Respiration PaO2/FiO2 mmHg (kPa)
<200 with respiratory support
<100 with respiratory support
Coagulation platelets (× 103/μL)
Liver bilirubin, mg/dL (μmol/L)
MAP ≥ 70 mmHg
MAP < 70 mmHg
Dopamine < 5 or dobutamine (any dose)
Dopamine 5.1–15 or epinephrine ≤ 0.1b or norepinephrine ≤ 0.1
Dopamine >15 or epinephrine > 0.1b or norepinephrine > 0.1
CNS Glasgow Coma Scale scorea
Renal creatinine, mg/dL (mol/L), urine output, mL/d
3.5–4.9 (300–440); <500
In pre-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least two of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA) : respiratory rate of 22/min or greater, altered mentation (defined by a Glasgow score < 15), or systolic blood pressure of 100 mmHg or less [6, 8].
However, recently, Shurpek et al. showed that early warning scores like Modified Early Warning Score (MEWS) and the National Early Warning Score (NEWS) seem to be more accurate than the qSOFA score for predicting death and ICU transfer in non-ICU patients (Shurpek et al. 2016). These results suggest that the qSOFA score should not replace general early warning scores when risk-stratifying patients with suspected infection. April et al. showed in a retrospective cohort chart review study of ED patients admitted to an ICU with suspected infection that among ED patients admitted to an ICU, the SIRS and qSOFA criteria had comparable prognostic value for predicting in-hospital mortality . Moreover, Giamarellos-Bourboulis et al. showed that qSOFA score has a low sensitivity for early prediction of death as compared to three and more SIRS criteria . Recently, Freund et al. in a European ED prospective study showed that qSOFA in patients visiting the ED with suspected infection, has a high prognostic accuracy for in-hospital mortality as compared to SIRS or severe sepsis .
Nevertheless, these recent controversies emphasize the need for prospective and multicentric clinical trials, especially in the older population to evaluate qSOFA performance. Nevertheless, the qSOFA score might be helpful in non-ICU settings (e.g., ED and geriatric units) for recognizing sepsis in a quicker manner, leading to more timely treatment, and potentially better outcomes .
It has been considered that the older patients have clinical manifestations different from the ones observed in middle-age adults during sepsis. The behavior of most clinical and laboratory variables suggests a less pronounced response of patients above 65 years of age who died 28 days after being diagnosed with sepsis [13, 14]. These special considerations must be taken into account when sepsis is suspected in older patients. Comorbidity and frailty will certainly impact the diagnostic process and the prognosis.
There are few data on the epidemiology of sepsis in older people. Angus et al. reported an annual incidence of severe sepsis of 3 cases/1000 population, which is more than 100 times greater than the incidence among those between 5 and 14 years of age (0.2/1000 in children to 5.3/1000 in patients aged 60–64 years and 26.2/1000 in patients ≥85) and that mortality increased from 10% in children to 26% in patients 60–64 and 38% in those ≥85 [1, 15]. Martin et al. reported a similar annual incidence of sepsis (2,4 cases/1000 population) and found that incidence of sepsis (all cases, not limited to severe sepsis) likewise increased exponentially across all adult ages, and this increased incidence was around 20% more in older population as compared to younger patients, with a case fatality rate of 27.7% for those >65 versus 17.7% for those <65 (Martin et al. 2006).
12.3 Causes of Sepsis
Pneumonia is the most common cause of infection in all ages, followed by intra-abdominal and urinary tract infections [1, 23–25]. In older patients, the most frequent infection site is respiratory tract, followed by genitourinary infections (Martin et al. 2006, [4, 6, 26, 27]). Blood and site cultures are negative in one third of cases [1, 24, 28, 29].
Classically, Staphylococcus aureus and Streptococcus pneumoniae are the most frequent Gram-positive pathogen isolated from cultures, and Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa predominate among Gram-negative isolates [24, 29–31]. Gram-negative pathogens are more frequently isolated in older patients probably because of frequent hospitalizations and procedures, which lead to antibiotic resistance (Martin et al. 2006, [26, 32, 33]).
