Effects of rapid fluid infusion on hemoglobin concentration: a systematic review and meta-analysis

The main objectives of fluid administration in acutely ill patients are to correct hypovolemia and increase cardiac output and oxygen delivery (DO₂), to restore adequate tissue perfusion [1‐3]. However, rapid administration of crystalloids and/or colloids may have a hemodiluting effect, resulting in a decrease in hemoglobin concentration (Hb). As a consequence, even when cardiac output increases, DO₂ may not increase as much as anticipated. For example, from the DO₂ equation (DO₂ = CO × (1.39 × [Hb] × SaO₂ + (0.003×PaO₂), at an SaO₂ of 100%, when Hb decreases from 10 to 9 g/dL cardiac output needs to increase by about 11% to keep DO₂ steady (and more when the hemoglobin is lower). Additionally, a decrease in Hb after a fluid bolus might be (mis)interpreted as anemia, resulting in an unnecessary blood transfusion [2].

Several studies have reported that fluid administration is associated with a transient decrease in Hb [1‐3], which sometimes [3‐5], but not always [6, 7], returns rapidly to baseline values after urination. Patients with circulatory shock may show a larger and more persistent hemodiluting effect [1, 2], especially when they are oliguric [8]. However, despite these reports and a clinical perception of Hb reduction after fluid administration, the magnitude of hemodilution in different clinical scenarios has not been objectively assessed.

We therefore conducted a systematic review with meta-analysis to quantify the decrease in Hb after rapid fluid administration in various adult populations.

This study was performed according to the PRISMA guidelines and registered on the PROSPERO database on the 28th of April 2020 (CRD42020165146). The protocol is available at: https://​www.​crd.​york.​ac.​uk/​PROSPERO/​display_​record.​php?​RecordID=​165146.

Our results show a significant reduction in Hb (a mean of 1.33 g/dL) after fluid administration in all groups of acutely and non-acutely ill subjects, despite marked heterogeneity across studies as evidenced by the high I² statistic. This reduction was larger with colloids than with crystalloids. Across the acutely ill population, the largest decrease in Hb was seen in the surgery/trauma subgroup.

Under physiological conditions, a decrease in Hb after rapid fluid administration is both intuitive, through a hemodiluting effect, and counterintuitive, as the kidneys should eliminate the excessive fluid and there may be a fluid shift toward the extravascular space. Interest in this concept was initially raised with the observations by Greenfield and colleagues [73] that rapid crystalloid administration in healthy volunteers was followed by a transient decrease in Hb that started to return toward baseline after 20 min. Studies examining fluid resuscitation in healthy volunteers are, however, different from those in more complex critically ill patients, in whom various dynamic factors act to influence physiological behavior.

The effects of fluid administration vary according to a number of factors, including type and amount of fluid [74‐76], renal clearance [14, 23, 24, 77, 78], endothelial integrity [79‐82], electrolyte cotransporters, metabolic channels, and aspects associated with a relative shift toward the extravascular space [4]. Colloids are at least one and a half times more effective at volume expansion than crystalloids [83]. As they are expected to remain longer in the bloodstream than crystalloids [84], they may potentially induce a greater reduction in Hb [28], as we observed. Meyer et al. reported that 6% HES (130/0.4) induced sustained hemodilution in critically ill patients with or without sepsis [51]. In patients with sepsis, the decrease in Hb was similar with colloids and crystalloids, suggesting that some capillary leakage may have abolished the differences between the two types of fluids. Moreover, sepsis and circulatory shock are characterized by diffuse endothelial injury and capillary hyperpermeability [14, 23, 79, 81, 82, 85], resulting in greater extravasation of fluid. Studies have shown that 5% or less of a crystalloid infusion remains in the intravascular volume after 1 h in septic patients [80, 86]. In our review, the reduction in Hb was less pronounced in patients with sepsis and shock than in surgery/trauma patients, compatible with greater egress of fluids outside the vascular space in these patients [51, 53].

