular Hg, myocardial infarction, liver disease, cancer status and nutritional status. The nomogram showed good predictive performance. In ICU patients receiving vasopressor drugs, patients receiving EN had a better survival rate than PN. Our nomogram had favourable predictive value for 28-d survival in patients. However, it needs further validation in prospective trials.

Clinical Response to Third-Line Angiotensin-II vs Epinephrine in Septic Shock: A Propensity-Matched Cohort Study.

BACKGROUND: The appropriate third-line vasopressor in septic shock patients receiving norepinephrine and vasopressin is unknown. Angiotensin-II (AT-II) offers a unique mechanism of action to traditionally used vasopressors in septic shock. OBJECTIVE: The objective of this study was to compare the clinical efficacy and safety of third-line AT-II to epinephrine in patients with septic shock. METHODS: A single-center, retrospective cohort study of critically ill patients was performed between April 1, 2019 and July 31, 2022. Propensity-matched (2:1) analysis compared adults with septic shock who received third-line AT-II to controls who received epinephrine following norepinephrine and vasopressin. The primary outcome was clinical response 24 hours after third-line vasopressor initiation. Additional efficacy and safety outcomes were investigated. RESULTS: Twenty-three AT-II patients were compared with 46 epinephrine patients. 47.8% of AT-II patients observed a clinical response at hour 24 compared with 28.3% of epinephrine patients (P = 0.12). In-hospital mortality (65.2% vs 73.9%, P = 0.45), cardiac arrhythmias (26.1% vs 26.1%, P = 0.21), and thromboembolism (4.3% vs 2.2%, P = 0.61) were not observed to be statistically different between groups. CONCLUSIONS AND RELEVANCE: Administration of AT-II as a third-line vasopressor agent in septic shock patients was not associated with significantly improved clinical response at hour 24 compared with epinephrine. Although underpowered to detect meaningful differences, the clinical observations of this study warrant consideration and further investigation of AT-II as a third-line vasopressor in septic shock.

Administration of methylene blue in septic shock: pros and cons.

Septic shock typically requires the administration of vasopressors. Adrenergic agents remain the first choice, namely norepinephrine. However, their use to counteract life-threatening hypotension comes with potential adverse effects, so that non-adrenergic vasopressors may also be considered. The use of agents that act through different mechanisms may also provide an advantage. Nitric oxide (NO) is the main driver of the vasodilation that leads to hypotension in septic shock, so several agents have been tested to counteract its effects. The use of non-selective NO synthase inhibitors has been of questionable benefit. Methylene blue, an inhibitor of soluble guanylate cyclase, an important enzyme involved in the NO signaling pathway in the vascular smooth muscle cell, has also been proposed. However, more than 25 years since the first clinical evaluation of MB administration in septic shock, the safety and benefits of its use are still not fully established, and it should not be used routinely in clinical practice until further evidence of its efficacy is available.

Mortality, morbidity & clinical outcome with different types of vasopressors in out of hospital cardiac arrest patients- a systematic review and meta-analysis.

