Sepsis: Immune Response MeltdownPage 7 of 14

5. Diagnosis of Sepsis

Severe sepsis and septic shock are unfortunately common, complicated and deadly conditions within the same pathophysiologic spectrum. If a clinician believes that a patient is exhibiting SIRS secondary to infection, that patient has sepsis. If that same patient has signs or symptoms of organ dysfunction, then that patient has severe sepsis. Septic shock is then characterized by overall tissue hypoperfusion, tissue hypoxia, or general hypotension that fails to respond to fluid resuscitation (Tannehill, 2012).

The initial management of sepsis requires rapid identification of sepsis. Delay in diagnosis and treatment often results in rapid progression to circulatory collapse, multiple organ failure, and eventual death. Emergency department triage systems are designed to classify patients by severity of illness, with an initial set of vital signs, chief complaint, and focused physical exam. During the first encounter with the healthcare delivery system, much information can be gleaned with respect to the presence or potential for the evolution of sepsis to septic shock. However, a definitive diagnosis of sepsis can be difficult (Perman et al., 2012).

Septic patients have an underlying infection with a systemic response. Septic patients should look ill and should have the classic signs of a systemic infection:

  • Fever
  • Tachypnea
  • Tachycardia
  • High white blood cell count

The severity of the septic reaction should also produce other warning signs, such as:

  • Hot, flushed skin
  • Newly altered mental status
  • Hypotension
  • Widened pulse pressure (Pulse pressure is the difference between the systolic and the diastolic blood pressure values.)
  • Elevated blood lactate level
  • Thrombocytopenia

It is important to stress that few if any patients in the early stages of the inflammatory responses to infection are diagnosed via the four SIRS criteria. Not all individuals who have SIRS criteria are septic and not all patients who are septic meet the SIRS criteria. The signs are non-specific and each sign can be produced by a wide range of causes. There is much overlap in the initial hemodynamic alterations with disease entities such as burns, trauma, and pancreatitis, and clinical judgment must be used in order to accurately diagnose the septic patient (Perman et al., 2012; Herlitz et al., 2012).

A second difficulty is that septic patients do not always present with the same list of signs. For example, a significant number—one study found 40%—of septic patients have a normal rate of respiration. Some septic patients—notably, the very young, the elderly, and the immunocompromised—present with no fever. Moreover, in some septic patients with an underlying infection, blood cultures are negative for microbes.

Despite a great many clinical studies of septic patients, none have found a simple test for sepsis. Likewise, no single list of signs, symptoms, and test values has been discovered that can faithfully identify the condition, especially early on. First-line emergency care practitioners should perform a thorough physical exam (Perman et al., 2012).

Test Your Knowledge

The best diagnostic tool for identifying sepsis is:

  1. The patient’s mean arterial pressure (MAP).
  2. The patient’s blood level of procalcitonin.
  3. The patient’s C-reactive protein (CRP) blood level.
  4. Clinical experience by identifying signs and symptoms.

Answer: D

Clinical Signs

Potential clinical signs of sepsis are shown in the following box.

Clinical Signs of Sepsis

A septic patient has an infection and a number of the following signs.

