Kenneth E. Remy

Washing older blood units before transfusion reduces plasma iron and improves outcomes in experimental canine pneumonia

In a randomized controlled blinded trial, 2-year-old purpose-bred beagles (n = 24), with Staphylococcus aureus pneumonia, were exchanged-transfused with either 7- or 42-day-old washed or unwashed canine universal donor blood (80 mL/kg in 4 divided doses). Washing red cells (RBC) before transfusion had a significantly different effect on canine survival, multiple organ injury, plasma iron, and cell-free hemoglobin (CFH) levels depending on the age of stored blood (all, P < .05 for interactions). Washing older units of blood improved survival rates, shock score, lung injury, cardiac performance and liver function, and reduced levels of non-transferrin bound iron and plasma labile iron. In contrast, washing fresh blood worsened all these same clinical parameters and increased CFH levels. Our data indicate that transfusion of fresh blood, which results in less hemolysis, CFH, and iron release, is less toxic than transfusion of older blood in critically ill infected subjects. However, washing older blood prevented elevations in plasma circulating iron and improved survival and multiple organ injury in animals with an established pulmonary infection. Our data suggest that fresh blood should not be washed routinely because, in a setting of established infection, washed RBC are prone to release CFH and result in worsened clinical outcomes.

Transfusion of older stored blood worsens outcomes in canines depending on the presence and severity of pneumonia

In experimental pneumonia we found that transfused older blood increased mortality and lung injury that was associated with increased in vivo hemolysis and elevated plasma cell‐free hemoglobin (CFH), non–transferrin‐bound iron (NTBI), and plasma labile iron (PLI) levels. In this study, we additionally analyze identically treated animals that received lower or higher bacterial doses.

Transfusion‐related immunomodulation: review of the literature and implications for pediatric critical illness

Transfusion‐related immunomodulation (TRIM) in the intensive care unit (ICU) is difficult to define and likely represents a complicated set of physiologic responses to transfusion, including both proinflammatory and immunosuppressive effects. Similarly, the immunologic response to critical illness in both adults and children is highly complex and is characterized by both acute inflammation and acquired immune suppression. How transfusion may contribute to or perpetuate these phenotypes in the ICU is poorly understood, despite the fact that transfusion is common in critically ill patients. Both hyperinflammation and severe immune suppression are associated with poor outcomes from critical illness, underscoring the need to understand potential immunologic consequences of blood product transfusion. In this review we outline the dynamic immunologic response to critical illness, provide clinical evidence in support of immunomodulatory effects of blood product transfusion, review preclinical and translational studies to date of TRIM, and provide insight into future research directions.

Role of granulocyte transfusions in invasive fusariosis: systematic review and single‐center experience

Invasive Fusarium infection is relatively refractory to available antifungal agents. Invasive fusariosis (IF) occurs almost exclusively in the setting of profound neutropenia and/or systemic corticosteroid use. Treatment guidelines for IF are not well established, including the role of granulocyte transfusions (GTs) to counter neutropenia.

Functional Expression of the TMEM16 Family of Calcium Activated Chloride Channels in Airway Smooth Muscle

Airway smooth muscle hyperresponsiveness is a key component in the pathophysiology of asthma. Although calcium-activated chloride channel (CaCC) flux has been described in many cell types, including human airway smooth muscle (HASM), the true molecular identity of the channels responsible for this chloride conductance remains controversial. Recently, a new family of proteins thought to represent the true CaCCs was identified as the TMEM16 family. This led us to question whether members of this family are functionally expressed in native and cultured HASM. We further questioned whether expression of these channels contributes to the contractile function of HASM. We identified the mRNA expression of eight members of the TMEM16 family in HASM cells and show immunohistochemical evidence of TMEM16A in both cultured and native HASM. Functionally, we demonstrate that the classic chloride channel inhibitor, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), inhibited halide flux in cultured HASM cells. Moreover, HASM cells displayed classical electrophysiological properties of CaCCs during whole cell electrophysiological recordings, which were blocked by using an antibody selective for TMEM16A. Furthermore, two distinct TMEM16A antagonists (tannic acid and benzbromarone) impaired a substance P-induced contraction in isolated guinea pig tracheal rings. These findings demonstrate that multiple members of this recently described family of CaCCs are expressed in HASM cells, they display classic electrophysiological properties of CaCCs, and they modulate contractile tone in airway smooth muscle. The TMEM16 family may provide a novel therapeutic target for limiting airway constriction in asthma.

