Yoke Lin Fung

Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study

IntroductionVital drugs may be degraded or sequestered in extracorporeal membrane oxygenation (ECMO) circuits, with lipophilic drugs considered to be particularly vulnerable. However, the circuit effects on protein-bound drugs have not been fully elucidated. The aim of this experimental study was to investigate the influence of plasma protein binding on drug disposition in ex vivo ECMO circuits.MethodsFour identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators and were used. The circuits were primed with crystalloid, albumin and fresh human whole blood and maintained at a physiological pH and temperature for 24xa0hours. After baseline sampling, known quantities of study drugs (ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin and thiopentone) were injected into the circuit to achieve therapeutic concentrations. Equivalent doses of these drugs were also injected into four polypropylene jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the controls and the ECMO circuits over 24xa0hours, and the concentrations of the study drugs were quantified using validated chromatographic assays. A regression model was constructed to examine the relationship between circuit drug recovery as the dependent variable and protein binding and partition coefficient (a measure of lipophilicity) as explanatory variables.ResultsFour hundred eighty samples were analysed. There was no significant loss of any study drugs in the controls over 24xa0hours. The average drug recoveries from the ECMO circuits at 24xa0hours were as follows: ciprofloxacin 96%, linezolid 91%, fluconazole 91%, ceftriaxone 80%, caspofungin 56% and thiopentone 12%. There was a significant reduction of ceftriaxone (P = 0.01), caspofungin (P = 0.01) and thiopentone (P = 0.008) concentrations in the ECMO circuit at 24xa0hours. Both protein binding and partition coefficient were highly significant, with the model possessing a high coefficient of determination (R2u2009=u20090.88, P <0.001).ConclusionsRecovery of the highly protein-bound drugs ceftriaxone, caspofungin and thiopentone was significantly lower in the ECMO circuits at 24xa0hours. For drugs with similar lipophilicity, the extent of protein binding may determine circuit drug loss. Future clinical population pharmacokinetic studies should initially be focused on drugs with greater lipophilicity and protein binding, and therapeutic drug monitoring should be strongly considered with the use of such drugs.

Osteopontin alters endothelial and valvular interstitial cell behaviour in calcific aortic valve stenosis through HMGB1 regulation

OBJECTIVESnCalcific aortic valve stenosis (CAVS) is an important clinical problem predominantly affecting elderly individuals. Studies suggest that the progression of CAVS is actively regulated with valve endothelial injury leading to inflammation, fibrosis and calcification. The aim of this study was to delineate the possible regulatory role of osteopontin (OPN) on high-mobility group box 1 (HMGB1) function and the associated inflammatory and fibrotic response in CAVS.nnnMETHODSnAortic valve leaflets were collected from CAVS patients undergoing aortic valve replacement (n = 40), and control aortic valve leaflets were obtained from heart transplant recipients (n = 15). Valves and plasma were analysed by quantitative real-time polymerase chain reaction (PCR), immunohistochemical staining and Western blot. Recombinant OPN or neutralizing OPN antibody was added to cultured endothelial and valvular interstitial cells (VICs), and cell proliferation scores and HMGB1 expression were assessed.nnnRESULTSnCAVS valves had a decreased total percentage of VICs but increased numbers of infiltrating macrophages relative to control valves. RT-PCR studies showed higher expression of OPN, the inflammatory cytokine tumour necrosis factor-alpha as well as markers of fibrosis, tissue inhibitor of matrix metalloproteinase 1 and matrix metalloproteinase 2 in CAVS valves. Elevated expression of OPN was also observed in plasma of CAVS patients compared with controls. HMGB1 was detected in the secretory granules of cultured valve endothelial and VICs derived from CAVS valves. The addition of exogenous OPN inhibited the proliferation of cultured endothelial and VICs from CAVS valves and was associated with the extracellular expression of HMGB1, whereas neutralizing OPN had the opposite effect.nnnCONCLUSIONSnWe conclude that altered OPN expression in CAVS affects cellular HMGB1 function inducing cytoplasmic translocation and secretion of HMGB1 in endothelial cells and VICs, thus indicating a regulatory role for OPN in the progression of CAVS through alteration of HMGB1 function.