  • Appearance
    • Acutely altered mental status
    • Edema
    • Looks ill
  • Vital signs
    • Abnormal body temperature: hypothermia, <96.8°F/36°C; or fever, >100.4°F/38.3°C
    • Hypotension: systolic BP <90 mm Hg or mean arterial pressure <70 mm Hg or a drop in systolic BP >40 mm Hg or the need for vasoactive drugs to maintain normal BP
    • Tachycardia (>90 beats/min)
    • Tachypnea (>20 breaths/min)
  • Blood chemistries
    • High blood level of C-reactive protein (CRP) (>2 std dev above normal)
    • High blood level of procalcitonin (>2 std dev above normal)
    • Hyperbilirubinemia (plasma total bilirubin >4 mg/dl [normal: 0.1–1.0 mg/dl])
    • Hyperglycemia (blood glucose >140 mg/dl) with no history of diabetes
    • Hyperlactatemia (lactate >3 mmol/l with normal = 0.5-2.2 mmol/l)
    • Unexplained base deficit >5.0 mEq/l (normal = <3.0 mEq/l)
  • Blood gases
    • Hypercapnia (PaCO2 >65 mm Hg [normal = 33–44 mm Hg] or PaCO2 >20 mm Hg above patient’s baseline)
    • Hypoxemia (PaO2/FIO2 <300 or mixed venous oxygen saturation (SVO2) <70% [normal ~75%])
  • Blood components
    • Abnormal white blood cell count (WBC)
  • Leukocytosis (WBC count >12,000 /mm3 with normal = 4,500–11,000 /mm3]) or
  • Leukopenia (WBC count <4000/mm3 with normal = 4,500–11,000 /mm3) or
  • Normal WBC count with >10% immature forms (normal = 3%–5%)
    • Coagulation dysfunction (INR >1.5 [normal = 0.9–1.2] or activated partial thromboplastin time >60 s [normal = 30–42 s])
    • Thrombocytopenia (platelet count <100,000/mm3 [normal = 150,000–400,000/mm3] or a drop of 50% in platelet count from patient’s high in past 3 d)
  • Heart function
    • Increased capillary refill time (>2 s)
    • Mottled skin
  • GI function
    • No bowel sounds (paralytic ileus)
  • Kidney function
    • Increasing blood levels of creatinine (>0.5 mg/dl above patient’s baseline)
    • Low urine output (<0.5 ml/kg/h) despite adequate fluid administration

Source: Jui, 2010; Gutovitz et al., 2011; Wang et al., 2012).

Vital Signs


Septic patients often have a fever, sometimes with chills and sometimes with an abrupt onset. However, the majority of septic patients are elderly, and this demographic brings with it a caution about using fever to recognize sepsis. Elderly patients develop fevers less readily than younger patients, and sepsis in elders can present without fever, with only a modest fever, or with hypothermia. (When an elder does present with a fever, the underlying illness tends to be more severe.) Other groups that are less likely to have a significant fever with sepsis are patients in renal failure and patients taking high doses of corticosteroids (Jui, 2010).

Body tissues need more oxygen with a fever, and this worsens the hypoxemia that organs are experiencing in sepsis. Septic patients who present with fevers are more likely than those without fevers to develop shock within the next 72 hours (Glickman et al., 2010).

Test Your Knowledge

Fever is a classic sign of a systemic infection. In Sepsis:

  1. Patients with sepsis always have a fever.
  2. Older patients tend to have a fever, but most patients have a normal or near-normal temperature.
  3. Patients often have a fever, although some septic patients can have normal temperatures or even hypothermia.
  4. Fever is rare in all sepsis patients.

Answer: C

Heart Rate and Respiratory Rate

Septic patients often have an increased heart rate and an increased respiratory rate. The body attempts to compensate for vasodilation and decreased intravascular fluid volume by increasing the heart rate (Ely & Goyette, 2005).

Tachypnea is often the first detectable clinical sign of developing sepsis for several reasons. Rapid breathing can be caused by fever, lactic acidosis, pulmonary edema, and because the lungs are the most common site of infection. In addition, the lung is often the first organ to undergo dysfunction during sepsis due to its early involvement in the inflammatory process. This can lead to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) (Assenzio & Martin-Conte, 2012).

Blood Pressure

Hypotension is a serious sign in sepsis. In general, hypotension can be caused by a decrease in blood volume, a decrease in vascular tone, or a decrease in cardiac output. The hypotension of sepsis can be caused by reductions in all three parameters. Initially, sepsis usually reduces blood volume by increasing capillary leakage, so the administration of fluids is an early priority during treatment (Munford, 2008).

In sepsis, the blood volume is not only reduced but it is redistributed ineffectively. Fluid resuscitation will usually refill the under-perfused arteries. In septic shock, poor vascular tone has been added to the patient’s other systemic problems. In shock, the administration of large amounts of fluids will not succeed in restoring normal blood pressure (Ely & Goyette, 2005).


