Andrew J. E. Seely

Complex systems and the technology of variability analysis

Characteristic patterns of variation over time, namely rhythms, represent a defining feature of complex systems, one that is synonymous with life. Despite the intrinsic dynamic, interdependent and nonlinear relationships of their parts, complex biological systems exhibit robust systemic stability. Applied to critical care, it is the systemic properties of the host response to a physiological insult that manifest as health or illness and determine outcome in our patients. Variability analysis provides a novel technology with which to evaluate the overall properties of a complex system. This review highlights the means by which we scientifically measure variation, including analyses of overall variation (time domain analysis, frequency distribution, spectral power), frequency contribution (spectral analysis), scale invariant (fractal) behaviour (detrended fluctuation and power law analysis) and regularity (approximate and multiscale entropy). Each technique is presented with a definition, interpretation, clinical application, advantages, limitations and summary of its calculation. The ubiquitous association between altered variability and illness is highlighted, followed by an analysis of how variability analysis may significantly improve prognostication of severity of illness and guide therapeutic intervention in critically ill patients.

Multiple organ dysfunction syndrome: exploring the paradigm of complex nonlinear systems.

Objectives The objectives of this article are to introduce and explore a novel paradigm based on complex nonlinear systems, and to evaluate its application to critical care research regarding the systemic host response and multiple organ dysfunction syndrome (MODS). Data Sources Published original work, review articles, scientific abstracts and books, as well as our personal files. Study Selection Studies were selected for their relevance to the applications of nonlinear complex systems, to critical care medicine, and to the concepts presented. Data Extraction We extracted all applicable data. Data Synthesis Following a brief review of MODS, an introduction to complex nonlinear systems is presented, including clear concepts, definitions, and properties. By examining the multiple, nonlinear, interrelated, and variable interactions between the metabolic, neural, endocrine, immune, and inflammatory systems; data regarding interconnected antibody networks; and the redundant, nonlinear, interdependent nature of the inflammatory response, we present the hypothesis that the systemic host response to trauma, shock, or sepsis must be evaluated as a complex nonlinear system. This model provides a new explanation for the failure of trials using various antimediator therapies in the treatment of patients with sepsis and MODS. Understanding the host response as a complex nonlinear system offers innovative means of studying critical care patients, specifically by suggesting a greater focus on systemic properties. We hypothesize that analysis of variability and connectivity of individual variables offer a novel means of evaluating and differentiating the systemic properties of a complex nonlinear system. Current applications of evaluating variability and connectivity are discussed, and insights regarding future research are offered. Conclusion The paradigm offered by the study of complex nonlinear systems suggests new insights to pursue research to evaluate, monitor, and treat patients with MODS.

Systematic Classification of Morbidity and Mortality After Thoracic Surgery

BACKGROUND Objective reporting of postoperative complications is the foundation of surgical quality assurance. We developed a system to identify both presence and severity of thoracic morbidity and mortality, and evaluated its feasibility and utility over the first two years of its implementation. METHODS The system was based on the Clavien-Dindo classification, in which the severity of a complication is proportional to the effort to treat it. Definitions were developed by peer review and questionnaire. All patients undergoing thoracic surgery (January 2008 to December 2009) were prospectively evaluated. RESULTS A total of 953 patients (mean age 61 years; range, 14 to 95) underwent thoracic surgery (total # cases 1260), of which 369 patients had at least one complication (29.3% procedures). Grades I and II include minor complications requiring no therapy or pharmacologic intervention only. Grades III and IV are major complications that require surgical intervention or life support. Grade V complications result in patient death. Grades I, II, III, and IV complications comprised 4.9%, 63.9%, 21.1%, and 7.8% of all complications; overall mortality rate (grade V) was 2.2%. The most common complications were prolonged air leak (18.8%) and atrial fibrillation (18.2%) after pulmonary resection, and atrial fibrillation (11.5%) after esophagectomy-gastrectomy. Prolonged air leak led to a major complication (13%), readmission (17%), or prolonged hospital stay (29%) to a greater extent than atrial fibrillation (3%, 2%, and 7%, respectively). CONCLUSIONS This standardized classification system for identifying presence and severity of thoracic surgical complications is feasible, facilitates objective comparison, identifies burden of illness of individual complications, and provides an effective method for continuous surgical quality assessment.

Review and classification of variability analysis techniques with clinical applications

Analysis of patterns of variation of time-series, termed variability analysis, represents a rapidly evolving discipline with increasing applications in different fields of science. In medicine and in particular critical care, efforts have focussed on evaluating the clinical utility of variability. However, the growth and complexity of techniques applicable to this field have made interpretation and understanding of variability more challenging. Our objective is to provide an updated review of variability analysis techniques suitable for clinical applications. We review more than 70 variability techniques, providing for each technique a brief description of the underlying theory and assumptions, together with a summary of clinical applications. We propose a revised classification for the domains of variability techniques, which include statistical, geometric, energetic, informational, and invariant. We discuss the process of calculation, often necessitating a mathematical transform of the time-series. Our aims are to summarize a broad literature, promote a shared vocabulary that would improve the exchange of ideas, and the analyses of the results between different studies. We conclude with challenges for the evolving science of variability analysis.