BACKGROUND & OBJECTIVE: Despite their continued use, the effectiveness and safety of vasopressors in post-cardiac arrest patients remain controversial. This study examined the efficacy of various vasopressors in cardiac arrest patients in terms of clinical, morbidity, and mortality outcomes. METHODS: A comprehensive literature search was performed using online databases (MeSH terms: MEDLINE (Ovid), CENTRAL (Cochrane Library), Embase (Ovid), CINAHL, Scopus, and Google Scholar) from 1997 to 2023 for relevant English language studies. The primary outcomes of interest for this study included short-term survival leading to death, return of spontaneous circulation (ROSC), survival to hospital discharge, neurological outcomes, survival to hospital admission, myocardial infarction, and incidence of arrhythmias. RESULTS: In this meta-analysis, 26 studies, including 16 RCTs and ten non-RCTs, were evaluated. The focus was on the efficacy of epinephrine, vasopressin, methylprednisolone, dopamine, and their combinations in medical emergencies. Epinephrine treatment was associated with better odds of survival to hospital discharge (OR = 1.52, 95%CI [1.20, 1.94]; p < 0.001) and achieving ROSC (OR = 3.60, 95% CI [3.45, 3.76], P < 0.00001)) over placebo but not in other outcomes of interest such as short-term survival/ death at 28-30 days, survival to hospital admission, or neurological function. In addition, our analysis indicates non-superiority of vasopressin or epinephrine vasopressin-plus-epinephrine therapy over epinephrine monotherapy except for survival to hospital admission where the combinatorial therapy was associated with better outcome (0.76, 95%CI [0.64, 0.92]; p = 0.004). Similarly, we noted the non-superiority of vasopressin-plus-methylprednisolone versus placebo. Finally, while higher odds of survival to hospital discharge (OR = 3.35, 95%CI [1.81, 6.2]; p < 0.001) and ROSC (OR = 2.87, 95%CI [1.97, 4.19]; p < 0.001) favoring placebo over VSE therapy were observed, the risk of lethal arrhythmia was not statistically significant. There was insufficient literature to assess the effects of dopamine versus other treatment modalities meta-analytically. CONCLUSION: This meta-analysis indicated that only epinephrine yielded superior outcomes among vasopressors than placebo, albeit limited to survival to hospital discharge and ROSC. Additionally, we demonstrate the non-superiority of vasopressin over epinephrine, although vasopressin could not be compared to placebo due to the paucity of data. The addition of vasopressin to epinephrine treatment only improved survival to hospital admission.

Droxidopa for Vasopressor Weaning in Critically Ill Patients with Persistent Hypotension: A Multicenter, Retrospective, Single-Arm Observational Study.

BACKGROUND: Persistent vasopressor requirements are a common reason for delayed liberation from the intensive care unit (ICU) and adjunct oral agents are sometimes used to hasten time to vasopressor discontinuation. We sought to describe the use of droxidopa for vasopressor weaning in critically ill patients with prolonged hypotension. MATERIALS AND METHODS: This retrospective, single-arm, observational study included adult patients admitted to an ICU at two academic centers between 06/2016-07/2023 who received droxidopa for vasopressor weaning. Patients who received droxidopa prior to admission or for another indication were excluded. The primary outcome was time to vasopressor discontinuation, defined as when vasopressors were stopped and remained off for at least 24 h. Secondary outcomes included rates of tachycardia and hypotension post-initiation, norepinephrine equivalents pre- and post-initiation, concomitant oral agent use, and dosing. A subgroup analysis was conducted in patients receiving droxidopa via feeding tubes. RESULTS: A total of 30 patients met inclusion criteria. Median age was 62 years old, 12 (40%) were female, and 73% were in a cardiac/cardiac surgical ICU. Patients were on vasopressors for a median of 16 days prior to droxidopa initiation. Median (IQR) time to vasopressor discontinuation was 70 h (23-192) and norepinephrine equivalents decreased immediately after initiation (0.08 vs 0.02 mcg/kg/min, p < 0.001). MAP increased after droxidopa initiation (68.8 vs 66.5 mm Hg, p = 0.008) while heart rates were unchanged (86 vs 84 BPM, p = 0.37) after initiation. Patients who weaned from vasopressors within 72 h versus longer than 72 h after droxidopa initiation were more likely to be on lower norepinephrine equivalents prior to initiation (0.05 vs 0.12 mcg/kg/min, p = 0.013). Feeding tube administration did not impact time to vasopressor discontinuation (p = 0.93). CONCLUSIONS: Droxidopa may be considered an adjunct therapy for vasopressor weaning. Effects were similar when analyzing patients receiving droxidopa via feeding tube.

Early Beta-Blocker Utilization in Critically Ill Patients With Moderate-Severe Traumatic Brain Injury: A Retrospective Cohort Study.

