The management of sepsis requires a life-saving set of skills that emergency physicians are increasingly relied upon to possess at expert-level competency. While many iterations of sepsis management have emerged in the literature, this article will focus on noninvasive management of sepsis by reviewing the epidemiology and evolution of sepsis and sepsis care, as well as highlighting the indications, contraindications, and benefits of non­invasive management of sepsis.

Epidemiology

Sepsis is the most expensive disease in the United States, costing the health care system approximately $50 billion annually.¹ Sepsis is the number 10 cause of mortality.² A large epidemiological study in 2001 placed the annual incidence at approximately 750,000 cases per year, with a mortality of 20%-30%.³ Sepsis disproportionately affects the elderly, with a 13-fold increase in relative risk for those older than 65. This same age group represents approximately 65% of total cases of sepsis.² With our aging population and increasing life expectancy, the emergency physician has the potential to have considerable impact on the care of this disease process.

Definition

Sepsis was originally described as the presence of an infectious source plus at least two systemic inflammatory response syndrome (SIRS) criteria (Table 1). Severe sepsis was defined as sepsis with evidence of organ dysfunction. Septic shock is sepsis with hypotension.⁴ An updated definition of sepsis identifies this disease process as an infection plus some of a larger set of criteria that includes traditional SIRS criteria, as well as other markers of hemodynamic instability, inflammation, and organ dysfunction4 (Table 2).

Evolution of Bundled Therapy

Combining multiple evidence-based treatments in a standardized, bundled approach to sepsis has been discussed since 1976. A study of sepsis in a dog model identified a synergistic effect of fluid resuscitation plus antibiotics.⁵ In 2001, Dr. Rivers demonstrated that an early, algorithmic application of antibiotics, source control, volume resuscitation, vasopressors for those still in shock, and transfusion in the anemic significantly lowered both mortality and resource utilization.⁶

The real mortality benefit of bundled therapy lies in a consistent and systematic treatment protocol applied to every septic patient. Results of the Surviving Sepsis Campaign showed that bundled therapy for management of sepsis decreased mortality from 37% to 30.8%.⁷ Mortality decreased the longer an institution used standardized bundle therapy.⁸ Further, bundle therapy saves hospital and health care resources.⁵ Studies continue to show that bundled therapy is underutilized in septic patients. Frequently cited barriers include unavailability or expense of central venous monitoring devices, lack of nursing staff able to operate central venous pressure monitoring, and challenges in identifying septic patients.⁹ Noninvasive sepsis management can help with all of these cited barriers.

The growing literature describes sepsis management that provides an alternative to the invasive central venous pressure (CVP) and mixed-venous oxygen saturation monitoring central to

early goal-directed therapy (EGDT). Noninvasive therapy focuses on using dynamic ultrasound assessment of inferior vena cava (IVC) collapsibility to estimate intravascular volume status as an alternative to invasive CVP monitoring. Also, this model follows lactate to measure response to therapy versus mixed-venous oxygen levels. While the noninvasive management of sepsis is not supported by a body of evidence as robust as that for invasive monitoring, the existing literature is compelling.

Indications for noninvasive sepsis management include:

• Lactate over 4 or MAP less than 65 mm Hg after 2 L 0.9 NS bolus.
• Multiple large-bore (up to 3 × 18 g) IV access that can run fluids and multiple antibiotics simultaneously.
• Goal of treatment is curative.
• Patient habitus allows visualization of the IVC.¹⁰ Contraindications for noninvasive sepsis management include:
• Poor peripheral access.
• Poor ultrasound visualization of IVC.
• Vasopressor requirement.
• Severe septic shock.
• Pulse oximetry less than 90% on supplemental oxygen.
• Respiratory distress.

Ultrasound of the IVC

Ultrasound is a key component of a noninvasive approach to sepsis. The clinical ability to estimate volume status is limited at best. Dialysis literature has shown that measuring IVC collapse by ultrasound is a reliable method for estimating volume status. Ultrasound also reveals discordances between patients’ stated “dry weight,” vital signs, physical exam, and the patient’s true volume status. IVC ultrasound has been used successfully at many dialysis centers to guide therapy in volume loading or reducing patients.¹⁰

Studies have correlated increased IVC collapse with low CVP in septic patients.⁹ A correlation between low right atrial pressures and increased IVC collapse has also been described.⁶ Also, IVC collapsibility decreases in response to fluid therapy.¹¹ Patients who were predicted to be volume responders (measured IVC collapse over 50%) showed statistically significant improvements in catheter-measured cardiac index, cardiac output, and mean arterial pressure after fluid resuscita­tion.¹² A decrease in IVC collapsibility was found using visual qualitative and quantitative measures following multiple fluid boluses (20 mL/kg). This study also found a high degree of correlation between visual qualitative and M-mode quantitative measurements. This finding suggests that visual impression is as meaningful as objective measurement.¹³ These studies support the notion that IVC ultrasound can be used to track volume status in real time, giving emergency physicians data to support the aggressive volume resuscitation required in the early hours after sepsis has been identified.

