Kristina E. Rudd

Clinical research during a public health emergency: a systematic review of severe pandemic influenza management.

Objective:Rigorous evaluation of clinical interventions in the setting of a public health emergency is necessary to identify best practices, to develop clinical management guidelines, and to inform resource allocation. The 2009 influenza A (H1N1) pandemic necessitated care of critically ill patients around the world. To inform the World Health Organization Public Health Research Agenda for Influenza, we conducted a systematic review to identify clinical interventions other than antiviral therapies that would benefit severely ill 2009 H1N1 influenza patients (adults and children) in both high- and low-resource settings. Data Sources:PubMed, EMBASE, Cochrane Central Register of Clinical Trials, and Cochrane Database of Systematic Reviews; hand search of abstracts from six professional society annual conferences and bibliographies of clinical review articles; and personal communication with leaders in the field. Study Selection:English language; human studies; citations added to databases from January 1, 2009 (Cochrane databases) or March 15, 2009 (PubMed and EMBASE) through January 31, 2012; randomized controlled trials, prospective cohort studies, or systematic reviews/meta-analyses of non-antiviral clinical interventions in hospitalized 2009 influenza A (H1N1) patients. Data Extraction:The search identified 2,452 articles. Thirty-six potentially relevant articles were read. Seven articles met criteria. All were observational studies. Data Synthesis:One study found benefit of convalescent plasma infusion, three studies found no benefit of corticosteroids, and three studies had mixed results on the benefit of extracorporeal lung support. No study was applicable to health care delivery in low-resource settings. Conclusions:There is a paucity of high quality clinical research to inform clinical care of severe H1N1 influenza, and we found no beneficial interventions appropriate for low-resource settings. This may be due to the logistical difficulties of conducting clinical research in response to a public health emergency. Our investigation underscores the need for the development of outbreak-ready research capacity in both high- and low-resource settings.

Counting Sepsis, an Imprecise but Improving Science

Sepsis, most succinctly defined as organ dysfunction due to infection, is estimated to account for more than 5 million deaths around the world each year and to cause or contribute to approximately half of all deaths occurring in hospitals in the United States.1,2 A 2016 report from the Healthcare Cost and Utilization Project estimated the cost of treating sepsis in US hospitals in 2013 at

Association of the Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) Score With Excess Hospital Mortality in Adults With Suspected Infection in Low- and Middle-Income Countries

24 billion, making it the most expensive condition treated in US hospitals among all payers.3 In recent years, the substantial burden of sepsis at the individual, health system, and societal levels has become increasingly recognized by the medical community and the public, culminating in the World Health Organization (WHO) adopting the Improving the Prevention, Diagnosis, and Management of Sepsis resolution at the World Health Assembly in May 2017.4 Despite the increased visibility of sepsis and increasing awareness of the global health challenge it poses, accurate quantification of sepsis incidence, mortality, and morbidity remains elusive. In the absence of a definitive diagnostic test for sepsis, the gold standard remains the clinical diagnosis of infection and identifying new organ dysfunction caused by the host response to that infection. This basic concept remains unchanged by the third consensus definition of sepsis promulgated in 2016, which, unlike the first 2 consensus definitions, proposed quantifying the degree of organ dysfunction needed to diagnose sepsis by using the Sequential Organ Failure Assessment (SOFA) score.5 Estimates for the incidence of sepsis in the United States vary between 850 000 and 3 000 000 cases annually, the greater than 3-fold difference explained by the variation in case definitions applied to hospital administrative databases.6 The only available global estimate, 19.4 million cases per year, is based on extrapolation of estimates of hospital-treated sepsis in high-income countries. This is likely an underestimate, given the near total lack of data from lowor middle-income countries, where the burden of infectious diseases is higher.1,7 Practical methods available to quantify the burden of sepsis include clinical diagnosis through prospective cohort studies or retrospective chart reviews, the use of administrative data (International Classification of Diseases [ICD] codes associated with hospital discharges, emergency department visits, or reimbursement claims), and, where they are available, interrogation of electronic health records (EHRs). To date, most largescale population-based studies have used administrative data and identified cases of sepsis via an “explicit” diagnosis if the patient was allocated an ICD code for severe sepsis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 995.92) or septic shock (785.52), or an “implicit” diagnosis when allocated a code indicating infection together with a code indicating acute organ dysfunction (eg, ICD-9-CM code 569.83, perforation of intestine, combined with 584, acute renal failure). The majority of such studies have used a combination of codes taken or adapted from the approach used by Angus et al.8 One important concern with this methodology is the inability to determine a causal relationship between infection and acute organ dysfunction, which might result in overcounting sepsis cases. A more recent concern with this methodology is so-called upcoding, in which the diagnosis of sepsis may be sensitive to changes in awareness of the diagnosis and may be influenced by financial incentives if coding for sepsis results in higher reimbursement. Collectively,approachesusingadministrativedatahavedemonstrated a substantial increase in sepsis incidence in the United States over the past 2 decades, accompanied by a significant decrease in sepsis-specific mortality.6 A 2017 report found that between 2005 and 2014, inpatient stays for “septicemia” in the United States almost tripled from 518 000 to 1 514 100 cases.9 Possibleexplanationsfortheseobservationsareanactualincrease in the incidence of sepsis with improved outcomes, improved coding of patients with sepsis but including patients with milder disease, a combination of the two, or so-called upcoding. In this issue of JAMA, Rhee and colleagues10 report the findings of a carefully conducted and analyzed study that seeks to determine whether the reported trends in sepsis incidence and mortality in the United States are real. Additionally and importantly, the authors provide estimates for the accuracy of 2 administrative data–based approaches in estimating the total number of sepsis cases. The study included more than 7 million adult hospitalizations over a 5-year period at 409 hospitals representative of all US hospitals in terms of geographic region, size, and teaching status. The authors generated estimates for sepsis incidence andmortalityfrom2009-2014using3methods.Thefirstmethod was based on an analysis of EHR clinical data, which the authors termed a “clinical surveillance” definition. The second method involved an administrative data–based method that replicated the methodology of Angus et al8 to identify sepsis through explicit or implicit ICD-9-CM coding. The authors refer to these as “claims-based” definitions, a somewhat US-centric view, as the ICD evolved from the International List of Causes of Death adopted by the International Statistical Institute in 1893. Entrusted to the WHO on its founding in 1948, its primary use globally is for epidemiology, health planning, and quality purposes rather than for financial claims. The third method used by Rhee et al was retrospective clinician chart review of 510 randomly selected hospitalizations, stratified by EHR definition (yes or no), drawn from3academiccentersand2communityhospitals.Theauthors reported the incidence and mortality rates derived from the EHR and administrative data approaches and assessed the sensitivRelated article Opinion

