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Malaria is considered as the most important parasitic disease of humans, causing seri- ous illness that can be fatal, if not diagnosed and treated immediately. It is a multisystem disorder affecting nearly every system of the body. The aim of the present study was to evaluate the involvement of cardiovascular system in severe malaria using non-invasive methods. This prospective study was conducted on patients of severe malaria who were admitted between June and November 2015 in the Department of Medicine, Rajendra Institute of Medical Sciences and Hospital, Ranchi, Jharkhand, India. A total of 27 cases (18 males and 9 females; age ranging between 15 and 70 yr) of severe malaria (P. falciparum 24; P. vivax 1; mixed 2) were diagnosed by microscopic examination of peripheral blood smear and bivalent rapid diagnostic test (RDT) kit. The assessment of cardiovascular system was done by clinical examination, chest X-ray, ECG and transthoracic echocardiography. In all, 7 (26%) patients were found to be suffering from circulatory failure, out of which one was P. vivax case and rest were cases of P. falciparum infection with high parasite density. One patient died due to cardiovascular collapse. ECG revealed sinus bradycardia [Heart rate (HR): 40-60] in 7% of the cases, extreme tachycardia (HR: 120-150) in 3.7% of cases and premature arterial ectopic with tachycardia in 3.7% of patients (p <0.05). The echo- cardiographic findings were global hypokinesia with decreased left ventricular ejection fraction (<55%) in 11.1%, grade 1 left ventricular diastolic dysfunction in 3.7%, mild tricuspid regurgitation (TR) with mild pulmonary artery hypertension (PAH) in 3.7% and mild pericardial effusion in 3.7% of the cases. The ECG and echocardiography changes indicated myocardial involvement in severe malaria. The present study indicated involvement of cardiovascular system in severe malaria as evidenced from ECG and echocardiography. The study also revealed that cardiovascular instabilities are common in falciparum malaria, but can also be observed in vivax malaria.

Recently, vivax malaria is also presenting as severe malaria causing multiorgan dysfunction similar to falciparum malaria. The present study was undertaken to evaluate the involvement of cardiovascular system in severe malaria. This is a clinical prospective study conducted on the cases of severe malaria in S.P. Medical College and PBM Hospital, Bikaner, India. In total, 100 cases (45 males, 55 females; age range 13-75 yr) of severe malaria (P. vivax 60; P. falciparum 28; and mixed 12) diagnosed by peripheral blood smear examination, rapid card test and PCR were studied. Evaluation of cardiovascular system was done by clinical examination, chest Xray, ECG, high resolution transthoracic echocardiography and estimation of cardiac markers. In all, 17% cases (9 P. falciparum, 5 P. vivax and 3 mixed) were found to be suffering from cardiovascular involvement (11% circulatory failure, 7% congestive cardiac failure and 2% pulmonary edema). ECG showed sinus tachycardia in all the 17 patients, one had atrial ectopic and eight had non-specific ST-T changes. Cardiomegaly was seen in eight cases and pulmonary edema in two on X-ray chest. Echocardiography was within normal range but cardiac dimensions were increased in all the 17 cases. Troponin-I and CPK-MB were increased in 14 cases. Cardiovascular involvement in P. falciparum and mixed infection was associated with high parasite density but P. vivax infection was associated with relatively low parasite density. Involvement of cardiovascular system was associated with increased hospital stay (7.67 ± 2.23 vs 6.59 ± 0.87 days; p <0.001) and high mortality (5 died out of 17 patients). Significant ECG changes and cardiac markers indicate myocardial involvement in severe malaria. The present study indicates involvement of cardiovascular system in severe malaria as evidenced by changes in ECG and cardiac markers (Trop 1 and CPK-MB). The present study also highlights that vivax malaria is no more benign and pathophysiology of vivax malaria should be re-evaluated.

