Impact of Adjuvant Use of Midodrine to Intravenous Vasopressors: A Systematic Review and Meta-Analysis.

PURPOSE: To evaluate the efficacy and safety of midodrine use in intensive care units (ICU) to facilitate weaning off intravenous vasopressors (IVV). METHODS: We searched PubMed/MEDLINE, Cochrane library, and Google Scholar (inception through October 18th, 2020) for studies evaluating adjuvant use of midodrine to IVV in the ICU. The outcomes of interest were ICU length of stay (LOS), hospital LOS, mortality, IVV reinstitution, ICU readmission, and bradycardia. Estimates were pooled using the random-effects model. We reported effect sizes as standardized mean difference (SMD) for continuous outcomes and risk ratios (RRs) for other outcomes with a 95% confidence interval (CI). RESULTS: A total of 6 studies were found that met inclusion criteria and had sufficient data for our quantitative analysis (1 randomized controlled trial and 5 retrospective studies). A total of 2,857 patients were included: 600 in the midodrine group and 2,257 patients in the control group. Midodrine use was not associated with a significant difference in ICU LOS (SMD 0.16 days; 95% CI -0.23 to 0.55), hospital LOS (SMD 0.03 days; 95% CI -0.33 to 0.0.39), mortality (RR 0.87; 95% CI 0.52 to 1.46), IVV reinstitution (RR 0.47; 95% CI 0.17 to 1.3), or ICU readmission (RR 1.03; 95% CI 0.71 to 1.49) when compared to using only IVV. However, there were higher trends of bradycardia with midodrine use that did not reach significance (RR 7.64; 95% CI 0.23 to 256.42). CONCLUSION: This meta-analysis suggests that midodrine was not associated with a significant decrease in ICU LOS, hospital LOS, mortality, or ICU readmissions.

A Rationale for Use of High Flow Nasal Cannula for Select Patients With Suspected or Confirmed Severe Acute Respiratory Syndrome Coronavirus-2 Infection.

Infection with the novel 2019 coronavirus (SARS-CoV-2) is associated with the development of a viral pneumonia with severe hypoxemia and respiratory failure. In many cases these patients will require mechanical ventilation; but in others the severity of disease is significantly less and may not need invasive support. High flow nasal cannula (HFNC) is a widely used modality of delivering high concentrations of oxygen and airflow to patients with hypoxemic respiratory failure, but its use in patients with SARS-CoV-2 is poorly described. Concerns with use of HFNC have arisen including aerosolization of viral particles to healthcare workers (HCW) to delaying intubation and potentially worsening of outcomes. However, use of HFNC in other coronavirus pandemics and previous experimental evidence suggest HFNC is low risk and may be effective in select patients infected with SARS-CoV-2. With the significant increase in resource utilization in care of patients with SARS-CoV-2, identification of those that may benefit from HFNC allowing allocation of ventilators to those more critically ill is of significant importance. In this manuscript, we review pertinent literature regarding the use of HFNC in the current SARS-CoV-2 pandemic and address many concerns regarding its use.

Hydrocortisone decreases lethality and inflammatory cytokine and nitric oxide production in rats challenged with B. anthracis cell wall peptidoglycan.

BACKGROUND: Lethal B. anthracis infection produces high proinflammatory peptidoglycan (PGN) burdens in hosts. We investigated whether the lethality and inflammation anthrax PGN can produce are related. METHODS: At 6 h before and the start of 24 h anthrax PGN infusions, rats (n = 198) were treated with diluent (controls) or one of three IV-doses of either hydrocortisone (125, 12.5 or 1.25 mg/kg) or TNF-soluble receptor (TNFsr; 2000, 1000 or 333 µg/kg), non-selective and selective anti-inflammatory agents, respectively. RESULTS: Compared to controls, hydrocortisone 125 and 12.5 mg/kg each decreased 7-day lethality (p ≤ 0.004). Hydrocortisone 125 mg/kg decreased IL-1ß, IL-6, TNFα, MCP, MIP-1α, MIP-2, RANTES and nitric oxide (NO) blood levels at 4 and 24 h after starting PGN (except MCP at 24 h). Each decrease was significant at 4 h (except MIP-1α that was significant at 24 h) (p ≤ 0.05). Similarly, hydrocortisone 12.5 mg/kg decreased each measure at 4, 24 and 48 h (except TNFα at 24 h and MIP-1α at 24 and 48 h and NO at 48 h). Decreases were significant for IL-6 and NO at 4 h and RANTES at 48 h (p ≤ 0.05). Hydrocortisone 1.25 mg/kg had non-significant effects. Each TNFsr dose decreased lethality but non-significantly. However, when doses were analyzed together, TNFsr decreased lethality in a potential trend (p = 0.16) and IL-6 and NO significantly at 4 h (p = 0.05). CONCLUSIONS: Peptidoglycan-stimulated host inflammation may contribute to B. anthracis lethality.

