Criteria used for determining fluid responsiveness included assessment of SVV with threshold greater than 10–15% in nine trials (23–25, 29–34), assessment of PPV with threshold greater than 10% in one trial (26), and the use of passive leg raise or mini fluid challenge with threshold of an increase in SV of 10% in three trials (21, 27, 28). Cointerventions and additional goal-directed therapy targets are itemized in Table 1. In control groups, patients were managed with traditional goal-directed therapy algorithms targeting static variables including the CVP in nine trials (21, 24, 25, 27, 28, 31–34), weight-based fluid loading in one trial (30), and standard care per treatment team in three trials (23, 26, 29). The protocolized fluid was colloid of any type in five trials (21, 25, 27, 32, 33), hydroxyethyl starch in three trials (24, 26, 29), and either crystalloid or physician choice in five trials (23, 28, 30, 31, 34). The intervention was delivered in the operating room (OR) prior to ICU admission in six trials (23, 26, 29, 32–34), the OR and ICU in four trials (24, 25, 27, 30), and the ICU only in three trials (21, 28, 31). The duration of the intervention ranged from 5 to 82 hours. Three trials were appraised as having unclear risk of bias; the remaining trials were at high risk of bias due to lack of blinding (Table 2). Five trials received funding from industry manufacturers of the device used in the intervention (21, 24, 29, 31, 32).
Data on mortality were available in 12 of 13 trials (21, 23–29, 31–34). Mortality was recorded at hospital discharge in seven trials (23–26, 29, 32, 34), 28–30 days in four trials (21, 27, 28, 33), and 90 days in one trial (31). Fluid therapy guided by FT-DYN was associated with decreased mortality compared with standard care (RR, 0.59; 95% CI, 0.42–0.83; I 2 = 0%; n = 1,586) (Fig. 2). The absolute risk reduction in mortality associated with FT-DYN was –2.9% (95% CI, –5.6% to –0.2%). Although funnel plot asymmetry appeared to exist for this outcome, trim and fill analysis where we imputed potentially unpublished trials showing no benefit or perhaps even harm associated with FT-DYN did not statistically modify the summary statistic for mortality (Fig. S1, Supplemental Digital Content 2, http://links.lww.com/CCM/C688—legend, Supplemental Digital Content 16, http://links.lww.com/CCM/C702). Mortality associated with FT-DYN was evaluated according to prespecified clinical (patient population [medical, surgical, cardiac surgical ICU], fluid responsiveness criteria [SVV, PPV, or threshold increase in SV], type of fluid administered [colloid unspecified, hydroxyethyl starch, crystalloid, or physician choice], timing [OR, ICU, OR and ICU], and duration of intervention [< 6, 6–24, > 24 hr]) and methodologic subgroups (risk of bias and source of funding). Summary effect estimates of mortality across clinical subgroups were consistent with varying confidence limits (Supplementary Table 1, Supplemental Digital Content 3, http://links.lww.com/CCM/C689; Fig. S2, Supplemental Digital Content 4, http://links.lww.com/CCM/C690; Fig. S3, Supplemental Digital Content 5, http://links.lww.com/CCM/C691; Fig. S4, Supplemental Digital Content 6, http://links.lww.com/CCM/C692; Fig. S5, Supplemental Digital Content 7, http://links.lww.com/CCM/C693—legend, Supplemental Digital Content 16, http://links.lww.com/CCM/C702; Fig. S6, Supplemental Digital Content 8, http://links.lww.com/CCM/C694; Fig. S7, Supplemental Digital Content 9, http://links.lww.com/CCM/C695; and Fig. S8, Supplemental Digital Content 10, http://links.lww.com/CCM/C696). The effect of funding source or adjudicated risk of bias was not statistically significant across subgroups.
Compared with usual care, FT-DYN was associated with reduced ICU length of stay (WMD, –1.16 d; 95% CI, –1.97 to –0.36; I 2 = 74%; n = 394) in six trials with extractable data (23–25, 29, 32, 34), with statistical heterogeneity attributable to varying treatment effects all favoring the intervention. Among four trials examining ICU length of stay but lacking measures of variance suitable for meta-analysis, two trials reported reduced ICU length of stay in patients receiving FT-DYN (26, 30), and two trials found no difference (28, 31). FT-DYN was also associated with a reduction in duration of mechanical ventilation (WMD, –2.98 hr (95% CI, –5.08 to –0.89); I 2 = 34%; n = 334, five trials) (23–25, 29, 32). There was no difference in hospital length of stay in four trials reporting data suitable for meta-analysis (WMD, –0.65 d; 95% CI, –3.25 to 1.94; I 2 = 86%; n = 270) (23–25, 34), with heterogeneity driven by a small trial reporting a shorter median but wide range of hospital length of stay in patients receiving FT-DYN (23). Of seven additional trials reporting hospital length of stay but lacking measures of variance suitable for meta-analysis, five trials reported shorter hospital length of stay in patients receiving FT-DYN (26, 27, 30, 32, 33), whereas two trials found no significant difference (21, 31).
FT-DYN was not associated with significant difference in the frequency of renal complications (RR, 0.54; 95% CI, 0.28–1.04; I 2 = 67%; n = 1,380, nine trials) (24–27, 29, 31–33). The frequency of renal complications was reported in a dichotomous manner with reference to AKIN in three trials (21, 24, 27), KDIGO in one trial (31), and RIFLE in one trial (29). Four trials defined renal complications as composite endpoints ranging from oliguria to the need for acute renal replacement therapy (25, 26, 32, 33). Requirement for renal replacement therapy was not reported as a distinct outcome. With a consistent summary estimate, heterogeneity was reduced (I 2 = 35%) after excluding a single small trial that reported an increased frequency of renal complications in the intervention group (31). Forest plots for secondary outcomes are presented in Fig. S9 (Supplemental Digital Content 11, http://links.lww.com/CCM/C697), Fig. S10 (Supplemental Digital Content 12, http://links.lww.com/CCM/C698), Fig. S11 (Supplemental Digital Content 13, http://links.lww.com/CCM/C699), Fig. S12 (Supplemental Digital Content 14, http://links.lww.com/CCM/C700), and Fig. S13 (Supplemental Digital Content 15, http://links.lww.com/CCM/C701).