The pathophysiologic mechanisms that underlie the process of aging on the immune system are complex and multifactorial. The immune system in the older population is in a state called immunosenescence, characterized by impairment of cell-mediated and humoral immune responses . However, aging does not necessarily lead to an unavoidable decline in immune function. Some authors think that it is better to use the concept of “senescent immune remodeling ” (Dewan 2012).
Aging is characterized by a chronic inflammatory status with increased pro-inflammatory cytokines, such as IL-6 and TNFα, which create oxidative stress and decrease cellular antioxidant capacity. So, alterations of inflammatory responses that occur in aging are responsible for the increased susceptibility of older people to infectious diseases. Sepsis is composed by hyperinflammation in the acute phase followed by immunosuppression.
There are functional changes in both cell-mediated immunity and humoral immune responses with age, which contribute to the increased incidence of infection in older patients. Within the adaptive immune system, B cell and plasma cell populations and generation of naïve T cells gradually decrease with aging . It was recently found that older patients with a decreased IgM production might be more susceptible to infection by Gram-negative bacteria and fungi . Impaired humoral immunity with increased exhausted B cells and insufficient immunoglobulin M production may be a critical immunological change in sepsis .
Older patients have decreased number of immunocompetent T cells , which are mostly represented by memory T cells [35, 39, 40]. In response to antigens, these memory cells cannot proliferate normally with low expression of co-stimulatory molecules, which reduce the activation of mitogen-activated protein kinase [35, 39].
Serum IL-6 levels in septic older patients are persistently high as compared to young patients . This excessive inflammation continues during the early phase of sepsis, and it was observed a persistent inflammation and T-cell exhaustion in older patients after sepsis with a high mortality compared to younger patients [35, 38–44]. Severe sepsis and mortality are associated with higher levels of pro-inflammatory markers; however, few clinical studies have compared sepsis-induced cytokine responses in young and older patients. Kale et al. reported no age-related difference in inflammatory markers IL-6, TNFα, or IL-10 at admission or over the first week of hospitalization in patients with community-acquired pneumonia; however, IL-6 levels at discharge were significantly higher in older patients suggesting an age-dependent delay in resolution of inflammation .
Genomic studies have detected several genes whose expression could be used to differentiate immune responses of the older patients from those of young people, including genes related to oxidative phosphorylation, mitochondrial dysfunction, and TGF-β signaling. These studies identified major molecular pathways that are affected in older patients during sepsis and could play a role in worsening outcomes compared with young people with sepsis .
During sepsis, there is a hyperactivation of the coagulation cascade inducing microvascular thrombosis responsible of hypoperfusion [47, 48]. Coagulation abnormalities play an important role in the pathophysiology of sepsis. Kale et al. suggested older patients might have a more exaggerated response to similar levels of inflammatory and thrombotic factors, which influences the development of organ dysfunction .
12.5 Risk Factors of Sepsis in Older Patients
Sepsis awareness is essential and includes identification of population-focused risk factors, recognition of clinical signs and symptoms, and timely implementation of interventions. Previous comorbid conditions are commonly associated with increased susceptibility to sepsis and organ dysfunction [1, 18, 32, 44, 52]. Other factors are involved such as poor functional status, frailty, polypharmacy, malnutrition, and nursing home residence .
Recurrent hospitalizations with exposure to instrumentation and procedures, such as urinary catheterizations and a higher rate of complications throughout their hospital course, are also identified as a risk factor for sepsis, particularly in the presence of compromised immunity [54–56].
Old age itself is an independent risk factor for predisposition to sepsis by increased colonization by Gram-negative organisms, which may be multidrug resistant (Martin et al. 2006, ). In the USA, up to one third of patients at 80 years of age reside in long-term care facilities where bacterial flora demonstrates a level of resistance higher than that seen in the community . In the UK, Marwick et al. found that residence in a long-term care facility was associated with a higher prevalence of resistant organisms . However, to live in a residence place was not an independent factor of 30-day mortality. Marwick et al. recommend that antibiotic therapies active against resistant organisms, guided by local resistance patterns, should be considered for all older patients admitted with sepsis regardless of their place of residence .
