How much fluid resuscitation is optimal in septic shock?

Abstract Smith and Perner report an observational cohort study of 164 patients with septic shock. For patients still alive on day 3, higher compared with lower fluid volume resuscitation was associated with lower 90-day mortality. This association of a relationship between fluid intake and decreased mortality aligns with the randomized controlled trial of early goal-directed therapy and later observational studies. I suggest careful individualization of fluid resuscitation to achieve adequate mean arterial pressure (about 60 to 70 mmHg) and normalization of arterial lactate levels in septic shock. Trial registration ISRCTN94845869

Despite decades of use, how much fl uid is optimal during resuscitation of patients who have septic shock remains uncertain. Excess ive fl uid increases intravascular pressure, and with increased permeability of sepsis this increases fl uid accu mulation and organ dysfunction. Conversely, inadequate fl uid resuscitation causes tissue hypoxia secon dary to inadequate global oxygen delivery. Furthermore, excess ive doses of vasopressors (consequent to inadequate fl uid resuscitation) constrict the microvascula ture, leading to tissue hypoxia.
Smith and Perner report an observational cohort study of 164 patients with septic shock [1]. Th ey recorded fl uid intake and correlated fl uid intake to clinical outcomes. For patients still alive on day 3, higher compared with lower fl uid volume resuscitation (10.9 l vs. 4.3 l) was associated with signifi cantly lower 90-day mortality (40% vs. 62%, P = 0.03). Th is association of a relationship between fl uid intake and decreased mortality aligns with the randomized controlled trial (RCT) of early goal-directed therapy (EGDT) by Rivers and colleagues [2]. In particular, Rivers and colleagues found that fl uid and vasopressor resuscitation titrated to increase and maintain central venous oxygen saturation above 70% in patients who had septic shock was associated with increased fl uid intake in the emergency department (fi rst 6 hours) and with signifi cantly decreased mortality [2].
Accordingly, sepsis guidelines [3] and Russell [4] have recommended EGDT fl uid management for the fi rst 6 hours of septic shock. Rivers and colleagues' RCT is being repeated in three large multicenter RCTs in the UK, the USA and Australia, and the results of those RCTs are awaited with considerable interest around the globe. Many case-control studies (often before and after implementation of sepsis guidelines, one component of which is use of Rivers and colleagues' protocol) suggest that EGDT bundles improve outcomes [5][6][7][8][9][10][11][12][13][14][15][16], including a meta-analysis [9] (Table 1).
Based on observational studies that found a positive association of early clearance of arterial lactate and better clinical outcomes [17], Jones and colleagues performed a RCT to compare titration of emergency resuscitation of patients who have septic shock with central venous oxygen saturation and with serial decrease of arterial lactate (which is less invasive). Th ey found that arterial lactate was not inferior to central venous oxygen saturation-guided resuscitation [18]. As a result, it is reasonable to target normalization of arterial lactate to guide fl uid intake and vasopressor use in patients with septic shock.
Th e strengths of Smith and Perner's study were that it was an observational cohort from six hospitals with no exclusions and that they carefully recorded volumes and types of fl uids administered over the fi rst 3 days of septic shock [1]. Th e study thus scores high on generalizability.
Several aspects of the study require consideration, however. First, their study was small, and so the clinical community would like to see other larger cohorts used to address this problem. Second, nutritional fl uids were not included in the calculations of fl uid intake and fl uid balance. Th e total of all fl uids given should be used in assessing eff ects of fl uid administration. Indeed, Smith and Perner found that their higher volume group received Abstract Smith and Perner report an observational cohort study of 164 patients with septic shock. For patients still alive on day 3, higher compared with lower fl uid volume resuscitation was associated with lower 90-day mortality. This association of a relationship between fl uid intake and decreased mortality aligns with the randomized controlled trial of early goal-directed therapy and later observational studies. I suggest careful individualization of fl uid resuscitation to achieve adequate mean arterial pressure (about 60 to 70 mmHg) and normalization of arterial lactate levels in septic shock. signifi cantly less volume of nutrition compared with the lower volume group (2.9 l vs. 3.4 l) [1]; the addition of nutritional fl uids could alter the results and their interpretation.
One should not confuse early resuscitation fl uid intake with studies of overall later fl uid balance, which have sometimes found association of more positive fl uid balance with increased mortality [19,20]. However, the cause-eff ect relationship is not resolved in such observational studies; more positive fl uid balance could alter outcomes or could simply be a marker of increased endothelial injury and third-spacing of fl uids in sicker patients (who have increased mortality because of increased endothelial injury and not necessarily due to more positive fl uid balance).
In summary, Smith and Perner report a small observational cohort [1] that must be placed in context of prior studies. Rivers and colleagues' RCT of EGDT and other observational studies show that more positive fl uid intake is associated with decreased mortality. Th e ongoing RCTs of EGDT in Australia, the USA and the UK will provide clearer evidence about how much fl uid resuscitation is optimal in septic shock. Until then, I suggest careful individuali zation of fl uid resuscitation to achieve adequate mean arterial pressure (about 60 to 70 mmHg) and normali zation of arterial lactate levels in septic shock.

Competing interests
JAR reports holding stock in and is on the board of Sirius Genomics Incorporated, which has submitted patents owned by the University of British Columbia and licensed to Sirius Genomics that are related to the genetics of sepsis and its treatment. The University of British Columbia has also submitted a patent related to the use of vasopressin in septic shock. JAR is an inventor on these patents. JAR also reports receiving consulting fees from Ferring Pharmaceuticals (which manufactures vasopressin and is developing selepressin), from Astra Zeneca (which is developing anti-TNFα), from BioCritica (which used to sell activated protein C in the USA), from MedImmune, from Grifols (which sells albumin) and from Sirius Genomics Inc. JAR also reports having received grant support from Sirius Genomics, Ferring Pharmaceuticals, Astra Zeneca and Eli Lilly that is provided to and administered by University of British Columbia. JAR has received speaking honoraria from Pfi zer and Eli Lilly.