Outcome data pertaining to the differential quantities of fluid administered with appropriate measures of variance were reported in six trials for crystalloid (21, 23, 24, 26, 32, 33), seven trials for colloid (21, 23, 24, 26, 29, 32, 33), and seven trials for cumulative fluids at end intervention (23, 24, 26, 29, 32–34). Fluid quantity outcomes in each trial are presented in Figure 3; high statistical heterogeneity combined with opposing treatment effects precluded meta-analysis of crystalloid quantity and cumulative IV fluids administered. This heterogeneity was not well explained by clinical or methodologic subgroup analysis. Patients receiving FT-DYN received greater quantity of colloids with statistical heterogeneity attributed to varying treatment effects all favoring FT-DYN (WMD, 0.44 L; 95% CI, 0.24–0.64; I 2 = 68%; n = 558, seven trials) (21, 23, 24, 26, 29, 32, 33). A significant reduction in serum lactate was observed at end intervention (–0.58 mmol/L, 95% CI, –1.05 to –0.11; I 2 = 92%; n = 419, six trials) (23, 24, 26, 30, 33, 34), with statistical heterogeneity attributed to varying treatment effects all favoring FT-DYN.
In our systematic review and meta-analysis, we observed a reduction in mortality among adults admitted to the ICU who received goal-directed therapy guided by FT-DYN for acute volume resuscitation compared with standard care. FT-DYN may also be associated with modest reductions in ICU length of stay, duration of mechanical ventilation, and serum lactate although data for these outcomes were limited.
In recent surveys, 89% of intensivists and up to 71% of anesthesiologists report titrating fluids to the CVP in clinical practice (35–37). Our analysis suggests that the widespread use of static measures to guide fluid therapy requires reexamination. Our findings are concordant with a recent consensus statement issued by an international panel of specialists in anesthesia and intensive care recommending that fluid therapy target fluid responsiveness in routine perioperative care (13). Conversely, the surviving sepsis guidelines, widely referenced by critical care practitioners, have historically supported static fluid therapy targets (38). More recently, these guidelines have issued a weak recommendation to incorporate dynamic rather than static variables to assess fluid responsiveness to guide initial resuscitation (39).
Our systematic review and meta-analysis builds on the findings of Benes et al (40) who found fluid therapy based on dynamic variables reduced perioperative morbidity compared with standard care in operative settings. Our review examined a broader population of patients receiving FT-DYN admitted to intensive care, and found a risk reduction in mortality. Although mechanisms through which FT-DYN may confer benefit in this population require further study, the differential mortality effects may be due to improved end-organ perfusion with FT-DYN, optimal timing of fluid bolus administration in relation to physiologic demand, or minimization of crystalloid volume (41, 42).
Our systematic review has several strengths. Our clinical question was well defined and addressed a timely and relevant topic in critical care. Our systematic review protocol was prospectively registered. To reduce the potential for both selection and performance bias, we were careful to include only RCTs. We designed an exhaustive search strategy to capture multiple dynamic methods to assess fluid responsiveness, and we excluded trials that used bioreactance technology which is reported to have limited accuracy in the ICU setting (19). Our systematic review focused on clinically relevant patient outcomes and was congruent with recognized guidelines for systematic review methodology.
This systematic review has potential limitations. The majority of trials in this analysis involved a postsurgical ICU population. The performance of FT-DYN in general intensive care may differ from a surgical ICU setting and requires consideration of limitations of individual dynamic variables in predicting fluid responsiveness. Some of these limitations include the presence of dysrhythmias, right ventricular dysfunction, intra-abdominal hypertension, spontaneous respiratory effort, and the use of low tidal volume ventilation; limitations that may be mitigated by incorporating a passive leg raise into dynamic assessments. The majority of trials were at high risk of bias due to lack of blinding in the intervention arms, which may have contributed to performance bias. Outcome assessment was however blinded to treatment allocation in the majority of trials which would serve to reduce the potential for systematic error. Mortality reported in trials was generally low, which may limit the generalizability of findings to ICU populations with greater illness severity. Secondary outcomes were largely underreported. Funnel plot asymmetry indicates potential publication bias with the underreporting of small trials showing null effects or harm associated with the intervention; however, statistical imputation of these trials did not significantly alter the summary effect measure for mortality. Statistical heterogeneity among pooled secondary outcomes was moderate, but generally explained by excluding a single outlier (with preserved summary effect measures) or by varying magnitude of treatment effects all favoring FT-DYN. Clinical heterogeneity also existed in the population analyzed based on fluid responsiveness criteria, type of fluid administered, and timing and duration of interventions; however, these factors were addressed in a thorough and extensive subgroup analysis.
In adult patients admitted to intensive care and requiring acute volume resuscitation, goal-directed therapy guided by assessment of fluid responsiveness appears to be associated with reduced mortality, ICU length of stay, and duration of mechanical ventilation. High risk of bias due to lack of blinding limits the internal validity of published trials. High-quality clinical trials in both medical and surgical ICU populations are warranted to inform routine care.
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fluid therapy; goal-directed; hemodynamic; meta-analysis; resuscitation
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