UPDATE, COHEN, 2011 Chapter 44 Sepsis William A Lynn (See healthmap.

org for outbreaks of Sepsis )

This chapter examines the consequences of the systemic effects of infection, broadly referred to as sepsis. EPIDEMIOLOGY Definition and nomenclature Physicians have long recognized that infection can lead to generalized circulatory collapse and death. In the 1990s Bone initiated a debate on the terminology of sepsis, identifying key clinical criteria and definitions.[1] Bone recognized that similar physiologic changes could occur in noninfective inflammatory processes, such as pancreatitis, and introduced the term the systemic inflammatory response syndrome (SIRS) to define a common set of diagnostic criteria for infected (sepsis) and noninfected patients.[1] The term SIRS has been criticized for being too imprecise[2] but the concept and definition of sepsis has remained.[3] It is important to remember that sepsis is a heterogeneous condition resulting from the interaction of host, pathogen and environmental factors. Some authors have questioned the validity of grouping all such patients together, particularly in research studies of new therapeutic agents.[4] Severe sepsis (Table 44.1) may be defined simply as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion.[5] The challenge for clinicians is to recognize the presentation of sepsis/severe sepsis (Table 44.2) and intervene early.

Table 44.1 -- Definitions of infection-related syndromes Bacteremia: viable bacteria cultured from bloodstream patient may or may not have evidence of sepsis/severe sepsis Sepsis: infection, documented or suspected, plus systemic manifestations (see Table 44.2) Severe sepsis: sepsis-induced organ dysfunction or tissue hypoperfusion (see Table 44.2) Septic shock: sepsis-induced hypotension not responding to fluid resuscitation

Table 44.2 -- Clinical signs and laboratory parameters in the diagnosis of sepsis Infection documented or suspected, plus some of the following: Clinical signs Fever temperature >110.4 F (38.3 C) or

Infection documented or suspected, plus some of the following: Hypothermia temperature <96.8 (36 C) Heart rate >90 beats/min Hypotension SBP <90 mmHg, MAP <70 mmHg, SBP fall of >40 mmHg from baseline Prolonged capillary refill time or tissue mottling indicates poor tissue perfusion Tachypnoea: respiratory rate >20 breaths/min or arterial CO2 tension <32 mmHg (4.3 kPa) Altered mental state from baseline WBC >12 000 cells/mm[3], <4000 cells/mm[3] or >10% immature forms (bands) Plasma C-reactive protein >2 normal range Procalcitonin >2 normal range Metabolic acidosis: elevated base deficit 5, increased blood lactate Hypoxia: Pao2/Fio2 <300 Oliguria: urine output <0.5 ml/kg for >2 h despite fluid resuscitation Creatinine rise from baseline >40 mol/l Coagulopathy: INR >1.5 in absence of anticoagulation, platelet count <100 10[9]/l Hyperbilirubinemia: bilirubin >4 mg/dl or 70 mol/l Hyperglycemia or hypoglycemia in nondiabetic

Inflammatory markers

Organ dysfunction

Adapted from Dellinger et al.[5] INR; international normalized ratio; MAP, mean arterial pressure; SBP; systolic blood pressure; WBC, white blood count.

Incidence and prevalence of sepsis Host and environmental factors interact in the development of sepsis with varying rates in different patient populations. Furthermore, variation in the organization of health care in different medical systems makes comparisons between countries difficult. Angus and co-workers examined the epidemiology of sepsis in the USA.[6] Using existing databases they analyzed discharge records of over 6 million patients from seven US states during 1995 and extrapolated the results for the whole US population. Data collected in this way should be viewed with some caution but the size of this study demands attention. They estimated an annual incidence for