Pulmonary tumor thrombotic microangiopathy and pulmonary veno-occlusive disease in a woman with cervical cancer treated with cediranib and durvalumab.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare cause of pulmonary hypertension that is associated with malignancies and is marked by the presence of non-occlusive tumor emboli and fibrocellular intimal proliferation of small pulmonary arteries leading to increased pulmonary vascular resistance and right heart failure. The diagnosis of PTTM is challenging to make pre-mortem and guidelines on treatment are lacking. CASE PRESENTATION: A 45-year-old woman with advanced squamous cell carcinoma of the cervix developed symptoms of dyspnea and evidence of right heart failure during a phase I clinical trial with cediranib and durvalumab. After an extensive evaluation, pre-capillary pulmonary hypertension was confirmed by right heart catheterization. Vasodilator therapy was initiated but resulted in the development of symptomatic hypoxemia and was discontinued. Despite continued supportive care, she continued to decline and was transitioned to hospice care. At autopsy, the cause of her right heart failure was found to be due to PTTM with features of pulmonary veno-occlusive disease (PVOD). CONCLUSION: PTTM and PVOD are important diagnoses to consider in patients with a malignancy and the development of right heart failure and may be manifestations of a spectrum of similar disease processes.

The Potential Pathogenic Contributions of Endothelial Barrier and Arterial Contractile Dysfunction to Shock Due to B. anthracis Lethal and Edema Toxins.

Shock with B. anthracis infection is particularly resistant to conventional cardiovascular support and its mortality rate appears higher than with more common bacterial pathogens. As opposed to many bacteria that lack exotoxins directly depressing hemodynamic function, lethal and edema toxin (LT and ET respectively) both cause shock and likely contribute to the high lethality rate with B. anthracis. Selective inhibition of the toxins is protective in infection models, and administration of either toxin alone in animals produces hypotension with accompanying organ injury and lethality. Shock during infection is typically due to one of two mechanisms: (i) intravascular volume depletion related to disruption of endothelial barrier function; and (ii) extravasation of fluid and/or maladaptive dilation of peripheral resistance arteries. Although some data suggests that LT can produce myocardial dysfunction, growing evidence demonstrates that it may also interfere with endothelial integrity thereby contributing to the extravasation of fluid that helps characterize severe B. anthracis infection. Edema toxin, on the other hand, while known to produce localized tissue edema when injected subcutaneously, has potent vascular relaxant effects that could lead to pathologic arterial dilation. This review will examine recent data supporting a role for these two pathophysiologic mechanisms underlying the shock LT and ET produce. Further research and a better understanding of these mechanisms may lead to improved management of B. anthracis in patients.

Anthrax immune globulin improves hemodynamics and survival during B. anthracis toxin-induced shock in canines receiving titrated fluid and vasopressor support.

BACKGROUND: Although anthrax immune globulin (AIG) improved survival in antibiotic-treated Bacillus anthracis-challenged animal models, whether it adds to the benefit of conventional hemodynamic support for B. anthracis toxin-associated shock is unknown. METHODS: We therefore tested AIG in sedated, mechanically ventilated canines challenged with 24-h B. anthracis lethal and edema toxin infusions and supported for 96 h with a previously demonstrated protective regimen of titrated normal saline and norepinephrine. RESULTS: Compared to controls, proportional survival (%) was increased with AIG treatment started 4 h before (33 vs. 100%, n = 6 each) or 2 h (17 vs. 86%, n = 6 and 7 respectively) or 5 h (0 vs. 67%, n = 3 each) after the start of toxin (p ≤ 0.05) and overall [3 survivors of 15 controls (20%) vs. 14 of 16 AIG animals (88%); p = 0.006]. Averaged across treatment times, AIG increased blood pressure at 48 h and decreased norepinephrine requirements at 72 h (p ≤ 0.02), increased left ventricular ejection fraction at 48 and 72 h (p ≤ 0.02), and increased urine output and decreased net fluid balance at 72 and 96 h (p ≤ 0.04). AIG also reduced acidosis and renal and hepatic injury markers between 24 and 96 h. CONCLUSIONS: These findings further support AIG's potential benefit for patients with B. anthracis infection and developing toxin-associated shock.

