Michael H. Ackerman

Does programmed cell death (apoptosis) play a role in the development of multiple organ dysfunction in critically ill patients? a review and a theoretical framework.

Objectives: To critically review the current understanding of the pathophysiologic events leading to the development of secondary multiple organ dysfunction (MODS) in critical illness and to examine the role of apoptosis (programmed cell death) as a mechanism involved in the progression of MODS. Data Sources: Research and review articles published since 1982 on the pathophysiology of MODS, particularly the role of cytokines, reactive oxygen species, heat shock proteins, and apoptosis. Research and review articles on the physiology of apoptosis. Articles include human/animal and in vitro/in vivo studies. Data Extraction: The most prevalent mediating factors of MODS were examined for their potential to induce apoptosis, as reported in the literature. The combination of several of the above factors was also examined in terms of apoptosis‐triggering potential. Data Synthesis: Specific pathophysiologic conditions related to the onset of MODS have been shown to affect apoptotic rates in organ tissue cells and their respective endothelial cells in animal and in vitro models. These conditions include the following: a) increased release of inflammation‐related cytokines; b) increased production of oxygen free radicals associated with ischemia/reperfusion injury and states of low tissue perfusion; c) expression and release of heat shock proteins from tissue cells and the liver; d) elevated glucocorticoid concentrations after adrenal cortex activation; and e) release of bacterial products into the systemic circulation. Conclusion: The most important MODS‐related pathophysiologic conditions known to date have been shown to affect programmed cell death rates in almost all cell types. Organ‐specific cell death involving both parenchymal and microvasculature endothelial cells is conceivably underlying organ dysfunction. The hypothesis that increased apoptotic rates are involved in organ dysfunction may provide a unifying theory for the pathophysiology of MODS.

A controlled trial of electronic automated advisory vital signs monitoring in general hospital wards

Objectives: Deteriorating ward patients are at increased risk. Electronic automated advisory vital signs monitors may help identify such patients and improve their outcomes. Setting: A total of 349 beds, in 12 general wards in ten hospitals in the United States, Europe, and Australia. Patients: Cohort of 18,305 patients. Design: Before-and-after controlled trial. Intervention: We deployed electronic automated advisory vital signs monitors to assist in the acquisition of vital signs and calculation of early warning scores. We assessed their effect on frequency, type, and treatment of rapid response team calls; survival to hospital discharge or to 90 days for rapid response team call patients; overall type and number of serious adverse events and length of hospital stay. Measurements and Main Results: We studied 9,617 patients before (control) and 8,688 after (intervention) deployment of electronic automated advisory vital signs monitors. Among rapid response team call patients, intervention was associated with an increased proportion of calls secondary to abnormal respiratory vital signs (from 21% to 31%; difference [95% confidence interval] 9.9 [0.1–18.5]; p = .029). Survival immediately after rapid response team treatment and survival to hospital discharge or 90 days increased from 86% to 92% (difference [95% confidence interval] 6.3 [0.0–12.6]; p = .04). Intervention was also associated with a decrease in median length of hospital stay in all patients (unadjusted p < .0001; adjusted p = .09) and more so in U.S. patients (from 3.4 to 3.0 days; unadjusted p < .0001; adjusted ratio [95% confidence interval] 1.03 [1.00–1.06]; p = .026). The time required to complete and record a set of vital signs decreased from 4.1 ± 1.3 mins to 2.5 ± 0.5 mins (difference [95% confidence interval] 1.6 [1.4–1.8]; p < .0001). Conclusions: Deployment of electronic automated advisory vital signs monitors was associated with an improvement in the proportion of rapid response team-calls triggered by respiratory criteria, increased survival of patients receiving rapid response team calls, and decreased time required for vital signs measurement and recording (NCT01197326).

Expression of Fas (CD95) and Fas ligand on peripheral blood mononuclear cells in critical illness and association with multiorgan dysfunction severity and survival.

