Patient Care

Evidence Supports Using End-Tidal Carbon Dioxide to Detect Prehospital Sepsis

Issue 9 and Volume 41.

The term sepsis was originally used over 2,700 years ago in the poems of Homer and in the writings of Hippocrates to describe the processes of “rotting” or “decaying.”1,2Sepsis is a major cause of emergency department (ED) visits and results in significant morbidity and mortality.3

With over a million Americans suffering from sepsis per year, the annual total treatment costs exceed $20 billion,4,5 making septicemia the most expensive inpatient condition to treat in the United States.5

Sepsis is caused by systemic inflammation that results from the release of enormous quantities of cytokines and chemokines into the bloodstream, causing an imbalance between the proinflammatory and anti-inflammatory responses.6

This maladaptive reaction arises in response to a blood infection causing coagulation dysfunction, an impaired immune response, metabolic abnormalities, and endothelial compromise which leads to tissue damage, organ failure, and death.6,7

As referenced earlier in this special JEMS focus on sepsis, the three accepted stages of sepsis according to the American College of Chest Physicians (ACCP), Society of Critical Care Medicine (SCCM), and Mayo Clinic are sepsis, severe sepsis, and septic shock.8,9

According to the ACCP and SCCM, the diagnostic criteria for sepsis involve exhibiting at least two of the following symptoms:

  • Fever greater than 38°C (100.4°F),
  • Heart rate greater than 90 beats per minute;
  • Respiratory rate more than 20 breaths per minute or arterial carbon dioxide tension (PaCO2) less than 32mmHg,
  • Abnormal white blood cell count (>12,000/µL or < 4,000/µL or >10% immature [band] forms); and
  • Suspected or confirmed infection.10

Severe sepsis is diagnosed when a patient has been confirmed to have sepsis in addition to hypotension, organ dysfunction, and hypoperfusion to at least one organ.10

Septic shock is diagnosed when a patient has severe sepsis along with persistent arterial hypotension despite adequate fluid administration.10

Sepsis has an in-hospital mortality rate between 14.7–29.9%,11,12 is the leading cause of death in non-coronary intensive care units,13 and is the 10th leading cause of death in the United States.13

A 2014 study published in JAMA found that sepsis contributed to 1 out of every 2 to 3 in-hospital deaths.14 This study also found that most of these patients had sepsis upon admission to the hospital.14

The “Surviving Sepsis Campaign” publishes guidelines to guide sepsis therapy and improve patient outcomes. According to the campaign’s most recent recommended guidelines, the timely identification of patients with sepsis, along with the implementation of early, goal-directed therapy, is crucial to improve morbidity and mortality.15 That is why EMS is now being tapped to play a major role in the early detection of sepsis.

Studies have been able to confirm that the implementation of early goal-directed therapy improves both short-term,3,16,17 and long-term18 outcomes.

In the ED, triage tools used to identify septic patients have been shown to:

  • Decrease the mean time to antibiotic administration,19,20
  • Decrease the need for ICU pulmonary artery catheterization,21
  • Increase vasopressor usage,22
  • Increase crystalloid volume administration,22
  • Decrease ED length of stay,23,24
  • Decrease the 24 hour mortality rate,25
  • Decrease overall in-hospital mortality rate,22,26,27 and
  • Reduce the risk for 28-day mortality.24

If the disease process is allowed to continue without aggressive intervention, patients with sepsis can progress into a more severe form of the disease. Therefore, the early identification and rapid clinical intervention for patients with any degree of sepsis is crucial for positive outcomes.3

Understanding Lactate

Lactate is an organic molecule, an ion with a negative charge, or an anion. Its chemical formula is C3H5O3. It is found in every cell in the body; it is on the skin and in sweat and saliva.  Lactate is synthesized as an end-product of glycolysis when anaerobic conditions are present and its synthesis is represented by the following equation:

                        Pyruvate + NADH + H+ ↔ Lactate + NAD+

Under normal physiological conditions, lactate production occurs in muscles (25%), skin (25%), brain (20%), red blood cells (20%), and in the intestine (10%).28

Hyperlactatemia, or an increased blood-lactate concentration, is typically found as a result of exercise29, cardiogenic shock30, open heart surgery,31 liver failure,32 critical illness,33 and sepsis.34

Nguyen et al. popularized the concept of achieving “lactate clearance” when they found that early lactate clearance in the hospital setting was an indicator of global tissue hypoxia resolution, was associated with a lower mortality rate, and higher clearance after six hours of ED intervention lead to superior outcomes.