Shock and lethality with anthrax edema toxin in rats are associated with reduced arterial responsiveness to phenylephrine and are reversed with adefovir.

Although edema toxin (ETx) and lethal toxin (LTx) contribute to Bacillus anthracis shock and lethality, the mechanisms underlying their cardiovascular effects are unclear. We have previously shown that ETx but not LTx inhibited phenylephrine-stimulated contraction of aortic rings prepared from healthy rats and that adefovir, a selective inhibitor of ETx cAMP production, blocked this effect. Here, we examined arterial function in rats that received 24-h ETx or LTx infusions. Compared with control rats, ETx reduced mean arterial pressure (MAP) and survival over 48 h (P ≤ 0.0003) and increased plasma cAMP at 4, 24, and 48 h (P < 0.0001) and nitric oxide (NO) at 24 and 48 h (P ≤ 0.01). Compared with control animals, at 24- and 48-h phenylephrine stimulation of aortic rings from ETx animals produced decreased maximal contractile force (MCF; P = 0.05 and 0.006) and in vivo phenylephrine infusion in ETx animals produced decreased proportional increases in MAP (P < 0.0001 and P = 0.05). In ETx-treated animals, compared with placebo-treated animals, adefovir treatment prevented all lethality (P = 0.01), increased MAP (P ≤ 0.0001), decreased plasma and aortic tissue cAMP at 24 and 48 h, respectively (P ≤ 0.03), and plasma NO at both times (P ≤ 0.004), and increased phenylephrine-stimulated increases in MCF in aortic rings and MAP in vivo at 48 h (P = 0.02). LTx decreased MAP and survival also, but it did not alter the response to phenylephrine of MCF in aortic rings prepared from LTx animals or of MAP in vivo. In conclusion, in rats, hypotension and lethality are associated with reduced arterial contractile function with ETx but not LTx and adefovir improves ETx-induced hypotension and lethality.NEW & NOTEWORTHY The most important aspects of the present study are the findings that 1) in vivo challenge with anthrax edema but not lethal toxin depresses arterial contractile function measured both ex vivo and in vivo and 2) adefovir inhibits the effects of edema toxin on arterial hypotension and improves survival with lethal dose of edema toxin challenge.

Parenteral irons versus transfused red blood cells for treatment of anemia during canine experimental bacterial pneumonia.

BACKGROUND: No studies have been performed comparing intravenous (IV) iron with transfused red blood cells (RBCs) for treating anemia during infection. In a previous report, transfused older RBCs increased free iron release and mortality in infected animals when compared to fresher cells. We hypothesized that treating anemia during infection with transfused fresh RBCs, with minimal free iron release, would prove superior to IV iron therapy. STUDY DESIGN AND METHODS: Purpose-bred beagles (n = 42) with experimental Staphylococcus aureus pneumonia rendered anemic were randomized to be transfused RBCs stored for 7 days or one of two IV iron preparations (7 mg/kg), iron sucrose, a widely used preparation, or ferumoxytol, a newer formulation that blunts circulating iron levels. RESULTS: Both irons increased the alveolar-arterial oxygen gradient at 24 to 48 hours (p = 0.02-0.001), worsened shock at 16 hours (p = 0.02-0.003, respectively), and reduced survival (transfusion 56%; iron sucrose 8%, p = 0.01; ferumoxytol 9%, p = 0.04). Compared to fresh RBC transfusion, plasma iron measured by non-transferrin-bound iron levels increased with iron sucrose at 7, 10, 13, 16, 24, and 48 hours (p = 0.04 to p < 0.0001) and ferumoxytol at 7, 24, and 48 hours (p = 0.04 to p = 0.004). No significant differences in cardiac filling pressures or performance, hemoglobin (Hb), or cell-free Hb were observed. CONCLUSIONS: During canine experimental bacterial pneumonia, treatment of mild anemia with IV iron significantly increased free iron levels, shock, lung injury, and mortality compared to transfusion of fresh RBCs. This was true for iron preparations that do or do not blunt circulating free iron level elevations. These findings suggest that treatment of anemia with IV iron during infection should be undertaken with caution.

Does Bacillus anthracis Lethal Toxin Directly Depress Myocardial Function? A Review of Clinical Cases and Preclinical Studies.