Physician Variation in Time to Antimicrobial Treatment for Septic Patients Presenting to the Emergency Department

Importance The quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score has not been well-evaluated in low- and middle-income countries (LMICs). Objective To assess the association of qSOFA with excess hospital death among patients with suspected infection in LMICs and to compare qSOFA with the systemic inflammatory response syndrome (SIRS) criteria. Design, Settings, and Participants Retrospective secondary analysis of 8 cohort studies and 1 randomized clinical trial from 2003 to 2017. This study included 6569 hospitalized adults with suspected infection in emergency departments, inpatient wards, and intensive care units of 17 hospitals in 10 LMICs across sub-Saharan Africa, Asia, and the Americas. Exposures Low (0), moderate (1), or high (≥2) qSOFA score (range, 0 [best] to 3 [worst]) or SIRS criteria (range, 0 [best] to 4 [worst]) within 24 hours of presentation to study hospital. Main Outcomes and Measures Predictive validity (measured as incremental hospital mortality beyond that predicted by baseline risk factors, as a marker of sepsis or analogous severe infectious course) of the qSOFA score (primary) and SIRS criteria (secondary). Results The cohorts were diverse in enrollment criteria, demographics (median ages, 29-54 years; males range, 36%-76%), HIV prevalence (range, 2%-43%), cause of infection, and hospital mortality (range, 1%-39%). Among 6218 patients with nonmissing outcome status in the combined cohort, 643 (10%) died. Compared with a low or moderate score, a high qSOFA score was associated with increased risk of death overall (19% vs 6%; difference, 13% [95% CI, 11%-14%]; odds ratio, 3.6 [95% CI, 3.0-4.2]) and across cohorts (P < .05 for 8 of 9 cohorts). Compared with a low qSOFA score, a moderate qSOFA score was also associated with increased risk of death overall (8% vs 3%; difference, 5% [95% CI, 4%-6%]; odds ratio, 2.8 [95% CI, 2.0-3.9]), but not in every cohort (P < .05 in 2 of 7 cohorts). High, vs low or moderate, SIRS criteria were associated with a smaller increase in risk of death overall (13% vs 8%; difference, 5% [95% CI, 3%-6%]; odds ratio, 1.7 [95% CI, 1.4-2.0]) and across cohorts (P < .05 for 4 of 9 cohorts). qSOFA discrimination (area under the receiver operating characteristic curve [AUROC], 0.70 [95% CI, 0.68-0.72]) was superior to that of both the baseline model (AUROC, 0.56 [95% CI, 0.53-0.58; P < .001) and SIRS (AUROC, 0.59 [95% CI, 0.57-0.62]; P < .001). Conclusions and Relevance When assessed among hospitalized adults with suspected infection in 9 LMIC cohorts, the qSOFA score identified infected patients at risk of death beyond that explained by baseline factors. However, the predictive validity varied among cohorts and settings, and further research is needed to better understand potential generalizability.

