Title: Management of severe sepsis and septic shock – past, present, future?
Author: Harold M. Hastings PhD CTO and Co-Founder
Facility: ImaCor Inc. Garden City NY

Let's consider the following:

• "Early" sepsis mortality pre-EGDT: 45%, EGDT produced significant reductions (Rivers, 2001)
• "Early" sepsis mortality 2014 standard of care or EGDT: 19-21% (ProCESS, 2014; ARISE – ANZICS, 2014)
• "Late" sepsis mortality (1 year and beyond) is a continuing challenge (Linder et al., 2014; Trzeciak, 2014)


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• What have we learned?
• Where do we go? How can we further reduce mortality?

Dr. Ryan Radecki (2014) posted an important and insightful comment in Emergency Medicine Literature of Note, University of Texas-Houston. Dr. Radecki began by observing that "usual care" has incorporated key lessons from EGDT without "unnecessary" "central venous catheters, more arterial catheters, and more frequent use of blood products."
"Both groups received substantial, early crystalloid resuscitation, early appropriate antibiotic coverage, and departed the Emergency Department to a critical care setting quite quickly.

"EGDT receives credit for making us aware the impact early identification and intervention can have on mortality. However, it is time to leave EGDT behind and identify new resuscitation targets and sensible strategies for achieving them." (emphasis added)

The major strategic thrust might appear simple: do it right; do it fast – use the right antibiotics to quickly attack the infectious microorganisms, and support perfusion to prevent multi-organ failure, and death before the infection is eliminated. As Dr. Antonio J. Dajer (2014) states "The critical change, though, is that ... we are urged to treat sepsis quickly on clinical evidence rather than on delayed bacteriologic evidence." (emphasis added)

What might new resuscitation targets include? Let's look to the evidence. For example: a recent editorial by Dr. James A. Russell (2014) begins "As fundamental as the issue is, there is no clear, high-level evidence to determine the most effective mean arterial pressure (MAP) for resuscitation of patients with septic shock." Moreover, "Cardiac dysfunction is often present in sepsis." It has several components, from systolic to diastolic dysfunction. The left ventricle and the right ventricle can be impaired together or in isolation" (Vieillard-Baron and Cecconi 2014). More precisely, the following "Main mechanisms of cardiac dysfunction:

• Depressed intrinsic myocardial performance (100%)
• RV systolic dysfunction (30-50%)
• LV diastolic dysfunction (50%), may overlap
• LV systolic dysfunction (up to 60% at day 3), may overlap (Vieillard-Baron and Cecconi 2014).

How does cardiac dysfunction affect the optimal patient-focused resuscitation strategy? How do we optimize the balance among fluids, inotropes, and pressors required to maintain adequate perfusion? We may not know the answers, but perhaps we would do better with better monitoring tools. Here is what Drs. Vieillard-Baron and Cecconi (2014) say: "Echocardiography is available in most units nowadays; it can provide a complete assessment of cardiac function in a noninvasive fashion. Echocardiographic evaluation has to be taken in the context of a clinical evaluation. Treatment of 'echocardiographic abnormalities' is not the final goal; the final goal is to improve tissue perfusion."

In fact, Drs. Vieillard-Baron and colleagues (2006) use trans-esophageal echocardiography to manage sepsis patients) and a recent editorial by Drs. Greenhalgh and Patrick (2012) stated that, "The development of a disposable probe designed for 48 hours of continuous use will, we think, be very helpful for the development of TOE [TEE] as a 'routine' monitor on intensive care units." Three case studies illustrate the utility of hTEE in sepsis resuscitation: a recent study by Drs. Lawless and Love (Memorial Hermann) in the present Newsletter , a study by Dr. Mykytenko et al. (2012) from Vanderbilt, and finally, an unpublished study by Dr. Reiff et al. (UAB)  It would be interesting to see the development and clinical study of an algorithm for echo-guided sepsis resuscitation.

Finally, a cautionary note and a hope. Dr. Stephen Trzeciak (2014): commented "Although it is indeed good news that advances in the field have decreased short-term sepsis-related mortality ... it is important to recognize that only half the patients in the ProCESS population were able to be discharged home from the hospital, and the 1-year mortality appears to be nearly double the short-term mortality. Other recent studies have found similar discordance." For example, Linder et al. (2014) observed that "Patients with severe sepsis without comorbidities had higher mortality from 1 to 10 years than general British Columbia population (p < 0.01). Younger patients with severe sepsis (< 60 yr) had the worst 1- to 5-year and 5- to 10-year mortality (hazard ratio [95% CI], 17.8 [13.4-24.8] and 6.0 [4-9]) compared with the general population. Patients with severe sepsis had significantly poorer 1- to 10-year mortality rates (30.5%) compared with patients with nonseptic critical illness (22.1%) and patients who have undergone cardiovascular surgery (15.9%)."

Let us all work hard and hope that continued efforts at improving sepsis management though advanced hemodynamic management will help prevent hypoperfusion early enough to minimize effects which cause not only early mortality, but long-lasting sequelae.

References
ARISE Investigators; ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, et al. 2014. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 371:1496-506. doi: 10.1056/NEJMoa1404380. Epub 2014 Oct 1.

Dajer AJ. 2014. Correspondence. Protocol-Based Care for Early Septic Shock. N Engl J Med 371:384-387. DOI: 10.1056/NEJMc1406745

Greenhalgh DL, Patrick MR. 2012. Perioperative transoesophageal echocardiography: past, present & future. Anaesthesia. 67:343-6. doi: 10.1111/j.1365-2044.2012.07103.x.

Linder A, Guh D, Boyd JH, Walley KR, Anis AH, Russell JA. 2014. Long-term (10-year) mortality of younger previously healthy patients with severe sepsis/septic shock is worse than that of patients with nonseptic critical illness and of the general population. Crit Care Med. 42:2211-8. doi: 10.1097/CCM.0000000000000503.

Mykytenko J, Levin R, Wagner CE. 2012. Right ventricular dysfunction in sepsis: Now you see it, now you don't. ICU Director 3:135-138. doi: 10.1177/1944451612442686 ICU Director. Epub 2012 April 13.

ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, et aal. 2014. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 370:1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18.

Radecki R. 2014. ARISE, and cast off the shackles of EGDT. Emergency Medicine Literature of Note, University of Texas-Houston, http://www.emlitofnote.com/2014/10/arise-and-cast-off-shackles-of-egdt.html, accessed November 11, 2014

Rivers E, Nguyen B, Havstad S, et al. 2001. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 345:1368-137.

Russell JA. 2014. Is there a good MAP for septic shock? N Engl J Med. 24;370:1649-51. doi: 10.1056/NEJMe1402066. Epub 2014 Mar 18.

Trzeciak S. 2014. Correspondence. Protocol-Based Care for Early Septic Shock. N Engl J Med 371:384-387. DOI: 10.1056/NEJMc1406745

Vieillard-Baron A, Cecconi M. 2014. Understanding cardiac failure in sepsis. Intensive Care Med. 40:1560-3. doi: 10.1007/s00134-014-3367-8. Epub 2014 Jun 26.

Vieillard-Baron A, Charron C, Chergui K, Peyrouset O, Jardin F. 2006. Bedside echocardiographic evaluation of hemodynamics in sepsis: is a qualitative evaluation sufficient? Intensive Care Med. 2006 Oct;32(10):1547-52. Epub 2006 Jul 20.