Lactate clearance, defined as the removal in lactate concentration over time (mL/min), is expressed by the equation:

                        [(Initial lactate – subsequent lactate)/initial lactate] x 100%35,36

The Surviving Sepsis Campaign Guidelines recommend the clearing of lactate to normal levels in septic patients with hyperlactatemia.15 This standard has become an end-point for early, goal-directed therapy.37 Whether hyperlactatemia or “stress hyperlactatemia” results from a maladaptive or protective response is unknown.38

The current controversy concerning the use of lactate clearance as an end-point for resuscitation has revolved around the unknown physiological roles of lactate as well as the methods by which its concentration both increases and decreases.37,38,39

Hyperlactatemia is traditionally viewed as a product of global tissue hypoxia or hypoperfusion; however, the complexity of its widespread production, utilization, and its intermediate role in most energy-related pathways38 indicates that its function in pathophysiology and its subsequent use as a valuable end-point for sepsis treatment may be erroneous.

This idea is evidenced by multiple animal and human studies that were unable to find an association between hyperlactatemia and indicators of perfusion, oxygenation, or of intracellular hypoxia.40–50

An alternative theorized explanation argues that hyperlactatemia is caused by inflammation51,52 and the glycolysis-inducing catecholamines epinephrine44,47,53–56 and norepinephrine57,58 leading to a hypermetabolic state rather than insufficient oxygen supply.

This supports the notion that lactate production is an adaptive response that is protective in nature and a part of the body’s stress response.

Despite the ongoing debate, knowledge and treatment of elevated serum lactate levels have been demonstrated to be significant in both the diagnostic and treatment phases for severe sepsis and septic shock.3,36,59–64

Serum lactate levels also serve as a valuable predictor of outcomes in patients with severe sepsis and septic shock.65–74

Additionally, a large, multicenter analysis of 28,150 subjects from the Surviving Sepsis Campaign database found that elevated lactate levels greater than 4 mmol/L, both in the presence and absence of hypotension frequently taken within six hours of ED presentation, are “significantly associated with in-hospital mortality and is associated with a significantly higher risk than intermediate levels (2–3 and 3–4 mmol/L).”75

This study strongly supports the use of lactate measurement or the importance of correlating EtCO2 readings with a lactate level to evaluate the initial severity and monitor the progression of sepsis despite the ongoing debate on its use as an end-point for sepsis resuscitation.

The Prehospital Impact on Sepsis

Septic patients are not always immediately recognized because they do not often appear to be severely ill or in crisis upon initial presentation to the emergency department. Since many of these patients arrive at the ED by EMS, potentially septic patients or patients at risk of progressing into severe sepsis or septic shock can be identified by their prehospital healthcare providers.

Studies have shown that septic patients, namely patients with a diagnosis of severe sepsis or septic shock, that were treated by prehospital healthcare providers have a shorter time to antibiotic administration,76–78 a shorter time to early goal-directed therapy (EGDT) initiation,76,78 and a shorter time to IV fluid administration,77 although not all of these studies found a lower in-hospital mortality benefit.

Prehospital interventions such as the attainment of IV access and the administration of fluids are both associated with decreased in-hospital mortality79 although there is conflict in the existing literature.80

A study published in the Journal of Intensive Care Medicine found that early sepsis intervention was associated with one life saved for every seven treated.81

Due to the demonstrated benefits of rapid identification, it is imperative to detect the disease process as early as possible.

Sepsis identification tools such as the Robson screening tool,82,83 BAS 90-30-90 scale,82,84 the modified Early Warning scale,84,85 and PRESEP score84 have shown low to moderate effectiveness (based on sensitivity and specificity) at identifying septic patients in the prehospital82 and emergency department setting.84

Recently, the development of a PRESS score demonstrated a high sensitivity;86 however, this score has yet to be validated.