It is recommended that assessment of older patients should include functional status (see Chap. 6). Preadmission functional status is much more important than comorbid illness and has been found to be an independent predictor of poor outcome in older patients [58, 52]. Wester et al. noted that non-specific functional deterioration, such as reduced ability to complete daily tasks, might be the only symptom of sepsis . Additional evidence reported by Nasa et al.  identified preadmission functional status as an independent predictor of outcome in older patients [54, 59].
Older people present unique pathophysiological characteristics that confer a great complexity, so in the face of any stressful event, injury, or a critical illness as sepsis, they are less able to meet the increased physiological demands because there is a reduction or a delay in the implementation of compensatory mechanisms, due to a reduction of organic functional reserve. The concept of frailty, as a state of vulnerability to adverse outcomes in which multiple body systems gradually lose their built-in reserves is becoming more and more essential in the management of older patients in the ED and should be assessed during disease conditions. Frailty is common in critically ill older patients and is independently associated with increased mortality and greater disability [60, 62]. Future studies should explore routine screening for clinical frailty in critically ill older patients.
A reliable biomarker for the prognosis of sepsis is critical. Thus far, there are no such biomarkers available for sepsis . SOFA and abbMEDS (abbreviated mortality in emergency department sepsis) scores were effective in predicting ICU admissions and the death of older sepsis patients in the ED, but biomarkers such as procalcitonin, IL-10, IL-6, and IL-5 although effective in predicting ICU admission were not effective in predicting death of older patients .
Recently, it was shown that the GYM (Glasgow < 15, tachypnea > 20, comorbidity charlson index ≥ 3) score showed better capacity than the classic and the modified sepsis criteria to predict 30-day mortality in older patients attended for infection in the ED .
12.6 Clinical Presentation and Diagnosis
Although sepsis is a serious life-threatening disease its recognition is often difficult. In addition to the difficulties of the diagnosis of sepsis in older patients, a clear history may not be available in many patients because of pre-existing dementia or prevalent delirium. It could be also difficult to obtain samples of blood, sputum, body fluids, or tissue from patients who are cognitively impaired, debilitated, dehydrated, or frail .
The decrease in the acuity of symptoms and delay in presentation can make the diagnosis of sepsis difficult. The clinical presentation in older patients is different than in younger patients. The initial inflammatory response of infection, which normally produces symptoms and signs of sepsis, are blunted or may be absent in older patients, while later presentation may be very severe  with rapid progression to septic shock [29, 32, 35, 43]. Unfortunately, the findings reported in Table 12.2 can also be present in noninfectious diseases making the diagnosis difficult ([32, 65, 66, 67, 69, 70]) (see Chap. 8).
Clinical presentation of sepsis in older patients
Possible chief complaints found in any infectiona
Findings with specific infectionsb
Change in cognition (e.g., delirium/agitation)
Failure to thrive
Change in baseline body temperature
Dyspnea, confusion, falls, hypotension
May be afebrile
May be afebrile
Cough and sputum production may be absent
May be afebrile
Peritoneal signs may be absent
Confusion, altered consciousness
Stiff neck may be absent
Weight loss, lethargy
Failure to thrive
May be afebrile
Urinary tract infection
May occur without dysuria, frequency, flank pain, or fever
It has been shown that the febrile response may be blunted in up to 47% of older septic patients . Although, fever is a cardinal sign of infection, its absence in older patients is frequent and may delay the diagnosis and the initiation of appropriate antimicrobial therapy . However, 40% of the afebrile nosocomial bacteremias of older patients occurred in those who were receiving antibiotics [71, 72]. Neither chills are always observed and are reported in only 35% of older patients, with a lower prevalence than younger patients . Site of measurement of temperature can influence the results, sublingual temperature readings detect one third of fevers, and rectal temperature measurement will detect fever in up to 86% of infected patients . Another explanation could be that in older patients, pathways involved in thermoregulation are impaired (Yoshikawa and [68, 75]). Hypothermia , which can be observed during the first 24 h of presentation, independently predicts hospital mortality in older septic patients .