The spread of inflammatory mediators to the lung damages the vascular endothelium, and the alveolar capillaries become leaky. This leads to edema, poor lung compliance, and decreased oxygenation of the blood. Thus, septic patients often have tachypnea, labored breathing, crackles on auscultation, hypoxemia, and hypercapnia. If ARDS develops, a chest x-ray usually shows diffuse bilateral pulmonary infiltrates.


In a septic patient who does not have a history of major heart problems, cardiac output (the volume of blood pumped by the left ventricle per minute) can remain fairly constant. The cumulative effects of the septic reaction begin to reduce the heart’s pumping power; nonetheless, the heart can often increase its output. This comes about because the ventricles dilate as the heart’s pumping force declines.

With expanded ventricles, each contraction expels more blood than usual. The increased cardiac output persists even when septic shock sets in. “Increased cardiac output and decreased systemic vascular resistance distinguish septic shock from cardiogenic, extracardiac obstructive, and hypovolemic shock” (Munford, 2008).

Clinical Assessment of Cardiac Output

Cardiac output is the volume of blood that the heart pumps per minute. When initially assessing any seriously ill hypotensive patient, it is important to know whether the patient’s cardiac output is adequate.

Clinically, a reduced cardiac output will produce:

  • Narrow pulse pressure
  • Cool extremities
  • Weak pulse
  • Delayed capillary refill

An increased cardiac output will produce:

  • Widened pulse pressure
  • Warm extremities
  • Bounding pulse
  • Rapid capillary refill

The classic presentation of sepsis includes an increased cardiac output. In early sepsis, hypotension is typically due to loss of intravascular volume, not to decreased cardiac output. When septic shock sets in, it is usually an extracardiac problem because the vasculature has lost the ability to maintain its tone by responsive arterial constriction.

Source: Kress & Hall, 2008.

Test Your Knowledge

The cardiac output is the:

  1. Summative ECG.
  2. Volume of blood that the heart pumps per minute.
  3. Heart rate plus the respiratory rate.
  4. Average of the systolic and diastolic blood pressures.

Answer: B

Much of the cardiovascular dysfunction caused by sepsis is reversible. The cardiovascular system is typically functioning normally again within 10 days of a patient’s recovery from an episode of sepsis (Shapiro et al., 2010).


Brain dysfunction in patients with severe sepsis is called septic encephalopathy. This condition manifests as a change in mental status, with disorientation, confusion, agitation, lethargy, or coma. Focal or unilateral neurologic signs are uncommon in septic encephalopathy. Reports of its frequency range widely from 10% to 70% of septic patients have been reported (Jui, 2010).

* * *

Finally, a full serum chemistry and urinalysis should be done.

Hematologic Signs

Blood work for a suspected case of sepsis includes a complete blood count, a platelet count, and a DIC panel (prothrombin time, activated partial thromboplastin time, and the serum concentrations of fibrinogen, D-dimer, antithrombin III, and lactate (Jui, 2010). Blood cultures should be drawn before antibiotics are administered (Dellinger et al., 2013b).

Red Blood Cells

Poor tissue perfusion is a hallmark problem in sepsis. To have an adequate oxygen carrying capacity, a patient needs a sufficient quantity of red blood cells. In sepsis, the initial treatment goals include maintaining a hematocrit >30% and a hemoglobin concentration >10 g/dl. The septic patient’s hematocrit and hemoglobin concentration will vary as fluids shift between compartments in the body, but over time these red blood cell values will drift lower because red cell production and survival times decrease during sepsis.

Complications, such as bleeding or hemolysis (as occurs in clostridial infections), can cause acute drops in the hematocrit (Shapiro et al., 2010).

Oxygen-carrying capacity declines during sepsis because sepsis causes changes in the body’s iron metabolism, so that less than the normal amount of iron is transferred into forming red blood cells (Jui, 2010).