The US outbreak of B.anthracis infection in 2001 and subsequent cases in the US and Europe demonstrate that anthrax is a continuing risk for the developed world. While several bacterial components contribute to the pathogenesis of B. anthracis, production of lethal toxin (LT) is strongly associated with the development of hypotension and lethality. However, the mechanisms underlying the cardiovascular instability LT produces are unclear. Some evidence suggests that LT causes shock by impairing the peripheral vasculature, effects consistent with the substantial extravasation of fluid in patients dying with B. anthracis. Other data suggests that LT directly depresses myocardial function. However a clinical correlate for this latter possibility is less evident since functional studies and post-mortem examination in patients demonstrate absent or minimal cardiac changes. The purposes of this review were to first present clinical studies of cardiac functional and histologic pathology with B. anthracis infection and to then examine in vivo, in vitro, and ex vivo preclinical studies of LT's myocardial effects. Together, these data suggest that it is unclear whether that LT directly depresses cardiac function. This question is important for the clinical management and development of new therapies for anthrax and efforts should continue to be made to answer it.

Long-term outcomes following alemtuzumab induction in lung transplantation.

OBJECTIVES: Alemtuzumab is a commonly used induction agent for solid-organ transplantation. Its use in lung transplantation with reduced immunosuppressive regimens, however, has yet to be well characterized. METHODS: From November 2006 to March 2008, 20 consecutive lung transplantation patients received alemtuzumab induction with a reduced maintenance immunosuppression regimen. Twenty consecutive case-controls who underwent transplantation between 2005 and 2006 were treated with a standard immunosuppression regimen without induction. Outcome variables were patient survival, acute rejection, infection, and bronchiolitis obliterans syndrome. RESULTS: Mean follow-up time was 1400 days in the alemtuzumab group and 1210 days in the control group. Double lung transplantation was performed in 21 patients (12 in the alemtuzumab group and 9 in the control group). There was no difference in survival between the alemtuzumab (n = 10) and control (n = 10) groups. There was also not a significant difference in time-adjusted death based on Kaplan-Meier analysis. The mean number of any grade of rejection event per patient was not significantly different (alemtuzumab 2.3 ± 2.7 vs. control 3.2 ± 2.35; P = .22). There was a trend toward the reduced incidence of infection requiring intravenous antibiotics per patient (alemtuzumab 2.4 vs. control 3.8; P = .08). The incidence of bronchiolitis obliterans syndrome was similar in both groups (alemtuzumab 55% vs. control 70%; P = .25). CONCLUSIONS: Alemtuzumab induction with reduced immunosuppression offers a comparable 5-year survival and rejection rate compared to standard-dose immunosuppression regimen.

At the twisted heart of nicotine addiction.

This case report reviews the ECG manifestations of chronic obstructive pulmonary disease (COPD). Distinct changes of the P-wave axis, QRS axis and morphology are a direct result of the pathophysiological and anatomical changes associated with COPD. These changes are illustrated in a patient with a history of COPD presenting with hypoxaemia and symptoms of shortness of breath.

Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells.

Cellular inactivation through killer immunoglobulin-like receptors (KIRs) may allow neoplastic cells to evade host natural killer (NK) cell-mediated immunity. Recently, alloreactive NK cells were shown to mediate antileukemic effects against acute myelogenous leukemia (AML) after mismatched transplantation, when KIR ligand incompatibility existed in the direction of graft-versus-host disease (GVHD). Therefore, we investigated whether solid tumor cells would have similar enhanced susceptibility to allogeneic KIR-incompatible NK cells compared with their KIR-matched autologous or allogeneic counterparts. NK populations enriched and cloned from the blood of cancer patients or healthy donors homozygous for HLA-C alleles in group 1 (C-G1) or group 2 (C-G2) were tested in vitro for cytotoxicity against Epstein-Barr virus-transformed lymphoblastic cell lines (EBV-LCLs), renal cell carcinoma (RCC), and melanoma (MEL) cells with or without a matching KIR-inhibitory HLA-C ligand. Allogeneic NK cells were more cytotoxic to tumor targets mismatched for KIR ligands than their KIR ligand-matched counterparts. Bulk NK populations (CD3(-)/CD2(+)/CD56(+)) expanded 10(4)-fold from patients homozygous for C-G1 or C-G2 had enhanced cytotoxicity against KIR ligand-mismatched tumor cells but only minimal cytotoxicity against KIR ligand-matched targets. Further, NK cell lines from C-G1 or C-G2 homozygous cancer patients or healthy donors expanded but failed to kill autologous or KIR-matched MEL and RCC cells yet had significant cytotoxicity (more than 50% lysis at 20:1 effector-target [E/T] ratio) against allogeneic KIR-mismatched tumor lines. These data suggest immunotherapeutic strategies that use KIR-incompatible allogeneic NK cells might have superior antineoplastic effects against solid tumors compared with approaches using autologous NK cells.