The cardiovascular system may have a limited or absent compensatory response to inflammation after an infectious insult, and the febrile response and recruitment of white blood cells may be blunted because of immunosenescence in aging. Older patients are more likely than young patients to present with polymorphonuclear lymphocyte counts of <2000 lymphocytes/mm3. In the presence of serious infections, approximately 60% of older patients will exhibit leukocytosis; however, its absence does not rule out an infection . Three of the four hallmark responses (temperature, heart rate, and white blood cell count) to systemic inflammation may be diminished in older adults as compared with younger adults . Recently, Valencia et al. showed that the course of most clinical and laboratory variables suggests a less pronounced response of patients above 65 years of age who died 28 days after being diagnosed with sepsis [13, 14]. Finally, most studies evaluate the ability of an isolated biomarker result to predict infection, whereas biomarkers probably will have the most value if combined with data from history, physical examination, imaging, and other laboratory testing.
In a model to predict bacteremia in emergency room patients, both PCT and CRP were included along with other clinical variables, and in doing so, the area under the curve was improved from 0.639 (CRP) and 0.737 (PCT) to 0.854 when biomarkers and clinical variables were combined .
Table 12.3 summaries the classical criteria for the diagnosis of sepsis [79, 80]. The major limitation is the absence of criteria for the specific subpopulation of older patients.
Diagnostic criteria for sepsis
Infection, documented or suspected, and some of the following:
Fever (>38.3 °C)
Hypothermia (core temperature < 36 °C)
Heart rate > 90/min or more than two SD above the normal value for age
Altered mental status
Significant edema or positive fluid balance (>20 mL/kg over 24 h)
Hyperglycemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence of diabetes
Leukocytosis (WBC count >12,000 μL−1), leukopenia (WBC count <4000 μL−1), normal WBC count with greater than 10% immature forms
Plasma C-reactive protein more than two SD above the normal value
Plasma procalcitonin more than two SD above the normal value
Arterial hypotension (SBP <90 mmHg, MAP <70 mmHg, or an SBP decrease >40 mmHg in adults or less than two SD below normal for age). In older patients, arterial hypotension could not follow guidelines criteria because of chronic hypertension
Organ dysfunction variables
Arterial hypoxemia (PaO2/FiO2 < 300)
Acute oliguria (urine output <0.5 mL/kg/h for at least 2 h despite adequate fluid resuscitation)
Creatinine increase >0.5 mg/dL or 44.2 μmol/L
Coagulation abnormalities (INR >1.5 or aPTT >60 s)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count <100,000 μL)
Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 μmol/L)
Tissue perfusion variables
Hyperlactatemia (≥2 mmol/L)
Decreased capillary refill or mottling
12.7 Management of Sepsis in Older Patients in the ED
The Surviving Sepsis Campaign (SSC) includes special guidelines for adults and pediatric patients on the basis of physiologic differences, but there are no special considerations on physiologic differences in older patients. Nevertheless, the management of sepsis and septic shock in older patients should follow the recommendations of the SSC guidelines , although they are not very specific for the older population as they fail to take the physiology of aging into consideration. Sepsis resuscitation and management bundles should be started early and have been shown to improve survival.
The SSC emphasizes two bundles of care. The initial bundle is focused on resuscitation to restore the impaired tissue perfusion and oxygenation. This is to be accomplished in the first 6 h of presentation. The second bundle is focused on further management and is to be accomplished in the ICU. Although excellent, the Surviving Sepsis Campaign guidelines are not very specific for older patients with sepsis and septic shock. The principles of management used in younger adults are used in older patients, including early antimicrobial therapy and source control, early resuscitation, and the use of low tidal volume during mechanical ventilation. Clinical conundrums that complicate clinical course of sepsis in older patients such as cardiac heart failure/atrial fibrillation, antibiotic resistance, chronic kidney disease/acute kidney injury, dysglycemia, malnutrition, ambulatory dysfunction, delirium, dementia, and polypharmacy need to be addressed .