Adequate fluid resuscitation is one of the most important components of early management following thermal injury (1). The overall aim is the balanced preservation of organ function while avoiding complications such as compartment syndromes and pulmonary edema from excessive fluid volume administration. A number of formulas can be utilized to calculate the amount of resuscitation fluid required for the first 24 h to ensure a burn patient remains hemodynamically stable (2–4). The most commonly used is the “Parkland” formula (Box 1).
The Parkland Formula (4). This represents a starting point for resuscitation titrated against HUO. It should be noted that the initial formula did not specify an optimal HUO.
Despite success in reducing mortality from burn shock and renal failure, controversies over resuscitation management remain (5–10). One of the principal controversies is the optimal resuscitation titration endpoint (8–11). While the majority of burns centers (94.9%) (3) utilize urinary output (UO) (3) as the principal endpoint, the increased availability of noninvasive cardiac monitoring has renewed the debate concerning the utility of hemodynamic resuscitation endpoints (12–14). The increasing use of echocardiography within intensive care units has also prompted an interest in this modality to monitor resuscitation (15–17).
A number of observational studies have claimed that despite a recommended UO of 0.5 mL · kg−1 · h−1 or greater, hypoperfusion may still be present (18–20). Monitoring of malperfusion markers (arterial base deficit and serum lactate) (21), tissue oxygenation, and the gastric mucosa as indicators of tissue and cellular function has been advocated (19).
While more sophisticated resuscitation endpoints are utilized to manage other forms of shock, the optimal endpoints in burn resuscitation remain unclear. This systematic review aims to investigate evidence for the use of alternative (i.e., other than hourly urine output [HUO]) endpoints of resuscitation in burn patients including hemodynamic monitoring, echocardiography, gastric tonometry, metabolic monitors, and microdialysis. The registration number for this review was CRD42014007424.
Paper identification and selection
A systematic review of both adult and pediatric published literature was conducted including prospective randomized controlled studies, controlled studies with a historical control, and cohort studies. To ensure inclusion of surrogate markers of resuscitation, single-group studies were included where resuscitation was completed utilizing HUO as the main endpoint while concurrently recording alternate resuscitation markers such as tissue oxygenation. Relevant systematic reviews were included and reviewed by the criteria according to Moher et al. (22). Inclusion and exclusion criteria are summarized in Table 1.
The primary outcomes of interest included all-cause mortality, complications of resuscitation namely organ failure, incidence of compartment syndromes (abdominal and peripheral), and pulmonary edema. Secondary outcomes were incidence of sepsis, total resuscitation volume, duration of mechanical ventilation, and length of intensive care and hospital stay. The surrogate outcomes of both mixed venous oxygenation (Svo2) and central mixed venous oxygenation (Scvo2) were also analyzed as they represent a marker for goal directed resuscitation.
MEDLINE, EMBASE, PUBMED, Web of Science, Cochrane Library and full-text clinicians’ health journals at OVID, from 1990 to January 2014, were searched with no language restrictions. For the final selection of comparative studies, the year 1990 was chosen as it was considered that after this year there were major breakthroughs in mechanical ventilation management in intensive care resulting in a decrease in mortality. Search subject headings were burns OR thermal injury AND fluid resuscitation AND monitoring OR endpoints.
The search was supplemented by citation tracking and key author searches. Three reviewers (J.D.P., E.D.P., and K.S.) independently assessed the titles and abstracts of articles identified by the initial search strategy. Full-text versions of relevant articles were obtained and scored by 3 independent reviewers (J.D.P, E.D.P., and K.S.) with arbitration by a fourth author when necessary (R.J.B.). Intraclass correlation coefficient was 0.9 between authors for the quality scores. Randomized controlled trials (RCTs) were rated by the Delphi scale (23), which has high interobserver reliability. Criteria include specification of eligibility criteria; random allocation; concealed allocation; similarity at baseline; blinding of all subjects, operators, and assessors; intention-to-treat principle; point measures; and measures of variability reported. Cohort studies and those with historical control groups were scored using modified criteria from a validated instrument for nonrandomized intervention studies (24). Criteria included a description of the study groups and distribution of prognostic factors, measurement taken at a similar point in their disease, reliable ascertainment of interventions or treatments, groups comparable on all potential confounding factors, appropriate adjustment for effects of confounding variables, controls randomly selected from source case population of the cases, outcome assessment blind to exposure status, adequate follow-up for the outcomes of interest, and appropriate statistical analysis used. Based on this criteria for both RCTs (23) and trials with historical controls (24), the levels of evidence (25) are listed in Table 2. Authors were contacted to clarify important points where necessary.
