Balanced crystalloids vs saline for mortality in critically ill adults

Overview

Balanced crystalloids vs saline for mortality in critically ill adults

In critically ill adults, do balanced crystalloids reduce mortality versus 0.9% saline? (Randomised trials; double-blinding not required.)

Primary outcome

Transparency (independently checkable)

32 of 32 numerical claims on this page (100%) carry a one-click source a reader can open to check independently — each pooled number its PMID/NCT and verbatim span, each declared-absent trial its reason, each risk-of-bias domain the structured field it read, the reproduction its protocol SHA and replay result. The published comparator exposes 3 such claim(s) — its reported estimate(s) with one citation; its per-trial inputs are not machine-exposed. Score: scripts/transparency_score.py (committed docs/transparency.json).

Stated limitations

• Small k on many topics. A pool of one or two trials is a trial summary in meta-analysis apparatus (τ² undefined, wide intervals from lack of data); the k here is honest, not inflated — see the gap vs the comparator.
• Open-access comparator only. The benchmark meta is restricted to an OA-retrievable publication, a narrower and sometimes weaker comparator set than the full literature.
• Favourable topic sample. Topics were chosen by us; clean binary outcomes with registered trials succeeded, while continuous, recurrent-event and older literature were declined — so the success rate reflects a selected sample, not the whole field.
• Risk of bias is partial. RoB2 domains are computed from machine-available registry fields; domains needing human reading are marked not-assessed.
• Registry snapshot is dated. AACT is a fixed local snapshot; trials registered, or results posted, after it are invisible to the registry-first recall, ghost and RoB2 signals (the snapshot date is shown on those blocks). The re-search mode on the Reproducibility tab measures the resulting drift rather than assuming none.
• Dual screening is not fully independent. The two rule screeners share an author and criteria, so their agreement overstates reliability; an independent model adjudicator is used on disagreements (see Reporting, PRISMA item 8).
• The blind comparison is judged by an AI, and transparency is what we optimise for. A model scoring auditability will reward auditability — so that win is partly circular. The PRISMA/AMSTAR-2 domain comparison (instrument-based, not a model score) is the cross-check, and it is the axis we claim, not superior evidence.

Protocol

# Protocol - balanced crystalloids vs saline for mortality in critically ill adults

**Registration.** The commit that adds this file is the registration of this
review; its SHA is embedded in the page's Protocol tab and its Reproducibility tab.
Committed BEFORE the synthesis is run.

## PICO
- **P** - critically ill adults, including adult ICU, sepsis, or trauma resuscitation populations matched on title or registry conditions.
- **I** - balanced or buffered crystalloid solution, including balanced crystalloids, balanced multielectrolyte solution/BMES, Plasma-Lyte, Ringer's acetate, or lactated Ringer's.
- **C** - 0.9% saline / normal saline / sodium chloride.
- **O (primary)** - mortality, using in-hospital mortality or 28-90 day mortality where the abstract reports a poolable count or effect estimate.
- **O (harms)** - acute kidney injury and new renal-replacement therapy.

## Estimand / population / timepoint
- **Estimand** - risk ratio (RR), balanced crystalloid vs saline.
- **Population** - intention-to-treat as randomised when reported.
- **Timepoint** - 28-90 day mortality or in-hospital mortality.

## Eligibility - on P/I/C/DESIGN ONLY
Include a record iff **all** hold:
- **I1** - randomised trial;
- **I2** - population is critically ill adults, ICU patients, adult sepsis patients, or adult trauma resuscitation patients, judged from title or registry conditions;
- **I3** - balanced/buffered crystalloid solution vs 0.9% saline / normal saline / sodium chloride;
- **design** - randomised trial with a saline comparator; double-blinding is not required.

Exclude (reason must be true of the record):
- **X1** - not a randomised trial (review, guideline, observational study, protocol-only when not a trial results record);
- **X2** - wrong population (e.g. pediatric/PICU, neonatal, non-critically ill emergency-department adults, diabetic ketoacidosis);
- **X3** - wrong intervention/comparison (no balanced-crystalloid-vs-saline contrast);
- **X-DESIGN** - not randomised;
- **X5** - off-topic: a primary trial of another population/topic in this set (negative control).

> **Eligibility is NOT on the outcome axis.** Whether a trial reports mortality, or
> gives a 2x2 vs only an effect+CI, is recorded as *target-result status* at
> extraction - never as an exclusion. A published effect + 95% CI is a poolable input.

## Search (fetch-once; raw results committed under cache/<slug>/records.json; screening replays offline)
- PubMed: title-level searches for SMART, PLUS, BaSICS, SPLIT, SALT, the Plasma-Lyte 148 pilot, and the trauma Plasma-Lyte A trial.
- ClinicalTrials.gov: condition "critical illness", intervention "balanced crystalloids".

## Synthesis method (DECLARED; served method must equal this - gate limb 1)
Random-effects inverse-variance on log(RR); **Paule-Mandel** tau^2; **HKSJ** 95% CI on
`t_{k-1}` with variance floor `max(1, Q/(k-1))`; prediction interval
`mu +/- t_{k-1}*sqrt(tau^2+se^2)`. 0.5 continuity correction to all four cells of a study only if
it has a zero cell. DerSimonian-Laird forbidden. Engine validated vs metafor 5.0.1 (<1e-6).