Learning to estimate CVP is easy for the novice with limited or no ultrasound experience. Trained internal medicine residents with no formal ultrasound training were able to accurately estimate CVP, which was subsequently confirmed by atrial pressure via right heart catheterization.¹⁷ The easiest method is a visual, qualitative measurement. The diameter of the IVC is noted; any variation of this diameter with the cardiac cycle or obvious collapse suggests potential for volume responsiveness.¹⁸ The formal measurement of IVC collapse occurs as the patient “sniffs.” Qualitative visual IVC collapse of 50%-100% with this negative inspiratory pressure maneuver is highly suggestive of intravascular depletion that is volume responsive. Quantitative measurement involves placing the M-mode indicator 2-3 cm below the RA/IVC junction and measuring the diameter over time. As the M-mode traces the IVC diameter across the screen, ask the patient to “sniff.” If the comparison of caliper measurements of the IVC diameter before and after this maneuver shows collapse ranging from 50% to 100%, the patient is likely to be volume responsive.¹⁹

Lactate

Following serum lactate is the other key component of the noninvasive approach to sepsis management. Lactate is an important marker used as a predictor for mortality in sepsis and shock.²⁰ Lactate is easily obtained from any peripheral source; there is a high correlation between levels from arterial and venous sources.²¹ Further, lactate is a very reliable point-of-care test.²² A recent multicenter, randomized, controlled trial used lactate-guided therapy in septic patients, which led to patients receiving vasopressors and fluids earlier in therapy. It was also noted that a decreasein lactate levels within the first 8 hours of sepsis correlated with a decrease in mortality and morbidity.²³ More specifically, a decrease in serum lactate of 10% over 2 hours in response to therapy corresponds with a significant decrease in mortality.²⁴

Comparing response to therapy with lactate levels versus mixed-venous oxygen levels showed a statistically significant difference in mortality between groups.²⁵ Further, lactate may be a superior marker for physicians to follow versus mixed-venous oxygenation. Response to therapy in patients undergoing EGDT showed that normalized mixed-venous oxygen saturation did not always predict an improvement in lactate or mortality.²⁴ Trending lactate as a peripheral marker of sepsis is a valuable and valid tool in identifying and treating this disease process.

Initiating Noninvasive Management

Multiple protocols have adapted Dr. Rivers’ EGDT protocol to a noninvasive approach. The below protocol is adapted from the STOP Sepsis Collaborative (http://emcrit.org/wp-content/uploads/non-invasive.pdf).

For initial resuscitation, all patients should have reliable 18-g IV access at multiple sites, be placed on supplemental O2, and have blood drawn and sent for basic labs, ABG/VBG, and lactate levels in addition to blood cultures. Draw cultures from all indwelling vascular access devices. This resuscitation should not be performed with a single IV or one that is positional. The following also apply:

• Antibiotics should be given as soon as possible. Giving broad-spectrum antibiotics within the first hour carries a clear mortality benefit.^25,26,28
• Source control is paramount.²⁹ Note if the patient has a tense belly, necrotic tissue, decubitus ulcers, signs of CNS infection, indwelling devices, or rales or other pulmonary infectious symptoms.²⁷
• Assess volume status using IVC ultrasound to estimate CVP/RA pressure. If greater than 50% collapse, large-volume resuscitation is needed.
• Administer 20-30 mL/kg crystalloid fluid bolus. Large volumes (over 6 L) of normal saline resuscitation will cause hyperchloremia and a resultant nongap acidosis. Consider lactated ringer’s for subsequent boluses if easily available.
• Be aware of laboratory values for evidence of severe sepsis (Table 2). Consider switching these patients to invasive management if they fail to improve their lactate by 10% in the first 2 hours.²⁴

For management of noninvasive resuscitation, the following apply:

• Perform serial ultrasound assessments of the IVC after each bolus of crystalloid.
• Continue giving 500-mL to 1,000-mL boluses of crystaloid every 20 minutes until the IVC no longer shows significant collapse on ultrasound. There still should be respiratory variation of about 30% collapse (Table 3).
• Recheck MAP: If the patient remains hypotensive (MAP under 65 mm Hg) after adequate fluid loading, switch to invasive strategy in order to begin vasopressor therapy.
• Evaluate response to therapy with lactate levels every 2 hours. Assess mental status and urine output.
• If the lactate has decreased by 10%, continue resuscitation and admit to a non-ICU monitored bed.
• If lactate is rising or has decreased to less than 10% and hemoglobin is less than 7 g/dL, transfuse 1 U of PRBC.
• Transfusion may be considered in patients with hemoglobin of 7-10 g/dL. Also, continue additional 1,000-mL crystalloid volume resuscitation or start peripheral dobutamine to improve cardiac output.
• If the above therapies fail to reduce lactate by the second lactate level measured 4 hours into resuscitation, switch to invasive sepsis management.

Nonresponse to Management

For patients refractory to noninvasive sepsis therapy, place a central line and admit to the ICU.

Summary

Noninvasive management of sepsis is a compelling therapy from a number of perspectives: 1) prevention of central line placement, 2) broad applicability to centers with limited resource to follow central venous monitoring, 3) quicker and individualized approach to resuscitation. Time and well-conducted prospective trials will tell the difference between the invasive and noninvasive approaches. Currently, the data suggest that noninvasive sepsis management is safe and effective in appropriate patient populations.

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