John F. Fraser

Optimal Management of the Critically Ill: Anaesthesia, Monitoring, Data Capture, and Point-of-Care Technological Practices in Ovine Models of Critical Care

Animal models of critical illness are vital in biomedical research. They provide possibilities for the investigation of pathophysiological processes that may not otherwise be possible in humans. In order to be clinically applicable, the model should simulate the critical care situation realistically, including anaesthesia, monitoring, sampling, utilising appropriate personnel skill mix, and therapeutic interventions. There are limited data documenting the constitution of ideal technologically advanced large animal critical care practices and all the processes of the animal model. In this paper, we describe the procedure of animal preparation, anaesthesia induction and maintenance, physiologic monitoring, data capture, point-of-care technology, and animal aftercare that has been successfully used to study several novel ovine models of critical illness. The relevant investigations are on respiratory failure due to smoke inhalation, transfusion related acute lung injury, endotoxin-induced proteogenomic alterations, haemorrhagic shock, septic shock, brain death, cerebral microcirculation, and artificial heart studies. We have demonstrated the functionality of monitoring practices during anaesthesia required to provide a platform for undertaking systematic investigations in complex ovine models of critical illness.

Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients

The use of extracorporeal membrane oxygenation (ECMO) for severe acute respiratory failure (ARF) in adults is growing rapidly given recent advances in technology, even though there is controversy regarding the evidence justifying its use. Because ECMO is a complex, high-risk, and costly modality, at present it should be conducted in centers with sufficient experience, volume, and expertise to ensure it is used safely. This position paper represents the consensus opinion of an international group of physicians and associated health-care workers who have expertise in therapeutic modalities used in the treatment of patients with severe ARF, with a focus on ECMO. The aim of this paper is to provide physicians, ECMO center directors and coordinators, hospital directors, health-care organizations, and regional, national, and international policy makers a description of the optimal approach to organizing ECMO programs for ARF in adult patients. Importantly, this will help ensure that ECMO is delivered safely and proficiently, such that future observational and randomized clinical trials assessing this technique may be performed by experienced centers under homogeneous and optimal conditions. Given the need for further evidence, we encourage restraint in the widespread use of ECMO until we have a better appreciation for both the potential clinical applications and the optimal techniques for performing ECMO.

Oxygen delivery through high-flow nasal cannulae increase end-expiratory lung volume and reduce respiratory rate in post-cardiac surgical patients.

BACKGROUND High-flow nasal cannulae (HFNCs) create positive oropharyngeal airway pressure, but it is unclear how their use affects lung volume. Electrical impedance tomography allows the assessment of changes in lung volume by measuring changes in lung impedance. Primary objectives were to investigate the effects of HFNC on airway pressure (P(aw)) and end-expiratory lung volume (EELV) and to identify any correlation between the two. Secondary objectives were to investigate the effects of HFNC on respiratory rate, dyspnoea, tidal volume, and oxygenation; and the interaction between BMI and EELV. METHODS Twenty patients prescribed HFNC post-cardiac surgery were investigated. Impedance measures, P(aw), ratio, respiratory rate, and modified Borg scores were recorded first on low-flow oxygen and then on HFNC. RESULTS A strong and significant correlation existed between P(aw) and end-expiratory lung impedance (EELI) (r=0.7, P<0.001). Compared with low-flow oxygen, HFNC significantly increased EELI by 25.6% [95% confidence interval (CI) 24.3, 26.9] and P(aw) by 3.0 cm H(2)O (95% CI 2.4, 3.7). Respiratory rate reduced by 3.4 bpm (95% CI 1.7, 5.2) with HFNC use, tidal impedance variation increased by 10.5% (95% CI 6.1, 18.3), and ratio improved by 30.6 mm Hg (95% CI 17.9, 43.3). A trend towards HFNC improving subjective dyspnoea scoring (P=0.023) was found. Increases in EELI were significantly influenced by BMI, with larger increases associated with higher BMIs (P<0.001). CONCLUSIONS This study suggests that HFNCs reduce respiratory rate and improve oxygenation by increasing both EELV and tidal volume and are most beneficial in patients with higher BMIs.