Continuous Multi-Parameter Heart Rate Variability Analysis Heralds Onset of Sepsis in Adults

Background Early diagnosis of sepsis enables timely resuscitation and antibiotics and prevents subsequent morbidity and mortality. Clinical approaches relying on point-in-time analysis of vital signs or lab values are often insensitive, non-specific and late diagnostic markers of sepsis. Exploring otherwise hidden information within intervals-in-time, heart rate variability (HRV) has been documented to be both altered in the presence of sepsis, and correlated with its severity. We hypothesized that by continuously tracking individual patient HRV over time in patients as they develop sepsis, we would demonstrate reduced HRV in association with the onset of sepsis. Methodology/Principal Findings We monitored heart rate continuously in adult bone marrow transplant (BMT) patients (n = 21) beginning a day before their BMT and continuing until recovery or withdrawal (12±4 days). We characterized HRV continuously over time with a panel of time, frequency, complexity, and scale-invariant domain techniques. We defined baseline HRV as mean variability for the first 24 h of monitoring and studied individual and population average percentage change (from baseline) over time in diverse HRV metrics, in comparison with the time of clinical diagnosis and treatment of sepsis (defined as systemic inflammatory response syndrome along with clinically suspected infection requiring treatment). Of the 21 patients enrolled, 4 patients withdrew, leaving 17 patients who completed the study. Fourteen patients developed sepsis requiring antibiotic therapy, whereas 3 did not. On average, for 12 out of 14 infected patients, a significant (25%) reduction prior to the clinical diagnosis and treatment of sepsis was observed in standard deviation, root mean square successive difference, sample and multiscale entropy, fast Fourier transform, detrended fluctuation analysis, and wavelet variability metrics. For infected patients (n = 14), wavelet HRV demonstrated a 25% drop from baseline 35 h prior to sepsis on average. For 3 out of 3 non-infected patients, all measures, except root mean square successive difference and entropy, showed no significant reduction. Significant correlation was present amongst these HRV metrics for the entire population. Conclusions/Significance Continuous HRV monitoring is feasible in ambulatory patients, demonstrates significant HRV alteration in individual patients in association with, and prior to clinical diagnosis and treatment of sepsis, and merits further investigation as a means of providing early warning of sepsis.

Melatonin as Adjuvant Cancer Care With and Without Chemotherapy A Systematic Review and Meta-analysis of Randomized Trials

Background. Melatonin (MLT) is known to possess potent antioxidant, antiproliferative, immune-modulating, and hormone-modulating properties. Clinical evidence suggests that MLT may have a possible role in the treatment of cancer. The authors systematically reviewed the effects of MLT in conjunction with chemotherapy, radiotherapy, supportive care, and palliative care on 1-year survival, complete response, partial response, stable disease, and chemotherapy-associated toxicities. Methods. The authors searched 7 databases: MEDLINE (1966-February 2010), AMED (1985-February 2010), Alt HealthWatch (1995-February 2010), CINAHL (1982-February 2010), Nursing and Allied Health Collection: Basic (1985-February 2010), the Cochrane Database (2009), and the Chinese database CNKI (1979-February 2010). They included all trials that randomized patients to treatment, including MLT or a similar control group without MLT. Results. The authors included data from 21 clinical trials, all of which dealt with solid tumors. The pooled relative risk (RR) for 1-year mortality was 0.63 (95% confidence interval [CI] = 0.53-0.74; P < .001). Improved effect was found for complete response, partial response, and stable disease with RRs of 2.33 (95% CI = 1.29-4.20), 1.90 (1.43-2.51), and 1.51 (1.08-2.12), respectively. In trials combining MLT with chemotherapy, adjuvant MLT decreased 1-year mortality (RR = 0.60; 95% CI = 0.54-0.67) and improved outcomes of complete response, partial response, and stable disease; pooled RRs were 2.53 (1.36-4.71), 1.70 (1.37-2.12), and 1.15 (1.00-1.33), respectively. In these studies, MLT also significantly reduced asthenia, leucopenia, nausea and vomiting, hypotension, and thrombocytopenia. Conclusion. MLT may benefit cancer patients who are also receiving chemotherapy, radiotherapy, supportive therapy, or palliative therapy by improving survival and ameliorating the side effects of chemotherapy.

Clinical review: A review and analysis of heart rate variability and the diagnosis and prognosis of infection

Bacterial infection leading to organ failure is the most common cause of death in critically ill patients. Early diagnosis and expeditious treatment is a cornerstone of therapy. Evaluating the systemic host response to infection as a complex system provides novel insights: however, bedside application with clinical value remains wanting. Providing an integrative measure of an altered host response, the patterns and character of heart rate fluctuations measured over intervals-in-time may be analysed with a panel of mathematical techniques that quantify overall fluctuation, spectral composition, scale-free variation, and degree of irregularity or complexity. Using these techniques, heart rate variability (HRV) has been documented to be both altered in the presence of systemic infection, and correlated with its severity. In this review and analysis, we evaluate the use of HRV monitoring to provide early diagnosis of infection, document the prognostic implications of altered HRV in infection, identify current limitations, highlight future research challenges, and propose improvement strategies. Given existing evidence and potential for further technological advances, we believe that longitudinal, individualized, and comprehensive HRV monitoring in critically ill patients at risk for or with existing infection offers a means to harness the clinical potential of this bedside application of complex systems science.