Data extraction and analysis
Data extraction was completed for all included studies. To compare results between trials, for continuous outcomes the unbiased effect size estimators (Hedges d) (26) with 95% confidence intervals were calculated, using Comprehensive Meta-analysis software (27). Dichotomous outcomes were expressed as risk ratios (RRs) with 95% confidence intervals. A meta-analysis for some outcomes was not possible because of lack of inclusion of measures of variability, reporting of median and interquartile range (IQR), heterogeneity in the method of measurement, and infrequent outcome measure inclusion in the studies. The data were pooled using the fixed-effects model; however, when heterogeneity was statistically significant (Q statistic P < 0.01), the data were reanalyzed using the random-effects model (27). The single-group studies were reported in a descriptive fashion (Table 3).
From 482 articles identified, 445 were eliminated on abstract review because of duplicate copies or meeting the a priori exclusion criteria (Fig. 1). The 37 remaining studies were full text reviewed and excluded if they were nonsystematic reviews (6, 28), a systematic review not on the actual topic of fluid resuscitation endpoints (29, 30), resuscitation where alternative resuscitation endpoints were not compared with HUO (14, 31–37), using markers of perfusion to predict mortality rather than as a comparison (21, 38, 39), or comparison of different formulas for resuscitation (40, 41). This systematic review was based on 20 studies including six RCTs (42–47), two cohort studies (48, 49), 11 single-group comparison studies (18, 19, 50–58), and one systematic review (16).
Demographics and setting
Specific details for comparative studies (RCT and cohort) are shown in Table 2. All studies were in adult tertiary intensive care settings. Three studies (43–45) were from the same center. Mean age overall was 45.2 years (range, 15–96 years). Mean total burn surface area (TBSA) was 43.3% (range, 20%–81%). The ratio of male to female was 2.5:1. The percentage of those with inhalation injury was 47%. The overall number of subjects was 311 (n ranging from 16 to 116). Nearly all studies excluded subjects on the basis of previous cardiac comorbidity (42, 46, 48) cardiac and renal comorbidities (43–45) or renal only (47).
Single-group studies are described in Table 3. The majority were also in adult units with two in combined adult pediatric settings (50, 53). Mean age was 42.8 years (2–89 years), and mean TBSA was 50.2% (20%–99%). Male-to-female ratio was 3:1.
Comparative studies—RCTs and cohort studies
All comparative studies compared HUO against hemodynamic endpoints. The majority (42–46, 48, 49) utilized a measure of preload as a titration point, and one used a measure of fluid responsiveness, stroke volume variation (SVV%) (47). Details on actual resuscitation for control and study groups are provided in Table 4. There were no comparative studies utilizing echocardiography, malperfusion markers, tissue monitoring, or gastric tonometry. Csontos et al. (43) did report insertion of gastric tonometry but did not report any measurements from the device.
All comparative studies followed the Parkland formula. Most studies infused only crystalloid in the first 24 h followed by colloid in the second 24 h onward. Three studies (47–49) included colloid for critical hypovolemia in the first 24 h. Seven studies had defined cutoff times from the time of burn for starting of fluid infusion (Table 2). Hemodynamic endpoints used the intrathoracic blood volume index (ITBVI) targeting ≥800 to 850 mL/m2 (42, 43–47). However, one study titrated the ITBVI to maintain a cardiac index (CI) of 2.2 L · min−1 · m−2 (48). Schiller et al. (49) aimed for hyperdynamic endpoints, titrating the end-diastolic ventricular pressure to achieve a CI of 4.1 L · min−1 · m−2 and an oxygen consumption (Vo2) of more than 350 mL/min.
Similarly, the descriptive studies (16, 19, 50–58) (Table 3) utilized the Parkland formula with HUO as the main endpoint. They concurrently measured pulmonary artery occlusion pressure (PAOP), CI, stroke volume index (SVI), and Svo2 from the pulmonary artery catheter (51–53, 56); CI and ITBVI from a thermodilution device (51, 65, 58); parameters from transesophageal echocardiography (TEE) (51, 56, 58); or tissue oxygenation of skin or gastric mucosa (18, 19, 57).
Study quality and design
The six prospective RCTs were well conducted but did not report the blinding of assessors (Table 2) (42–47). As patients were heavily sedated at this stage, they were assumed to be blinded. It was stated in several studies (44–46) that treating staff were blinded to the hemodynamic measures, however, this did not fully blind caregivers. Quality scores for the comparative studies are provided in Appendices 1 and 2. All studies excluding one (42) were single center, which decreases external generalizability. One retrospective study utilized post hoc subgroup analysis to compare survivors to nonsurvivors (49). The control group in both retrospective studies (48, 49) were measured several years prior to the intervention group without adjustments of secular trends in mortality.
