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Focus On: The Non-Invasive Management of Sepsis

By Andrew Pendley, M.D. and James Ahn, M.D.

Contributors
Dr. Pendley is a third-year resident at the University of Chicago’s Emergency Medicine Residency Program. Dr. Ahn is a Medical Education Fellow and Clinical Instructor in the Section of Emergency Medicine at the University of Chicago Medical Center. Dr. Robert Solomon is Medical Editor of ACEP News and editor of the Focus On series, core faculty in the emergency medicine residency  at Allegheny General Hospital, Pittsburgh, and Assistant Professor in the Department of Emergency Medicine at Temple University School of Medicine, Philadelphia.

Disclosures
In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards and American College of Emergency Physicians policy, all individuals in control of content must disclose to the program audience the existence of significant financial interests in or relationships with manufacturers of commercial products that might have a direct interest in the subject matter.

Dr. Pendley, Dr. Ahn, and Dr. Solomon have disclosed that they have no significant relationships with or financial interests in any commercial companies that pertain to this article.

Disclaimer
ACEP makes every effort to ensure that contributors to College-sponsored programs are knowledgeable authorities in their fields. Participants are nevertheless advised that the statements and opinions expressed in this article are provided as guidelines and should not be construed as College policy. The material contained herein is not intended to establish policy, procedure, or a standard of care. The views expressed in this article are those of the contributors and not necessarily the opinion or recommendation of ACEP. The College disclaims any liability or responsibility for the consequences of any actions taken in reliance on those statements or opinions. 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 the emerging non-invasive approach to management of sepsis by reviewing the epidemiology and evolution of sepsis and sepsis care, as well as highlighting the indications, contraindications, and benefits of the non-invasive management of sepsis.

Questionnaire Is Available Online
This educational activity is designed for emergency physicians and should take approximately 1 hour to complete. Participants will need an Internet connection through Firefox,Safari or Internet Explorer 6.0 or above to complete this Web-based activity. The CME test and the evaluation form are located online at www.ACEP.org/focuson

The participant should, in order, review the learning objectives, read the article, and complete the CME post-test/evaluation form to receive up to 1 ACEP Category I credit and 1 AMA PRA Category 1 CreditTM. You must score at least 70 percent to receive credit. You will be able to print your CME certificate immediately. 

This article was published online April 1, 2012. The credit for this CME activity expires March 31, 2015.

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Learning Objectives
After reading this Web-based article, the physician should be able to:
  • Explain the evidence available for non-invasive sepsis strategy
  • Choose appropriate patient populations for non-invasive sepsis strategy
  • Apply non-invasive sepsis strategy in appropriate patient populations

Epidemiology 
April 2012 Focus On Table 1Sepsis is the most expensive disease in the United States, costing the health care system approximately $50 billion annually.(1) According to a 2004 article by the AMA, sepsis is the number 10 cause of mortality.(2) A large epidemiological study by Angus and colleagues in 2001 places the annual incidence at approximately 750,000 cases per year, with a mortality between 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 2 systemic inflammatory response syndrome (SIRS) criteria.(Table 1A,B) 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 dysfunction.(4) (Table 2)April 2012 Focus On Table 2

The 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) Data from the 2010 Surviving Sepsis Campaign International program identified early fluid resuscitation and antibiotics, and source control as being individually associated with improvement in mortality.(7)

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 demonstrated that institutions implementing bundled therapy for management of sepsis decreased mortality from 37% to 30.8%.(7) Additionally, mortality decreased the longer an institution participated with standardized bundled therapy.(8) Further, bundled therapy saves hospital and health care resources.(5) Unfortunately, studies continue to show that bundled therapy is underutilized in septic patients. Frequently cited barriers include availability or expense of central venous monitoring devices, lack of nursing staff able to operate central venous pressure monitoring, and challenges in identification of septic patients.(9) Non-invasive sepsis management can help with all of these cited barriers.

Burgeoning literature describes management of sepsis that provides an alternative to the invasive central venous pressure (CVP) and mixed-venous oxygen saturation monitoring central to early goal directed therapy (EGDT). Non-invasive 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 non-invasive management of sepsis is not supported by a body of evidence as robust as that for invasive monitoring in the management of sepsis, the existing literature is compelling.