Collagen in the scarless fetal skin wound: Detection with Picrosirius-polarization

Our group has developed an ovine model of deep dermal, partial‐thickness burn where the fetus heals scarlessly and the lamb heals with scar. The comparison of collagen structure between these two different mechanisms of healing may elucidate the process of scarless wound healing. Picrosirius staining followed by polarized light microscopy was used to visualize collagen fibers, with digital capture and analysis. Collagen deposition increased with fetal age and the fibers became thicker, changing from green (type III collagen) to yellow/red (type I collagen). The ratio of type III collagen to type I was high in the fetus (166), whereas the lamb had a much lower ratio (0.2). After burn, the ratios of type III to type I collagen did not differ from those in control skin for either fetus or lamb. The fetal tissue maintained normal tissue architecture after burn while the lamb tissue showed irregular collagen organization. In conclusion, the type or amount of collagen does not alter significantly after injury. Tissue architecture differed between fetal and lamb tissue, suggesting that scar development is related to collagen cross‐linking or arrangement. This study indicates that healing in the scarless fetal wound is representative of the normal fetal growth pattern, rather than a “response” to burn injury.

Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation

Extracorporeal membrane oxygenation (ECMO) is a form of prolonged cardiopulmonary bypass used to temporarily sustain cardiac and/or respiratory function in critically ill patients. Extracorporeal membrane oxygenation further complicates the management of critically ill patients who already have profound physiologic derangements with consequent altered pharmacokinetics. The purpose of this study is to identify and critically review the published literature describing pharmacokinetics in the presence of ECMO. This review revealed a dearth of data describing pharmacokinetics during ECMO in critically ill adults, with most of the available data originating in neonates. Of concern, the present data indicate substantial variability and a lack of predictability in drug behavior in the presence of ECMO. The most common mechanisms by which ECMO affects pharmacokinetics are sequestration in the circuit, increased volume of distribution, and decreased drug elimination. While lipophilic drugs and highly protein-bound drugs (eg, voriconazole and fentanyl) are significantly sequestered in the circuit, hydrophilic drugs (eg, β-lactam antibiotics, glycopeptides) are significantly affected by hemodilution and other pathophysiologic changes that occur during ECMO. Although the published literature is insufficient to make any meaningful recommendations for adjusting therapy for drug dosing, this review systematically describes the available data enabling clinicians to make conclusions based on available data. Furthermore, this review serves to highlight the need for well-designed and conducted clinical and laboratory-based studies to provide the data from which robust dosing guidance can be developed to improve clinical outcomes in this most unwell cohort of patients.

Characterization of banked umbilical cord blood hematopoietic progenitor cells and lymphocyte subsets and correlation with ethnicity, birth weight, sex, and type of delivery: a Cord Blood Transplantation (COBLT) Study report

BACKGROUND: The Cord Blood Transplantation (COBLT) Study banking program was initiated in 1996. The study goals were to develop standard operating procedures for cord blood (CB) donor recruitment and banking and to build an ethnically diverse unrelated CB bank to support a transplantation protocol.

Impact of blood product transfusion on short and long-term survival after cardiac surgery: more evidence

BACKGROUND Despite the proven benefits in hemorrhagic shock, blood transfusions have been linked to increased morbidity and mortality. The short-term adverse effects of blood transfusion in cardiac surgical patients are well documented but there are very few studies that adequately assess the long-term survival. This study was undertaken to evaluate the effects of transfusion on both short-term and long-term survival after cardiac surgery. METHODS Data from 5,342 patients who underwent a cardiac surgical procedure from January 2002 to December 2005 at our institution were reviewed. The effect of transfusion of packed red blood cells (PRBC) and other blood products was tested in a 2-level approach of transfusion (any) versus no transfusion, and also a 4-level approach of transfusion (PRBC, other blood products, and both blood and blood products) versus no transfusion. Long-term survival data of these patients were obtained. Cox proportional hazard models, Kaplan-Meier survival plots, and hazard functions were used to compare the groups. RESULTS A total of 3,013 of the 5,342 study patients (56.4%) received transfusion during or within 72 hours of their cardiac surgery. Median time to death was significantly lower for patients who received transfusions; 1.15 years for PRC and 0.83 years for any transfusion, compared with 4.68 years in the non-transfused group. The overall 30-day mortality was 1.7%, but in patients who received transfusions (3.6%) was significantly higher than the non-transfused group (0.3%, p<0.001). The 1-year mortality (overall 3.9%) in the transfused group (7.3%, p<0.001) was also significantly higher than that in the non-transfused group (1.3%). The 5-year mortality rate in the transfused group was more than double that in the non-transfused group (16% vs 7%). After correction for comorbidities and other factors, transfusion was still associated with a 66% increase in mortality. CONCLUSIONS This study suggests that blood or blood product transfusion during or after cardiac surgery is associated with increased short-term and long-term mortality. It reinforces the need for prospective randomized controlled studies for evaluation of restrictive transfusion triggers and objective clinical indicators for transfusion in the cardiac surgical patient population.