ObjectiveThis was an exploratory study with three goals: a) to quantify the expression of the apoptotic receptor Fas and its ligand (FasL) on peripheral blood mononuclear cells (PBMCs) in patients with, or at risk for, multiple organ dysfunction syndrome (MODS); b) to compare this expression with the respective expression in matched controls; and c) to explore the association with MODS severity and survival. DesignRepeated-measures correlational and cross-sectional design. SettingThe surgical, medical, and the trauma/burn intensive care unit of an academic institution. PatientsThirty-five adult, critically ill patients meeting the diagnostic criteria for systemic inflammatory response syndrome (SIRS) with MODS, or at risk for MODS, were followed for 14 days. Thirty-five non-SIRS controls matched with patients for age, gender, and race comprised the control group. InterventionsPeripheral blood sampling every 48 hrs. Measurements/Main Results T cells were considerably depleted in SIRS/MODS patients (p < .001), and Fas and FasL expression on PBMCs (flow cytometric analysis) was elevated significantly compared with controls (p < .001). In contrast to controls, non-T cells were the major sources of Fas and FasL in SIRS/MODS patients (p < .01). Expression of Fas and FasL exhibited a bimodal correlation with severity (p < .03). High severity patients demonstrated increasing Fas and FasL expression with increasing severity in contrast to declining expression in moderately severe patients. Fas and FasL measurements were significantly and positively associated with the likelihood of survival (p < .05). ConclusionsDysregulation in the expression of apoptotic receptors Fas and FasL, at least in PBMCs, may be involved in the pathophysiology of SIRS, the related lymphocytopenia, and the onset of MODS and the related morbidity and mortality rates.

Serum leptin levels are higher but are not independently associated with severity or mortality in the multiple organ dysfunction/systemic inflammatory response syndrome: a matched case control and a longitudinal study

Hypercatabolism and immune dysfunction are closely associated with the development of systemic inflammatory response–multiple organ dysfunction (SIRS/MODS) in critical illness. It remains unclear however, whether leptin, an adipocyte‐derived hormone whose levels are influenced by several cytokines and which regulates immune function, food‐intake and energy expenditure is independently related to the development of and/or severity and mortality from SIRS/MODS.

Soluble fas levels correlate with multiple organ dysfunction severity, survival and nitrate levels, but not with cellular apoptotic markers in critically ill patients

Apoptosis is a mode of programmed cell death (PCD). Transduction of apoptotic signals results in cellular suicide. Organ specific apoptosis has been proposed as a factor in multiple organ dysfunction syndrome (MODS). Fas is a widely occurring apoptotic signal receptor molecule expressed by almost any type of cell, which is also released in a soluble circulating form (circulating fas, sfas). In this exploratory study, we investigated the association of sfas with severity, survival, known mediators of multiple organ dysfunction, and cellular apoptotic markers on peripheral blood mononuclear cells (PBMC) in a group of 35 patients with MODS and in 35 matched controls. Critically ill patients with MODS had significantly elevated sfas levels compared to controls over time (P < .001). Increased serum concentration of circulating fas was associated with increased severity of multiple organ dysfunction. Non-survivors exhibited significantly higher sfas levels compared to survivors (P < .01) and increasing sfas was inversely associated with the likelihood of survival (P < .05). Circulating fas levels correlated highly with serum nitrate concentration, but not with fas and fasL expression on PBMC of critically ill patients. TNF-alpha and IL-6, although they appear to be mediators of both apoptosis and MODS, had no association with sfas. These results are suggestive of the need for further investigation on the role of apoptotic signaling in the development of MODS. They also suggest a potential prognostic value of sfas for SIRS/MODS clinical outcomes.

A review of normal saline instillation: implications for practice.

Nurses commonly use normal saline instillation (NSI) as a component of the suctioning procedure. The current research on NSI has not clearly identified many positive aspects of the procedure. Much of the research suggests it may actually be harmful. There has been little investigation into the reasons NSI is used. It is presumed that NSI is used to increase secretion removal when patients have thick endotracheal secretions due to inadequate humidity to the airway. Nurses need to be aware of the potential negative effects of routine NSI as well as alternative methods for maintaining adequate airway humidification.