Indications for Non-Invasive Sepsis Management

  • Septic patient with a lactate >4 or MAP <65mmHg after 2L 0.9NS bolus
  • Multiple large bore (up to 3x 18g) 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 non-invasive sepsis management

  • Poor peripheral access
  • Poor visualization of the IVC by US
  • Vasopressor requirement
  • Severe septic shock
  • Pulse oximetry <90% on supplemental oxygen
  • Respiratory distress

Ultrasound of the IVC 
Ultrasound is a key component of a non-invasive approach to sepsis. The clinical ability to estimate volume status is limited at best. Dialysis literature has shown that measuring inferior vena cava collapse by ultrasound is a reliable method for estimating volume status. Ultrasound also reveals discordances among patients' stated "dry weight," vital signs, physical exam, and the patient's true volume status. Inferior vena cava (IVC) ultrasound has been used successfully in many dialysis centers to guide therapy in volume loading or reducing patients. (10)

Studies have correlated increased IVC collapse with low central venous pressures 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 >50%) demonstrated 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 (20ml/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) Taken together, 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 measured via right-heart catheterization .(17)  The IVC is identified in longitudinal view with the ultrasound probe placed just below the xyphoid process. The probe indicator should be orientated toward the patient's head. At this position, the right atrium (RA) and the junction of the RA and IVC can be visualized. (18) For purposes of standardization, measurements of the IVC are taken 2-3cm caudal to the RA/IVC junction in two ways.

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 2-3cm 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 50-100%, then the patient is likely to be volume responsive. (19)

Lactate 
Following serum lactate is the other key component of the non-invasive approach to sepsis management. Lactate is an important marker used as a predictor for mortality in sepsis and shock.(20) This laboratory value becomes especially significant in the non-invasive management of sepsis. 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 decrease in 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 demonstrated a statistically significant difference in mortality between the 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. The mixed-venous oxygen saturation was normal (>70%) in a subgroup that failed to clear lactate and consequently had higher mortality.(24) In conclusion, trending lactate as a peripheral marker of sepsis management is a valuable and valid tool in identifying and treating this disease process.

Initiating Non-Invasive Sepsis Management 
Multiple protocols have evolved adapting Dr. Rivers' EGDT protocol to a non-invasive approach. The below protocol is adapted from the NY Sepsis Initiative (http://emcrit.org/wp-content/uploads/non-invasive.pdf)

Initial Resuscitation:

All patients should have multiple, reliable 18g IV access, be placed on supplemental O2, be monitored, 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.

  • 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, rales or other pulmonary infectious symptoms.(27)
  • Assess volume status using IVC US to estimate CVP/RA pressure. If greater than 50% collapse, then the patient will require large volume resuscitation.
  • Administer 20-30ml/kg crystalloid fluid bolus. Large volumes (>6L) of normal saline resuscitation will cause hyperchloremia and a resultant non-gap acidosis. Consider lactated ringers 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)

April 2012 Focus On Table 3Management of Non-invasive resuscitation

  • Perform serial ultrasound assessments of the IVC after each bolus of crystalloid.
  • Continue aggressive fluid resuscitation: do not be gingerly in the administration of fluids. Continue giving 500-1000ml boluses of crystalloid every 20 minutes until the IVC no longer demonstrates significant collapse by ultrasound assessment. There still should be some small respiratory variation of approximately 30% collapse. (Table 3)
  • Recheck MAP: If the patient remains hypotensive (MAP < 65mmHg) after adequate fluid loading, switch to invasive strategy in order to begin vasopressor therapy.
  • Evaluate response to non-invasive therapy with lactate levels every 2 hours. Assess mental status and urine output.
    • If the lactate has decreased by 10%, then continue resuscitation and admit to a non-ICU monitored bed.
    • If the lactate is rising or has decreased <10% and hemoglobin <7g/dL, then transfuse 1 unit of PRBC. Transfusion may be considered in patients with hemoglobin of 7-10g/dL. Also, continue additional 1000mL 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, then switch to invasive sepsis management.

Troubleshooting Complications and Non-response to Management
For patients refractory to non-invasive sepsis therapy, then place central line and admit to the ICU.

Summary 
The non-invasive 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 resources 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 non-invasive approaches. Currently, the data suggest that non-invasive sepsis management is safe and effective in appropriate patient populations.