The amount of fluid given is an important factor in the likely degree of hemodilution induced. The degree by which the Hb decreased was directly related to the amount of fluid given, up to 1000 mL, during the first hour in the non-acutely ill population. However, this trend was not evident in acutely ill patients, likely because of the altered physiological mechanisms in acute illness described previously, notably the fluid extravasation.

In acutely and non-acutely ill populations, the Hb decrease was greatest when the baseline Hb was > 14 g/dL; this may have been due to initial hemoconcentration in some patients [70]. In some groups, the decrease in Hb was as large as 20% (surgery/trauma subgroup) when the baseline Hb was > 14 g/dL. In septic patients, the decrease was more limited, consistent with the expected extravasation phenomenon in patients with sepsis.

In the surgery/trauma subgroup, the type and duration of the procedure [22, 87], the influence of anesthesia on different factors, such as vasodilation and increase in vascular compliance, and a potential reduction in glomerular filtration rate may influence the effect of fluid administration on Hb [88], but we have no data on these aspects. The greater reduction in Hb in the surgical subgroup in our analysis may be explained by the stable and previously healthy condition of many of the patients (elective surgery, interventions performed during induction of anesthesia), physiologically similar to that of non-acutely ill subjects [2, 89].

In the presence of hypovolemia, fluid administration may result in an increase in cardiac output via the Frank-Starling mechanism [90], although this effect may be transient [7, 53], whereas the reduction in Hb may last up to 72 h [91]. This persistent reduction in Hb may limit the ability of fluid administration to achieve the desired objective, i.e., to increase DO₂ and tissue oxygenation. In subjects in whom Hb decreased, DO₂ either increased [1, 54‐56, 60, 64, 65] or remained stable [62, 66] when cardiac index increased, but decreased [1, 60] when cardiac index did not increase, suggesting that it may be deleterious to administer fluids if cardiac index does not increase.

Of note, hemodilution may also have beneficial effects. For example, hemodilution has been shown to promote cerebral blood flow in preclinical cardiac arrest studies [92, 93]. The decrease in blood viscosity associated with hemodilution can increase red blood cell velocity, facilitating red blood cell influx into the capillaries and therefore improving oxygen transfer to the tissues [94, 95].

Strengths of this study are the exhaustive review of clinical studies in different settings. We excluded major confounders, such as acute bleeding and transfusion, and classified the risk of bias [96‐98].

However, we acknowledge that there was considerable heterogeneity in the included patient populations, in terms of the underlying fluid status of the patients, the fluid tonicity, the timing of the fluid bolus in relation to resuscitation status, the type, amount, and duration of fluid administration, and the timing of observations, which might create bias and limit the interpretation and application of any aggregate quantification. Moreover, there may have been some overlap among groups; for example, some of the patients in the sepsis studies may have had septic shock. Despite our exclusion criteria, in some cases (especially in surgical settings) unrecognized bleeding may have influenced the results. We were also unable to investigate the longer-term effects of rapid fluid administration. None of the studies was specifically designed to evaluate hemoglobin decrease, so we were unable to assess patient-centered outcomes. We extracted some data from graphs, which may have reduced the accuracy of these values, although the participation of two reviewers in this process reduced any observation bias. When needed, we assigned a standard weight and height to calculate fluid amounts and indexes. Finally, the clinical implications of the magnitude of pooled decrease in hemoglobin are not clear, as our study was not designed for this purpose.

Notwithstanding the study heterogeneity and moderate certainty of evidence, our observations were consistent across studies, showing a systematic decrease in Hb after rapid fluid administration and raising uncertainty about the effects of fluid on DO₂ in fluid non-responders, i.e., when cardiac index does not increase during the fluid challenge. These observations add a cautious note to the enthusiastic performance of fluid challenges and remind us how important it is to stop the test when cardiac output does not increase.