Tangkapan Layar 2024-03-14 Pada 16.23.17
Tangkapan Layar 2024-03-14 Pada 16.23.17
Abstract
Background: Crystalloids and different component colloids, used for volume resuscitation, are sometimes associated
with various adverse effects. Clinical trial findings for such fluid types in different patients’ conditions are conflicting.
Whether the mortality benefit of balanced crystalloid than saline can be inferred from sepsis to other patient group
is uncertain, and adverse effect profile is not comprehensive. This study aims to compare the survival benefits and
adverse effects of seven fluid types with network meta-analysis in sepsis, surgical, trauma, and traumatic brain injury
patients.
Methods: Searched databases (PubMed, EMBASE, and Cochrane CENTRAL) and reference lists of relevant articles
occurred from inception until January 2020. Studies on critically ill adults requiring fluid resuscitation were included.
Intervention studies reported on balanced crystalloid, saline, iso-oncotic albumin, hyperoncotic albumin, low molecu-
lar weight hydroxyethyl starch (L-HES), high molecular weight HES, and gelatin. Network meta-analyses were con-
ducted using random-effects model to calculate odds ratio (OR) and mean difference. Risk of Bias tool 2.0 was used to
assess bias. Confidence in Network Meta-Analysis (CINeMA) web application was used to rate confidence in synthetic
evidence.
Results: Fifty-eight trials (n = 26,351 patients) were identified. Seven fluid types were evaluated. Among patients with
sepsis and surgery, balanced crystalloids and albumin achieved better survival, fewer acute kidney injury, and smaller
blood transfusion volumes than saline and L-HES. In those with sepsis, balanced crystalloids significantly reduced
mortality more than saline (OR 0.84; 95% CI 0.74–0.95) and L-HES (OR 0.81; 95% CI 0.69–0.95) and reduced acute
kidney injury more than L-HES (OR 0.80; 95% CI 0.65–0.99). However, they required the greatest resuscitation volume
among all fluid types, especially in trauma patients. In patients with traumatic brain injury, saline and L-HES achieved
lower mortality than albumin and balanced crystalloids; especially saline was significantly superior to iso-oncotic
albumin (OR 0.55; 95% CI 0.35–0.87).
Conclusions: Our network meta-analysis found that balanced crystalloids and albumin decreased mortality more
than L-HES and saline in sepsis patients; however, saline or L-HES was better than iso-oncotic albumin or balanced
crystalloids in traumatic brain injury patients.
Trial registration: PROSPERO website, registration number: CRD42018115641).
*Correspondence: [email protected]
1
Institute of Epidemiology and Preventive Medicine, National Taiwan
University, Room 539, No. 17, Xu-Zhou Rd., Taipei 10055, Taiwan
Full list of author information is available at the end of the article
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Tseng et al. Crit Care (2020) 24:693 Page 2 of 12
Introduction Methods
Fluid resuscitation is one of the most common and Data sources and searches
important methods in managing critically hypotensive We registered our systematic review process on
patients. Crystalloids, mineral salts, or other water-sol- the PROSPERO website [13] (registration number:
uble molecule solutions have been used for more than CRD42018115641). This NMA followed the preferred
100 years for fluid resuscitation [1, 2]. In the past dec- reporting items for systematic reviews and meta-analyses
ades, several colloids, larger insoluble molecular solu- (PRISMA) extension guideline which incorporated NMA
tions, have been developed to improve intravascular for healthcare interventions (Additional file 1: appendix
volume more effectively. However, since the integrity pp. 8–13) [14]. Electronic databases, including PubMed,
of the endothelial glycocalyx layer might be interrupted EMBASE, and Cochrane CENTRAL, were searched from
under inflammatory conditions, such as sepsis, surgery, their inception until January 2020. The search strategies
trauma, or traumatic brain injury, evaluation of the effi- combined terms for patients’ conditions, clinical out-
cacy and safety of colloids in such patients is challeng- comes, and fluid types (Additional file 1: appendix pp.
ing [3, 4]. 14–15).
Insoluble molecules in colloids include starch,
bovine protein (gelatin), and human protein (albumin).