Can physicochemical properties of antimicrobials be used to predict their pharmacokinetics during extracorporeal membrane oxygenation? Illustrative data from ovine models

IntroductionEx vivo experiments in extracorporeal membrane oxygenation (ECMO) circuits have identified octanol-water partition coefficient (logP, a marker of lipophilicity) and protein binding (PB) as key drug factors affecting pharmacokinetics (PK) during ECMO. Using ovine models, in this study we investigated whether these drug properties can be used to predict PK alterations of antimicrobial drugs during ECMO.MethodsSingle-dose PK sampling was performed in healthy sheep (HS, nu2009=u20097), healthy sheep on ECMO (E24H, nu2009=u20097) and sheep with smoke inhalation acute lung injury on ECMO (SE24H, nu2009=u20096). The sheep received eight study antimicrobials (ceftriaxone, gentamicin, meropenem, vancomycin, doripenem, ciprofloxacin, fluconazole, caspofungin) that exhibit varying degrees of logP and PB. Plasma drug concentrations were determined using validated chromatographic techniques. PK data obtained from a non-compartmental analysis were used in a linear regression model to predict PK parameters based on logP and PB.ResultsWe found statistically significant differences in pH, haemodynamics, fluid balance and plasma proteins between the E24H and SE24H groups (pu2009<u20090.001). logP had a strong positive linear relationship with steady-state volume of distribution (Vss) in both the E24H and SE24H groups (pu2009<u20090.001) but not in the HS group (pu2009=u20090.9) and no relationship with clearance (CL) in all study groups. Although we observed an increase in CL for highly PB drugs in ECMO sheep, PB exhibited a weaker negative linear relationship with both CL (HS, pu2009=u20090.01; E24H, pu2009<u20090.001; SE24H, pu2009<u20090.001) and Vss (HS, pu2009=u20090.01; E24H, pu2009=u20090.004; SE24H, p =0.05) in the final model.ConclusionsLipophilic antimicrobials are likely to have an increased Vss and decreased CL during ECMO. Protein-bound antimicrobial agents are likely to have reductions both in CL and Vss during ECMO. The strong relationship between lipophilicity and Vss seen in both the E24H and SE24H groups indicates circuit sequestration of lipophilic drugs. These findings highlight the importance of drug factors in predicting antimicrobial drug PK during ECMO and should be a consideration when performing and interpreting population PK studies.

Subcutaneous Immunoglobulin Therapy for Hypogammaglobulinemia Secondary to Malignancy or Related Drug Therapy

Immunoglobulin replacement therapy (IRT) has an important role in minimizing infections and improving the health-related quality of life (HRQoL) in patients with immunodeficiency, who would otherwise experience recurrent infections. These plasma-derived products are available as intravenous immunoglobulin (IVIg) or subcutaneous immunoglobulin (SCIg). The global demand for these products is growing rapidly and has placed pressure on supply. Some malignancies and their treatment (as well as other medical therapies) can lead to secondary hypogammaglobulinemia or secondary immunodeficiency (SID) requiring IRT. Although IVIg use in this cohort has well-established therapeutic benefits, little is known about SCIg use. A literature search in July 2015 found only 7 published articles on SCIg use. These articles found that both IRT modes had equivalent efficacy in regard to reduction of bacterial infections. In addition, SCIg was reported to produce higher serum IgG trough levels compared with IVIg on equivalent dosage with the added benefit of fewer adverse effects. Patient HRQoL reports demonstrate preference for SCIg because of reduced adverse effects and hospital visits. There are no health economic models published on SCIg use in SID, but models on primary immunodeficiency disease and IRT conclude that SCIg provided greater economic benefits than IVIg. The findings of this small number of reports suggest that SCIg therapy for patients with SID is likely to be beneficial for both the patient and health care providers. To substantiate wider use of SCIg in SID, larger and more detailed studies are needed to accurately quantify the effectiveness of SCIg.

