Caution when analyzing zero events in both arms: reanalysis of anaphylaxis risk for gelatin solutions

Fluid administration is essential for maintaining organ perfusion in patients experiencing hypovolemic or vasodilatory shock. Succinylated gelatin, the main component of gelatin solution used clinically as colloid fluid, is one of the options for volume expansion. In the past five years, two randomized controlled trials (RCTs) have reported benefits of gelatin solutions [1, 2]. One RCT found that gelatin better maintains blood viscosity and stabilizes the body's oxygenation balance [1]. Another RCT demonstrated that a smaller volume of gelatin was as effective as a larger volume of crystalloid at expanding blood volume, increasing cardiac output, and causing less interstitial space expansion [2]. However, there remains insufficient research examining its role in shock reversal.

Systematic reviews with meta-analysis (SRMA) pooling RCTs are frequently used as references for developing critical care guidelines. The lack of statistical significance in improving mortality and kidney replacement therapy outcomes from studies included in meta-analyses (which are generally small and include mostly postoperative patients) has led to concerns about administering gelatin solutions in adults with sepsis/septic shock. The surviving sepsis campaign 2021 [3] has noted 'moderate' undesirable effects based on meta-analytic data indicating higher anaphylaxis risk compared to alternative fluids [4]. However, this statistical finding warrants further discussion after careful examination.

In meta-analyses examining anaphylaxis in patients receiving gelatin fluids versus albumin or crystalloid solutions, a significant proportion (7 out of 10) of trials have zero events in both intervention and control groups (so-called zero total event trials), resulting in 'not estimable' risk ratios (RRs) [4]. Consequently, pooled estimates with significant RRs are derived solely from a small subset (3 out of 10) of RCTs. Meta-analyses omitting zero total event trials yield larger effect sizes than those including them, though experts recommend their inclusion to provide the most generalizable estimate of treatment effect [5]. Several approaches exist for handling meta-analyses with zero total event trials, and a straightforward method is to present the data using risk difference (RD) [5]. When the meta-analysis by Moeller et al. [4] was re-calculated with RD as the effect measure, all ten studies were weighed in the analysis. We also performed an updated SR on this issue, and no new RCTs were suitable for inclusion. As shown in Fig. 1A, the pooled estimate revealed a RD of 0.02 (95% CI − 0.02 to 0.06). Among the included studies, the RCT showing a statistically significant increase in gelatin-associated anaphylaxis had its weight reduced from 83.3 to 6%. The pooled estimates not only fail to reach a statistically significant difference but, from an evidence-based-medicine perspective, may also not fully exceed the threshold of minimal important differences. Therefore, the increased risk of anaphylaxis from gelatin infusion should be considered inconclusive.

Fig. 1

A Forest plot and B trial sequential analysis of risk difference in anaphylaxis rate in patients receiving gelatin fluids vs albumin or crystalloid solutions. M–H = Mantel–Haenszel, CI = Confidence Interval, RIS = required information size

Full size image

Although traditional meta-analyses can statistically examine pooled effect size, the 95% CI threshold may lead to false-positive (type I errors) or false-negative (type II errors) conclusions, especially when too few studies and participants are enrolled. Advanced meta-analysis methodology such as trial sequential analysis (TSA) can be employed for examination in such situations, and RD can be used to present pooled estimates. TSA software version 0.9.5.10 beta was applied, with type I error and power set at 5% and 80%, respectively. The O'Brien–Fleming monitoring boundary using the random-effects model of the Biggerstaff–Tweedie method was applied, and incidences from intervention and control arms were extracted from the crude calculation. For zero event handling, a constant model was chosen, and a value of 0.5 was applied as a correction. Figure 1B illustrates that the end of the cumulative Z-curve does not cross the conventional test boundary and only just enters the futility boundary, suggesting a high possibility of true negative results. The cumulative sample size was 606, while the required information sample size was 871, indicating insufficient cases to definitively confirm the anaphylaxis risk of gelatin. Consequently, further studies are necessary.

Current clinical practice guidelines regarding gelatin solutions may benefit from reassessment, and meta-analysis results regarding anaphylactic reactions should be approached cautiously. Special attention is required when presenting statistics from meta-analyses including numerous zero total event trials reporting no observed adverse events. Ideally, the most rigorous assessment of fluid-induced anaphylaxis should be conducted through sequential network meta-analysis for more conclusive findings.

No datasets were generated or analysed during the current study.

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Authors and Affiliations

1. Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

   Hsiang‑Yi Hung

2. Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan

   Hsiang‑Yi Hung

3. Education Center, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan

   Pei‑Chun Lai

4. Department of Pediatrics, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan

   Pei‑Chun Lai

5. Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, No. 138, Shengli Road, Tainan, 701, Taiwan

   Yen-Ta Huang & Chao-Han Lai

6. Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

   Chao-Han Lai

7. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

   Chao-Han Lai

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Methodology: PC Lai, YT Huang; Original draft writing: HY Hung; Formal analysis: PC Lai, YT Huang; Writing—review and editing: YT Huang, CH Lai; Project administration: YT Huang. All authors read and approved the final manuscript.

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Hung, H., Lai, P., Huang, YT. et al. Caution when analyzing zero events in both arms: reanalysis of anaphylaxis risk for gelatin solutions. Crit Care 29, 151 (2025). https://doi.org/10.1186/s13054-025-05388-6

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• Received: 19 March 2025

• Accepted: 26 March 2025

• Published: 14 April 2025

• DOI: https://doi.org/10.1186/s13054-025-05388-6

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