Journal Club

Omar Albaroudi, EM Senior Fellow

Tim Harris, EM Senior Consultant
OBJECTIVES
• Fluids types
• Crystalloids/Colloids
• Key trials

• PICO, inclusions/exclusions
• NMA?
• SNMA
• SUCRA
• CINeMA

• OR
• RoBiS
 Hamburger: forgotten father of 0.9% saline?
• 1883: studied effect of different salt solutions on
haemolysis
• concluded 0.9% saline ‘‘isotonic with the blood of
most warm-blooded animals including man”

• 1896: 1st reference to Hamburger suggesting 0.9%

saline ‘normal’ for mammalian blood

• in-vitro study >> in-vivo IVF?

Awad S, Allison SP, Lobo DN. The history of 0.9% saline. Clin Nutr. 2008;27(2):179-88.
 Sydney Ringer & Alexis Hartmann
• 1883: Ringer solution
• bathed frog heart in different salt solutions
• found 0.75% saline “makes excellent circulating fluid”

• 1932: Hartmann solution

• added sodium lactate to Ringer solution
• to reduce acidosis seen in infants with diarrhoea

Lee JA. Sydney Ringer (1834-1910) and Alexis Hartmann (1898-1964). Anaesthesia. 1981;36(12):1115-21.
 Stewart Approach
• Electroneutrality. In aqueous solutions, sum of all
positively charged ions = sum of all negatively charged ions
• Strong electrolytes. fully dissociated in aqueous
solution, such as Na+, or Cl-
Normal Saline = 0.9% saline
• Na = Cl = 154 mEq/L
= hyperchloremic
• SID = Na 154 – Cl 154 = 0
• pH = 5.5 (4.5-7.0)
= acidotic

• Tonicity = 308 mOsm/L

= hypertonic
Balanced Crystalloids (BC)
• Lactated Ringer’s solution = Hartmann’s solution
• SID = Na 130 + K 4 + Ca 3 – Cl 109 = 28 mEq/L
• Buffer = lactate = 28 mEq/L
• pH = 6.5 (6.0-7.5)
• Tonicity = 273 mOsm/L = hypotonic

• Plasma-Lyte = Normosol-R
• SID = Na 140 + K 5 + Mg 3 – Cl 98 = 50 mEq/L
• Buffer = acetate 27 + gluconate 23 = 50 mEq/L
• pH = 7.4
• Tonicity = 294 mOsm/L
COLLOIDS: human-plasma derivatives
• albumin
• iso-oncotic [5%]: for fluid resuscitation
• hyper-oncotic [25%]: to maintain target serum albumin

• Plasma Protein Fraction (PPF) 5%

= albumin 90% + globulins 10%
COLLOIDS: semi-synthetic preparations
• HydroxyEthyl Starch (HES)
• low MW:
• tetra-starch 6% (Voluven)
• penta-starch 10% (Pentaspan)
• high MW: >> AKI & coagulopathy
• heta-starch 6% (Hespan or Hextend)

• gelatin
• 4% (Gelaspan)
• >> anaphylaxis
2013- CRISTAL trial
• P: 2857 patients with hypovolaemic shock (most had severe sepsis)
• I: crystalloids (isotonic or hypertonic saline or LR)
• C: colloids (gelatins, dextrans, HES, or 5% or 25% albumin)
• O: 28-days mortality:
• colloid group: 25.4%
• crystalloid group: 27.0%
• RR 0.96 [0.88–1.04]

• limitations:
• open-label design
• lengthy study period (2003-2012)
• heterogeneity of fluids
2015- SPLIT trial
• P: 2278 ICU patients (4 ICUs in New Zealand)
• I: plasma-lyte 148
• C: 0.9% saline
• O: AKI
• PL group: 9.6%
• saline group: 9.2%
• absolute difference 0.4% [-2.1%–2.9%]

• limitations:
• no sample size calculation (feasibility study)
• median 2L IVF + 1L PL before enrolment
• 15% admitted from ED (most from elective surgery)
2018- SMART trial
• P: 15,802 ICU patients (5 ICUs at single university hospital)
• I: BC (LR or plasma-lyte A)
• C: 0.9% saline
• O: composite of death, new RRT, or persistent renal dysfunction
• BC group: 14.3%
• saline group: 15.4%
• OR 0.91 [0.84–0.99]

• limitations:
• not blinded
• not truly randomized
• median 1L IVF
• 50% admitted from ED
2021- BaSICS trial
• P: 10,520 ICU patients + ≥1 risk factor for AKI (75 ICUs in Brazil)
• I: plasma-lyte 148
• C: 0.9% saline
• O: 90-day survival
• PL group: 26%
• saline group: 27%
• HR 0.97 [0.90–1.05]

• limitations:
• median 3L IVF + 1L before enrolment
• 50% admitted from elective surgery
• PL vs. LR?
METHODOLOGY
• Registered on PROSPERO
• Followed PRISMA