Background  Circulatory failure is classified into four types of shock (obstructive, cardiogenic, distributive, and hypovolemic) that must be distinguished as each requires a different treatment. Point-of-care ultrasound (POCUS) is widely used in clinical practice for acute conditions, and several diagnostic protocols using POCUS for shock have been developed. This study aimed to evaluate the diagnostic accuracy of POCUS in identifying the etiology of shock. Methods We conducted a systematic literature search of MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Web of Science, Clinicaltrial.gov, European Union Clinical Trials Register, WHO International Clinical Trials Registry Platform, and University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) until June 15, 2022. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and assessed study quality using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis was conducted to pool the diagnostic accuracy of POCUS for each type of shock. The study protocol was prospectively registered in UMIN-CTR (UMIN 000048025). Results Of the 1553 studies identified, 36 studies were full-text reviewed, and 12 studies with 1132 patients were included in the meta-analysis. Pooled sensitivity and specificity were 0.82 [95% confidence interval (CI) 0.68–0.91] and 0.98 [95% CI 0.92–0.99] for obstructive shock, 0.78 [95% CI 0.56–0.91] and 0.96 [95% CI 0.92–0.98] for cardiogenic shock, 0.90 [95% CI 0.84–0.94] and 0.92 [95% CI 0.88–0.95] for hypovolemic shock, and 0.79 [95% CI 0.71–0.85] and 0.96 [95% CI 0.91–0.98] for distributive shock, respectively. The area under the receiver operating characteristic curve for each type of shock was approximately 0.95. The positive likelihood ratios for each type of shock were all greater than 10, especially 40 [95% CI 11–105] for obstructive shock. The negative likelihood ratio for each type of shock was approximately 0.2. Conclusions  The identification of the etiology for each type of shock using POCUS was characterized by high sensitivity and positive likelihood ratios, especially for obstructive shock.

Vasoplegia is a ubiquitous phenomenon in all advanced shock states, including septic, cardiogenic, hemorrhagic, and anaphylactic shock. Its pathophysiology is complex, involving various mechanisms in vascular smooth muscle cells such as G protein-coupled receptor desensitization (adrenoceptors, vasopressin 1 receptors, angiotensin type 1 receptors), alteration of second messenger pathways, critical illness-related corticosteroid insufficiency, and increased production of nitric oxide. This review, based on a critical appraisal of the literature, discusses the main current treatments and future approaches. Our improved understanding of these mechanisms is progressively changing our therapeutic approach to vasoplegia from a standardized to a personalized multimodal treatment with the prescription of several vasopressors. While norepinephrine is confirmed as first line therapy for the treatment of vasoplegia, the latest Surviving Sepsis Campaign guidelines also consider that the best therapeutic management of vascular hyporesponsiveness to vasopressors could be a combination of multiple vasopressors, including norepinephrine and early prescription of vasopressin. This new approach is seemingly justified by the need to limit adrenoceptor desensitization as well as sympathetic overactivation given its subsequent deleterious impacts on hemodynamics and inflammation. Finally, based on new pathophysiological data, two potential drugs, selepressin and angiotensin II, are currently being evaluated.

PurposeNet ultrafiltration (UFNET) during continuous renal replacement therapy (CRRT) can control fluid balance (FB), but is usually 0 ml·h−1 in patients with vasopressors due to the risk of hemodynamic instability associated with CRRT (HIRRT). We evaluated a UFNET strategy adjusted by functional hemodynamics to control the FB of patients with vasopressors, compared to the standard of care.MethodsIn this randomized, controlled, open-label, parallel-group, multicenter, proof-of-concept trial, adults receiving vasopressors, CRRT since ≤ 24 h and cardiac output monitoring were randomized (ratio 1:1) to receive during 72 h a UFNET ≥ 100 ml·h−1, adjusted using a functional hemodynamic protocol (intervention), or a UFNET ≤ 25 ml·h−1 (control). The primary outcome was the cumulative FB at 72 h and was analyzed in patients alive at 72 h and in whom monitoring and CRRT were continuously provided (modified intention-to-treat population [mITT]). Secondary outcomes were analyzed in the intention-to-treat (ITT) population.ResultsBetween June 2021 and April 2023, 55 patients (age 69 [interquartile range, IQR: 62; 74], 35% female, Sequential Organ Failure Assessment (SOFA) 13 [11; 15]) were randomized (25 interventions, 30 controls). In the mITT population, (21 interventions, 24 controls), the 72 h FB was −2650 [−4574; −309] ml in the intervention arm, and 1841 [821; 5327] ml in controls (difference: 4942 [95% confidence interval: 2736–6902] ml, P < 0.01). Hemodynamics, oxygenation and the number of HIRRT at 72 h, and day-90 mortality did not statistically differ between arms.ConclusionIn patients with vasopressors, a UFNET fluid removal strategy secured by a hemodynamic protocol allowed active fluid balance control, compared to the standard of care.

