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The

new england journal

of

medicine

editorials

The ProCESS Trial — A New Era of Sepsis Management

Craig M. Lilly, M.D.

The importance of early detection and treatment

creased mortality to delays in the administration

for reducing the mortality associated with sepsis

of appropriate antibiotics

6

suggested that early

has been a tenet of medical training since the

administration of antibiotics increased survival

middle ages, when it was noted that “. . . the

in all groups of the trial. Indeed, in the ProCESS

physicians say it happens in hectic fever, that in

trial, the early or facilitated recognition of sep-

the beginning of the malady it is easy to cure but

tic shock, administration of intravenous antibi-

difficult to detect, but in the course of time, not

otics, and other best practices were associated

having been either detected or treated in the be-

with rates of survival that were higher than pro-

ginning, it becomes easy to detect but difficult

jected and higher than predicted on the basis of

to cure.”

1,2

The critical role of the clinician in the scores on the Acute Physiology and Chronic

early recognition of sepsis continues to this day Health Evaluation (APACHE) II,

7

and a thought-

to be fundamental to our efforts to improve the ful design allowed the sample size of the trial to

rate of survival.

3

Identification of the combina-be recalculated to preserve the power of the

tion of signs and symptoms that make up the sys-study to test the primary outcome. One impor-

temic inflammatory response syndrome (SIRS)

4

tant contribution of the ProCESS trial is the evi-

in the context of an infection allows the astute dence it provides regarding the ongoing role of

clinician to recognize the recognition of and antibiotic treatment for

Early recognition of sepsis was incorporated sepsis in improving survival.

into the trial design, prompts, and protocols of The ProCESS trial also provides transforma-

the Protocolized Care for Early Septic Shock tive insights about the treatments for septic

(ProCESS) trial, the results of which are now re-shock that bring generalizable benefits when

ported in the Journal.

5

For all the groups in the septic shock is recognized in the first hours af-

trial, the goal was early recognition of sepsis, as ter arrival in the emergency department. The use

specified in the Surviving Sepsis Campaign guide-of central hemodynamic and oxygen-saturation

lines,

3

and the design called for early treatment monitoring in the protocol-based early goal-

with antimicrobial agents

6

and conservative directed therapy (EGDT) group did not result in

transfusion thresholds; in addition, the patients

better outcomes than those that were achieved

received low tidal-volume ventilation and had

with clinical assessment of the adequacy of cir-

culation. The finding that adjusting therapies to

moderate glycemic control.

Indeed, septic shock was recognized early in

surrogate physiological targets measured with

a majority of the patients; 76% of the patients

invasive catheters was not required to reduce

received antimicrobial agents by the time they

mortality is consistent with the results of a study

underwent randomization, which occurred a

that showed that serial measurement of blood

mean of approximately 3 hours after patients’

lactate levels was noninferior to catheter-derived

arrival in the emergency department. The rate of

measurements

8

and of analyses that have not

intravenous antimicrobial administration 6 hours found benefits of the use of pulmonary-artery

after randomization was approximately 97%, a catheters.

9

State legislation and clinical guide-

finding that suggests that notification that sep-lines, including those endorsed by the National

tic shock is present encourages the administra-Quality Forum, should be updated to remove

tion of antibiotics. A study that attributed in-the requirement for central hemodynamic moni-

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n engl j med 370;18 may 1, 2014

The New England Journal of Medicine

Downloaded from at Yale University on May 12, 2014. For personal use only. No other uses without permission.

Copyright © 2014 Massachusetts Medical Society. All rights reserved.

editorials

toring and to focus on less costly, lower-risk,

and equally effective alternatives.

The ProCESS trial identifies early recognition

The association of the implementation of the

of sepsis, early administration of antibiotics,

multifaceted EGDT intervention with significantly

early adequate volume resuscitation, and clinical

lower mortality in an earlier study

10

launched the

assessment of the adequacy of circulation as the

EGDT era of sepsis management. This milestone

elements we should focus on to save lives. The

study encouraged coordinated efforts

3

to improve

publication of the ProCESS trial launches the era

the outcomes in patients with this common

11

of early recognition and treatment in the man-

and life-threatening condition. These efforts

agement of sepsis.