Hydroxyethyl starch (HES) of higher molecular weight Study selection
has a longer half-life in plasma, but it reduces plasma We included randomized controlled trials (RCTs) on crit-
coagulation factors more than HES of lower molecu- ically ill adult patients (more than 18 years old) who pre-
lar weight [5] and albumin [6]. Starch macromolecule sented with systemic hypoperfusion and required fluid
accumulation also impairs glomerular filtration and is resuscitation. We excluded trials on children with dengue
associated with a higher risk of acute renal failure than fever, those on burn injury patients, or those on mixed
gelatin [7]; however, gelatin is associated with a higher populations without reporting subgroup data (Additional
incidence of anaphylactic shock [8, 9]. Compared to file 1: appendix pp. 17–20).
iso-oncotic albumin, hyperoncotic albumin leads to
a higher osmotic pressure, which may alter intraglo-
merular oncotic force and osmotic nephrosis, and is Data extraction and quality assessment
associated with worse kidney damage [10]. Chemical We divided patients requiring fluid resuscitation into the
components, molecular weights, and colloid concentra- following groups for extraction of data and separate anal-
tion might expose the human body to different levels of yses: sepsis, surgical, trauma, and traumatic brain injury.
hazards [11]. Among crystalloids, saline worsens acido- The 7 interventions included 2 crystalloids [balanced
sis and bleeding tendency compared to balanced crys- crystalloids, including lactated Ringer’s, Ringer acetate
talloids [12]. Consequently, classifying resuscitation or PlasmaLytes and saline (0.9% sodium chloride)], and
fluids into either colloids or crystalloids was no longer 5 colloids [iso-oncotic albumin (4%, 5%); hyperoncotic
enough. albumin (20%, or 25%); HES with molecular weight
From 2012 to 2018, of 15 meta-analyses published on ≦ 130 k (L-HES); HES with molecular weight ≧ 200 k
fluid resuscitation in critically ill patients (Additional (H-HES); and gelatin]. The outcomes included:
file 1: appendix pp. 5–7), 12 (80%) grouped high and
low chloride crystalloids or colloids of different com- (1) All-cause mortality rate. If a study reported out-
ponents into a single type of treatment, and 5 (33.3%) comes at multiple time points, we chose the longest
grouped sepsis, surgical, and trauma patients into one observation.
meta-analysis. Furthermore, no meta-analyses com- (2) Fluid resuscitation volume. The resuscitation target
pared the required fluid volumes for the resuscitation is the reversal of organ hypoperfusion.
target. This study aimed to compare the survival benefit (3) Acute kidney injury, referring to the degree of renal
and any potential adverse effects of seven fluid types dysfunction, based on a 5-level scoring system to
using network meta-analysis (NMA) in sepsis, surgical, evaluate risk, injury, failure, loss, and end-stage
trauma, and traumatic brain injury patients, and inves- renal failure (RIFLE).
tigated the trend in treatment difference using sequen- (4) Transfusion volume.
tial NMA. (5) Allergic reaction rate.
Tseng et al. Crit Care (2020) 24:693 Page 3 of 12
Two authors (CH Tseng and TT Chen) screened the functions [22], the two interventions showed no dif-
studies on RCTs independently, extracted data, and ference in their effects. We used the R software pack-
assessed the risk of bias of studies using the revised age “sequentialnma” to undertake sequential NMA [23].
Cochrane risk of bias tool (RoB 2 tool) at study level [15]. Results from these additional analyses were then com-
A third reviewer (YK Tu) was consulted to resolve any pared to the results from the NMA.
disagreement in data extraction or assessment.