Aligning institutional priorities: engaging house staff in a quality improvement and safety initiative to fulfill Clinical Learning Environment Review objectives and electronic medical record Meaningful Use requirements

Objectives: Delayed initiation of appropriate antimicrobials is linked to higher sepsis mortality. We investigated interphysician variation in septic patients’ door-to-antimicrobial time. Design: Retrospective cohort study. Setting: Emergency department of an academic medical center. Subjects: Adult patients treated with antimicrobials in the emergency department between 2009 and 2015 for fluid-refractory severe sepsis or septic shock. Patients who were transferred, received antimicrobials prior to emergency department arrival, or were treated by an attending physician who cared for less than five study patients were excluded. Interventions: None. Measurements and Main Results: We employed multivariable linear regression to evaluate the association between treating attending physician and door-to-antimicrobial time after adjustment for illness severity (Acute Physiology and Chronic Health Evaluation II score), patient age, prehospital or arrival hypotension, admission from a long-term care facility, mode of arrival, weekend or nighttime admission, source of infection, and trainee involvement in care. Among 421 eligible patients, 74% received antimicrobials within 3 hours of emergency department arrival. After covariate adjustment, attending physicians’ (n = 40) median door-to-antimicrobial times varied significantly, ranging from 71 to 359 minutes (p = 0.002). The percentage of each physician’s patients whose antimicrobials began within 3 hours of emergency department arrival ranged from 0% to 100%. Overall, 12% of variability in antimicrobial timing was explained by the attending physician compared with 4% attributable to illness severity as measured by the Acute Physiology and Chronic Health Evaluation II score (p < 0.001). Some but not all physicians started antimicrobials later for patients who were normotensive on presentation (p = 0.017) or who had a source of infection other than pneumonia (p = 0.006). The adjusted odds of in-hospital mortality increased by 20% for each 1 hour increase in door-to-antimicrobial time (p = 0.046). Conclusions: Among patients with severe sepsis or septic shock receiving antimicrobials in the emergency department, door-to-antimicrobial times varied five-fold among treating physicians. Given the association between antimicrobial delay and mortality, interventions to reduce physician variation in antimicrobial initiation are likely indicated.

Mortality outcomes based on ED qSOFA score and HIV status in a developing low income country

BACKGROUND House staff quality improvement projects are often not aligned with training institution priorities. House staff are the primary users of inpatient problem lists in academic medical centers, and list maintenance has significant patient safety and financial implications. Improvement of the problem list is an important objective for hospitals with electronic health records under the Meaningful Use program. METHODS House staff surveys were used to create an electronic problem list manager (PLM) tool enabling efficient problem list updating. Number of new problems added and house staff perceptions of the problem list were compared before and after PLM intervention. RESULTS The PLM was used by 654 house staff after release. Surveys demonstrated increased problem list updating (P = .002; response rate 47%). Mean new problems added per day increased from 64 pre-PLM to 125 post-PLM (P < .001). CONCLUSIONS This innovative project serves as a model for successful engagement of house staff in institutional quality and safety initiatives with tangible institutional benefits.

Presentation, management, and outcomes of sepsis in adults and children admitted to a rural Ugandan hospital: A prospective observational cohort study

Objective: To evaluate the utility of the quick Sepsis‐related Organ Failure Assessment (qSOFA) score to predict risks for emergency department (ED) and hospital mortality among patients in a sub‐Saharan Africa (SSA) setting. Methods: This retrospective cohort study was carried out at a tertiary‐care hospital, in Kigali, Rwanda and included patients ≥15 years, presenting for ED care during 2013 with an infectious disease (ID). ED and overall hospital mortality were evaluated using multivariable regression, with qSOFA scores as the primary predictor (reference: qSOFA = 0), to yield adjusted relative risks (aRR) with 95% confidence intervals (CI). Analyses were performed for the overall population and stratified by HIV status. Results: Among 15,748 cases, 760 met inclusion (HIV infected 197). The most common diagnoses were malaria and intra‐abdominal infections. Prevalence of ED and hospital mortality were 12.5% and 25.4% respectively. In the overall population, ED mortality aRR was 4.8 (95% CI 1.9–12.0) for qSOFA scores equal to 1 and 7.8 (95% CI 3.1–19.7) for qSOFA scores ≥2. The aRR for hospital mortality in the overall cohort was 2.6 (95% 1.6–4.1) for qSOFA scores equal to 1 and 3.8 (95% 2.4–6.0) for qSOFA scores ≥2. For HIV infected cases, although proportional mortality increased with greater qSOFA score, statistically significant risk differences were not identified. Conclusion: The qSOFA score provided risk stratification for both ED and hospital mortality outcomes in the setting studied, indicating utility in sepsis care in SSA, however, further prospective study in high‐burden HIV populations is needed.