Disclosure forms provided by the author are available with the

translated into the earlier identification of septic

full text of this article at .

shock and into an increased number of patients

receiving earlier administration of a larger vol-

From the Division of Pulmonary, Allergy and Critical Care Medi-

cine, University of Massachusetts Medical School, UMass Me-

ume of resuscitation fluid. The ProCESS trial

morial Medical Center, Worcester.

allows refinement of the EGDT approach to fluid

administration by defining lower boundaries

This article was published on March 18, 2014, at .

that are associated with equivalent outcomes

1.

Machiavelli N. Il principe. S.l. [nach Ebert vielleicht Genf];

and setting limits that are needed to avoid the

1550.

twin problems of renal failure from too little

2.

Idem. The prince. Ann Arbor, MI: Borders Classics, 2006.

3.

Vassalos A, Rooney K. Surviving sepsis guidelines 2012. Crit

fluid and pulmonary dysfunction from fluid over-

Care Med 2013;41:e485-6.

load. Another interesting and seemingly paradox-

4.

Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/

ical finding is that patients in whom sepsis was

ACCP/ATS/SIS International Sepsis Definitions Conference. Crit

Care Med 2003;31:1250-6.

managed without a protocol had an outcome as

5.

The ProCESS Investigators. A randomized trial of protocol-

good as those in patients in whom the sepsis

based care for early septic shock. N Engl J Med 2014;370:1683-

was managed with the use of a protocol. If one

93.

6.

Kumar A, Roberts D, Wood KE, et al. Duration of hypoten-

assumes that the treatments for septic shock, as

sion before initiation of effective antimicrobial therapy is the

well as the timing of the treatments, that would

critical determinant of survival in human septic shock. Crit Care

be administered in all emergency departments,

Med 2006;34:1589-96.

7.

Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE

regardless of size or available resources, would

II: a severity of disease classification system. Crit Care Med

be equivalent to those used in the no-protocol

1985;13:818-29.

(usual-care) group of the ProCESS trial (which

8.

Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA,

Kline JA. Lactate clearance vs central venous oxygen saturation

included strategies for early recognition of sep-

as goals of early sepsis therapy: a randomized clinical trial.

sis), one could come to the dubious conclusion

JAMA 2010;303:739-46.

that protocols and decision prompts do not have

9.

Rajaram SS, Desai NK, Kalra A, et al. Pulmonary artery cath-

eters for adult patients in intensive care. Cochrane Database Syst

a role in the treatment of septic shock. I prefer

Rev 2013;2:CD003408.

to think differently. I believe that the prompt-

10.

Rivers E, Nguyen B, Havstad S, et al. Early goal-directed

ing, serum lactate screening and assessment of

therapy in the treatment of severe sepsis and septic shock. N Engl

J Med 2001;345:1368-77.

SIRS criteria, and reporting of activities that

11.

Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Car-

were parts of the study by Rivers et al. and the

cillo J, Pinsky MR. Epidemiology of severe sepsis in the United

ProCESS trial can be applied in clinical practice

States: analysis of incidence, outcome, and associated costs of

care. Crit Care Med 2001;29:1303-10.

to ensure early diagnosis and treatment for all

patients with septic shock.

DOI: 10.1056/NEJMe1402564

Copyright © 2014 Massachusetts Medical Society.

Left Bundle-Branch Block Myopathy in Heart Failure

Jeffrey J. Goldberger, M.D., M.B.A.

Cardiac-resynchronization therapy (CRT), also factorial, with effects on contractile function,

known as biventricular pacing, has emerged as a β-adrenergic responsiveness, and other cellular

pivotal therapy in selected patients with heart functions.

1

The dramatic clinical improvement

failure with reduced ejection fraction. The mech-that has been observed in some patients with

anism of benefit of CRT is complex and not yet New York Heart Association (NYHA) class III or

completely understood, but it is probably multi-IV heart failure

2

has prompted the evaluation of

n engl j med 370;18 may 1, 2014

The New England Journal of Medicine

Downloaded from at Yale University on May 12, 2014. For personal use only. No other uses without permission.

Copyright © 2014 Massachusetts Medical Society. All rights reserved.

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