Results
Data synthesis and analysis The literature search identified 18,802 citations, and 377
Transitivity assumption was assessed by checking the full-text articles were assessed for eligibility. Of 58 RCTs
distribution of potential confounding variables across which included 26,351 patients in the analysis, 5 large
studies grouped by interventions. The variables examined RCTs included more than one condition—sepsis, surgery,
included age, male percentage, disease severity scores, trauma, and traumatic brain injury. Thus, we extracted
source of sepsis from the lung, and publication year. We the subgroup data of patients with different conditions.
first used the “network” suite of STATA version 14.0 As a result, 23 RCTs on sepsis patients, 24 on surgi-
[16] (StataCorp, Texas, USA) statistical software, which cal patients, 10 on trauma patients, and 4 on traumatic
implements a frequentist approach to the contrast-based brain injury patients were included for further analysis
model meta-analyses [16], to undertake a random-effect (Fig. 1, Additional file 1: appendix pp. 17–48). We pre-
NMA [17]. We then used network map to illustrate the sent the risk of bias assessment for each included study
distribution of the direct and indirect evidence between in Additional file 1: appendix 7 (appendix pp. 61–70);
all treatment comparisons. The size of the nodes in the eFigure 7.1 shows the overall risk of bias in five domains
map was proportional to the number of patients who in sepsis trials, eFigure 7.2 shows the risk of bias for the
received this intervention in the network, and the width individual studies, and eFigure 7.3 explains the reasons
of the edges was proportional to the number of trials that for upgrading or downgrading in every study (Additional
compared the two treatments. Certainty of the evidence file 1: appendix pp. 60–63, 64–66, 67–69). The reasons
was assessed using CINeMA (Confidence in Network to downgrade are mostly inadequate randomization pro-
Meta-Analysis) web application, which allows for confi- cess, open-labeled design, or no detailed information.
dence in the results to be graded as high, moderate, low, No significant differences in baseline variables between
and very low. This approach was based on a methodology interventions were observed within our NMA (Addi-
developed by the Grading of Recommendations Assess- tional file 1: appendix pp. 49–60).
ment, Development and Evaluation Working Group for
pairwise meta-analyses [18]. Sepsis patients
Surface under the cumulative ranking (SUCRA) prob- Most RCTs used the 2001 International Sepsis Defini-
abilities is the ratio of the area under the cumulative tions Conference sepsis definition [24] and included
ranking curve to the entire area in the plot. The more sepsis patients with shock status or those who had
quickly the cumulative ranking curve approaches one, evidence of tissue or organ hypoperfusion (Additional
the closer to unity this ratio is. SUCRA values may be file 1: eTable 5.2, appendix pp. 23–26). The timing
seen as the percentage of safety a treatment achieves in for fluid resuscitation is when the patient meets the
relation to an imaginary treatment that is always the best enrollment criteria: systemic hypoperfusion defined
without any uncertainty [19]. To adjust for the multiplic- by low blood pressure, low central venous pressure or
ity of statistical testing, we further conducted sequential wedge pressure and elevated lactate level. We com-
NMA, proposed by Nikolakopoulor et al., who extended pared the mean arterial pressure among interventions
the rationales of sequential meta-analyses for defining at baseline (Additional file 1: appendix pp. 56), rang-
sample-path, efficacy boundaries, futility boundaries, ing from 69.0 to 73.9 mmHg, and found no statisti-
and information size in meta-analyses [20]. In sequential cally significant differences among seven fluid types.
NMA, we undertook a series of NMA, providing a path Besides, in Additional file 1: eTable 5.4 (appendix pp.
of estimates for each pairwise comparison, by includ- 29–31), and Additional file 1: eTable 5.6 (appendix
ing studies incrementally into the analysis according to pp. 35–36), we compared resuscitation targets among
their publication years [20]. When the path crossed the included trials. The resuscitation goals are generally to
efficacy boundaries, defined by the α-spending function maintain wedge pressure around 15–18 mmHg or cen-
derived from the O’Brien–Fleming method [21], the dif- tral venous pressure around 8–12 mmHg. The average
ference between the two treatments exceeded the thresh- mean study fluid volume was 2397.4 mL ± 1019.1 mL
old for statistical significance. In contrast, when the path in each arm, and the total resuscitation fluid vol-
fell within the futility area defined by the β-spending ume was 7615.6 mL ± 1729.7 mL (Additional file 1:
Tseng et al. Crit Care (2020) 24:693 Page 4 of 12
appendix pp. 21), we provided the details of mortal- the comparison between balanced crystalloids and gela-
ity outcome used in our analysis, including in-hospital tin (Fig. 3). According to SUCRA, balanced crystalloid
mortality, 30 day-mortality, and 90-day mortality. If appeared to be the best option; however, saline, L-HES,
multiple time points were reported in a study, we chose and H-HES were not favored (Fig. 4).
