The pathophysiology of sepsis - 2021 update: Part 2, organ dysfunction and assessment.

PURPOSE: This is the second article in a 2-part series discussing the pathophysiology of sepsis. Part 1 of the series reviewed the immunologic response and overlapping pathways of inflammation and coagulation that contribute to the widespread organ dysfunction. In this article (part 2), major organ systems and their dysfunction in sepsis are reviewed, with discussion of scoring systems used to identify patterns and abnormal vital signs and laboratory values associated with sepsis. SUMMARY: Sepsis is a dysregulated host response to infection that produces significant morbidity, and patients with shock due to sepsis have circulatory and cellular and metabolic abnormalities that lead to a higher mortality. Cardiovascular dysfunction produces vasodilation, reduced cardiac output and hypotension/shock requiring fluids, vasopressors, and advanced hemodynamic monitoring. Respiratory dysfunction may require mechanical ventilation and attention to volume status. Renal dysfunction is a frequent manifestation of sepsis. Hematologic dysfunction produces low platelets and either elevation or reduction of leukocytes, so consideration of the neutrophil:lymphocyte ratio may be useful. Procoagulant and antifibrinolytic activity leads to coagulation that is stimulated by inflammation. Hepatic dysfunction manifest as elevated bilirubin is often a late finding in sepsis and may cause reductions in production of essential proteins. Neurologic dysfunction may result from local endothelial injury and systemic inflammation through activity of the vagus nerve. CONCLUSION: Timely recognition and team response with efficient use of therapies can improve patient outcome, and pharmacists with a complete understanding of the pathophysiologic mechanisms and treatments are valuable members of that team.

Steady-state pharmacokinetics of intravenous levetiracetam in neurocritical care patients.

STUDY OBJECTIVES: To characterize the steady-state pharmacokinetics of intravenous levetiracetam in neurocritical care patients requiring seizure prophylaxis after a neurologic injury and to determine which dosing regimens achieve serum concentrations within the recommended therapeutic range of 6-20 µg/ml. DESIGN. Prospective, open-label, steady-state pharmacokinetic study. SETTING: Neurocritical care unit in a tertiary care medical center. PATIENTS. Twelve adults (five men, seven women) admitted to the neurocritical care unit who required prophylactic anticonvulsant therapy after subarachnoid hemorrhage, subdural hematoma, or traumatic brain injury. INTERVENTION: Patients received an intravenous infusion of levetiracetam 500 mg over 15 minutes every 12 hours. MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected from all patients after a minimum of four doses of therapy. Serum levetiracetam concentrations were determined by ultraperformance liquid chromatography with tandem mass spectrometry detection, and pharmacokinetic data were analyzed by compartmental and noncompartmental methods. Monte Carlo simulations were performed for multiple levetiracetam dosing regimens to determine the probability of achieving a target trough concentration of 6 µg/ml or greater, 20 µg/ml or greater, and 6-20 µg/ml. The mean ± SD levetiracetam maximum serum concentration was 28.0 ± 8.0 µg/ml, minimum serum concentration 3.1 ± 1.8 µg/ml, half-life 5.2 ± 1.2 hours, systemic clearance 5.6 ± 1.8 L/hour, and volume of distribution at steady state 36.8 ± 6.3 L. Increasing the doses of levetiracetam increased the probability of achieving a target trough concentration of 6 µg/ml or greater but also increased the probability of achieving trough concentrations greater than 20 µg/ml. Levetiracetam doses of 1000 mg every 8 hours and 1500-2000 mg every 12 hours provided the highest probability of achieving a target trough concentration between 6 and 20 µg/ml. CONCLUSION: Compared with previously published results in healthy volunteers and adults in status epilepticus, levetiracetam systemic clearance was faster and the terminal elimination half-life was shorter in neurocritical care patients. Higher doses or more frequent dosing may be needed to achieve target trough concentrations of 6-20 µg/ml.

The research agenda in ICU telemedicine: a statement from the Critical Care Societies Collaborative.

ICU telemedicine uses audiovisual conferencing technology to provide critical care from a remote location. Research is needed to best define the optimal use of ICU telemedicine, but efforts are hindered by methodological challenges and the lack of an organized delivery approach. We convened an interdisciplinary working group to develop a research agenda in ICU telemedicine, addressing both methodological and knowledge gaps in the field. To best inform clinical decision-making and health policy, future research should be organized around a conceptual framework that enables consistent descriptions of both the study setting and the telemedicine intervention. The framework should include standardized methods for assessing the preimplementation ICU environment and describing the telemedicine program. This framework will facilitate comparisons across studies and improve generalizability by permitting context-specific interpretation. Research based on this framework should consider the multidisciplinary nature of ICU care and describe the specific program goals. Key topic areas to be addressed include the effect of ICU telemedicine on the structure, process, and outcome of critical care delivery. Ideally, future research should attempt to address causation instead of simply associations and elucidate the mechanism of action in order to determine exactly how ICU telemedicine achieves its effects. ICU telemedicine has significant potential to improve critical care delivery, but high-quality research is needed to best inform its use. We propose an agenda to advance the science of ICU telemedicine and generate research with the greatest potential to improve patient care.