BACKGROUND: There is limited evidence that beta-blockers may provide benefit for patients with moderate-severe traumatic brain injury (TBI) during the acute injury period. Larger studies on utilization patterns and impact on outcomes in clinical practice are lacking. OBJECTIVE: The present study uses a large, national hospital claims-based dataset to examine early beta-blocker utilization patterns and its association with clinical outcomes among critically ill patients with moderate-severe TBI. METHODS: We conducted a retrospective cohort study of the administrative claims Premier Healthcare Database of adults (≥17 years) with moderate-severe TBI admitted to the intensive care unit (ICU) from 2016 to 2020. The exposure was receipt of a beta-blocker during day 1 or 2 of ICU stay (BB+). The primary outcome was hospital mortality, and secondary outcomes were: hospital length of stay (LOS), ICU LOS, discharge to home, and vasopressor utilization. In a sensitivity analysis, we explored the association of beta-blocker class (cardioselective and noncardioselective) with hospital mortality. We used propensity weighting methods to address possible confounding by treatment indication. RESULTS: A total of 109 665 participants met inclusion criteria and 39% (n = 42 489) were exposed to beta-blockers during the first 2 days of hospitalization. Of those, 42% received cardioselective only, 43% received noncardioselective only, and 14% received both. After adjustment, there was no association with hospital mortality in the BB+ group compared to the BB- group (adjusted odds ratio [OR] = 0.99, 95% confidence interval [CI] = 0.94, 1.04). The BB+ group had longer hospital stays, lower chance of discharged home, and lower risk of vasopressor utilization, although these difference were clinically small. Beta-blocker class was not associated with hospital mortality. CONCLUSION: In this retrospective cohort study, we found variation in use of beta-blockers and early exposure was not associated with hospital mortality. Further research is necessary to understand the optimal type, dose, and timing of beta-blockers for this population.

A Guide to the Use of Vasopressors and Inotropes for Patients in Shock.

Shock is a life-threatening circulatory failure that results in inadequate tissue perfusion and oxygenation. Vasopressors and inotropes are vasoactive medications that are vital in increasing systemic vascular resistance and cardiac contractility, respectively, in patients presenting with shock. To be well versed in using these agents is an important skill to have in the critical care setting where patients can frequently exhibit symptoms of shock. In this review, we will discuss the pathophysiological mechanisms of shock and evaluate the current evidence behind the management of shock with an emphasis on vasopressors and inotropes.

Perioperative hypotension and use of vasoactive agents in non-cardiac surgery: A scoping review.

BACKGROUND: Perioperative hypotension is common and associated with adverse patient outcomes. Vasoactive agents are often used to manage hypotension, but the ideal drug, dose and duration of treatment has not been established. With this scoping review, we aim to provide an overview of the current body of evidence regarding the vasoactive agents used to treat perioperative hypotension in non-cardiac surgery. METHODS: We included all studies describing the use of vasoactive agents for the treatment of perioperative hypotension in non-cardiac surgery. We excluded literature reviews, case studies, and studies on animals and healthy subjects. We posed the following research questions: (1) in which surgical populations have vasoactive agents been studied? (2) which agents have been studied? (3) what doses have been assessed? (4) what is the duration of treatment? and (5) which desirable and undesirable outcomes have been assessed? RESULTS: We included 124 studies representing 10 surgical specialties. Eighteen different agents were evaluated, predominantly phenylephrine, ephedrine, and noradrenaline. The agents were administered through six different routes, and numerous comparisons between agents, dosages and routes were included. Then, 88 distinct outcome measures were assessed, of which 54 were judged to be non-patient-centred. CONCLUSIONS: We found that studies concerning vasoactive agents for the treatment of perioperative hypotension varied considerably in all aspects. Populations were heterogeneous, interventions and exposures included multiple agents compared against themselves, each other, fluids or placebo, and studies reported primarily non-patient-centred outcomes.

Risk of arrhythmia in post-resuscitative shock after out-of-hospital cardiac arrest with epinephrine versus norepinephrine.