the longest observation period for mortality analy-
sis. Balanced crystalloids reduced mortality more than
saline and L-HES with odds ratios (OR) of 0.84 (95% Sepsis patients—fluid resuscitation volume
CI 0.74–0.95) and 0.81 (95% CI 0.69–0.95), respectively Thirteen trials with 10,970 participants reported usable
(Fig. 2a). Sequential NMA further supported the differ- results for fluid resuscitation volume in sepsis patients.
ence in mortality rate between balanced crystalloids ver- Balanced crystalloids and saline required more fluid
sus saline and L-HES by demonstrating that the trend in volume than iso-oncotic albumin with mean differ-
cumulative evidence exceeded the efficacy boundary. The ences (MD) of 2122 mL (95% CI − 300 to 4544 mL) and
cumulative evidence exceeded the futility boundary in 1964 mL (95% CI 89–3840 mL), respectively (Fig. 2b).
the comparison between balanced crystalloids and albu- SUCRA revealed that the colloids were associated with
min, but fell between efficacy and futility boundary in less resuscitation fluid volume than crystalloids (Fig. 4).
Fig. 2 Network geometry and forest plot in sepsis patients with four outcomes. a Mortality, b fluid resuscitation amount, c acute kidney injury, d
transfusion amount. The difference among each comparison is visualized with forest plot, and the effect size and evidence rating are labeled on the
right-hand side. The bold characters are to emphasize significant contrasts. The 95% confidence intervals in the forest plot are clipped to arrows,
when they exceed the limit of x-axis. Abbreviations: OR odds ratio; *p < 0.0.5; **p < 0.01; H high confidence rating, M moderate confident rating,
L low confidence rating, VL very low confidence rating, BC balanced crystalloids, Iso-albumin iso-oncotic albumin, Hyper-albumin hyperoncotic
albumin, L-HES low molecular weight hydroxyethyl starch, H-HES high molecular weight hydroxyethyl starch
Tseng et al. Crit Care (2020) 24:693 Page 6 of 12
Fig. 3 Sequential network meta-analyses (SNMA) over sepsis patient mortality analysis among a balanced crystalloids versus saline, b balanced
crystalloids versus low molecular weight hydroxyethyl starch (L-HES), c balanced crystalloids versus albumin, and d balanced crystalloids versus
gelatin. Y-axis represent the z scores for effect sizes, and green dots (trials) and green line along the X-axis show the trend of cumulating evidence
toward achieving maximal information. The blue line represents the SNMA efficacy boundary, and orange line represents the futility boundary.
The green dots and green line start in the middle; when they pass the blue line, this indicates that a significant difference in the outcome between
the two treatments has been attained. When they pass the orange line, this suggests no difference in the outcome between the two treatments. I
iso-oncotic albumin, H hyperoncotic albumin
Fig. 4 Surface under the cumulative ranking curve area (SUCRA) for mortality, fluid resuscitation volume, acute kidney injury, and blood transfusion
volume among sepsis, surgical, trauma, and traumatic brain injury patients. Dark color bar represents significantly better or worse interventions, and
the differences between fluid types are shown above the bars
crystalloid were associated with less mortality than gela- were associated with less acute kidney injury than HES
tin, HES, and saline (Fig. 4). and gelatin.
Fig. 5 Network geometry and forest plot in surgical patients with four outcomes. a Mortality, b fluid resuscitation amount, c acute kidney injury,
d transfusion amount. The difference among each comparison is visualized with forest plot, and the effect size and evidence rating are labeled on
the right-hand side. The bold characters are to emphasize significant contrasts. The 95% confidence intervals in the forest plot are clipped to arrows,
when they exceed the limit of x-axis. OR odds ratio; *p < 0.05; **p < 0.01; H high confidence rating, M moderate confident rating, L low confidence
rating, VL very low confidence rating, BC balanced crystalloids, Iso-albumin iso-oncotic albumin, Hyper-albumin hyperoncotic albumin, L-HES low
molecular weight hydroxyethyl starch, H-HES high molecular weight hydroxyethyl starch
Previous studies and important differences from this study patients, and greater fluid volume and hypotonic solu-
In many previous meta-analyses on fluid resuscita- tion may further raise intracranial pressure, leading to a
tion, sepsis, surgical, trauma, and traumatic brain injury higher mortality [30].