severe sepsis of 3 cases per 1000 (2.26 cases/100 hospital discharges), equivalent to 751 000 cases each year. Incidence rose from 0.2/1000 in childhood to 26/1000 over the age of 85. Severe sepsis was estimated to cost around $16 billion per year. In a separate study, Martin et al. reported similar figures and also that the incidence of sepsis in the USA was rising at around 9% per year, reaching 240/100 000 in 2000.[7] A review of 330 million emergency department attendances in the USA showed that 0.69% were for severe sepsis.[8] In Europe Van Gestel et al. performed a point prevalence study in 47 intensive care units (ICU) across the Netherlands, showing that 29.5% of patients fulfilled severe sepsis criteria.[9] Extrapolating from these data indicated that severe sepsis was responsible for 0.61% of all hospital admissions but 11% of admissions to intensive care in The Netherlands. Similar data showed a point prevalence for severe sepsis in ICU admissions of 28.7% in the UK[10] and 27% in France.[11] In Australia and New Zealand severe sepsis has been estimated in 0.77 per 1000 of the population and is responsible for 11.8/100 ICU admissions.[12] Morbidity and mortality rates The mortality of sepsis varies because of variations in infection prevalence, case definition, ICU facilities and patient populations. In an analysis of four large sepsis trials, 14-day mortality averaged 26% and 28-day mortality 42%.[1] In the Angus study cited above overall mortality was 28.6%, equivalent to 215 000 deaths per annum in the USA.[6] In this study mortality in childhood was around 10%, rising to 38.4% in those over age 85.[6] Factors associated with early death include the number of organ systems involved,[13] acidosis, and shock.[14] Late deaths are associated with medical co-morbidities, underlying illness and multiple sources of infection. Pseudomonas aeruginosa , Candida spp. and mixed infections have a higher attributable mortality than other agents. Patients with sepsis often have serious comorbidity, but even when this is taken into account the attributable mortality from severe sepsis is still 25%,[15] increasing to over 60% if four or more organs are failing.[13] Long-term mortality is high after an episode of severe sepsis.[16] Some studies have suggested that while the incidence of severe sepsis continues to increase, there has been a recent improvement in mortality, possibly due to the introduction of a more systematic approach to recognition and therapy.[10,][17] Update: New Content Added Date Added: 16 December 2010 Long-term effects of severe sepsis Jonathan Cargan, MD, W. Powderly, MD, FRCPI, Editor Summary The long-term effects of severe sepsis in terms of functional status have not been well characterized. This observational study found that severe sepsis was associated with persistent cognitive and functional impairments and may be an inciting event for decline in elderly patients. The study used data from the Health and Retirement Study (HRS), which follows a nationally representative cohort of community-dwelling adults older than 50 years of age in the U.S. The study was initiated in 1992, and participants are interviewed every 2 years. Nearly 17,000

participants have given permission for use of linked Medicare data; participants included in this study were those with at least one interview from 1998-2004 for whom cognitive and physical functioning data were available and who were hospitalized for severe sepsis from 1998-2005. Participants had to have at least one interview after hospitalization. The study used a validated claims-based definition of severe sepsis that consisted of evidence of infection combined with new-onset organ dysfunction. Investigators also identified a control cohort without sepsis for comparison. Participants in the survey were queried about functional status in terms of activities of daily living (e.g., walking and dressing) and instrumental activities of daily living (e.g., cooking and grocery shopping). Proxies provided this information when participants were unable to answer by themselves. Cognitive assessments were also performed, and impairment was classified as mild, moderate, or severe. The analyses included 516 participants. Mean age of surviving patients was 76.9 years. The investigators found that severe sepsis was associated with moderate to severe cognitive impairment. Based on fixed-effects regression, moderate to severe cognitive impairment increased 10.6 percent among participants with severe sepsis and was associated with an odds ratio (OR) of 3.34 (95 percent CI 1.53-7.25; P = .002). Severe sepsis was also associated with the development of new functional impairment. Based on multivariable analysis among patients with no previous limitations, severe sepsis was associated with the development of 1.57 (95 percent CI 0.99-2.15) new limitations. Severe sepsis was also associated with an increased rate of new limitations per year. Almost 60 percent of hospitalizations for severe sepsis were associated with decreased cognitive or physical function at the time of the next survey. Nonsepsis hospitalizations were not associated with moderate to severe cognitive impairment (OR 1.15; 95 percent CI 0.80-1.67; P for difference = .01). Nonsepsis hospitalizations were associated with fewer functional impairments among patients with no limitations before hospitalization. The authors conclude that severe sepsis is independently associated with lasting cognitive impairment and functional limitations and that these effects of sepsis are an unrecognized problem. Based on sepsis and cognitive impairment rates in the U.S. among adults 65 years old or older, the authors estimate that sepsis may be responsible for roughly 20,000 new cases of moderate to severe cognitive impairment annually. Limitations of the study include its observational design, that the study focused only on long-term effects of sepsis, and that the analyses are based on a claims-based definition of severe sepsis rather than clinical assessment. Also, this study does not establish a causal relationship. Nevertheless, such a relationship is biologically plausible, and there are several possible mechanisms whereby severe sepsis or its treatment, or both, may contribute to cognitive decline, including host inflammatory responses, hypotension, hypoxia, and prolonged immobility as a consequence of mechanical ventilation. References 1. Iwashyna TJ, Ely EW, Smith DM, et al: Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010; 304(16):1787-1794. Risk factors for sepsis

Broadly speaking, risk factors for sepsis are those factors that weaken/breach host defenses, increasing the likelihood of bacterial invasion of otherwise sterile tissue as summarized in Figure 44.1. Fig. 44.1 Potential risk factors leading to sepsis. Complex interaction of factors that may influence both the susceptibility to and clinical outcome of severe sepsis.