OBJECTIVE: To determine the rates of clinically significant tachyarrhythmias and mortality in the management of post-resuscitative shock after return of spontaneous circulation (ROSC) in patients with out-of-hospital cardiac arrest (OHCA) who receive a continuous epinephrine versus norepinephrine infusion. DESIGN: Retrospective cohort study. SETTING: A large multi-site health system with hospitals across the United States. PATIENTS: Adult patients admitted for OHCA with post-resuscitative shock managed with either epinephrine or norepinephrine infusions within 6 h of ROSC. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between May 5th, 2018, to January 31st, 2022, there were 221 patients admitted for OHCA who received post-resuscitative epinephrine or norepinephrine infusions. There was no difference in the rate of tachyarrhythmias between epinephrine and norepinephrine infusion in univariate (47.1% vs 41.7%, OR 1.24, 95% CI 0.71-2.20) or multivariable analysis (OR 1.34, 95% CI 0.68-2.62). Patients treated with epinephrine were more likely to die during hospitalization than those treated with norepinephrine (90.0% vs 54.3%, OR 6.21, 95% CI 2.37-16.25, p < 0.001). Epinephrine treated patients were more likely to have re-arrest during hospital admission (55.7% vs 14.6%, OR 5.77, 95% CI 2.74-12.18, p < 0.001). CONCLUSION: There was no statistically significant difference in clinically significant cardiac tachyarrhythmias in post-OHCA patients treated with epinephrine versus norepinephrine infusions after ROSC. Re-arrest rates and in-hospital mortality were higher in patients who received epinephrine infusions in the first 6 h post-ROSC. Results of this study add to the literature suggesting norepinephrine may be the vasopressor of choice in post-OHCA patients with post-resuscitative shock after ROSC.

Norepinephrine versus epinephrine for hemodynamic support in post-cardiac arrest shock: A systematic review.

PURPOSE: The preferred vasopressor in post-cardiac arrest shock has not been established with robust clinical outcomes data. Our goal was to perform a systematic review and meta-analysis comparing rates of in-hospital mortality, refractory shock, and hemodynamic parameters in post-cardiac arrest patients who received either norepinephrine or epinephrine as primary vasopressor support. METHODS: We conducted a search of PubMed, Cochrane Library, and CINAHL from 2000 to 2022. Included studies were prospective, retrospective, or published abstracts comparing norepinephrine and epinephrine in adults with post-cardiac arrest shock or with cardiogenic shock and extractable post-cardiac arrest data. The primary outcome of interest was in-hospital mortality. Other outcomes included incidence of arrhythmias or refractory shock. RESULTS: The database search returned 2646 studies. Two studies involving 853 participants were included in the systematic review. The proposed meta-analysis was deferred due to low yield. Crude incidence of in-hospital mortality was numerically higher in the epinephrine group compared with norepinephrine in both studies, but only statistically significant in one. Risk of bias was moderate to severe for in-hospital mortality. Additional outcomes were reported differently between studies, minimizing direct comparison. CONCLUSION: The vasopressor with the best mortality and hemodynamic outcomes in post-cardiac arrest shock remains unclear. Randomized studies are crucial to remedy this.

The concomitant use of ultra short beta-blockers with vasopressors and inotropes in critically ill patients with septic shock: A systematic review and meta-analysis of randomized controlled trials.

Background: Septic shock is associated with systemic inflammatory response, hemodynamic instability, impaired sympathetic control, and the development of multiorgan dysfunction that requires vasopressor or inotropic support. The regulation of immune function in sepsis is complex and varies over time. However, activating Beta-2 receptors and blocking Beta-1 receptors reduces the proinflammatory response by influencing cytokine production. Evidence that supports the concomitant use of ultra short beta-blockers with inotropes and vasopressors in patients with septic shock is still limited. This study aimed to evaluate the use of ultra short beta-blockers and its impact on the ICU related outcomes such as mortality, length of stay, heart rate control, shock resolution, and vasopressors/inotropes requirements. Methods: A systematic review and meta-analysis of randomized controlled trials including critically ill patients with septic shock who received inotropes and vasopressors. Patients who received either epinephrine or norepinephrine without beta-blockers "control group" were compared to patients who received ultra short beta-blockers concomitantly with either epinephrine or norepinephrine "Intervention group". MEDLINE and Embase databases were utilized to systematically search for studies investigating the use of ultra short beta-blockers in critically ill patients on either epinephrine or norepinephrine from inception to October 10, 2023. The primary outcome was the 28-day mortality. While, length of stay, heart rate control, and inotropes/ vasopressors requirements were considered secondary outcomes. Results: Among 47 potentially relevant studies, nine were included in the analysis. The 28-day mortality risk was lower in patients with septic shock who used ultra short beta-blockers concomitantly with either epinephrine or norepinephrine compared with the control group (RR (95%CI): 0.69 (0.53, 0.89), I2=26%; P=0.24). In addition, heart rate was statistically significantly lower with a standardized mean difference (SMD) of -22.39 (95% CI: -24.71, -20.06) among the beta-blockers group than the control group. The SMD for hospital length of stay and the inotropes requirement were not statistically different between the two groups (SMD (95%CI): -0.57 (-2.77, 1.64), and SMD (95%CI): 0.08 (-0.02, 0.19), respectively). Conclusion: The use of ultra short beta-blockers concomitantly with either epinephrine or norepinephrine in critically ill patients with septic shock was associated with better heart rate control and survival benefits without increment in the inotropes and vasopressors requirement.