Outcomes of restrictive versus liberal transfusion strategies in older adults from nine randomised controlled trials: a systematic review and meta-analysis

BACKGROUNDnGuidelines for patient blood management recommend restrictive transfusion practice for most adult patients. These guidelines are supported by evidence from randomised controlled trials (RCTs); however, one of the patient groups not explicitly examined in these studies is the geriatric population. We examined RCTs relevant to transfusion outcomes in older patients. Our aim was to determine whether special guidelines are warranted for geriatric patients, recognising the different pathophysiological characteristics of this group.nnnMETHODSnFor this systematic review and meta-analysis, we searched PubMed, Scopus, and the Cochrane Library databases from their inception to May 5, 2017, for evidence relating to transfusion outcomes in adults aged 65 years and older. This criterion was widened to include RCTs where a substantial proportion of the study population was older than 65 years. We also included study populations of all clinical settings, and did not limit the search by date, language, or study type. For articles not in English, only available translations of the abstracts were reviewed. Studies were excluded if they did not specify age. Observational studies and duplicate patient and outcome data from studies that generated multiple publications were also excluded. We screened bibliographies of retrieved articles for additional publications. We analysed data extracted from published RCTs comparing restrictive and liberal transfusion strategies in older adults. We generated fixed effects risk ratios (RR) for pooled study data using the Mantel-Haenszel method. Primary outcomes were 30-day and 90-day mortality events for patients enrolled in restrictive and liberal transfusion study groups. We included intention-to-treat outcome data in the meta-analysis when available, otherwise we used per-protocol outcome data.nnnFINDINGSn686 articles were identified by the search, and a further 37 by the snowball approach. Of these articles, 13 eligible papers described findings from nine RCTs (five trials investigating orthopaedic surgery, three cardiac surgery, and one oncology surgery; including 5780 patients). The risk of 30-day mortality was higher in older patients who followed a restrictive transfusion strategy than in those who followed a liberal transfusion strategy (risk ratio [RR] 1·36, 95% CI 1·05-1·74; p=0·017). The risk of 90-day mortality was also higher in those who followed a restrictive transfusion strategy than in those who followed a liberal transfusion strategy (RR 1·45, 95% CI 1·05-1·98; p=0·022).nnnINTERPRETATIONnLiberal transfusion strategies might produce better outcomes in geriatric patients than restrictive transfusion strategies. This outcome contradicts current restrictive transfusion approaches. Population ageing will challenge resources globally, and this finding has implications for blood supply and demand, and optimal care of older adults. Further research is needed to formulate evidence-based transfusion practice across clinical specialties specific to the geriatric population, and to examine resource effects.nnnFUNDINGnAustralias National Blood Authority.

Authors' reply to comment Blood transfusion strategies in elderly patients

1 Murphy MF, Estcourt L, Goodnough LT. Blood transfusion strategies in elderly patients. Lancet Haematol 2017; published online September 11. http://dx.doi.org/10.1016/ S2352-3026(17)30173-4. 2 Simon GI, Craswell A, Thom O, Fung YL. Outcomes of restrictive versus liberal transfusion strategies in older adults from nine randomised controlled trials: a systematic review and meta-analysis. Lancet Haematol 2017; published online September 11. http://dx.doi.org/10.1016/ S2352-3026(17)30141-2 3 Carson JL, Stanworth SJ, Roubinian N, et al. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev 2016; 10: CD002042. Authors’ reply to comment “Blood transfusion strategies in elderly patients”

How different animal models help us understand TRALI

Transfusion‐related acute lung injury (TRALI) is still one of the leading causes of transfusion‐associated mortality, despite increased awareness and the implementation of various mitigation strategies. TRALI may be either antibody or non‐antibody mediated. Understanding the underlying mechanism through clinical cases has been challenging because of the low and unpredictable incidence. Thus, animal models provide an important tool for investigating the mechanism of TRALI in a controlled and systematic fashion. One of the earliest animal models, an ex vivo rabbit lung model, revealed the role of anti‐5b (anti‐HNA‐3a) and granulocytes. In vivo models with mice, rats and pig models have provided further insights into the mechanisms of antibody‐mediated TRALI. There is evidence for contributions from neutrophils, neutrophil extracellular traps, platelets, lymphocytes, monocytes and endothelial cells. Elevated levels of C‐reactive proteins and cardiopulmonary bypass may predispose to TRALI, while protective roles have been identified with lymphocytes, T‐regulatory cells and dendritic cells. Mouse models have shown that IL‐10 infusion protects from TRALI if administered prophylactically and successfully treats TRALI reaction if administered therapeutically. Silliman et al. introduced the non‐immune mechanism of TRALI with rat models, and since then, there have been sheep and pig models. Non‐immune animal models have demonstrated the importance of a priming event (e.g. endotoxin administration) and a role for the protein and lipid biological response modifiers (BRMs) that accumulate during routine blood product storage. This paper focuses on how the key ex vivo and in vivo animal models have progressed our understanding of the mechanisms leading to TRALI.