The Role of Echocardiography in the Management of Patients Supported by Extracorporeal Membrane Oxygenation

Extracorporeal life support can be viewed as a spectrum of modalities based on modifications of a cardiopulmonary bypass circuit to provide cardiac and respiratory support, which can be used for extended periods, from hours to several weeks. Extracorporeal membrane oxygenation (ECMO) is among the most frequently used forms of extracorporeal life support. It can be configured for venovenous blood flow, to provide adequate oxygenation and carbon dioxide removal in isolated refractory respiratory failure, or in a venoarterial configuration, when support is required for cardiac and/or respiratory failure. Echocardiography plays a fundamental role throughout the entire journey of a patient supported on ECMO. It provides information that assists in patient selection, guides the insertion and placement of cannulas, monitors progress, detects complications, and helps in determining cardiac recovery and the weaning of ECMO support. Although there are extensive published data regarding ECMO, particularly in the pediatric population, there is a paucity of data outlining the role of echocardiography in guiding the management of adult patients supported by ECMO. ECMO is likely to become an increasingly used form of cardiorespiratory support within the critical care setting. Hence, clinicians and sonographers who work within echocardiography departments at institutions with ECMO programs require specific skills to image these patients.

The seasonality in heart failure deaths and total cardiovascular deaths

Objectives: To examine the seasonal pattern in heart failure (HF) and cardiovascular disease (CVD) by climate and cause of death in Australia.

Procalcitonin Algorithm in Critically Ill Adults with Undifferentiated Infection or Suspected Sepsis A Randomized Controlled Trial

RATIONALE The role of procalcitonin (PCT), a widely used sepsis biomarker, in critically ill patients with sepsis is undetermined. OBJECTIVES To investigate the effect of a low PCT cut-off on antibiotic prescription and to describe the relationships between PCT plasma concentration and sepsis severity and mortality. METHODS This was a multicenter (11 Australian intensive care units [ICUs]), prospective, single-blind, randomized controlled trial involving 400 patients with suspected bacterial infection/sepsis and expected to receive antibiotics and stay in ICU longer than 24 hours. The primary outcome was the cumulative number of antibiotics treatment days at Day 28. MEASUREMENTS AND MAIN RESULTS PCT was measured daily while in the ICU. A PCT algorithm, including 0.1 ng/ml cut-off, determined antibiotic cessation. Published guidelines and antimicrobial stewardship were used in all patients. Primary analysis included 196 (PCT) versus 198 standard care patients. Ninety-three patients in each group had septic shock. The overall median (interquartile range) number of antibiotic treatment days were 9 (6-21) versus 11 (6-22), P = 0.58; in patients with positive pulmonary culture, 11 (7-27) versus 15 (8-27), P = 0.33; and in patients with septic shock, 9 (6-22) versus 11 (6-24), P = 0.64; with an overall 90-day all-cause mortality of 35 (18%) versus 31 (16%), P = 0.54 in the PCT versus standard care, respectively. Using logistic regression, adjusted for age, ventilation status, and positive culture, the decline rate in log(PCT) over the first 72 hours independently predicted hospital and 90-day mortality (odds ratio [95% confidence interval], 2.76 [1.10-6.96], P = 0.03; 3.20 [1.30-7.89], P = 0.01, respectively). CONCLUSIONS In critically ill adults with undifferentiated infections, a PCT algorithm including 0.1 ng/ml cut-off did not achieve 25% reduction in duration of antibiotic treatment. Clinical trial registered with http://www.anzctr.org.au (ACTRN12610000809033).