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“He walked away across the room, his cowboy boots echoing like pistol shots."
Implicit in resuscitation is speed. Throughout training we are zealously instructed that ‘time is tissue’ for all manners of compromised perfusion. We envision spendthrift mitochondria chewing through oxygen without regard to withering supply; as such, when confronted with signs and/or symptoms of dwindling blood flow, our therapeutic reflex is brisk.
Yet in 2011 a landmark randomized, controlled trial measured the effect that an intravenous bolus had on mortality in children with severe febrile illness in 3 African countries. Those randomized to either saline or albumin died in greater proportion as compared to those who were randomized to no volume. A subsequent exploratory analysis of this study implied that the increased risk of death was driven by delayed hemodynamic compromise; this retrospective finding was confirmed in an ovine study. Septic sheep randomized to early, rapid volume resuscitation had greater vasopressor requirements 12 hours after initial fluid bolus. It is suggested that rapid, fluid resuscitation generates an abrupt rise in atrial natriuretic peptide, shears the glycocalyx which then impairs vascular reactivity. Arguably, this might be mitigated by slower volume administration.
And so, Zampieri and colleagues recently released the Balanced Solutions in Intensive Care Study [BaSICS], comparing two types of crystalloid resuscitation fluid, discussed previously, as well as two infusions rates of these fluids, considered below.
What they did
Across 75 intensive care units in Brazil, adult patients were enrolled who:
1.] needed at least 1 fluid expansion,
2.] were anticipated to stay in the ICU beyond 24 hours,
3.] had at least one of the following risk factors: a.] older than 65 years; b.] hypotension; c.] sepsis – defined as suspected or confirmed infection plus acute organ dysfunction; d.] required invasive or non-invasive mechanical ventilation [including high-flow nasal cannula] for at least 12 hours; e.] early signs of kidney dysfunction [either oliguria or serum creatinine >1.2 or > 1.4 mg/d for women and men, respectively; or f.] had cirrhosis or acute hepatic failure.
These patients were randomized in a two-by-two factorial design to either a balanced IV solution or 0.9% saline as well as to two different infusion rates of said fluids. The rates of crystalloid delivery were either 999 mL/hour or 333 mL/hour. These rates were chosen because they represented the upper limit of delivery by an infusion pump and were less than the 25th percentile in the FENICE cohort, respectively.
The primary outcome was 90-day survival. Secondary outcomes included: the need for kidney replacement therapy up to 90 days; acute kidney injury defined as the progression KDIGO stage 0 or 1 at enrollment to at least 2 at days 3 and 7; SOFA score; and the number of days not requiring mechanical ventilation within 28 days. The tertiary outcomes were ICU and hospital mortality and ICU and hospital length of stay.
What they found
11,052 patients were randomized and 10,520 patients were available for final analysis; 5,276 patients were randomized to 333 mL/hr and 5,244 to 999 mL/hr. The mean fluid delivered as a bolus between the two groups in the first 7 days were comparable, with slightly over 1 L given to both groups on day 1.
At 90 days there was no statistically significant difference in mortality between the two groups [i.e., 26.6% in the 333 mL/hr group and 27.0% in the 999 mL/hr group].
In total 19 secondary outcomes were evaluated. At day 3, the slower infusion group had lower SOFA scores, as well as lower frequency of elevated hemodynamic and respiratory SOFA scores [i.e., more than 2]. Yet, the lower infusion group also had a higher frequency of coagulation score more than 2.
There is an important, subtle distinction that might be lost in the current discourse surrounding BaSICS with respect to infusion rate – the difference between a fluid bolus and a fluid challenge. As discussed previously, a fluid challenge typically denotes a small-volume, rapid, diagnostic volume infusion whereas a fluid bolus is larger-volume, slower and therapeutic in nature.
What is the point of a diagnostic fluid challenge and how fast are they usually delivered? This terminology is extracted from studies that acutely alter cardiac preload in an attempt to measure the slope of the Frank-Starling, or Sarnoff, cardiac function curve. Notably, these volume challenges are typically quite rapid. For example, in one of the first studies to evaluate the passive leg raise maneuver [i.e., an internal volume challenge of 250-300 mL], the hemodynamic response occurred within 30-60 seconds in all subjects. Similarly, a 50 mL crystalloid infusion over 10 seconds prompts an immediate cardiac response; 50 mL over 10 seconds is an infusion rate of 300 mL/min! More typically, ‘mini fluid challenges’ are on the order of 50-100 mL/min – an infusion rate usually needing an IV lumen of 20 gauge or larger and a pressure bag – and less than 500 mL in volume.
Importantly, the aforementioned diagnostic, challenges are distinct from therapeutic, boluses, considered in BaSICS. In other words, the fluid boluses delivered in BaSICS were larger volume and a corrective response for signs or symptoms of hypoperfusion [e.g., hypotension, long capillary refill, skin mottling, etc.]. As opposed to being 50-300 mL/min above, the BaSICS investigators looked at two infusion rates: 5.6 mL/min [i.e., 333 mL/hour] versus 16.7 mL/min [i.e., 999 mL/hour]. Both of these rates have external validity as they were extracted from the FENICE evaluation and they reflect real, clinical practice. Nevertheless, these are lower rates than some of the oft-cited fluid-bolus studies. For example, the FEAST investigators administered 20 mL/kg over 1 hour – extrapolating that rate to a 70 kg adult would be 23.3 mL/min. The abovementioned ovine resuscitation study gave a fluid bolus at 40 mL/kg over 1 hour – a rate of 47 mL/min in a 70 kg adult. Further, the Simplified Severe Sepsis Protocol [SSSP-2], employed by Andrews and colleagues in Zambia called for an initial, therapeutic bolus at 33.3 mL/min, or twice the fastest infusion rate in BaSICS.
Notably most, if not all, of the studies cited by Zampieri and colleagues used considerably higher infusion rates within their protocols, therefore, the lack of difference in BaSICS may have been due to inadequate physiological differentiation. Further, as discussed in the balanced versus 0.9% saline section of their study, a large fraction of patients received at least 1 litre of volume in the 24 hours prior to enrollment. While this may have contaminated their results, this bias should have been equally distributed. In addition, what might also be apparent is that it is probably wise to normalize infusion rates to patient weight in future investigations. While a 70 kg and 140 kg patient might receive the same absolute bolus volume over the same duration, the volume per kilogram per unit time is different by a factor of 2. Might infusion rate normalized to body habitus have an effect on the purported rise in atrial natriuretic peptide discussed above?
As in the fluid composition portion of their investigation, it is hard to draw firm conclusions from subgroup analyses, especially given the number of secondary end-points studied. Nevertheless, there is some biological plausibility to patients having a lower hemodynamic and respiratory SOFA score when receiving slower infusions. Importantly, however, none of the differences were sustained by day 7. This was also true for the difference in coagulation SOFA score.
In summary, BaSICS is a very important clinical study worthy of praise. The sheer magnitude of coordinating this investigation across 75 intensive care units in over 10,000 patients is remarkable. The infusion rates of fluid boluses in BaSICS are well-reasoned, but are less than rates administered in other, recent, resuscitation studies. As well, the difference between a fluid bolus and a fluid challenge is important. The former refers to fluid given as therapy in the face of hypoperfusion while the latter is meant to diagnose the functional state of the heart. If performed, the fluid challenge, should precede a bolus, for if the challenge uncovers a preload intolerant heart, the bolus is arguably moot and harmful. With ANDROMEDA-SHOCK-2 enrolling patients, this distinction could become more salient.