Variation in Fluid and Vasopressor Use in Shock With and Without Physiologic Assessment

Shock can be defined as inadequate supply of blood or oxygen, which results in organ damage or failure.^1,2 The goal of resuscitation in shock is to restore or preserve normal cellular metabolism and homeostasis by ensuring the adequate delivery of oxygen or other substrates to tissues.³ Increasing perfusion by augmenting cardiac output or arterial tone is a crucial component of therapy. Sepsis is a common cause of shock and represents a substantial public health burden.⁴ In patients with sepsis-induced hypotension or hypoperfusion, expert guidelines recommend prompt fluid resuscitation.⁵ New York State law and the US Centers for Medicare and Medicaid Services (CMS) require hospitals to report compliance with intravenous fluid (IVF) resuscitation as a key metric of quality care. Despite these recommendations, evidence to support the effectiveness of IVF is scant.

Enthusiasm for rapid IVF resuscitation in sepsis is based largely on an a single-center study, which showed a large decrease in the risk of death associated with a resuscitation protocol that included repeated boluses of isotonic crystalloid to achieve a goal central venous pressure of 8 to 12 mm Hg.⁶ More recent research has cast doubt on the safety and efficacy of this strategy. Well-designed animal studies question current physiological concepts of sepsis, low blood flow, and organ failure.⁷ Clinical studies suggest that early vasopressor use is associated with less IVF administration and similar or better patient outcomes.^8,9 Three large, multicenter, prospective, randomized controlled trials did not replicate the large decrease in mortality reported in the original publication.^10-12 Further studies found harm associated with early and rapid infusions of IVF, although the low-income setting and prevalence of malaria of these trials raised questions about the generalizability of the observations to higher-income settings.^13,14 A recent expert review concluded that significant knowledge gaps about IVF administration remain. ¹⁵

The fundamental goal of an IVF bolus is to cause a sustained increase in venous return to the right heart with the hope of increasing left ventricular end-diastolic volume, then left ventricular stroke volume (LVSV), then cardiac output (CO), and thus adequate regional distribution and improvement in microcirculatory perfusion, thereby improving cellular oxygen delivery. Multiple studies suggest that many patients with shock are not fluid responsive.¹⁶ That is, many patients with shock do not show an increase in LVSV or CO when they receive an IVF bolus. Whether such an increase is likely to occur depends on the interaction between left ventricular function (described by the Frank-Starling curve) and the venous return curve, and these functions tend to vary substantially among patients and even over time within the same patient.¹⁷ A physiologic assessment (PA) is a maneuver that is often used to help bedside clinicians determine the chances that the patient under their care is likely to be fluid-responsive. The last 20 to 25 years have witnessed the growth of research in this field, with many different kinds of PA tested for their ability to identify fluid-responsive patients.¹⁸ Reviewing this vast body of investigation, some salient facts emerge. First, static PA measurements, such as central venous pressure (CVP) or pulmonary artery occlusion pressure (PAOP) have poor diagnostic accuracy for identifying fluid responsiveness.^19,20 Second, measuring the cardiac output is important in determining fluid responsiveness.²¹ Third, dynamic PA maneuvers, such as pulse pressure variation (PPV) or stroke volume variation(SVV), end-expiratory occlusion, or passive leg raising are highly accurate in critically ill patients.¹⁸ Finally, despite decades of research, PA maneuvers are not used commonly by clinicians to make decisions about IVF resuscitation.²²

The FENICE study²² described worldwide IVF practice. How do clinicians in the US decide to give IVF? That is the question that JT Chen and colleagues try to answer in the Observation of Variation in Fluids Administered - Characterization of Vasopressor Requirements in Shock (VOLUME CHASERS) study, recently published in Critical Care Medicine.²³ The VOLUME investigators evaluated IVF prescribing in over 1600 patients (60% with septic shock) at multiple US centers, focusing on the 24 hours after shock diagnosis. They found that PA is used in about 40% of decisions to give an IVF bolus. The most common PA used was critical care ultrasound (CCUS), followed by static measures such as CVP and PAOP. Dynamic PA such as PPV or SVV were used rarely. When clinicians used CCUS, they examined the heart in approximately two-thirds of cases, the inferior vena cava in approximately one-third of cases, and the lungs in about one-quarter of cases. Patients who underwent PA had higher APACHE III scores and were nearly twice as likely to receive vasopressors, suggesting that clinicians may have reserved PA to make IVF decisions for sicker patients. PA was not associated with the total volume of IVF administered or with mortality risk. Compared with the FENICE study, where CVP and PAOP were commonly used, the frequency of CCUS in America suggests a trend away from invasive hemodynamic monitoring.