Towards a Definition of Life

This article offers a new definition of life as a “self-contained, self-regulating, self-organizing, self-reproducing, interconnected, open thermodynamic network of component parts which performs work, existing in a complex regime which combines stability and adaptability in the phase transition between order and chaos, as a plant, animal, fungus, or microbe.” Open thermodynamic networks, which create and maintain order and are used by all organisms to perform work, import energy from and export entropy into the environment. Intra- and extracellular interconnected networks also confer order. Although life obeys the laws of physics and chemistry, the design of living organisms is not determined by these laws, but by Darwinian selection of the fittest designs. Over a short range of normalized energy consumption, open thermodynamic systems change from deeply ordered to chaotic, and life is found in this phase transition, where a dynamic balance between stability and adaptability allows for homeokinesis. Organisms and cells move within the phase transition with changes in metabolic rate. Seeds, spores and cryo-preserved tissue are well within the ordered regime, while health probably cannot be maintained with displacements into the chaotic regime. Understanding life in these terms may provide new insights into what constitutes health and lead to new theories of disease.

Selenium and Lung Cancer: A Systematic Review and Meta Analysis

Background Selenium is a natural health product widely used in the treatment and prevention of lung cancers, but large chemoprevention trials have yielded conflicting results. We conducted a systematic review of selenium for lung cancers, and assessed potential interactions with conventional therapies. Methods and Findings Two independent reviewers searched six databases from inception to March 2009 for evidence pertaining to the safety and efficacy of selenium for lung cancers. Pubmed and EMBASE were searched to October 2009 for evidence on interactions with chemo- or radiation-therapy. In the efficacy analysis there were nine reports of five RCTs and two biomarker-based studies, 29 reports of 26 observational studies, and 41 preclinical studies. Fifteen human studies, one case report, and 36 preclinical studies were included in the interactions analysis. Based on available evidence, there appears to be a different chemopreventive effect dependent on baseline selenium status, such that selenium supplementation may reduce risk of lung cancers in populations with lower baseline selenium status (serum<106 ng/mL), but increase risk of lung cancers in those with higher selenium (≥121.6 ng/mL). Pooling data from two trials yielded no impact to odds of lung cancer, OR 0.93 (95% confidence interval 0.61–1.43); other cancers that were the primary endpoints of these trials, OR 1.51 (95%CI 0.70–3.24); and all-cause-death, OR 0.93 (95%CI 0.79–1.10). In the treatment of lung cancers, selenium may reduce cisplatin-induced nephrotoxicity and side effects associated with radiation therapy. Conclusions Selenium may be effective for lung cancer prevention among individuals with lower selenium status, but at present should not be used as a general strategy for lung cancer prevention. Although promising, more evidence on the ability of selenium to reduce cisplatin and radiation therapy toxicity is required to ensure that therapeutic efficacy is maintained before any broad clinical recommendations can be made in this context.

Vitamin A and Retinoid Derivatives for Lung Cancer: A Systematic Review and Meta Analysis

Background Despite reported antiproliferative activity of vitamin A and its common use for cancer, there is no comprehensive synthesis of its safety and efficacy in lung cancers. To address this issue we conducted a systematic review of the safety and efficacy of vitamin A for the treatment and prevention of lung cancers. Methods and Findings Two independent reviewers searched six electronic databases from inception to July 2009 for clinical, observational, and preclinical evidence pertaining to the safety and efficacy of vitamin A and related retinoids for lung cancers. 248 studies were included for full review and analysis. Five RCTs assessed treatment of lung cancers, three assessed primary prevention, and three looked at secondary prevention of lung cancers. Five surrogate studies, 26 phase I/II, 32 observational, and 67 preclinical studies were also included. 107 studies were included for interactions between vitamin A and chemo- or radiation- therapy. Although some studies demonstrated benefits, there was insufficient evidence overall to support the use of vitamin A or related retinoids for the treatment or prevention of lung cancers. Retinyl palmitate combined with beta carotene increased risk of lung cancer in smokers in the large CARET trial. Pooling of three studies pertaining to treatment and three studies on secondary prevention revealed no significant effects on response rate, second primary tumor, recurrence, 5-year survival, and mortality. There was a small improvement in event free survival associated with vitamin A compared to controls, RR 1.24 (95% CI 1.13–1.35). The synthetic rexinoid bexarotene increased survival significantly among a subset of patients in two RCTs (p<0.014, <0.087). Conclusions There is a lack of evidence to support the use of naturally occuring retinoids for the treatment and prevention of lung cancers. The rexinoid bexarotene may hold promise for use among a subset of patients, and deserves further study.