Implementation and Evaluation of Weight-Based Vasopressors in Intensive Care Units.

Background: Vasopressors, including norepinephrine, epinephrine, and phenylephrine are commonly used to maintain mean arterial pressure (MAP) in critically ill patients. Despite their frequent use, the optimal dosing strategy for vasopressors remains understudied. Objective: The purpose of this study is to evaluate the implementation of a weight-based (WB) dosing strategy using ideal body weight compared to a non-weight-based (NWB) dosing strategy for vasopressors in critically ill patients. Methods: This is a retrospective chart review of patients admitted to intensive care units receiving vasopressor medications for greater than or equal to 4 hours. Patients received either an NWB or a WB vasopressor dosing strategy. The primary endpoint was the time to achieve goal MAP. Results: This study included 153 patients in the NWB vasopressor dosing group and 183 in the WB dosing group. The median time to achieve goal MAP in the NWB group was 24 minutes versus 21 minutes in the WB group (P = 0.1713). There were no significant differences in secondary outcomes including number of vasoactive agents required, hospital length of stay, and duration of mechanical ventilation. Subgroup analysis of patients with extremes of body mass index did not show a difference in time to achieve goal MAP. In a subgroup analysis of patients with septic shock, a higher percentage of patients in the WB group received corticosteroids than the NWB group patients (14% vs. 54%; P ≤ 0.001). Conclusion and relevance: There was no difference in time to achieve goal MAP when using a WB or NWB vasopressor dosing approach. Institutions should employ a consistent dosing strategy for vasopressors with either an NWB or WB approach.

Hemodynamics: Strangers to Lung-kidney Crosstalk in ARDS?

How to cite this article: Magoon R, Sharma AG, Yadav N, Choupoo NS. Hemodynamics: Strangers to Lung-kidney Crosstalk in ARDS? Indian J Crit Care Med 2024;28(2):177-178.

Society for Maternal-Fetal Medicine Consult Series #67: Maternal sepsis.