It is important to note that these scales do not consider lactate levels or end-tidal carbon dioxide (EtCO2) measurements in the determination of the current degree of sepsis or the potential for patients with sepsis to progress to severe sepsis or septic shock.

The Role of CO2 Levels in Sepsis Assessment & Detection

Carbon dioxide (CO2) is a product of the conversion of pyruvic acid to acetyl-CoA, as well as from the Krebs cycle during aerobic cellular metabolism. CO2 is transported by venous circulation to the lungs where it diffuses out and is expelled through exhaled air.

The partial pressure or maximum CO2 concentration, known as end-tidal carbon dioxide (EtCO2), can be measured upon exhalation by a capnometer which displays a capnogram.87 

EtCO2 is a non-invasive and rapidly obtainable method by which a healthcare provider can assess a patient’s metabolism, circulation, and ventilation.87 Normally, an exhaled breath consists of 5–6% CO2, which is equivalent to 35–45mmHg. This measurement is generally equivalent to arterial carbon dioxide levels provided that there is no ventilation to perfusion mismatch.87

EtCO2 is increasingly being used in the prehospital and emergency department setting for many conditions (see Table 1, below.). The American Society of Anesthesiologists (ASA) recommends the implementation of end-tidal capnography as a standard of care for general anesthesia, moderate sedation, and deep sedation.88

EtCO2 is valuable in assessing prehospital sepsis

In the diagnostic and treatment phases for patients with sepsis or suspected sepsis, both EtCO2 as well as lactate levels, and potentially their correlation, may be significant. This hypothesis is beginning to draw the attention of contemporary emergency researchers. The use and potential value of EtCOin septic patients has begun to be studied over the past few years, with promising findings.70, 98–103

Studies have found a significant inverse correlation between EtCO2 and lactate levels in adult patients with shock,100 fever,102 those requiring prehospital advanced life support,103 penetrating trauma requiring a trauma team,99 and in those diagnosed with severe sepsis or septic shock.98,101 Lactate levels are valuable in determining the severity of sepsis but are not always rapidly obtained.104

EtCO2 provides an immediate and non-invasive method, which may have the potential to play a significant role in the early diagnosis of sepsis or identify patients that will likely progress into a more severe form of the disease because it rapidly identifies potentially critical septic patients. Although EtCOas a valuable triage tool has not been fully elucidated and requires further study, it is showing great potential in assisting in the recognition of sepsis and septic shock. 

Two studies performed by Hunter et al. helped advance the idea of using EtCO2 for potentially septic patients.98,103

One study concluded that EtCO2 was the best predictor for mortality and therefore can indicate disease severity which can aid ED staff during the triage process; however, a more specified investigation of the role of EtCO2 measurements in septic patients would need to be performed in order to make more definitive conclusions regarding the role of EtCO2 in this patient population.103

The second found a significant inverse correlation between EtCO2 and lactate levels in ED patients diagnosed with sepsis, severe sepsis, and septic shock and that EtCO2 was also correlated with mortality but in the end found that more studies need to be performed in order to determine whether or not EtCO2 is able to reduce the time to recognition, and the study therefore cannot be used to determine the effectiveness of EtCO2 or lactate levels in determining the initial severity of sepsis or evaluate the potential a patient has to progress into a more serious form of the disease.98

The potential for EtCO2 to serve as a valuable triage tool for sepsis is feasible; however, it is unlikely to serve as a surrogate for therapy cessation as evidenced by one study which found that the change in EtCO2 over a six-hour period was not associated with a change in lactate,101 therefore suggesting that EtCO2 was not a good end-point for resuscitation.

Another study found that EtCO2 was correlated with both lactate and Sequential Organ Failure Assessment (SOFA) scores;102 however, this study contained some significant flaws and results were unlikely to be clinically significant.105

Conclusion

Currently, the role of EtCO2 in the prehospital and emergency department setting has yet to be fully investigated and its potential role in predicting the worsening of the condition has not been adequately studied. Even though future studies are needed to determine the value of EtCO2 in septic patients, several EMS systems, as described in this special JEMS septic shock section, are having success in the use of EtCO2 to zero in on septic patients. Therefore, EtCO2 may prove to be, in conjunction with other vital signs, a valuable tool in identifying septic patients before they arrive at the ED.

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