Although all studies followed the intention-to-treat principle, it was stated by Aboelatta and Abdelsalam (42) that resuscitation in the hemodynamic group was stopped prior to reaching the endpoints of resuscitation because of tissue edema and concerns regarding occurrence of pulmonary edema or compartment syndrome. In addition, the cohort study by Schiller et al. (49) stated that 13 of the “control group” received a pulmonary artery catheter and were resuscitated by this method because of failure of resuscitation.
The included systematic review (16) was well conducted by set criteria (22) but looked at the overall utilization of TEE in burns without comparing endpoints in the early resuscitation period
Summary of Findings
Results are presented in Table 5 summarizing the effect sizes, whereas forest plots for mortality and incidence of renal failure are shown in Figures 2, 3, and 4.
There were six studies [one article (49) included two study groups within one article] (42, 43, 45–47, 49) that compared survival between the resuscitation endpoints UO and hemodynamic monitoring. A fixed-effects model (i2 = 0.00) found an improved survival with hemodynamic guided resuscitation (RR, 0.58; 95% confidence interval, 0.42–0.85; P < 0.004) (Fig. 2). However, when the cohort study (49) was eliminated, the effect became nonsignificant (RR, 0.72; 95% confidence interval, 0.43–1.19; P = 0.19) (Fig. 3). The cohort study (49) had a relative weight of 42.46 in the meta-analysis (Fig. 2). Caution should also be applied to the results of the first meta-analysis (Fig. 2) as there are a number of differing definitions of mortality reported including in-hospital (45, 46, 49), intensive care (43), or undefined mortality (43, 47).
Single and multiorgan failure
It was difficult to pool results between studies because of differing definitions of organ dysfunction or nonparametric data. Multiorgan and single-organ dysfunctions were either undefined (46) or used organ dysfunction severity scores such as the Multiorgan Dysfunction Score (MODS) (43, 45, 59) or the Sepsis-Related Organ Failure Assessment (60) score (47). To further increase heterogeneity of outcomes, organ dysfunction scores were reported as scores for one organ (43), daily scores (43, 45), or total score over 10 days (48). The incidence of multiorgan failure was reported in two studies (45, 46) with an overall nonsignificant result between groups (RR, 1.28; 95% confidence interval, 0.48–3.32; P = 0.64). Individual results reported in Table 5 on the whole studies found no difference between the groups or favored hemodynamic fluid guidance. No study revealed results in favor of HUO steered fluid resuscitation.
Length of stay (hospital ICU, time on mechanical ventilation)
While a number of studies investigated days on mechanical ventilation (43, 45–47), intensive care length of stay (43, 45, 47), or length of hospital stay (42, 45, 46, 49), almost all of these were reported as median and IQR or did not include an SD, hampering inclusion in the overall analysis. Results for each study are reported in Table 5. A meta-analysis of two studies (46, 47) found no significance between groups for days on mechanical ventilation (Hedges g = 0.26; 95% confidence interval, 0.73–0.21; P = 0.28).
Results for fluid volumes administered in the first 24 h were conflicting, with some studies (42–46) (Table 5) using significantly higher volumes in the hemodynamic group in the first 24 h, whereas others (47) found a nonsignificant increase in the control group. Of note, the study finding decreased fluid volumes in the hemodynamic group (47) utilized a measure of fluid responsiveness (SVV%) as a titration endpoint compared with the measure of preload (ITBVI) utilized in other studies. When reporting daily fluid requirements expressed as mL/kg per TBSA%, an overall meta-analysis was unable to be calculated because of the nonparametric expression of data (Table 5).
Complications of resuscitation
Despite a number of studies showing a large increase in the fluid volume, there were no specific studies reporting pulmonary edema (43, 45), abdominal compartment syndrome (42, 44), and either no escharotomy procedures required (42) or no significance between groups (48). A combined analysis found a nonsignificant RR between groups for the incidence of renal failure (42, 43, 46) (RR, 0.77; 95% confidence interval, 0.39–1.43; P = 0.38) (Fig. 4).
Incidence of sepsis (without a specific definition) was investigated by two studies (45, 46), but a random-effects model (i2 = 56.4) overall found no difference between the two groups (RR, 1.35; 95% confidence interval, 0.54–3.39; P = 0.53).
Mixed venous and central mixed venous oxygenation
Svo2 is a global indicator of the balance between oxygen delivery (DO2) and oxygen consumption (Vo2). Scvo2 is a surrogate measure of largely head and upper body perfusion. The criterion standard, Svo2, was commonly measured from pulmonary artery catheters, and early-model thermodilution monitors are reported in older studies (46). Central mixed venous oxygenation is utilized in more modern noninvasive monitors such as the PiCCO or Vigileo (43–45).
