ARTICLE REVIEW

The CLASSIC Trial

Background
Fluid resuscitation is the cornerstone in the management in a patient with septic shock. Whilst the administration of fluid optimises intravascular volume and perfusion pressure of vital organs, excessive fluid administration can be detrimental. The point at which further administration of fluid may become detrimental is unclear. Cumulative positive fluid balance over the first few days of sepsis is independently associated with a poor prognosis (1), and conservative fluid administration may be associated with less harm (2).

Objective
Hjortrup et al. designed the Conservative vs. Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial with the objective to assess the feasibility and effects of a protocol restricting resuscitation fluid after initial resuscitation on fluid volumes and balances and clinically relevant explorative outcomes in intensive care unit (ICU) patients with septic shock (3). Patients were randomised to restrictive fluid resuscitation or standard care across 9 Danish ICUs.

The primary outcome investigated was the amount of fluid administered. Secondary ‘exploratory’ outcomes included death within 90 days after randomisation, time to death with censoring 90 days after the last patient had been randomised, days alive without the use of mechanical ventilation or renal replacement therapy in the 90-day period, the number of patients with ischaemic events during the ICU stay, maximum change in plasma creatinine during the ICU stay, and number of patients with worsening of acute kidney injury (AKI) according to the KDIGO criteria.

Population
Patients with ‘circulatory impairment (systolic blood pressure <90 mmHg, heart rate >140 beats/min, lactate >4 mmol/L, or use of vasopressor) within 12hrs of ICU admission were considered for the study.

Intervention and Comparison
In the fluid restriction group, isotonic crystalloid fluid boluses of 250–500 mL were given in the case of severe hypoperfusion defined as either
(1) Lactate of at least 4 mmol/L
(2) MAP below 50 mmHg in spite of the infusion of norepinephrine
(3) Mottling beyond the edge of the kneecap (mottling score greater than 2)
(4) Oliguria, but only in the first 2 h after randomisation

MAP target was 65mmHg (or as per discretion of the clinician) and crystalloid fluid resuscitation was administered. In the standard care group fluid boluses could be given as long as haemodynamic variables improved including dynamic (e.g. stroke volume variation) or static (e.g. blood pressure, heart rate) variable(s).

Outcome
76 patients were allocated to the fluid restriction group and 77 to the standard care group.
Fluid volumes given in the ICU at day 5 after randomisation and during the entire ICU stay were lower in the fluid restriction group vs. the standard care group [mean difference -1.2 L (95 % CI − 2.0 to − 0.4); P  < 0.001 and −1.4 L (95 % CI −2.4 to −0.4); P < 0.001 respectively.
The only secondary outcome that was different between treatment groups was the number of patients with worsening of acute kidney injury in the 90-day period was lower in the fluid restriction group than in the standard care group.

Discussion
A restrictive approach to fluid therapy after initial resuscitation in sepsis did not have any serious adverse effect, and may have had a beneficial effect on renal function. The study was not powered to detect any differences in organ failure. The authors mention that there were “relatively high number of protocol violations, including the administration of resuscitation fluid to patients who did not fulfil the criteria in the fluid restriction group”.

In summary, a protocol aimed at restricting resuscitation fluid was feasible and safe in ICU patients with septic shock who had undergone initial resuscitation. Additional high-quality trials are needed to assess the effects on patient-centred outcomes of protocols aimed at restricting volumes of resuscitation fluid in these patients.
Article review submitted by Nish Arulkumaran on behalf of the ESICM Journal Review Club (EJRC).

References

(1). Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Critical Care Medicine 2011;39(2):259–65.

(2). Comparison of Two Fluid-Management Strategies in Acute Lung Injury. N Engl J Med 2006; 354:2564-2575

(3). Peter B. Hjortrup, Nicolai Haase, Helle Bundgaard, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med 2016; 42:11; 1695 – 1705