patients were put together as a single group. In 2013,
Perel et al. published a meta-analysis [26] of critically Hydroxyethyl starch (HES): L-HES and H-HES
ill patients of all causes, and another meta-analysis on HES of higher molecular weight has been retracted from
HES [27], including patients with different causes being the market, but the HES of lower molecular weight is still
grouped together. Our analyses separated patients’ con- in use in daily practice, especially in surgical or trauma
ditions, thereby providing more precise information patients. However, this study found that L-HES was asso-
applied to specific subgroups of patients. Furthermore, ciated with the highest mortality rate in sepsis, surgical,
previous meta-analyses also combined different fluid and trauma patients, and a greater risk of acute kidney
types into a single treatment. Our network meta-analysis injury and greater transfusion volume was required dur-
used a more comprehensive classification of resuscitation ing the resuscitation period. However, for traumatic
fluids according to the current knowledge, yielding more brain injury patients, L-HES and saline, both hyper-
clinically meaningful information. tonic solutions, were associated with better survival than
hypotonic solution, including iso-oncotic albumin and
Crystalloids: balanced crystalloids and saline balanced crystalloid.
Several meta-analyses and current sepsis guideline rec-
ommended that crystalloids are the fluid of choice for Gelatin
resuscitation [26, 28]. The present study found that Many review articles are opposed to gelatin use for fluid
among crystalloids, balanced crystalloids show better resuscitation due to the risk of anaphylaxis and acute
survival benefit and renal function for sepsis and surgi- kidney injury, but those opinions were based on animal
cal patients than saline does, and the reverse was found studies, case series, or RCTs designed for other purposes
in traumatic brain injury patients. Instead of considering [11, 31, 32]. Recent large RCTs reveal conflicting results,
crystalloids as one treatment group, we could be more in that gelatin is associated with a nonsignificant, lower
specific in considering balanced crystalloids for sep- mortality than balanced crystalloids and saline3. Our
sis and surgical patients, and saline for traumatic brain sequential NMA demonstrated that the z-score trend for
injury patients. However, both crystalloids required a the difference between balanced crystalloids and gelatin
higher volume to achieve resuscitation goals. Therefore, has not yet exceeded the efficacy or futility boundary,
in addition to evaluate fluid responsiveness with passive indicating that the evidence was still insufficient (Fig. 2).
leg raising or other static tests continuously, choosing
optimal fluid types could also prevent fluid overload. [29]. Strengths and limitations
The present NMA analyzed all outcomes from previous
Albumin: iso-oncotic and hyperoncotic albumin RCTs, especially on the fluid resuscitation volume, which
The osmotic pressure in iso-oncotic solution was simi- has never been considered in previous meta-analyses.