Questioning the benefit of restrictive transfusion practice in older adults

Restrictive transfusion practice is widely promoted, with many international guidelines recommending haemoglobin thresholds of 70 to 80 g/l for adult patients who are asymptomatic. Randomized controlled trials comparing outcomes associated with liberal and restrictive transfusion strategies underpin this approach. Meta‐analyses including trials of adult patients >18 years of age have concluded that restrictive practice is noninferior to liberal transfusion approaches. A restrictive approach to transfusion reduces resource consumption and cost, as well as the hazards associated with unnecessary exposure to blood products. Although adults aged ≥65 years consume over half of the blood supply, there are few randomized controlled transfusion trials exclusive to this cohort. Our 2017 meta‐analysis of a small number of trials focussed on older adults found that higher transfusion haemoglobin thresholds were associated with lower mortality and fewer cardiac complications in this age group. Other studies have also shown that higher transfusion haemoglobin thresholds are beneficial in older adults. This paper presents recent evidence regarding transfusion outcomes in older adults and discusses aspects of the pathophysiology of ageing that impact on the reduced resilience of older patients to anaemic states. This evidence challenges the use of Hb thresholds that apply across the adult lifespan, regardless of age. It proposes that older age be considered as a risk factor in assessing transfusion requirements, and that transfusion practice in older adults may require higher haemoglobin thresholds than for younger adults.

A retrospective explanatory case study of the implementation of a bleeding management quality initiative, in an Australian cardiac surgery unit

BACKGROUNDnBleeding management in cardiac surgery is challenging. Many guidelines exist to support bleeding management; however, literature demonstrates wide variation in practice. In 2012, a quality initiative was undertaken at The Prince Charles Hospital, Australia to improve bleeding management for cardiac surgery patients. The implementation of the quality initiative resulted in significant reductions in the incidence of blood transfusion, re-exploration for bleeding; superficial leg and chest wound infections; length of hospital stay, and cost. Given the success of the initiative, we sought to answer the question; How and why was the process of implementing a bleeding management quality initiative in the cardiac surgery unit successful, and sustainable?nnnMETHODSnA retrospective explanatory case study design was chosen to explore the quality initiative. Analysis of the evidence was reviewed through phases of the Knowledgeto Action planned change model. Data was derived from: (1) document analysis, (2) direct observation of the local environment, (3) clinical narratives from interviews, and analysed with a triangulation approach. The study period extended from 10/2011 to 6/2013.nnnRESULTSnResults demonstrated the complexity of changing practice, as well as the significant amount of dedicated time and effort required to support individual, department and system wide change. Results suggest that while many clinicians were aware of the potential to apply improved practice, numerous barriers and challenges needed to be overcome to implement change across multiple disciplines and departments.nnnCONCLUSIONSnThe key successful components of the QI were revealed through the case study analysis as: (1) an appropriately skilled project manager to facilitate the implementation process; (2) tools to support changes in workflow and decision making including a bleeding management treatment algorithm with POCCTs; (3) strong clinical leadership from the multidisciplinary team and; (4) the evolution of the project manager position into a perpetual clinical position to support sustainability.

Lessons from sheep models of transfusion

Animal models have been a valuable tool for research into blood products and outcomes of blood transfusions. Small animal models have been applied extensively and large animal models less frequently. This review describes the experience and details the findings from a recent series of in vivo sheep transfusion models.