• Searched PubMed, EMBASE & Cochrane CENTRAL

• Inception >> Jan/2020

• 2 authors (CH Tseng and TT Chen) independently screened RCTs,

extracted data, & assessed RoB using RoB 2 tool
• 3rd reviewer (YK Tu) was consulted to resolve any disagreement
Patient Acute ill patients requiring fluid resuscitation
1. sepsis
2. surgery
3. trauma
4. traumatic brain injury
Intervention Crystalloid solutions
1. high chloride solution (saline)
2. low chloride solutions (Ringer’s lactate, Ringer’s acetate, or Plasmalytes)
Comparator Colloid solutions
1. iso-oncotic albumin (4%, 5%)
2. hyperoncotic albumin (20%, or 25%)
3. high HES (MW≧200)
4. low HES (MW≦130)
5. gelatin
Outcomes 1. all-cause mortality
2. fluid resuscitation volume
3. acute kidney injury
4. transfusion volume
5. allergic reaction rate
Inclusion 1. RCT.
criteria 2. ≧18 yo
3. Indication for acute fluid resuscitation
4. Allocation to resuscitation fluid with one with another among above fluid types

Exclusion 1. Observational study designs, cross-over trial, or single arm study

criteria 2. No specified patients clinical conditions for volume resuscitation
3. Comparator used is whole blood or blood products
NMA (Network Meta-Analysis)
• Network map
• Direct/indirect evidence
• Transitivity assumption

• SNMA
• SUCRA

• CINeMA
Transitivity assumption
• Valid NMA relies on the assumption that included trials in analysis are
similar in all important factors that may affect treatment effects

• Variables examined included:

• age
• male percentage
• disease severity scores
• source of sepsis from the lung
• publication year
 Transitivity assumption in sepsis trials

90
80

80
70

MAP
Age

70
60
50

60
40

50
BC 0.9% saline Iso-Alb Hyper-Alb L-HES H-HES Gelatin BC 0.9% saline Iso-Alb Hyper-Alb L-HES H-HES Gelatin
SNMA (Sequential NMA)
• To adjust for multiplicity of statistical testing
• Multiplicity = inflation of false positive rate due to multiple testing
• multiple treatment arms
• multiple subgroup comparisons
• multiple outcomes

• Sequence of NMA by including studies incrementally into the analysis

according to their publication years
SUCRA (Surface Under Cumulative Ranking curve
Area)
• Method for ranking treatments
• To address difficulty in interpreting NMA results

• Range from 0% (bottom rank) to 100% (top rank)

• Does not take into account the quality of the evidence
SUCRA in sepsis trials
Risk-of-Bias in sepsis trials
Publication bias in sepsis trials

Mortality in sepsis patients Acute kidney injury in sepsis patients

CINeMA (Confindence In NMA)
• Grade the confidence in results as high/moderate/low & very low

• Modification to the 5 domains of standard GRADE system to fit NMA

• Study limitations (= RoB)
• Publication bias (= funnel plot)
• Imprecision (= 95% CI)
• Indirectness (= transitivity assumption )
• Inconsistency
• Heterogeneity (between direct comparisons)
• Incoherence (between direct and indirect comparisons)
CINeMA for mortality in sepsis trials
Limitations
• in sepsis trials (n = 14,659) the evidence was adequate between
balanced crystalloids and saline, L-HES, and albumin, but insufficient
between balanced crystalloids and gelatin.

• in traumatic trials (n = 5076) the confidence rating was low, because

the sample size was insufficient and confidence intervals were wide.

• for traumatic brain injury trials (n = 1970) the confidence rating was
very low, because the direct and indirect evidence was inconsistent
and sample sizes were insufficient.
RoBIS (RoB In SR) tool
1. assess relevance (optional)
2. identify concerns with the review process
• Study eligibility criteria
• Identification and selection of studies
• Data collection and study appraisal
• Synthesis and findings
3. judge RoB
Qualitative summary for sepsis trials
Qualitative summary for trauma trials
Conclusions
• Among sepsis, balanced crystalloids and albumin attained
lower mortality rates, lower risks of acute kidney injury, and
less red blood transfusion volume than did saline and L-HES.
• In traumatic brain injury patients, saline and L-HES showed
better mortality rates than hypotonic solutions, including iso-
oncotic albumin and balanced crystalloids.
SO, WHAT DO YOU THINK?
Links for further readings
• https://www.annemergmed.com/article/S0196-0644(20)30139-6/fulltext
• https://training.cochrane.org/handbook/current/chapter-11
• https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/s13643-017-0473-z

• https://training.cochrane.org/grade-approach
• https://cinema.ispm.unibe.ch

• https://www.bristol.ac.uk/population-health-sciences/projects/robis/
References
1. Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declère AD, et al. Effects of fluid resuscitation
with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic
shock: the CRISTAL randomized trial. Jama. 2013;310(17):1809-17.
2. Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, et al. Effect of a Buffered
Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care
Unit: The SPLIT Randomized Clinical Trial. JAMA. 2015;314(16):1701-10.
3. Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, et al. Balanced
Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018;378(9):829-39.
4. Zampieri FG, Machado FR, Biondi RS, Freitas FGR, Veiga VC, Figueiredo RC, et al. Effect of
Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in
Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA. 2021;326(9):818-29.
5. Tseng CH, Chen TT, Wu MY, Chan MC, Shih MC, Tu YK. Resuscitation fluid types in sepsis,
surgical, and trauma patients: a systematic review and sequential network meta-analyses. Crit
Care. 2020;24(1):693.