lar to plasma, and hyperoncotic solution was higher This study also analyzed seven fluid types and patients’
than plasma. Iso-oncotic albumin was designed for fluid conditions separately and demonstrated that the benefit
resuscitation and has volume-sparing effect; hyperon- or harmful effects of the fluid types were largely depend-
cotic albumin was used to maintain target serum albu- ent on patients’ conditions. We present results from
min concentration, which helps to maintain effective NMA followed by those from sequential NMA, in which
volume by recruiting endogenous fluid11. This study the dynamic updates of the effect size help to corrobo-
found that iso-oncotic albumin was associated with bet- rate the NMA results and estimate evidence uncertainty
ter survival benefit in sepsis patients who suffer hypov- by depicting the trend and making allowance for mul-
olemia due to extravascular fluid loss caused by increased tiple testing. Our NMA also has some limitations: first,
vascular permeability. However, hyperoncotic albumin in sepsis trials (sample size [n] = 14,659), the evidence
achieved better survival possibilities in surgical patients, was adequate between balanced crystalloids and saline,
whose blood loss was caused by uncorrected blood loss. L-HES, and albumin, but insufficient between balanced
This indicated that iso-oncotic albumin helps with pro- crystalloids and gelatin. The confidence rating was low
viding more volume for sepsis resuscitation, while hyper- in surgical (n = 3871) and traumatic trials (n = 5076)
oncotic albumin is more beneficial for uncorrected blood because the sample size was insufficient and confidence
loss patients with normal vascular permeability. Besides, intervals were wide. The confidence rating was very low
iso-oncotic albumin in hypotonic solution was associ- for traumatic brain injury trials (n = 1970) because the
ated with higher mortality rate in traumatic brain injury direct and indirect evidence was inconsistent and sample
Tseng et al. Crit Care (2020) 24:693 Page 10 of 12
sizes were insufficient. Secondly, the benefit or harm of physician decision in the included trials. In Additional
gelatin could not be determined from the current evi- file 1: appendix 8.1.5 (appendix pp. 74–75), we listed the
dence. Acute kidney injury was ranked best for gelatin in blood transfusion volume and number of bleeding events
sepsis patients (only one trial) but was worse in surgical requiring transfusion.Finally, the amount of investiga-
patients (only two trials). Survival benefit was also incon- tion fluid was often very limited in many trials, and large
sistent between sepsis and surgical patients (Table 1). As volumes of these resuscitation fluids have not been well
very few trials included gelatin, the evidence on gelatin investigated. Some undetected adverse events may occur
should be interpreted with cautions. Third, blood trans- if larger volumes are used.
fusion thresholds are unclear and largely dependent on
Table 1 Characteristics of the fluids assessed and qualitative summary from this network meta-analysis
Components Plasma Balanced Saline Albumin (Iso-/ L-HES Gelatin
crystalloid Hyperoncotic)
Osmolarity (mOsm/ 291 Hypotonic (254–273) Isotonic (286) Hypotonic (4%, 260; Isotonic to Hyper- Isotonic to Hypertonic
kg) 5%, 250; 20%, 200; tonic (283–304) (274–301)
25%, 250)
Na/Cl (mmol/l) 140/103 130–140/98–111 154/154 130–160/128–130 137–154/110–154 145–154/120–145
K/Ca (mmol/l) 40/4 4–5/2–2.7 0/0 < 2/0 0–4/0–2.5 0–5.1/0–6.25
Conditions Outcome Balanced Saline Albumin L-HES Gelatin
crystalloid
Sepsis NMA results Lowest mortality Higher mortality Lower mortality (Iso- Highest mortality
Lowest acute kidney More fluid volume oncotic) More acute kidney
injury required Least fluid volume injury
Lowest transfusion required More transfusion
volume volume
More fluid volume
required
Comments Fluid of choice for Not favored for sepsis Iso-oncotic albumin Not favored for Require further trials
sepsis for sepsis patients sepsis
with risk of fluid
overload
Surgery NMA results Most fluid volume More fluid volume Lower mortality Highest mortality Less fluid volume
required required (Hyper-oncotic) Less fluid volume required
Lower acute kidney More blood transfu- Less fluid volume required
injury sion volume required
Less acute kidney
injury
Less blood transfu-
sion volume
Comments More favored for Less favored for Favored for surgery Not favored for Require further trials
surgery surgery surgery
Trauma Mortality Lower mortality Lower mortality Higher mortality Higher mortality
Less acute kidney More acute kidney Less acute kidney
injury injury injury
Less transfusion More transfusion Less transfusion
volume volume volume
More fluid volume
required
Comments More favored for Damage control
trauma resuscitation. May
consider blood
products for resus-
citation
Traumatic brain Mortality Higher mortality Lower mortality Highest mortality Lowest mortality
injury (TBI) (Iso-oncotic)
Comments Hypotonic solution Favored for TBI Iso-oncotic albumin May consider for TBI Require further trials
was not suggested with hypotonic
for TBI solution was not
favored for TBI
Tseng et al. Crit Care (2020) 24:693 Page 11 of 12
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