Update: New Content Added Date Added: 05 August 2010 Causes of racial differences in severe sepsis Jonathan Cargan, MD, S. Opal, MD, Editor Summary Epidemiologic studies have suggested a higher incidence of severe sepsis among black patients compared with white patients in the U.S. Potential explanations for this difference include differences in susceptibility to infection and risk of acute organ dysfunction. An analysis of hospital records showed that both of these factors may play a role in explaining racial differences in severe sepsis. This was a retrospective, population-based study of hospitalization records from 2005 from seven states in the U.S. that examined racial differences in severe sepsis. The seven states selected account for roughly one fourth of the U.S. population and different regions of the U.S.; the states were Massachusetts, New York, New Jersey, and Maryland from the northeast and mid-Atlantic regions; Florida and Texas from the southern U.S.; and Arizona from the western U.S. Only non-Hispanic whites and blacks were included in the analysis. National Hospital Ambulatory Medical Care Survey (NHAMCS) data were used as a baseline for rates of hospital admission from the emergency department. Relevant International Classification of Diseases (ICD-9) codes were used to identify hospitalizations complicated by bacterial or fungal infection. Severe sepsis was defined as documented infection accompanied by acute organ dysfunction. Presence of mechanical ventilation was required for documentation of respiratory dysfunction. Patients with human immunodeficiency virus (HIV) infection were excluded because of greater likelihood of developing severe sepsis. Greater than 8.5 million hospitalizations were included. Of these, 26.1% (2,261,857 of 8,661,227) were hospitalizations related to infection. Of these hospitalizations, 16.8% (381,787 of 2,261,857) were identified as severe sepsis cases owing to the presence of acute organ dysfunction. Respiratory infection was the most common type of infection and accounted for one third of cases. There were differences in characteristics of the racial groups. Black patients hospitalized for infection were younger than white patients (51.6 years old vs. 63.1 years old, P < .001). Although comorbid conditions were also more common among blacks, there were large disparities noted for certain diseases. Diabetes (23.6% vs. 17.8%) and chronic kidney disease (3.5% vs. 2.6%) were more common among black patients (P < .001 for both). These differences were still found after stratification for age older or younger than 65. Respiratory disease was

more common among whites. Among patients with severe sepsis, a similar difference in mean age was found (62.0 years for black patients vs. 70.3 years for white patients, P < .001). Overall, comorbid conditions were similar but with similar significant differences in diabetes and chronic kidney disease. Diabetes was more common among black patients with severe sepsis (22.3% vs. 15.5%, P < .001) as was chronic kidney disease (6.7% vs. 5.7%, P < .001). The rate of hospitalization for severe sepsis was 67% greater among black patients compared with white patients. The rate for black patients was 9.4 per 1000 population (95% CI 9.3-9.5) versus 5.6 per 1000 population for white patients (95% CI 5.6-5.6). The incidence rate ratio was 1.67, and the difference between the two groups was statistically significant (P < .001). This difference was partly accounted for by a higher infection hospitalization rate among black patients. This group of patients also had a higher hospitalization rate for sepsis. Black patients had higher rates of gram-negative and gram-positive infections. Black patients with infections had a higher risk of developing acute organ dysfunction. The ageadjusted and sex-adjusted odds ratio was 1.20 (95% CI 1.27-1.30, P < .001). A similar difference was found for acute organ dysfunction among patients with sepsis. The age-adjusted and sexadjusted odds ratio was 1.38 (95% CI 1.36-1.41, P < .001). When adjustments for poverty and hospital effect were made, the difference persisted but was reduced (odds ratio 1.15, 95% CI 1.14-1.17). Mortality risk and rates showed a similar, statistically significant racial difference. With regard to invasive pneumococcal infections, hospitalization rates were higher for blacks, and a larger percentage occurred in patients younger than 65 years. One fourth of pneumococcal infections occurred in black patients who are not covered by the recommendation for immunization based on age. The authors conclude that differences in severe sepsis based on race may be traced to an increased likelihood of being hospitalized for infection and greater likelihood of acute organ dysfunction among black patients. They note previous research showing that polymorphisms in immune proteins involved in response to infection may affect susceptibility to infection among persons of African descent. They also suggest that pneumococcal immunization recommendations for black persons may need to be revised to include immunization at an earlier age and that better management of chronic comorbidities is needed. The authors note that the increased risk of acute organ dysfunction among black patients was found regardless of hospital, suggesting that there are unidentified factors besides differences in hospitals that may account for this finding. Limitations of the study include accuracy of ICD-9 coding and lack of data about health habits that could affect susceptibility to infection. Editors note: This is an important study that indicates African-Americans have a higher incidence of severe infections requiring hospitalization and a higher incidence of complications including severe sepsis than white Americans. Many explanations might account for these differences, including socioeconomic and cultural factors, less access to care, higher prevalence of obesity and metabolic syndrome, hypertensive kidney disease, sickle cell trait and other abnormal hemoglobins causing splenic hypofunction and increased risk of pneumococcal

disease, and genetic polymorphisms in immune response genes. All these factors and perhaps others disadvantage black patients with respect to sepsis risk. More research is needed to determine the best way to improve the factors that lead to these racial disparities. References 1. Mayr FB, Yende S, Linde-Zwirble WT, et al: Infection rate and acute organ dysfunction risk as explanations for racial differences in severe sepsis. JAMA 2010; 303(24):2495-2503.