Abstract Purpose Acute circulatory failure leads to tissue hypoperfusion. Capillary refill time (CRT) has been widely studied, but its predictive value remains debated. We conducted a meta-analysis to assess the ability of CRT to predict death or adverse events in a context at risk or confirmed acute circulatory failure in adults. Method MEDLINE, EMBASE, and Google scholar databases were screened for relevant studies. The pooled area under the ROC curve (AUC ROC), sensitivity, specificity, threshold, and diagnostic odds ratio using a random-effects model were determined. The primary analysis was the ability of abnormal CRT to predict death in patients with acute circulatory failure. Secondary analysis included the ability of CRT to predict death or adverse events in patients at risk or with confirmed acute circulatory failure, the comparison with lactate, and the identification of explanatory factors associated with better accuracy. Results A total of 60,656 patients in 23 studies were included. Concerning the primary analysis, the pooled AUC ROC of 13 studies was 0.66 (95%CI [0.59; 0.76]), and pooled sensitivity was 54% (95%CI [43; 64]). The pooled specificity was 72% (95%CI [55; 84]). The pooled diagnostic odds ratio was 3.4 (95%CI [1.4; 8.3]). Concerning the secondary analysis, the pooled AUC ROC of 23 studies was 0.69 (95%CI [0.65; 0.74]). The prognostic value of CRT compared to lactate was not significantly different. High-quality CRT was associated with a greater accuracy. Conclusion CRT poorly predicted death and adverse events in patients at risk or established acute circulatory failure. Its accuracy is greater when high-quality CRT measurement is performed.

Background The optimal timing for initiating norepinephrine in septic shock is debated. This updated systematic review and meta-analysis aimed to evaluate the impact of early versus delayed norepinephrine initiation on mortality and clinical outcomes in adults with septic shock. Methods A systematic search in Pubmed, EMbase and the Cochrane Library to identify eligible randomized controlled trials, propensity score matching (PSM) and observational studies that compare early norepinephrine initiation with non-early norepinephrine initiation in patients with acute circulatory failure. The primary outcome was mortality in intensive care unit. Secondary outcomes included intensive care unit length of stay, fluid volume received at 6 h, norepinephrine dose, mechanical ventilation-free days, renal replacement therapy free days, and time to achieve a targeted mean arterial pressure (MAP). Meta-analysis and subgroup analysis were conducted to calculate odds ratio (OR) or mean difference with 95% confidence interval (95%CI) using random-effect model. Trial sequential analysis was conducted to evaluate the conclusiveness of evidence. Results Ten studies (two RCT, three PSM and five observational studies) involving 4767 patients were included. Early norepinephrine significantly reduced mortality in RCT (OR 0.49, 95%CI 0.25–0.96; I 2  = 45%, p  = 0.04), pooled RCT and PSM (OR 0.65, 95%CI 0.42–0.99; I 2  = 74%, p  = 0.05), and observational studies (OR 0.71, 95%CI 0.54–0.94; I 2  = 66%). The trial sequential analysis indicated more data are needed. Subgroup analyses showed reduced mortality with early norepinephrine when lactate was ≤ 3mmol/L and administered within 1 h. Secondary outcomes showed a reduced fluid volume at 6h (RCT + PSM: mean difference −502 mL, 95%CI −899 to −106; I 2  = 91%, p  = 0.01), faster MAP target achievement (RCT + PSM: mean difference −1.30h, 95%CI −1.75 to −0.85; I 2  = 0%, p  < 0.01), more mechanical ventilation-free days (RCT + PSM: mean difference 3.99 days, 95%CI 2.42–5.57; I 2  = 32%, p  < 0.01) and smaller cumulative norepinephrine dose (Observational: mean difference –3.44 mcg/kg, 95%CI -6.13 to -0.76; I 2  = 0%, p = 0.01) in the early initiation group compare to the non-early initiation group. Conclusion Early norepinephrine introduction in septic shock is associated with reduced mortality, decreased fluid volume administered at 6 h, faster time to achieve MAP target and more mechanical ventilation-free days. However, the trial sequential analysis indicates that further RCT are still needed to confirm these findings.