Transfusion of recently donated (fresh) red blood cells (RBCs) does not improve survival in comparison with current practice, while safety of the oldest stored units is yet to be established: a meta-analysis.

Preclinical studies generated the hypothesis that older stored red blood cells (RBCs) can increase transfusion risks. To examine the most updated and complete clinical evidence and compare results between two trial designs, we assessed both observational studies and randomized controlled trials (RCTs) studying the effect of RBC storage age on mortality.

B. anthracis edema toxin increases cAMP levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model.

B. anthracis edema toxin (ET) and lethal toxin (LT) are each composed of protective antigen (PA), necessary for toxin uptake by host cells, and their respective toxic moieties, edema factor (EF) and lethal factor (LF). Although both toxins likely contribute to shock during infection, their mechanisms are unclear. To test whether ET and LT produce arterial relaxation, their effects on phenylephrine (PE)-stimulated contraction in a Sprague-Dawley rat aortic ring model were measured. Rings were prepared and connected to pressure transducers. Their viability was confirmed, and peak contraction with 60 mM KCl was determined. Compared with PA pretreatment (control, 60 min), ET pretreatment at concentrations similar to those noted in vivo decreased the mean (±SE) maximum contractile force (MCF; percent peak contraction) in rings generated during stimulation with increasing PE concentrations (96.2 ± 7.0 vs. 57.3 ± 9.1) and increased the estimated PE concentration producing half the MCF (EC50; 10(-7) M, 1.1 ± 0.3 vs. 3.7 ± 0.8, P ≤ 0.002). ET inhibition with PA-directed monoclonal antibodies, selective EF inhibition with adefovir, or removal of the ring endothelium inhibited the effects of ET on MCF and EC50 (P ≤ 0.02). Consistent with its adenyl cyclase activity, ET increased tissue cAMP in endothelium-intact but not endothelium-denuded rings (P < 0.0001 and 0.25, respectively). LT pretreatment, even in high concentrations, did not significantly decrease MCF or increase EC50 (all P > 0.05). In rings precontracted with PE compared with posttreatment with PA (90 min), ET posttreatment produced progressive reductions in contractile force and increases in relaxation in endothelium-intact rings (P < 0.0001) but not endothelium-denuded rings (P = 0.51). Thus, ET may contribute to shock by producing arterial relaxation.

In a canine pneumonia model of exchange transfusion, altering the age but not the volume of older red blood cells markedly alters outcome.

Massive exchange transfusion of 42‐day‐old red blood cells (RBCs) in a canine model of Staphylococcus aureus pneumonia resulted in in vivo hemolysis with increases in cell‐free hemoglobin (CFH), transferrin‐bound iron (TBI), non–transferrin‐bound iron (NTBI), and mortality. We have previously shown that washing 42‐day‐old RBCs before transfusion significantly decreased NTBI levels and mortality, but washing 7‐day‐old RBCs increased mortality and CFH levels. We now report the results of altering volume, washing, and age of RBCs.

Transfused older stored red blood cells improve the clinical course and outcome in a canine lethal hemorrhage and reperfusion model.

In canine models, transfused older stored red blood cells (RBCs) hemolyze in vivo resulting in significantly increased intravascular cell‐free hemoglobin (CFH) and non–transferrin‐bound iron (NTBI). During canine bacterial pneumonia with septic shock, but not in controls, older stored RBCs were associated with significantly increased lung injury and mortality. It is unknown if in shock without infection transfusion of older RBCs will result in similar adverse effects.

The influence of the storage lesion(s) on pediatric red cell transfusion

Purpose of review This article will analyze and evaluate the current evidence regarding the use of older, longer-stored red blood cells (RBCs) for transfusion in pediatric patients and will examine some of the postulated mechanisms of injury related to prolonged refrigerated storage of RBCs and studies reporting clinical outcomes. Recent findings Three randomized controlled trials and seven observational studies have been conducted entirely in pediatric patients. The outcomes, mortality and morbidity in critically ill patients and children undergoing cardiac surgery, and necrotizing enterocolitis in premature infants, have been inconsistent. However, many of these studies have been confounded by study design, mixed patient populations, red cell preparation, and other factors. Summary Further exploration into the possible deleterious effects of older, longer-stored RBC transfusions on mortality and morbidity in different pediatric populations is merited. Understanding the potential mechanisms of injury should help explain the clinical findings.