Maternal sepsis is a significant cause of maternal morbidity and mortality, and is a potentially preventable cause of maternal death. This Consult aims to summarize what is known about sepsis and provide guidance for the management of sepsis during pregnancy and the postpartum period. Most studies cited are from the nonpregnant population, but where available, pregnancy data are included. The following are the Society for Maternal-Fetal Medicine recommendations: (1) we recommend that clinicians consider the diagnosis of sepsis in pregnant or postpartum patients with otherwise unexplained end-organ damage in the presence of a suspected or confirmed infectious process, regardless of the presence of fever (GRADE 1C); (2) we recommend that sepsis and septic shock in pregnancy be considered medical emergencies and that treatment and resuscitation begin immediately (Best Practice); (3) we recommend that hospitals and health systems use a performance improvement program for sepsis in pregnancy with sepsis screening tools and metrics (GRADE 1B); (4) we recommend that institutions develop their own procedures and protocols for the detection of maternal sepsis, avoiding the use of a single screening tool alone (GRADE 1B); (5) we recommend obtaining tests to evaluate for infectious and noninfectious causes of life-threatening organ dysfunction in pregnant and postpartum patients with possible sepsis (Best Practice); (6) we recommend that an evaluation for infectious causes in pregnant or postpartum patients in whom sepsis is suspected or identified includes appropriate microbiologic cultures, including blood, before starting antimicrobial therapy, as long as there are no substantial delays in timely administration of antibiotics (Best Practice); (7) we recommend obtaining a serum lactate level in pregnant or postpartum patients in whom sepsis is suspected or identified (GRADE 1B); (8) in pregnant or postpartum patients with septic shock or a high likelihood of sepsis, we recommend administration of empiric broad-spectrum antimicrobial therapy, ideally within 1 hour of recognition (GRADE 1C); (9) after a diagnosis of sepsis in pregnancy is made, we recommend rapid identification or exclusion of an anatomic source of infection and emergency source control when indicated (Best Practice); (10) we recommend early intravenous administration (within the first 3 hours) of 1 to 2 L of balanced crystalloid solutions in sepsis complicated by hypotension or suspected organ hypoperfusion (GRADE 1C); (11) we recommend the use of a balanced crystalloid solution as a first-line fluid for resuscitation in pregnant and postpartum patients with sepsis or septic shock (GRADE 1B); (12) we recommend against the use of starches or gelatin for resuscitation in pregnant and postpartum patients with sepsis or septic shock (GRADE 1A); (13) we recommend ongoing, detailed evaluation of the patient's response to fluid resuscitation guided by dynamic measures of preload (GRADE 1B); (14) we recommend the use of norepinephrine as the first-line vasopressor during pregnancy and the postpartum period with septic shock (GRADE 1C); (15) we suggest using intravenous corticosteroids in pregnant or postpartum patients with septic shock who continue to require vasopressor therapy (GRADE 2B); (16) because of an increased risk of venous thromboembolism in sepsis and septic shock, we recommend the use of pharmacologic venous thromboembolism prophylaxis in pregnant and postpartum patients in septic shock (GRADE 1B); (17) we suggest initiating insulin therapy at a glucose level >180 mg/dL in critically ill pregnant patients with sepsis (GRADE 2C); (18) if a uterine source for sepsis is suspected or confirmed, we recommend prompt delivery or evacuation of uterine contents to achieve source control, regardless of gestational age (GRADE 1C); and (19) because of an increased risk of physical, cognitive, and emotional problems in survivors of sepsis and septic shock, we recommend ongoing comprehensive support for pregnant and postpartum sepsis survivors and their families (Best Practice).

Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock.

BACKGROUND: Extracellular histones have been associated with severity and outcome in sepsis. The aim of the present study was to assess the effects of sodium-ß-O-Methyl cellobioside sulfate (mCBS), a histone-neutralizing polyanion, on the severity and outcome of sepsis in an experimental model. METHODS: This randomized placebo-controlled experimental study was performed in 24 mechanically ventilated female sheep. Sepsis was induced by fecal peritonitis. Animals were randomized to three groups: control, early treatment, and late treatment (n = 8 each). mCBS was given as a bolus (1 mg/kg) followed by a continuous infusion (1 mg/kg/h) just after sepsis induction in the early treatment group, and 4 h later in the late treatment group. Fluid administration and antimicrobial therapy were initiated 4 h T4 after feces injection, peritoneal lavage performed, and a norepinephrine infusion titrated to maintain mean arterial pressure (MAP) between 65-75 mmHg. The experiment was blinded and lasted maximum 24 h. RESULTS: During the first 4 h, MAP remained > 65 mmHg in the early treatment group but decreased significantly in the others (p < 0.01 for interaction, median value at T4: (79 [70-90] mmHg for early treatment, 57 [70-90] mmHg for late treatment, and 55 [49-60] mmHg for the control group). mCBS-treated animals required significantly less norepinephrine to maintain MAP than controls (p < 0.01 for interaction) and had lower creatinine (p < 0.01), lactate (p < 0.01), and interleukin-6 (p < 0.01) levels, associated with reduced changes in H3.1 nucleosome levels (p = 0.02). Early treatment was associated with lower norepinephrine requirements than later treatment. Two control animals died; all the mCBS-treated animals survived. CONCLUSIONS: Neutralization of extracellular histones with mCBS was associated with reduced norepinephrine requirements, improved tissue perfusion, less renal dysfunction, and lower circulating IL-6 in experimental septic shock and may represent a new therapeutic approach to be tested in clinical trials.