References

  1. Shorr, A. Economic implications of an evidence-based sepsis protocol: Can we improve outcomes and lower costs? Crit Care Med. 2007; 35(5)1257-1262
  2. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27:1230-1251
  3. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303-1310
  4. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303-1310
  5. American College of Chest Physicians/Society of Critical Care Medicine. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20:864-874
  6. Rivers EP. Point: adherence to early goal-directed therapy: does it really matter? Yes. After a decade, the scientific proof speaks for itself. Chest. 2010 Sep;138(3):476?80; discussion 484-5
  7. Emanuel Rivers, M.D Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock
  8. 7.Levy MM, Dellinger RP, et al.; Surviving Sepsis Campaign. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010 Feb;38(2):367?74.
  9. Dellinger RP, Levy MM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008 Jan; 36(1):296?327. Erratum in: Crit Care Med. 2008 Apr;36(4):1394?6.
  10. Carlbom DJ, Rubenfeld GD. Barriers to implementing protocol-based sepsis resuscitation in the emergency department? results of a national survey. Crit Care Med. 2007 Nov; 35(11):2525?32.
  11. Brennan JM, Ronan A, et al. Handcarried ultrasound measurement of the inferior vena cava for assessment of intravascular volume status in the outpatient hemodialysis clinic. Clin J Am Soc Nephrol. 2006 Jul;1(4):749-53. Epub 2006 May 24.
  12. Carr, Brendan G., Dean, Anthony J., et al.; Intensivist Bedside Ultrasound (INBU) for Volume Assessment in the Intensive Care Unit: A Pilot Study. Journal of Trauma: Injury Infection & Critical Care. 2007 Sept: 63(3): 495-502.
  13. Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava. Am J Cardiol. 1990  Aug;66(4):493-6.
  14. Weekes A., Tassone H., Tayal V.S. et al. 233: The Sonodynamic Study: Comparison of Qualitative Versus Quantitative Assessment and Inter-Rater Reliability In Serial Ultrasonography Evaluations of Inferior Vena Cava Dynamics and Left Ventricular Systolic Function In Fluid Resuscitation of Emergency Department Patients With Symptomatic Hypotension. Annals of Emergency Medicine. 2010 Sept: 56(3), Supplement , Page S77.
  15. Murphy, C. The importance of fluid management in acute lung injury secondary to septic shock. Chest, Jul 2009; 136(1)102-109
  16. Dorrestrijn, Mirrin. Iso-osmolar prehydration shifts the cytokine response towards a more anti-inflammatory balance in human endotoxemia. J Endotox Res. 2007;11(5)287
  17. Ospina-Tascon, G. Effects of fluids on microvascular perfusion in patients with severe sepsis.  Crit Care Med. 2010 Jun; 36(6)949-55
  18. Brennan JM, Blair JE, et al. A comparison by medicine residents of physical examination versus hand-carried ultrasound for estimation of right atrial pressure. Am J Cardiol. 2007 Jun;99(11):1614-6. Epub 2007 Apr 18
  19. Nagdev AD, Merchant RC, et al. Emergency department bedside ultrasonographic measurement of the caval index for noninvasive determination of low central venous pressure. Ann Emerg Med. 2010 Mar;55(3):290-5. Epub 2009 Jun 25.
  20. Yanagawa, Youichi; Sakamoto, Toshihisa; Okada, Yoshiaki. Hypovolemic Shock Evaluated by Sonographic Measurement of the Inferior Vena Cava During Resuscitation in Trauma Patients. Journal of Trauma; Injury Infection & Critical Care. 2007 Dec. 63(6):1245-1248.
  21.  Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med. 2004;32(8):1637-1642.
  22. Gallagher EJ, Rodriguez K, Touger M. Agreement between peripheral venous and arterial lactate levels. Ann Emerg Med. 1997;29:479-483.
  23. Shapiro NI, Fisher C, Donnino M, et al. The fea- sibility and accuracy of point-of-care lactate measure- ment in emergency department patients with sus- pected infection [published online ahead of print September 1, 2009]. J Emerg Med. doi:10.1016/j .jemermed.2009.07.021.
  24. Jansen TC, van Bommel J, et al for the LACTATE study group. Early lactate-guided therapy in Intensive Care Unit patients: A multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010 Sept;182(6): 752-761
  25. Arnold RC, Shapiro NI, Jones AE, et al. Multi- center study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock. 2009;32(1):35-39.
  26. Jones AE, Shapiro NI, et al.; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb;303(8):739-46.
  27. Rivers EP, Coba V, Whitmill M. Early goal-directed therapy in severe sepsis and septic shock: a contemporary review of the literature. Curr Opin Anaesthesiol. 2008;21(2):128-140. (Review)
  28. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med. 2010;38(4):1045- 1053.
  29. Marshall J, Maier R, Jimenez M, et al. Source control in the management of severe sepsis and septic shock: an evidence- based review. Crit Care Med. 2004;32(11 Suppl):S513-S526. (Review)

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