White Blood Cells

Sepsis usually produces an elevated white blood cell count, with an increased number of neutrophils and an increased percentage of immature forms called bands (ie, a left shift, or bandemia) (Munford, 2008).

The absence of an elevation of the white blood cell count does not rule out sepsis. Some septic patients develop an abnormally low white blood cell count (leukopenia). Leukopenia with a fever is a particularly worrisome combination and increases the risk of a fatal outcome (Shapiro et al., 2010).

Test Your Knowledge

The white blood cell count of a septic patient is:

  1. Generally in the normal range.
  2. Always high.
  3. Always low.
  4. Can be either high or low.

Answer: D

Platelets, Coagulation Factors, and Protein C

Approximately half of all patients with sepsis have low platelet counts (thrombocytopenia). As the sepsis worsens, platelet counts will continue to drop.

Approximately 10% of septic patients have other coagulation abnormalities. There can be:

  • Increased prothrombin or activated partial thromboplastin times or
  • Decreased levels of fibrinogen or antithrombin III or
  • Increased levels of fibrin monomer, fibrin split products, or D-dimer (Jui, 2010)

When a septic patient has a combination of coagulation abnormalities the risk of DIC is increased. DIC occurs in 2% to 3% of septic patients and more frequently in patients with septic shock (Munford, 2008).

Protein C is a natural anticoagulant factor that helps to counteract the coagulation cascade. A low blood concentration of activated protein C is typical of sepsis, because the cytokines that are released in the inflammatory condition of sepsis make it more difficult for protein C to be activated. Decreased levels of activated protein C in the circulation are associated with thrombi, microthrombi, and fibrin deposition in septic patients (Shapiro et al., 2010).


Recent attention has focused on the topic of biomarkers (measurable characteristics used as indicators of a disease state). Serum lactate has been the most studied. Lactic acid is a product of cell metabolism and is produced by the breakdown of carbohydrates when oxygen levels are low. Whether it is caused by poor perfusion or an impaired clearance secondary to organ dysfunction, multiple studies have shown that elevation in serum lactate is an effective marker to measure the risk of severe sepsis. Studies have demonstrated that elevations in serum lactate without hypotension were associated with increased mortality in patients who present to the ED with severe sepsis. Recent studies suggest that serum lactate may perform well as a screening test in the medical decision-making process regarding early ED management and disposition of the septic patient (Perman et al., 2012).

As early as 1964 it was proposed that serum lactate measured during critical illness correlated with adverse outcomes. Another study in a group of patients with mixed critical illness showed that individuals with a lactate of at least 4 mmol/l had a mortality rate of 87%. This finding was further validated in 1994 and is now suggested by the Surviving Sepsis Campaign as an inclusion criterion for the 3-hour and 6-hour bundles for septic patients. This can help identify and treat severe sepsis patients earlier in their clinical course so as to halt the inflammatory cascade and reverse perfusion abnormalities. Lactate should be re-measured within the first 6 hours of treatment to assess for normalization of levels after oxygen, antibiotics, and fluid support are given (Dellinger et al., 2013b).

Microbiologic Analysis

We have seen that sepsis can be triggered by an infection of any type of microbe. Sepsis is a system-wide reaction, but it can occur even when the microbes are localized and have not invaded the bloodstream. Blood cultures will be negative (ie, they will not find bacteria or fungi) in approximately 2 in 5 cases of septic shock, 3 in 5 cases of severe sepsis, and 4 in 5 cases of sepsis (Kibe et al., 2011). In those cases, in which microbes are detected in a septic patient’s blood, about 70% of the microbes found are bacteria.

Photo of Blood Culture Tubes

Source: James Heilman, Wikimedia Commons.

Test Your Knowledge

When it is possible to identify a microbe causing sepsis, the microbe is most often a:

  1. Virus.
  2. Fungus.
  3. Bacterium.
  4. Protozoan.

Answer: C

Cultures should be taken of all other potentially infected sites. Despite having a negative result, cultures of the bloodstream should be taken prior to administration of antibiotics (Dellinger et al., 2013b). A successful identification of the microbe will eventually allow the optimal antibiotic to be given.