Serial assessments of cardiac output and mixed venous oxygen saturation in comatose patients after out-of-hospital cardiac arrest.

AIM: To assess the association with outcomes of cardiac index (CI) and mixed venous oxygen saturation (SvO2) in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: In the cohort study of 789 patients included in the "BOX"-trial, 565 (77%) patients were included in this hemodynamic substudy (age 62 ± 13 years, male sex 81%). Pulmonary artery catheters were inserted shortly after ICU admission. CI and SvO2 were measured as soon as possible in the ICU and until awakening or death. The endpoints were all-cause mortality at 1 year and renal failure defined as need for renal replacement therapy. RESULTS: First measured CI was median 1.7 (1.4-2.1) l/min/m2, and first measured SvO2 was median 67 (61-73) %. CI < median with SvO2 > median was present in 222 (39%), and low SvO2 with CI < median was present in 59 (11%). Spline analysis indicated that SvO2 value < 55% was associated with poor outcome. Low CI at admission was not significantly associated with mortality in multivariable analysis (p = 0.14). SvO2 was significantly inversely associated with mortality (hazard ratioadjusted: 0.91 (0.84-0.98) per 5% increase in SvO2, p = 0.01). SvO2 was significantly inversely associated with renal failure after adjusting for confounders (ORadjusted: 0.73 [0.62-0.86] per 5% increase in SvO2, p = 0.001). The combination of lower CI and lower SvO2 was associated with higher risk of mortality (hazard ratioadjusted: 1.54 (1.06-2.23) and renal failure (ORadjusted: 5.87 [2.34-14.73]. CONCLUSION: First measured SvO2 after resuscitation from OHCA was inversely associated with mortality and renal failure. If SvO2 and CI were below median, the risk of poor outcomes increased significantly. REGISTRATION: The BOX-trial is registered at clinicaltrials.gov (NCT03141099, date 2017-30-04, retrospectively registered).

Mega-dose sodium ascorbate: a pilot, single-dose, physiological effect, double-blind, randomized, controlled trial.

BACKGROUND: Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown. METHODS: We conducted a pilot, single-dose, double-blind, randomized controlled trial. We enrolled patients with septic shock within 24 h of diagnosis. We randomly assigned them to receive a single mega-dose of NaAscorbate (30 g over 1 h followed by 30 g over 5 h) or placebo (vehicle). The primary outcome was the total 24 h urine output (UO) from the beginning of the study treatment. Secondary outcomes included the time course of the progressive cumulative UO, vasopressor dose, and sequential organ failure assessment (SOFA) score. RESULTS: We enrolled 30 patients (15 patients in each arm). The mean (95% confidence interval) total 24-h UO was 2056 (1520-2593) ml with placebo and 2948 (2181-3715) ml with NaAscorbate (mean difference 891.5, 95% confidence interval [- 2.1 to 1785.2], P = 0.051). Moreover, the progressive cumulative UO was greater over time on linear mixed modelling with NaAscorbate (P < 0.001). Vasopressor dose and SOFA score changes over time showed faster reductions with NaAscorbate (P < 0.001 and P = 0.042). The sodium level, however, increased more over time with NaAscorbate (P < 0.001). There was no statistical difference in other clinical outcomes. CONCLUSION: In patients with septic shock, mega-dose NaAscorbate did not significantly increase cumulative 24-h UO. However, it induced a significantly greater increase in UO and a greater reduction in vasopressor dose and SOFA score over time. One episode of hypernatremia and one of hemolysis were observed in the NaAscorbate group. These findings support further cautious investigation of this novel intervention. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN12620000651987), Date registered June/5/2020.