Circulating dipeptidyl peptidase 3 is a new biomarker linked to circulatory failure prognosis and pathophysiology and is a potential actionable therapeutic target. In this short review intended for the clinician, a question-and-answer format provides key insights on the nature of this biomarker and the therapeutical potential of its targeted inhibition in critically ill patients.

Background Alterations in the renin–angiotensin system have been implicated in the pathophysiology of septic shock. In particular, angiotensin 1–7 (Ang-(1–7)), an anti-inflammatory heptapeptide, has been hypothesized to have beneficial effects. The aim of the present study was to test the effects of Ang-(1–7) infusion on the development and severity of septic shock. Methods This randomized, open-label, controlled study was performed in 14 anesthetized and mechanically ventilated sheep. Immediately after sepsis induction by bacterial peritonitis, animals received either Ang-(1–7) ( n  = 7) or placebo ( n  = 7) intravenously. Fluid resuscitation, antimicrobial therapy, and peritoneal lavage were initiated 4 h after sepsis induction. Norepinephrine administration was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg. Results There were no differences in baseline characteristics between groups. Septic shock was prevented in 6 of the 7 animals in the Ang-(1–7) group at the end of the 24-h period. Fluid balance and MAP were similar in the two groups; however, MAP was achieved with a mean norepinephrine dose of 0.4 μg/kg/min in the Ang-(1–7) group compared to 4.3 μg/kg/min in the control group. Heart rate and cardiac output index were lower in the Ang (1–7) than in the control group, as were plasma interleukin-6 levels, and creatinine levels. Platelet count and PaO 2 /FiO 2 ratio were higher in the Ang-(1–7) group. Mean arterial lactate at the end of the experiment was 1.6 mmol/L in the Ang-(1–7) group compared to 7.4 mmol/L in the control group. Conclusions In this experimental septic shock model, early Ang-(1–7) infusion prevented the development of septic shock, reduced norepinephrine requirements, limited interleukine-6 increase and prevented renal dysfunction.

Background Acute kidney injury (AKI) is a frequent and severe complication among critically ill patients. Circulating dipeptidyl peptidase 3 (cDPP3), an enzyme released upon cellular injury, has been implicated in hemodynamic instability and organ dysfunction. Its role in severe AKI remains poorly defined. We aimed to assess the prognostic significance of cDPP3 in critically ill patients with severe AKI. Methods In this post hoc analysis of the AKIKI 2 study, we included ICU patients with severe AKI (KDIGO stage 3) who were receiving (or had received) invasive mechanical ventilation and/or vasopressor support and had available blood samples at inclusion. Patients were stratified according to cDPP3 concentration using a predefined cutoff of 40 ng/mL. The primary outcome was 28-day mortality; secondary outcomes were organ support–free days. Results Among 287 included patients, 143 (49.8%) had cDPP3 concentrations above 40 ng/mL. High cDPP3 was associated with increased 28-day mortality (hazard ratio 1.95; 95% confidence interval 1.37–2.87, p  < 0.001). Furthermore, high cDPP3 was associated with fewer days alive without vasopressors (mean difference − 5.59; 95% CI − 8.29 to − 2.78, p  < 0.001), invasive mechanical ventilation (mean difference − 6.23; 95% CI − 8.89 to − 3.36, p  < 0.001), or renal replacement therapy (mean difference − 6.35; 95% CI − 9.14 to − 3.26, p  < 0.001). After adjustment for baseline markers of severity, both the associations with 28-day mortality and organ support-free days remained significant. Conclusions In critically ill patients with severe AKI, a high cDPP3 concentration at diagnosis is associated with increased short-term mortality and prolonged dependence on organ support.