The mean amount of fluid administered to patients with severe sepsis and septic shock in the USA during the first ICU day is less than that recommended by the Surviving Sepsis Campaign guidelines. The administration of more than 5 L of fluid during the first ICU day is associated with a significantly increased risk of death and significantly higher hospital costs.

BACKGROUND: Fluid and vasopressor management in septic shock remains controversial. In this randomized controlled trial, we evaluated the efficacy of dynamic measures (stroke volume change during passive leg raise) to guide resuscitation and improve patient outcome. RESEARCH QUESTION: Will resuscitation that is guided by dynamic assessments of fluid responsiveness in patients with septic shock improve patient outcomes? STUDY DESIGN AND METHODS: We conducted a prospective, multicenter, randomized clinical trial at 13 hospitals in the United States and United Kingdom. Patients presented to EDs with sepsis that was associated hypotension and anticipated ICU admission. Intervention arm patients were assessed for fluid responsiveness before clinically driven fluid bolus or increase in vasopressors occurred. The protocol included reassessment and therapy as indicated by the passive leg raise result. The control arm received usual care. The primary clinical outcome was positive fluid balance at 72 hours or ICU discharge, whichever occurred first. RESULTS: In modified intent-to-treat analysis that included 83 intervention and 41 usual care eligible patients, fluid balance at 72 hours or ICU discharge was significantly lower (À1.37 L favoring the intervention arm; 0.65 AE 2.85 L intervention arm vs 2.02 AE 3.44 L usual care arm; P ¼ .021. Fewer patients required renal replacement therapy (5.1% vs 17.5%; P ¼ .04) or mechanical ventilation (17.7% vs 34.1%; P ¼ .04) in the intervention arm compared with usual care. In the all-randomized intent-to-treat population (102 intervention, 48 usual care), there were no significant differences in safety signals. INTERPRETATION: Physiologically informed fluid and vasopressor resuscitation with the use of the passive leg raise-induced stroke volume change to guide management of septic shock is safe and demonstrated lower net fluid balance and reductions in the risk of renal and respiratory failure. Dynamic assessments to guide fluid administration may improve outcomes for patients with septic shock compared with usual care.

SUMMARY1. Right medullary and various cardiovascular responses to stimulation of the peripheral end of the splanchnic nerve have been investigated in the presence and absence of exogenous adrenocorticotrophin, ACTH1 24, (5 ng min-kg-'). The adrenal-clamp technique was employed in conscious calves, after the pituitary stalk had been cauterized and they had recovered from anaesthesia.2. The intravenous infusion ofACTH1 24increased the plasma ACTH concentration by about 1100 pg ml-' and right adrenal venous output of cortisol by about 400 ng min' kg body weight-'. Stimulation of the splanchnic nerve at 4 Hz for 10 min had no effect on either arterial plasma ACTH concentration or the adrenal output of cortisol.3. Closely similar amounts of both adrenaline and noradrenaline were released in response to nerve stimulation in the presence and absence of exogenous ACTH. In contrast, the fall in adrenal vascular resistance of about 40 %, which normally occurred in response to splanchnic nerve stimulation, was completely abolished by ACTH.4. The adrenal produced relatively large quantities of met-enkephalin-containing peptides. During splanchnic nerve stimulation the output of these increased 20-100-fold, at which time free met5-enkephalin accounted for only 10-20 o of total. During ACTH infusion the output of free met5-enkephalin was reduced at rest and during nerve stimulation, but that of total met-enkephalin-containing peptides was unaffected. These results indicate that ACTH or an adrenal steroid may alter the processing of proenkephalin in the adrenal medulla acutely but not total opiate secretion. Alternatively, the presence ofACTH could act by influencing the population of chromaffin cells activated by splanchnic nerve stimulation.

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