Hepatic abscess-associated Clostridial bacteraemia presenting with intravascular haemolysis and severe hypertension

Objectives Limited data are available on sepsis in low-resource settings, particularly outside of urban referral centers. We conducted a prospective observational single-center cohort study in May 2013 to assess the presentation, management and outcomes of adult and pediatric patients admitted with sepsis to a community hospital in rural Uganda. Methods We consecutively screened all patients admitted to medical wards who met sepsis criteria. We evaluated eligible patients within 24 hours of presentation and 24–48 hours after admission, and followed them until hospital discharge. In addition to chart review, mental status evaluation, peripheral capillary oxygen saturation, and point-of-care venous whole blood lactate and glucose testing were performed. Results Of 56 eligible patients, we analyzed data on 51 (20 adults and 31 children). Median age was 8 years (IQR 2–23 years). Sepsis accounted for a quarter of all adult and pediatric medical ward admissions during the study period. HIV prevalence among adults was 30%. On enrollment, over half of patients had elevated point-of-care whole blood lactate, few were hypoglycemic or had altered mental status, and one third were hypoxic. Over 80% of patients received at least one antibiotic, all severely hypoxic patients received supplemental oxygen, and half of patients with elevated lactate received fluid resuscitation. The most common causes of sepsis were malaria and pneumonia. In-hospital mortality was 3.9%. Conclusions This study highlights the importance of sepsis among adult and pediatric patients admitted to a rural Ugandan hospital and underscores the need for continued research on sepsis in low resource settings.

Clinical epidemiology and outcomes of community acquired infection and sepsis among hospitalized patients in a resource limited setting in Northeast Thailand: A prospective observational study (Ubon-sepsis)

Clostridium perfringens bacteraemia is a potentially fatal condition, and its early identification is paramount to maximise chances of survival. Prompt recognition of intravascular haemolysis, a known complication of C. perfringens bacteraemia, can help guide clinical decision-making before microbiology data becomes available. We present a novel finding of severe hypertension in a fatal case of Clostridial bacteraemia with massive haemolysis. A 58-year-old man with no known medical history presented to the emergency department with malaise, fever and hypertension. He developed abdominal pain and a hepatic abscess was identified on CT imaging. Within 4 h of presentation, he developed massive intravascular haemolysis, extreme hypertension, pulmonary oedema and respiratory failure. He died less than 8 h after presentation. His blood cultures subsequently grew C. perfringens. This case underscores the importance of early recognition of intravascular haemolysis complicating C. perfringens bacteraemia, and discusses the rare complication of hypertensive emergency in this setting.

The global burden of sepsis: barriers and potential solutions

Infection and sepsis are leading causes of death worldwide but the epidemiology and outcomes are not well understood in resource-limited settings. We conducted a four-year prospective observational study from March 2013 to February 2017 to examine the clinical epidemiology and outcomes of adults admitted with community-acquired infection in a resource-limited tertiary-care hospital in Ubon Ratchathani province, Northeast Thailand. Hospitalized patients with infection and accompanying systemic manifestations of infection within 24 hours of admission were enrolled. Subjects were classified as having sepsis if they had a modified sequential organ failure assessment (SOFA) score ≥2 at enrollment. This study was registered with ClinicalTrials.gov, number NCT02217592. A total of 4,989 patients were analyzed. Of the cohort, 2,659 (53%) were male and the median age was 57 years (range 18–101). Of these, 1,173 (24%) patients presented primarily to the study hospital, 3,524 (71%) were transferred from 25 district hospitals or 8 smaller hospitals in the province, and 292 (6%) were transferred from one of 30 hospitals in other provinces. Three thousand seven hundred and sixteen (74%) patients were classified as having sepsis. Patients with sepsis had an older age distribution and a greater prevalence of comorbidities compared to patients without sepsis. Twenty eight-day mortality was 21% (765/3,716) in sepsis and 4% (54/1,273) in non-sepsis patients (p<0.001). After adjusting for gender, age, and comorbidities, sepsis on admission (adjusted hazard ratio [HR] 3.30; 95% confidence interval [CI] 2.48–4.41, p<0.001), blood culture positive for pathogenic organisms (adjusted HR 2.21; 95% CI 1.89–2.58, p<0.001) and transfer from other hospitals (adjusted HR 2.18; 95% CI 1.69–2.81, p<0.001) were independently associated with mortality. In conclusion, mortality of community-acquired sepsis in Northeast Thailand is considerable and transferred patients with infection are at increased risk of death. To reduce mortality of sepsis in this and other resource-limited setting, facilitating rapid detection of sepsis in all levels of healthcare facilities, establishing guidelines for transfer of sepsis patients, and initiating sepsis care prior to and during transfer may be beneficial.