To the best of our knowledge, this is the first, multicenter, longitudinal study indicating the effect of continuous HTS infusion on in-hospital outcome among msTBI patients while addressing simultaneously the time-varying nature of this type of exposure. We found that the utility of HTS was not independently associated with mortality, but with better neurological outcomes, increased infection complications, DVT, hyperchloremia, hypernatremia, LOS, and sedation duration. By characterizing the ICP trajectories of patients, we also identified that HTS was associated with better neurological outcome in the medium and low ICP subgroups.
Of note, cerebral edema develops from several pathologic mechanisms following TBI, leading to cerebral herniation and a rapid worsening of prognosis[24, 25]. Nevertheless, the availability of neurosurgical interventions in most medical facilities is limited, means of inducing a hyperosmolar environment including HTS are currently proposed[26]. Accordingly, the effects of HTS on TBI patients need to be further explored.
As expected, in this passage, both hypernatremia and hyperchloremia are both causes and results of HTS. Similarly, previous studies have also concluded that if not properly controlled, continuous infusion of HTS may bring hypernatremia and hyperchloremia, accompanied by the increased in-hospital mortality[27, 28].
Moreover, in this study, continuous HTS infusion did significantly improve neurological outcome as assessed by the GCS value on the day of discharge. Relatively more severe TBI (moderate: 747 vs severe: 1208) patients have increased the power to indicate the impact of HTS owing to the fact that the risk of intracranial hypertension or brain edema is higher in this population[29]. The precise regulatory mechanism remains to be further elucidated. Perhaps, the efficacy of HS in brain edema resulting from TBI was closely associated with the downregulation of aquaporin-4 (AQP4), the restoration of brain blood barrier (BBB) integrity and the suppression of inflammatory factors including Interleukin (IL‑1β), tumor necrosis factor (TNF-α), NF‑κB[30].
Furthermore, our study provided evidence that continuous HTS infusion was not significantly associated with mortality. It is worth noting that our passage was able to elucidate that the mortality described was related to an underlying medical condition itself, not other confounders, including hypernatremia or hyperchloremia. Congruently, a 2021COBI RCT published in JAMA found that there was no significant difference in 6-month mortality between the HTS group and control group[31]. Likewise, Tan SK et al[15] found that HTS was not associated with hospital mortality in patients with severe TBI. Yet one systematic review concluded that HTS was associated with a reduction of in-ICU mortality[32]. Given the heterogeneity of the included population, we planned a subgroup analysis to account for this possibility. Specifically, restricting the analysis to the subgroup of obesity patients did demonstrate a higher mortality. In this regard, studies conducted by Brown CV et al, Chabok SY et al had similar results to ours[33, 34]. Further, this adverse effect seems to be due to age, lower admission blood pressure, and more associated chest injury, rather than a direct result of the obese state, however, this speculation needs further validation[33].
In addition, our findings added additional evidence to previous studies suggesting that continuous HTS infusion did not result in increased AKI, suggesting no harm to the kidney[35, 36]. An important factor may be that, in ICU, patients were kept in euvolemia or mild hypervolemia, despite supraphysiologic serum sodium and serum osmolarity.
Nevertheless, a concerning finding was the association between continuous HTS infusion and increased infection and LOS. Previous clinical trials concerning continuous HTS infusion and infection were limited with mixed results; some reported increased infection[35] while others did not[37, 38]. Physiologically, high sodium levels have demonstrated suppressive effects on leukocyte activation and could theoretically impair the immune system, resulting in higher infection rates[39]. As hypothesized, previous studies have suggested that increased LOS may be due to multiple complications, especially, hypernatremia and infection. Further studies might be needed to confirm the above assumptions.
To further explore the association of HTS on in-hospital outcomes and provide an insight into the mechanisms by which ICP level produces this effect, we characterized the ICP trajectories and estimated the impact of ICP burden on outcomes. Indeed, the heterogeneity of the included population in terms of ICP evolution pattern was evidenced. Although case mixes were different from one subgroup to the others, a protective effect was found in the low and medium ICP subgroups, which was consistent with the result of MSCM, adding the robustness to our findings.
The strength of our study lied in a population-based longitudinal cohort from multi-center in US, a high-quality data with granular temporal detail, a homogeneous population, accordingly, ensuring the robustness, reliability, generalizability of the findings. Apart from this, to estimate the causal effect of HTS administration on in-hospital outcome, we employed MSCM, which helped align results from an observational study with those of actual randomized controlled trials. Moreover, by implementing multiple imputation to missing data, the analysis gave a relatively robust conclusion to reduce the estimation bias and improve validity. Unmeasured confounders were also treated by E-Value. When compelling randomized trials are not yet forthcoming, it is incrementally valuable that credible evidence for the effect of the HTS in TBI patients was supplied in our study.
This study had several limitations, consistent with those inherent to many large administrative database studies. First, based on electronic records of routine clinical practice, missing data and outliers were common. Second, we did not have data on functional outcomes after discharge, which was arguably an important indicator in this study. Second, as a retrospective study, unmeasured confounding was inevitable. Thus, to quantify the potential implications of it, E-Value sensitivity analysis was used, which demonstrated that the results obtained would be different only if we had omitted the major covariates, which was often not the case in our study. Third, instead of outcome adjudication, our outcomes were defined by ICD-9 and ICD-10 diagnosis codes. Incorrect codes or misclassification bias inevitably exist, so the codes we used were all verified by previous articles[40, 41].