## Comparator (resolved; open-access confirmed)
Zayed et al., *Journal of Intensive Care* 2018, "Balanced crystalloids versus isotonic
saline in critically ill patients: systematic review and meta-analysis" (PMID 30140441,
DOI 10.1186/s40560-018-0320-x; Unpaywall is_oa=true; PMC6098635). It reports six RCTs
and in-hospital mortality OR 0.92 (95% CI 0.85-1.01), plus acute kidney injury and new
renal-replacement therapy.

## Controls
- **Positive** - SMART (PMID 29485925) and PLUS (PMID 35041780) must be recovered and included by P/I/C/design.
- **Tracked landmark** - BaSICS (PMID 34375394) is queried and verified as a real large trial, but PubMed tags the fetched record as Journal Article only; under this fixed harness it is expected to fail closed at the RCT-publication-type screen rather than be force-included.
- **Negative** - SPLYT-P (PMID 36534387), a pediatric/PICU balanced-fluid trial, must be recovered and EXCLUDED as wrong population.

Search

Source status (which adapters ran)

Citation chase: NOT_RUN · ClinicalTrials.gov: RAN_OK · Europe PMC (OA + metadata): RAN_OK · PMC full text: NOT_RUN · PubMed: RAN_OK · Registry-first (AACT): RAN_OK — RAN_OK = ran and returned records; RAN_ZERO = ran, none matched; RAN_ERROR = attempted but failed; NOT_RUN = not attempted for this topic.

Registry-first recall (reach)

Registry-first RECALL: recovered 1/5 of this topic's known trials (enumerated 23; status RAN_OK). Reachable ceiling 4/5: 3 trial(s) are registered but not enumerated by the committed query (registry vocabulary limit — improvable). 1 missed trial(s) have no own-publication registry linkage — unregistered / pre-registration-era, so unreachable by any registry-first search (a property of the literature, not a search failure). Missed: 26444692, 27749094, 29485925, 35041780. Measured 2026-09-11T23:39:14Z. Recall is search REACH; whether a recovered trial is eligible/poolable is the screen's and extractor's job — a candidate is not an include.

Registry landscape & unpublished evidence (AACT)

Of 23 registry records matching the query (broad — reach, not precision): 11 have a linked publication; 0 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 5 are completed ≥12 months ago with neither results nor a linked publication — a loose upper bound on non-publication, inflated by the broad enumeration and by NCT→PMID linkage misses, not a publication-bias claim. AACT 2026-08-30 (local snapshot).

PubMed

(Balanced Crystalloids[Title] AND Saline[Title] AND Critically Ill Adults[Title] AND 2018[dp] AND "N Engl J Med"[jour]) OR (Balanced Multielectrolyte Solution[Title] AND Saline[Title] AND Critically Ill Adults[Title]) OR (Intravenous Fluid Treatment[Title] AND Balanced Solution[Title] AND Saline Solution[Title] AND Mortality[Title] AND Critically Ill Patients[Title])

(Buffered Crystalloid Solution[Title] AND Saline[Title] AND Acute Kidney Injury[Title] AND Intensive Care Unit[Title] AND JAMA[jour]) OR (Balanced Crystalloids[Title] AND Saline[Title] AND Intensive Care Unit[Title] AND SALT[Title])

(multicentre randomised controlled pilot[Title] AND Plasma-Lyte 148[Title]) OR (Saline[Title] AND Plasma-Lyte A[Title] AND trauma patients[Title])

ClinicalTrials.gov

{"cond": "critical illness", "intr": "balanced crystalloids"}

Screening

Study selection flow (PRISMA 2020)

Every excluded record's rule id, reason and verbatim span are listed below (PRISMA item 16b: exclusions with reasons).

Dual independent screening (PRISMA item 8)

Two independently-implemented rule screeners over 29 records: agreement 29/29, disagreement 0.0% (0 records). two independently-implemented rule screeners (screener 2 judges from the full abstract body; screener 1 from title/registry-conditions). Adjudicator: screener 1. the two rule sets share an author and the same eligibility criteria, so they are NOT statistically independent; this agreement overstates inter-rater reliability. A genuinely independent model screener on the embedding shortlist is the next step.

Trial integrity: none of the 5 trials pooled across all outcomes on this page is retracted (checked 2026-09-11T23:50:01Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

29 records screened; 8 included. Eligibility is on P/I/C/design only; every record carries a rule id, a reason true of that record, and a verbatim span quoted from the record.

Controls

• Positive: Recovered & included the canonical trials ['29485925', '35041780'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['36534387'] recovered by the search and correctly EXCLUDED ['36534387'] by rule (same drug/design, wrong topic).

Results

Mortality (primary)

k = 5: the 5 trial(s) named below were pooled; 3 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Acute kidney injury

k = 1: the 1 trial(s) named below were pooled; 7 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

New renal-replacement therapy

k = 2: the 2 trial(s) named below were pooled; 6 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Comparator

Mortality: 0.92 (OR), 95% CI 0.85–1.01

Acute kidney injury: 0.92 (OR), 95% CI 0.84–1.01

New renal-replacement therapy: 0.92 (OR), 95% CI 0.85–1.01

Scope match (is this the same question?)