Adverse drug events in intensive care units: risk factors, impact, and the role of team care.

Advances in diagnostic tests, technological interventions, and pharmacotherapy have resulted in spectacular results for many intensive care unit (ICU) patients who, in earlier generations, would have succumbed to their critical illness. At the same time, the complexity and intensity of care required for ICU patients is also associated with greater risks for harm resulting from care. As in other inpatient areas, medications are the most common type of therapy in ICUs and are also associated with the most frequent type of ICU adverse events. Critically ill patients are at high risk for adverse drug events for many reasons, including the complexity of their disease that creates challenges in drug dosing, their vulnerability to rapid changes in pharmacotherapy, the intensive care environment providing ample distractions and opportunity for error, the administration of complex drug regimens, the numerous high-alert medications that they receive, and the mode of drug administration. The clinical outcomes of adverse drug events can result in end-organ damage and even death. The costs of an adverse drug event can be substantial to healthcare systems with an additional $6,000-$9,000 for each event. The multiprofessional patient care team is one approach to promoting patient safety in the ICU.

Prioritizing the organization and management of intensive care services in the United States: the PrOMIS Conference.

OBJECTIVE: Adult critical care services are a large, expensive part of U.S. health care. The current agenda for response to workforce shortages and rising costs has largely been determined by members of the critical care profession without input from other stakeholders. We sought to elicit the perceived problems and solutions to the delivery of critical care services from a broad set of U.S. stakeholders. DESIGN: A consensus process involving purposive sampling of identified stakeholders, preconference Web-based survey, and 2-day conference. SETTING: Participants represented healthcare providers, accreditation and quality-oversight groups, federal sponsoring institutions, healthcare vendors, and institutional and individual payers. SUBJECTS: We identified 39 stakeholders for the field of critical care medicine. Thirty-six (92%) completed the preconference survey and 37 (95%) attended the conference. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Participants expressed moderate to strong agreement with the concerns identified by the critical care professionals and additionally expressed consternation that the critical care delivery system was fragmented, variable, and not patient-centered. Recommended solutions included regionalizing the adult critical care system into "tiers" defined by explicit triage criteria and professional competencies, achieved through voluntary hospital accreditation, supported through an expanded process of competency certification, and monitored through process and outcome surveillance; implementing mechanisms for improved communication across providers and settings and between providers and patients/families; and conducting market research and a public education campaign regarding critical care's promises and limitations. CONCLUSIONS: This consensus conference confirms that agreement on solutions to complex healthcare delivery problems can be achieved and that problem and solution frames expand with broader stakeholder participation. This process can be used as a model by other specialties to address priority setting in an era of shifting demographics and increasing resource constraints.

Addition of dexmedetomidine to standard sedation regimens after cardiac surgery: an outcomes analysis.

STUDY OBJECTIVE: To characterize inpatient use of intravenous sedatives in the real-world setting, and to evaluate clinical and economic outcomes when dexmedetomidine was used with midazolam and propofol for select cardiovascular procedures. DESIGN: 12-month retrospective analysis. DATA SOURCE: An administrative claims database of operational data from a nationally representative sample of 250 medical and surgical hospitals. PATIENTS: Patients who received midazolam plus propofol (9996 patients) or dexmedetomidine, midazolam, plus propofol (356 patients) after cardiac valve or vessel surgery. MEASUREMENTS AND MAIN RESULTS: The source of patient demographics (e.g., age, sex, Charlson Comorbidity Index) and outcomes (e.g., charges, length of stay, mortality rate) was the hospital billing claim form. Patients in the dexmedetomidine-midazolam-propofol cohort tended to be younger and male and to have fewer comorbidities than those midazolam-propofol cohort. The primary outcomes for the three-drug cohort showed significant reductions in total charges/patient (approximately $18,000, p<0.05), total hospital length of stay (0.6 days, p<0.0001), days in the intensive care unit or cardiac care unit (3.87 days, p<0.0001), and mortality (2%, p=0.0142). Although pharmacy charges were higher (approximately $4000/patient), lower charges for the intensive care or cardiac care unit, operating room, room and board, and respiratory services were observed in the dexmedetomidinemidazolam-propofol cohort compared with the two-drug cohort. Also, mechanical ventilation was shorter by approximately 0.5 day in the three-drug cohort (p<0.01). CONCLUSION: These initial findings of a real-world assessment of dexmedetomidine use with other agents suggest favorable clinical and economic outcomes. Further research through randomized clinical trials of dexmedetomidine is warranted to better understand its optimum patient population, dosage, and the causality of the results, and to confirm the potential clinical and economic benefits observed in our patients.