Brian Theodore Wicks.

As a vet working in mixed practice, he relished the camaraderie of working with colleagues, farmers and clients, and developed a special interest in cattle fertility. He was considered to be a ray of sunshine.

Are autopsy findings still relevant to the management of critically ill patients in the modern era?

OBJECTIVES: The purpose of this study was to determine the accuracy of clinical diagnoses compared to autopsy findings in critically ill patients in the current medical era. DESIGN: We conducted a retrospective, blinded review of matched medical records and postmortem findings in patients who died between June 2006 and June 2011. SETTING: An ICU of a major university teaching hospital in Dublin, Ireland. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: A modification of the Goldman criteria was used to classify diagnostic error. There were 629 ICU deaths during the study period. Two hundred and seven patients underwent autopsy and 204 records were available for review. The mean age was 59 ± 18.1 years, 62% were male, 70% were postoperative patients, and median length of ICU stay was 3 days. Admission diagnosis, admission source, and admission specialty were similar between autopsy and nonautopsy patients. Five patients (2.4%; CI, 0.8-5.6%) had a class I discrepancy and 11 patients (5.4%; CI, 2.4-9.7%) had a class II discrepancy. Minor missed diagnoses were present in 31 patients (15.2%; CI, 4.5-12.4%). There was complete concordance between clinical and postmortem findings (class V) in 161 patients (79%; CI, 72.7-84.3%). In more than half the cases of discrepancy, it was not possible for physicians to make the diagnosis antemortem in the time available, despite appropriate investigations. CONCLUSIONS: We detected a lower rate of clinicopathological discrepancy in critically ill patients than previously reported. Potential reasons for such findings include advances in diagnostic techniques and the use of a more robust definition to classify diagnostic discrepancies. Autopsy can still identify discrepancies in diagnosis even in patients who have undergone appropriate investigations. Prospective research is required to accurately define discrepancy rates in the critically ill population and to identify the patient subgroups in whom autopsy will continue to yield valuable information.

Pulmonary vascular dysfunction in ARDS.

Acute respiratory distress syndrome (ARDS) is characterised by diffuse alveolar damage and is frequently complicated by pulmonary hypertension (PH). Multiple factors may contribute to the development of PH in this setting. In this review, we report the results of a systematic search of the available peer-reviewed literature for papers that measured indices of pulmonary haemodynamics in patients with ARDS and reported on mortality in the period 1977 to 2010. There were marked differences between studies, with some reporting strong associations between elevated pulmonary arterial pressure or elevated pulmonary vascular resistance and mortality, whereas others found no such association. In order to discuss the potential reasons for these discrepancies, we review the physiological concepts underlying the measurement of pulmonary haemodynamics and highlight key differences between the concepts of resistance in the pulmonary and systemic circulations. We consider the factors that influence pulmonary arterial pressure, both in normal lungs and in the presence of ARDS, including the important effects of mechanical ventilation. Pulmonary arterial pressure, pulmonary vascular resistance and transpulmonary gradient (TPG) depend not alone on the intrinsic properties of the pulmonary vascular bed but are also strongly influenced by cardiac output, airway pressures and lung volumes. The great variability in management strategies within and between studies means that no unified analysis of these papers was possible. Uniquely, Bull et al. (Am J Respir Crit Care Med 182:1123-1128, 2010) have recently reported that elevated pulmonary vascular resistance (PVR) and TPG were independently associated with increased mortality in ARDS, in a large trial with protocol-defined management strategies and using lung-protective ventilation. We then considered the existing literature to determine whether the relationship between PVR/TPG and outcome might be causal. Although we could identify potential mechanisms for such a link, the existing evidence does not allow firm conclusions to be drawn. Nonetheless, abnormally elevated PVR/TPG may provide a useful index of disease severity and progression. Further studies are required to understand the role and importance of pulmonary vascular dysfunction in ARDS in the era of lung-protective ventilation.

The α and Δ isoforms of CREB1 are required to maintain normal pulmonary vascular resistance.

Chronic hypoxia causes pulmonary hypertension associated with structural alterations in pulmonary vessels and sustained vasoconstriction. The transcriptional mechanisms responsible for these distinctive changes are unclear. We have previously reported that CREB1 is activated in the lung in response to alveolar hypoxia but not in other organs. To directly investigate the role of α and Δ isoforms of CREB1 in the regulation of pulmonary vascular resistance we examined the responses of mice in which these isoforms of CREB1 had been inactivated by gene mutation, leaving only the ß isoform intact (CREB(αΔ) mice). Here we report that expression of CREB regulated genes was altered in the lungs of CREB(αΔ) mice. CREB(αΔ) mice had greater pulmonary vascular resistance than wild types, both basally in normoxia and following exposure to hypoxic conditions for three weeks. There was no difference in rho kinase mediated vasoconstriction between CREB(αΔ) and wild type mice. Stereological analysis of pulmonary vascular structure showed characteristic wall thickening and lumen reduction in hypoxic wild-type mice, with similar changes observed in CREB(αΔ). CREB(αΔ) mice had larger lungs with reduced epithelial surface density suggesting increased pulmonary compliance. These findings show that α and Δ isoforms of CREB1 regulate homeostatic gene expression in the lung and that normal activity of these isoforms is essential to maintain low pulmonary vascular resistance in both normoxic and hypoxic conditions and to maintain the normal alveolar structure. Interventions that enhance the actions of α and Δ isoforms of CREB1 warrant further investigation in hypoxic lung diseases.