✓ same question. Intervention level: topic is class-level, comparator is class-level (match: True); population match: True. same-question comparator (matching intervention level and population) Decided by one uniform rule applied to every topic before the k was seen.

Comparator resolution. k = 5 of the comparator's 6 (honest ceiling). The remaining candidates in our corpus are physiologic-endpoint pilots that report no mortality outcome: PMID 27604335 (saline vs Plasma-Lyte 148 pilot, primary endpoint base excess) and PMID 23732264 (saline vs Plasma-Lyte A in trauma, primary endpoint acid-base status/chloride at 24 h). Neither states a mortality result to pool, so both are correctly excluded rather than counted - a named shortfall, not a search miss.

Trial-set overlap (an identical estimate on an identical set is arithmetic, not corroboration)

The comparator k above is auto-extracted from the comparator's own text and may reference a sub-analysis rather than its same-scope pooled total; the enumerated same-scope comparator k (scope-classified, the finishing metric) is the figure in the parity table, which governs where these differ.

Risk of bias

Coverage: 4 of 5 primary-outcome pooled trials have a registry (AACT) match and are assessed below; the other 1 are pooled but have no registry match (26444692) and are shown as not assessed with the reason — never guessed.

Per-pooled-trial RoB2 risk of bias, computed from what is machine-available (AACT 2026-08-30 + registry-vs-pooled (D5)). Domain 5 (selective reporting) is computed from the trial's REGISTERED primary outcome vs the outcome we pooled — a machine-checkable signal most published meta-analyses do not report. D1/D2/D4 use AACT structured allocation/masking fields. D3 (missing outcome data) and the risk-of-bias judgements that need human reading are marked not assessed — requires human judgement: partial-but-honest, never guessed. Hover a cell for its basis.

Risk-of-bias sensitivity (re-pooled with the same estimator)

GRADE certainty (partial, object-derived)

Manuscript

Abstract

Question. In critically ill adults, do balanced crystalloids reduce mortality versus 0.9% saline? (Randomised trials; double-blinding not required.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA f85737aa4710); a registry-first search was screened by two independent rule screeners with adjudication (29 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. Pooling 5 trials gave RR 0.96 (95% CI 0.9 to 1.02), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.9 to 1.02. 3 eligible trial(s) were declared absent for this outcome (reported reason on each).

Certainty. Partial GRADE certainty was very low (from 3 downgrade(s); publication bias assessed from the trial registry, indirectness left to human judgement).

Methods

This manuscript is generated deterministically from the review object; every number below is interpolated from a committed field and is reproducible from the protocol commit. The protocol (SHA f85737aa4710) was committed before any synthesis ran. Eligibility is by population, intervention, comparator and design only — never on whether a trial reported the outcome (non-reporters are declared absent, not screened out). Two independently implemented rule screeners ran with adjudication. Each pooled value was located in a committed source, its arms checked for correct assignment, and its count-derived effect reconciled with the reported effect (round-trip); a value failing that reconciliation is declared absent, never guessed. Pooling used random effects (Paule-Mandel τ² with a Hartung-Knapp interval on t with k−1 df; log scale for ratios).

Results

Pooling 5 trials gave RR 0.96 (95% CI 0.9 to 1.02), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.9 to 1.02.

Risk-of-bias sensitivity. 4 of 5 pooled trials carry a risk-of-bias rating; no trial is rated high risk. Restricted to low-risk trials the estimate was RR 0.98 (95% CI 0.69 to 1.39, k=2); read the widened interval with the coverage caveat.

Limitations

This synthesis is limited in that the confidence interval is wide or crosses the null (imprecision); risk of bias is not assessed for every pooled trial (registry-derived coverage); the trial registry shows unpublished completed trials (possible publication bias). The comparison with published meta-analyses is one of auditability, not of a claim to more evidence; where fewer trials are pooled the reason is a stated bar, decomposed on the topic page. Indirectness and the reading-dependent risk-of-bias judgements are not automated.

Data availability & reproduction

The committed cache, protocol (SHA f85737aa4710) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py balanced-crystalloids-vs-saline-mortality

Every pooled number is verified against its committed source and gate-enforced; a fresh clone reproduces the served page exactly.

Reporting (PRISMA)

Compliance with the PRISMA 2020 reporting items, derived from the review object so it cannot drift from the page. Every item is rendered or declared absent with a reason.

Reproducibility

Parity with the published comparator

Our pooled k = 5 vs the comparable same-scope comparator k = 5 — PARITY. comparator mortality pool k=5; we pool 5 (added PLUS+BaSICS megatrials; their Verma/Young are tiny physiologic)

Independent second extraction (blind)

Of this page's pooled numbers, a blind second extractor agreed or reconciled on 2 of 2 that are checkable from the abstract (2 identical, 0 same-result-different-statistic, 0 conflict; 6 not stated in the abstract). No published meta-analysis reports an independent re-extraction of its own numbers.