It can take days to receive microbiologic culture results, and successful resolution of sepsis requires the early administration of general antibiotics. Therefore, as soon as culture samples have been taken, patients are started on wide spectrum antibiotics, with the plan of reassessing the effectiveness daily and customizing the antibiotic once the cultures are available.

Direct Laboratory Identification

Not all patients with sepsis-like symptoms have an infection. The same reaction, SIRS, can be triggered by noninfectious causes, and in such cases it is risky to expose the patient to unnecessary nephrotoxic antibiotics. For decades, scientists have been trying to find a rapid laboratory test that will give a quick and reliable diagnosis of sepsis. This has been a disappointing quest: “the search for a highly accurate biomarker of sepsis has become one of the holy grails of medicine” (Kibe et al., 2011).

Sepsis is a complex syndrome. It produces a great many changes in the body’s chemistry, and each of these changes is a potential marker for the disease. To date, however, no single physiologic change has been found to be a specific and sensitive identifier for sepsis. Among the many molecules being studied, three that appear to be the most useful are C-reactive protein, complement C3a, and procalcitonin.

An elevated level of C-reactive protein (CRP, a different molecule from protein C), is a useful marker for systemic inflammation in general. In patients with sepsis, CRP levels rise rapidly, mirroring the course of the infection (Ely & Goyette, 2005); however, the rise is not specific to sepsis.

Systemic infections raise the levels of molecules in the complement cascade. One of these molecules, C3a, has proved to be a sensitive and specific marker that can distinguish sepsis from similar-looking cases of noninfectious SIRS (Ely & Goyette, 2005).

An elevated level of procalcitonin (the precursor molecule to the hormone calcitonin) will also distinguish sepsis from noninfectious SIRS. A useful feature of procalcitonin is that its blood levels are good reflections of the severity of a patient’s sepsis (Kibe et al., 2011).

Test Your Knowledge

Blood molecules useful to identify sepsis include all but one of the following:

  1. Dopamine.
  2. C-reactive Protein.
  3. C3a.
  4. Procalcitonin.

Answer: A

Differential Diagnosis

At times the diagnosis of sepsis is straightforward. A patient can present with tachycardia, hypotension, tachypnea, fever, leukocytosis, metabolic acidosis, and signs of a serious infection such as pneumonia, acute pyelonephritis, or acute peritonitis.

At other times, however, sepsis presents with only a few classic symptoms. This is especially true in the early stages of the disease when the patient may not yet look severely ill and the underlying infection may not be obvious.

Another confusing initial presentation occurs in the patient with sepsis who has acute and dramatic dysfunction of an organ. This draws the physician’s attention to that organ and away from the systemic cause for the organ failure.

There can also be diagnostic difficulties when a patient presents with a mix of complaints. Sepsis tends to take hold in patients who already have illnesses, injuries, or infirmities. In these cases, to identify sepsis the clinician must recognize its symptoms aside from the signs and symptoms of the patient’s other problems.

For these reasons, the differential diagnosis for sepsis is broad, as seen in the following box.

Differential Diagnosis for Sepsis

  • Anaphylaxis
  • Cardiac
    • Cardiac contusion
    • Congestive heart failure
  • Endocrine
    • Adrenal dysfunction
    • Diabetic ketoacidosis
    • Hyperthyroidism
  • Metabolic disturbance
  • Neurologic
    • Hypothalamic brain injury
  • Pancreatitis
  • Respiratory
    • Acute respiratory distress syndrome (ARDS)
    • Hypoxia
  • Toxic
    • Drug misuse/overdose
    • Neuroleptic malignant syndrome
    • Poisoning
  • Trauma/Burn
  • Vascular
    • Anemia
    • Dehydration
    • Disseminated intravascular coagulation (DIC)
    • Hemorrhage
    • Vasculitis

Source: Shapiro et al., 2010.