Incidence, pathogenesis, and management of sepsis: an overview.

Sepsis is a complex condition that occurs as a result of the systemic manifestation of infection. It is associated with high morbidity and mortality risks for critically ill patients. Assessment and monitoring aimed at early recognition and treatment, on the basis of evidence-based guidelines, are advocated for optimizing outcomes for patients with severe sepsis. Awareness of the risk factors, clinical signs and symptoms, pathophysiology, and updates in the management of sepsis can enhance the nursing care for patients with severe sepsis to promote best practices for sepsis care in the intensive care unit. This article reviews the incidence and pathophysiology of sepsis, highlighting updates in treatment and implications for nursing care.

Technologic approaches to determining proper placement of enteral feeding tubes.

E delivery of nutritional support is an important component of overall management of critically ill patients. In the presence of a functioning gastrointestinal (GI) tract, enteral nutrition generally is preferred over parenteral nutrition, as it is less expensive, and also may help to reduce infectious complications. Early enteral nutrition in the intensive care unit (ICU) has been shown to decrease bacterial translocation from the intestinal tract while preserving gut barrier function and enhancing its role as an immune organ. Research also has demonstrated that early enteral feeding enhances nitrogen balance and wound healing, decreases hypermetabolic response to tissue injury, and augments cellular antioxidant systems, resulting in an overall decrease in the incidence of sepsis. Therefore, access to the small bowel is essential to improve outcomes for critically ill patients. However, critically ill patients are at high risk for adverse outcomes from clinical mishaps associated with feeding tube insertion. Complications from malpositioning of feeding tubes have included “isocalothorax,” resulting from feedings instilled into the lungs rather than into the GI tract, and pneumothorax following feeding tube placement with the use of a guidewire. Other complications associated with both the insertion and use of enteral feeding tubes include atelectasis, pleural effusion, bronchopleural fistula, hydrothorax, empyema, mediastinitis, pneumonitis, esophageal perforation, and pneumonia. Predisposing factors, such as the presence of an endotracheal tube or tracheostomy, altered mental status, decreased ability to comply with instructions during procedures, and hampered ability to report chest discomfort or dyspnea following feeding tube insertion, are additional factors that warrant serious consideration in the search for new empirically validated techniques for ensuring patient safety and optimal nutritional outcomes in the ICU.

Neutralizing ageism in critical care via outcomes research.

Ageism, as a mind-set, amplifies a belief that intensive care for the elderly is ineffectual. However, there are little data to support the notion that advanced chronological age alone predicts unfavorable outcomes in response to intensive care. A lack of outcome data, combined with ageism, may place older patients at risk for rationing of intensive care. Currently, neither public policy nor cultural norms directly support a limitation in services to the elderly. However, as pressure to reduce health care costs increases, critically ill elderly patients may be targeted for rationing. In this context, outcomes research involving elderly populations is crucial. The purpose of this report is to explicate the risk of ageism in the delivery of intensive care and to describe methods for implementing outcomes assessment for critically ill elderly patients as an essential element in a continuum of care.

Association of proinflammatory molecules with apoptotic markers and survival in critically ill multiple organ dysfunction patients.

Recent evidence supports the involvement of apoptosis in multiple organ dysfunction (MODS). The authors examined the hypothesis that nitric oxide (NO), interleukin (IL)-6, tumor necrosis factor (TNF)-α, and cortisol correlate with Fas and Fas ligand (FasL) expression on peripheral blood mononuclear cells and that Fas and FasL, therefore, mediate their association with MODS severity. Thirty-five critically ill adult MODS patients were followed for up to 14 days and were compared to non-MODS matched controls. Fas, FasL, nitrate, cortisol, and IL-6 were elevated in MODS patients (P < 0.05). Nitrate and cortisol correlated with Fas expression (P < 0.05). All factors studied, except for TNF-α, correlated with MODS severity (P < 0.05); however, by multivariate analyses, Fas and FasL were independently associated with severity and survival (P < 0.05). The inflammatory molecules studied may mediate the association of apoptotic constituents with MODS severity and survival only in part.