By Kathryn Radigan, MD

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Dr. Radigan reports no financial relationships relevant to this field of study.

SYNOPSIS: Earlier crystalloid initiation in patients with sepsis and septic shock was associated with decreased mortality.

SOURCE: Leisman DE, Goldman C, Doerfler ME, et al. Patterns and outcomes associated with timeliness of initial crystalloid resuscitation in a prospective sepsis and septic shock cohort. Crit Care Med 2017;45:1596-1606.

Although the most recent Surviving Sepsis Campaign (SSC) guidelines authorized completion of 30 mL/kg of IV crystalloid within three hours of the recognition of sepsis and septic shock, there remains controversy regarding the benefits and harms of early, aggressive crystalloids, especially in specific patient populations. To better understand the patterns of early crystalloid resuscitation and determine the association between crystalloid resuscitation and hospital mortality, mechanical ventilation, ICU use, and length of stay, Leisman et al conducted a consecutive-sample, observational cohort trial across nine hospitals in a single U.S. health system from Oct. 1, 2014 through March 31, 2016. All adult sepsis and septic shock patients with suspected or confirmed infection, two or more systemic inflammatory response criteria, and one or more organ dysfunction criteria were captured in a prospective quality improvement database. The primary exposure was crystalloid initiation within ≤ 30 minutes, 31-120 minutes, or > 120 minutes from the time of sepsis identification.

Out of 11,182 patients identified, crystalloid initiation was more timely for patients in the ED (ß, -141 minutes; 95% confidence interval [CI], -159 to -125; P < 0.001) and patients with baseline hypotension (ß, -39 minutes; 95% CI, -48 to -32; P < 0.001), fever, urinary, or skin/soft tissue sources of infection. Resuscitation was slower for patients with heart failure (ß, 20 minutes; 95% CI, 14-25; P < 0.001) and renal failure (ß, 16 minutes; 95% CI, 10-22; P < 0.001). A total of 5,336 patients had crystalloid initiated in ≤ 30 minutes, 2,388 patients in 31-120 minutes, and 3,458 patents in > 120 minutes. Mortality was time-dependent, with the lowest mortality in patients receiving fluids within 30 minutes (949) vs. 31-120 minutes (446) and > 120 minutes (846). Compared to patients who received fluid administration > 120 minutes after the time of identification, the adjusted odds ratio for mortality was 0.76 (95% CI, 0.64-0.90; P = 0.002) for ≤ 30 minutes and 0.76 (95% CI, 0.62-0.92; P = 0.004) for 31-120 minutes. When assessed as a continuous variable, the time to fluid resuscitation was associated with 1.09 times greater odds of mortality per hour increase (95% CI, 1.03-1.16; P = 0.002). Earlier fluid administration also was associated with lower rates of mechanical ventilation, ICU use, and length of stay. Furthermore, there was no significant increased risk of mortality between time of fluid administration and baseline heart failure, renal failure, hypotension, acute kidney injury, altered gas exchange, or ED vs. inpatient presentation.

In summary, crystalloid fluid resuscitation was initiated significantly later in patients with comorbid heart failure and renal failure, in those without fever or hypotension, and in patients developing sepsis while hospitalized. Even with consideration of comorbidities and severity of illness, more timely crystalloid initiation was associated with decreased mortality.


Severe sepsis accounts for almost 10% of all deaths.1 The most recent SSC guidelines authorized completion of 30 mL/kg of IV crystalloid within three hours of the recognition of sepsis and septic shock. Despite this recommendation, little is known regarding the patterns of fluid resuscitation and associated outcomes. Leisman et al conducted a consecutive-sample observational study of 11,182 sepsis and septic shock patients. Fluid resuscitation was faster for patients who presented to the ED, patients who were hypotensive or febrile, patients with a higher lactate, and patients with urine or soft-tissue infections. Fluids were delayed in patients with heart failure or renal failure, altered gas exchange, or those treated at a tertiary medical center. Compared to patients who waited for fluids for more than 120 minutes, crystalloid administration in less than 30 minutes and 31-120 minutes was associated with significantly lower hospital mortality, mechanical ventilation, ICU admission, length of stay, and ICU days.

Interestingly, this study highlights that a delay in minutes in the administration of fluids made a significant difference for patients with sepsis and septic shock. Most importantly, special attention is needed for patients already admitted to the hospital. Although not addressed in this study, the identification of sepsis is paramount and often missed by both doctors and nurses. For example, in a single-center, prospective study, investigators found that bedside nurses and ordering providers agreed on the presence of infection only 17% of the time (kappa = 0.12).2

In addition to timely identification and fluid resuscitation of inpatients, clinicians also need to be more aggressive with patients who experience renal failure, heart failure, or relative hypoxia. Patients with heart failure and renal failure were associated with fluid initiation 20 and 16 minutes later, and 14 mL/kg and 15 mL/kg lower volume of crystalloid resuscitation, respectively.

Although 20% of patients were identified as exhibiting altered gas exchange, which was defined as a new increase in oxygen requirement to maintain oxygen saturation > 90% or a PaO2/FiO2 ratio < 300, it would have been more informative to see this category further divided according to severity of altered gas exchange. It is possible most of these patients carried low oxygen requirements and were at low risk for decompensation, especially in the setting of appropriate fluid administration.

Under-resuscitation is an issue and may be mitigated not only by more aggressive, closely monitored physician interventions but also improved by bundle compliance. Other institutions have shown that bundle compliance can be improved with the initiation of a multidisciplinary quality improvement team that can be key in identifying severe sepsis and septic shock, standardizing quantitative resuscitation and triage decisions, and monitoring compliance with feedback to the providers. Simulation center training targeting sepsis activation and standardized treatment protocols also can be helpful in specifically targeting patient populations that typically are under-rescuscitated.3

Although early identification of the patient and appropriate fluid administration is vital, it is also important that the treatment plan is tailored to the specific patient at a specific time point. It is now stressed that patients are to be evaluated with multiple methods of fluid responsiveness that can include physical exam, passive leg raise, central venous pressure measurement, and/or bedside ultrasound. Based on a combination of these, a clinician should make an assessment, develop an appropriate intervention, and then follow up on the intervention to ensure the patient responded as expected. Obviously, as portrayed in this study, patients who appeared to be sicker (e.g., hypotensive, elevated lactic acid, febrile) often received fluids faster. Similarly, it is also important to find those who may be under-resuscitated initially. Again, it was noted that patients receiving < 20 mL/kg demonstrated a higher risk of mechanical ventilation than patients who received > 35 mL/kg within the first six hours of resuscitation. Although an explanation for this finding is not detailed in the manuscript, this may be because patients who did not receive adequate fluids early in resuscitation may receive more fluids later in resuscitation, which may lead to more mechanical ventilation and poorer outcomes. The administration of late fluids in these patients may have been diminished if the patients were reassessed for signs of fluid responsiveness prior to an attempt to “catch up” on fluid resuscitation.

More timely crystalloid initiation was associated with decreased mortality. Early resuscitation efforts must focus on groups that often are missed, including patients with comorbid heart failure and renal failure, those without fever or hypotension, and in patients who develop sepsis while hospitalized. Future studies are necessary to further optimize patient outcomes.


  1. 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.
  2. Bhattacharjee P, Churpek MM, Snyder A, et al. Detecting sepsis: Are two opinions better than one? J Hosp Med 2017;12:256-258.
  3. Grek A, Booth S, Festic E, et al. Sepsis and shock response team: Impact of a multidisciplinary approach to implementing surviving sepsis campaign guidelines and surviving the process. Am J Med Qual 2017;32:500-507.