Although individual studies (43–45) found a significant increase in Scvo2 in the hemodynamic group over the first 24 h (Table 5), an overall meta-analysis was unable to be calculated because of nonparametric data. There were no significant differences between groups in any studies on days 2 and 3. Csontos et al. (43) found that the MODS score for days 2 and 3 correlated significantly with Scvo2 on day 1 (r = −0.68 [P = 0.004] and r = −0.68 [P = 0.003], respectively).
Overall, the descriptive studies (Table 3) found deterioration in tissue oxygenation despite adequate global parameters (18, 19, 57, 58), abnormal invasive hemodynamics despite maximal HUO (50, 53, 55, 56, 58), impaired LV distensibility despite acceptable HUO (54), and a suggestion that a more rapid infusion normalized the hemodynamic parameters sooner (51, 52).
The initial animal work conducted by Baxter and Shires (4) dramatically advanced the management of burn shock and decreased the high rate of mortality from burn injury. The Parkland formula with varying modifications has subsequently become the cornerstone of burn resuscitation (2, 11). Yet, the optimal HUO was never stated definitely and has not been tested in a controlled trial.
Overall, this study had equivocal results. Although a mortality advantage was demonstrated in Figure 2 for all comparative trials, the result relied heavily on one cohort study with weak methodology (49). Two studies (43, 45) did report significantly better organ function on days 2 and 3, but a meta-analysis was unable to be performed. There were a number of limitations to this review, including the small number of studies, low subject numbers, and lack of assessor blinding. Pooled effect sizes could not be calculated for some outcome measures because of reporting of medians and IQR or heterogeneity of outcomes. However, the limited evidence indicates that a large multicenter randomized trial is warranted.
The understanding of shock overall has moved from global parameters to one of abnormalities of microcirculation and cellular metabolism, with sophisticated, relatively noninvasive technologies capable of real-time measurement (63, 66). There is some evidence mainly from observational studies that, during burn resuscitation, macroscopic parameters (blood pressure, urine output) can be satisfactory yet tissue perfusion inadequate (18, 20, 53, 57). While decreased UO indicates renal hypoperfusion, normal urine output cannot exclude the presence of malperfusion.
There are a number of reasons alternate endpoints to HUO may theoretically have an advantage in burns resuscitation. In the initial 48 h of burn, shock patients are known to be in the “ebb” stage with a generalized capillary leak, low PAOP, depressed cardiac function, and high systemic vascular resistance. After 48 to 72 h, cardiovascular parameters alter with systemic vasodilatation and high cardiac output. A number of authors utilizing hemodynamic endpoints (43, 52) reported earlier normalization of this stage with almost normal cardiac output at 5 h (52). It is not yet known whether this is a mechanical effect from targeting increased preload or the effect of improving oxygen delivery.
Previous studies (64, 65) in other forms of shock (sepsis, hemorrhage) have found that provision of oxygen delivery compatible with tissue demands for oxygen consumption results in a trend for improved outcomes. In burn patients (31, 52), oxygen consumption correlates with oxygen delivery (DO2) when cardiac output is augmented with increased volume loading. There is a suggestion that the critical value at which consumption becomes dependent on oxygen delivery is shifted higher in the burn patients perhaps because of the higher metabolism of the burn patients (31). While an animal model receiving hyperdynamic resuscitation (67) demonstrated no benefit over titration with HUO, the resuscitation continued for only 8 h.
The clinical implications of various monitoring devices are detailed in Table 6. While a method of monitoring may provide valuable information, it may be unsafe or not valid in certain situations.
The ideal endpoint for burn resuscitation remains elusive. Although a measure of preload has been used in the majority of studies, authors note the difficulty in reaching the target ITBVI (46–52), with the CI reaching target figures despite an abnormal ITBVI (52). Hemodynamic monitoring during burn resuscitation has often been reserved for patients with cardiac or renal comorbidities arguing that previously healthy patients with normal function will have a favorable outcome using HUO as an endpoint (1, 2). Despite the patients included in these studies being classed as “healthy” as nearly all studies in this review excluded patients with cardiac and/or renal comorbidities, there was some limited evidence that outcomes were improved with the addition of alternate monitoring.
Hourly urine output remains the most commonly used endpoint for burn resuscitation. This review has demonstrated limited evidence that alternative methods can result in an improvement in outcome. A decrease in mortality was demonstrated with the use of hemodynamic monitoring with a trend toward less renal failure. Using HUO as a measure is still practical in areas where resuscitation is conducted in transit or in regional health centers by relatively burn inexperienced health personnel. Large multicenter trials are presently required to determine optimum methods of fluid resuscitation in burns and utilize newer methods of determining tissue oxygenation. Ideally, future trials would be large enough to support a priori–determined subgroup analysis of benefit in populations such as pediatric burns and those with preexisting comorbidities. Further studies comparing alternative endpoints with urine output could provide updated guidelines with regard to rate of infusion for management of burn shock.
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