Discrepancies between clinical and autopsy diagnosis in liver transplant recipients - a case series.

The utility of the autopsy in patients who have undergone prior orthotopic liver transplantation (OLT) has not previously been defined. We sought to investigate the role of the autopsy in liver transplantation by comparing the clinically derived cause of death with the autopsy cause of death in a cohort of liver transplant recipients at our institution. This study was undertaken in the setting of declining autopsy rates worldwide. Between 2006 and 2011 twenty-nine patients died who had previously undergone OLT, of on whom 19 postmortem examinations were performed. We retrospectively reviewed all post mortem findings, and separately we examined the corresponding medical records to determine the clinical impression of the cause of death. Discrepancies between the post mortem and clinical findings were categorised according to a modification of Goldman's criteria. Our case series demonstrated a discrepancy between the clinical and post mortem examination (PME) findings in 54% of patients. Two patients had major diagnoses (Goldman Class 1) not detected clinically and in seven patients the PME revealed additional undetected minor diagnoses. This case series demonstrates that, even in the modern era of advanced diagnostic imaging techniques, the post mortem examination continues to be a valuable tool in confirming diagnostic accuracy and improving standards in the care of liver transplant recipients.

Horses for courses: a DNA-based test for race distance aptitude in thoroughbred racehorses.

Variation at the myostatin (MSTN) gene locus has been shown to influence racing phenotypes in Thoroughbred horses, and in particular, early skeletal muscle development and the aptitude for racing at short distances. Specifically, a single nucleotide polymorphism (SNP) in the first intron of MSTN (g.66493737C/T) is highly predictive of best race distance among Flat racing Thoroughbreds: homozygous C/C horses are best suited to short distance races, heterozygous C/T horses are best suited to middle distance races, and homozygous T/T horses are best suited to longer distance races. Patent applications for this gene marker association, and other linked markers, have been filed. The information contained within the patent applications is exclusively licensed to the commercial biotechnology company Equinome Ltd, which provides a DNA-based test to the international Thoroughbred horse racing and breeding industry. The application of this information in the industry enables informed decision making in breeding and racing and can be used to assist selection to accelerate the rate of change of genetic types among distinct populations (Case Study 1) and within individual breeding operations (Case Study 2).

The pathophysiological basis of chronic hypoxic pulmonary hypertension in the mouse: vasoconstrictor and structural mechanisms contribute equally.

Chronic hypoxic pulmonary hypertension is characterized by a sustained increase in pulmonary arterial pressure due to abnormally elevated pulmonary vascular resistance. This increased vascular resistance was previously thought to be due largely to changes in the structure of the pulmonary vasculature, i.e. lumen narrowing due to wall hypertrophy and loss of vessels. Recently, this model has been challenged by the demonstration that hypoxic pulmonary hypertension in the rat is caused almost completely by sustained vasoconstriction. The contribution of this vasocontriction to hypoxic pulmonary hypertension has not been examined directly in other species. We exposed groups of mice to hypoxia (10% O(2)) or normoxia for 3 weeks, following which the lungs were removed post mortem, and vascular resistance was measured in an isolated, ventilated, perfused preparation. Mean pulmonary vascular resistance was significantly increased in hypoxic compared with control normoxic lungs. The rho kinase inhibitor Y27635 (10(-4)m) (Tocris Bioscience, Bristol, United Kingdom.) significantly reduced the mean (± SEM) hypoxia induced increase by 45.4 (10.8)%, implying that structural vascular changes acounted for the remainder of the hypoxic increase. Stereological quantification showed a significant reduction in the mean lumen diameter of the fully relaxed vessels in hypoxic lungs compared with normoxic control lungs; there was no intra-acinar vessel loss. Thus, in contrast to the rat, hypoxic pulmonary hypertension in the mouse is due to two mechanisms contributing equally: sustained vasoconstriction and structural lumen narrowing of intra-acinar vessels. These important species diferences must be considered when using genetically mutated mice to investigate the mechanisms underlying pulmonary hypertension.

The very elderly in intensive care: admission characteristics and mortality.

OBJECTIVE: It is often assumed that critical care outcomes in the elderly are uniformly poorer than those in younger populations. We examined the pattern of admissions to our intensive care unit in Dublin, Ireland, between 2002 and 2005 to determine the admission characteristics and mortality in those aged 80 years and older. METHODS: Data were collected retrospectively from a local audit database and patient charts. RESULTS: The very elderly represented 5.1% of ICU admissions over the period with an ICU mortality of 15.4%. Age-adjusted APACHE II scores were similar to those in the younger group (median, 7 for both groups). The average length of ICU stay (+/-SD) was similar in the very elderly and younger groups (4.03+/-0.51 v 4.86+/-0.31 days; P=0.52), as were readmission rates (5.7% v 5.2%). Age was not predictive of ICU mortality. The most important determinants of ICU mortality were emergency (versus elective) admission, non-operative (versus postoperative) source of admission and higher age-adjusted APACHE II score. CONCLUSIONS: The nature of the admission and severity of illness, but not age, are determinants of ICU survival. Evidence-based criteria are needed to assess the appropriateness of ICU admission in the very elderly. Clear criteria would help to prevent initiation of futile therapies and also to ensure that the very elderly are not denied potentially beneficial ICU care. We need to study triage patterns and outcome data further to ensure that the very elderly have the same opportunities to access appropriate intensive care treatment as the rest of the population.