Recent studies suggest that pairing CO measurements with PA is associated with less IVF administration, a lower risk for mechanical ventilation, a lower risk for renal replacement therapy, and a possible reduction in the risk of death (although the probability that the latter finding is due to type I error is high.^24-26 The persistence of using CVP and PAOP to make decisions about IVF therapy, observed in both FENICE and VOLUME, is potentially concerning as the data that suggest the poor diagnostic accuracy for identifying fluid responsiveness are decades old.¹⁶ (CVP and PAOP remain useful, but not for the prediction of fluid responsiveness.²⁷)

The prevalence of CCUS used to perform PA observed in the VOLUME study raises many questions. CCUS is undoubtedly useful in many situations, and it is often available in many different parts of the hospital, unlike invasive hemodynamic monitors, which are often found only in the ICU, operating theaters, and post-anesthesia units. Unfortunately, the utility of using CCUS to perform PA is questionable.²⁸ CCUS rarely measures CO, which is crucial for accurate PA. Single or even serial evaluations of ventricular contractility or IVC diameter do not have strong diagnostic accuracy for identifying fluid responsiveness. Invasive monitoring of CO with pulmonary artery catheterization or calibrated arterial catheters provides highly accurate information about fluid responsiveness with dynamic PA. The lack of adoption of dynamic PA in the US is disappointing since these parameters have been available for decades. We should hope that in the future more clinicians will use dynamic PA with the advent of newer noninvasive continuous CO monitors, and, although their measurement of the CO may be inaccurate, their excellent linearity may provide valuable information about fluid responsiveness.^29,30

Most importantly, despite the robust findings of the FENICE and VOLUME investigations, we still lack answers to important questions about IVF prescription.

• What observations should prompt us to consider resuscitation? For example, is an elevated blood lactate sufficient to prompt treatment, or should clinicians use several parameters to make their decisions?¹⁵
• Are IVF boluses the best way to increase venous return when a patient is fluid-responsive? Some data suggest that alpha adrenergic receptor agonists (such as norepinephrine or phenylephrine) may increase venous return in selected patients.^31,32
• How often does IVF result in a sustained hemodynamic improvement? The hemodynamic effects of crystalloids are often not durable.^33,34 Do different IVF formulations have different pharmacodynamics?
• How often does fluid responsiveness identify patients who will have lasting physiologic and clinical benefits from IVF? An important limitation to the concept of fluid responsiveness is that increasing the CO with IVF may not always lead to an increase in microcirculatory perfusion or tissue substrate utilization. This concept, known as hemodynamic incoherence, is an important limitation on the potential benefits of IVF.³⁵ We lack good data about how often hemodynamic incoherence is present, how we can usefully measure it clinically, and whether giving IVF to patients who show fluid responsiveness but hemodynamic incoherence is beneficial or harmful.
• Even if fluid responsiveness is present and an IVF bolus results in increased microvascular perfusion, what is the risk–benefit balance of giving additional IVF, especially when interstitial edema might be forming? Do different IVF formulations have different risk–benefit profiles? When might a colloid solution be more suitable than a crystalloid?

The use of IVF for resuscitation is a hoary practice, first described by Thomas Latta in 1832.³⁶ Nearly 200 years later, we have valuable information about how clinicians make decisions about IVF. Future research should focus on trying to answer crucial questions about how to use IVF to improve patient-centered outcomes.

Acknowledgment: Thanks to Jan Bakker, MD, PhD, for his invaluable comments. 

References

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