Acidosis and increased tonicity in plasma can mediate pathologic changes in the membrane and cytoplasm of sickle red blood cells (sRBCs). These changes contribute to intravascular hemolysis, endothelial damage, and endothelial adhesion with propensity to microvascular occlusion, resulting in vaso-occlusive episodes (VOE) and end organ damage.¹ Kidney dysfunction, in particular, is common among adults with sickle cell disease (SCD) and is a major contributor to early mortality.^{1, 2} While adults with SCD seek emergency department (ED) care for VOE and other complications that may lead to hospitalization, selecting the most appropriate interventions, such as which crystalloid for hydration, remains a challenge and is still being studied.³ How these interventions impact end-organ injury also remain unknown. Evidence-based guidelines for optimal treatment of SCD in the ED do not recommend a specific fluid type,⁴ but recent pre-clinical models suggest increased extracellular fluid tonicity (i.e., higher sodium and chloride) can increase sRBC stiffness and endothelial adhesion, and subsequently higher risk of VOE under physiologic conditions.⁵ Further, normal saline (NS), which is the most commonly administered intravenous (IV) fluid in the ED, can cause hyperchloremic metabolic acidosis which may contribute to negative outcomes in patients with SCD.^{6, 7}

The seminal Saline Against Lactated Ringer's or Plasma-Lyte in the Emergency Department (SALT-ED) trial was a single-center, pragmatic, unblinded, multiple-crossover prospective randomized controlled trial (RCT) that enrolled non-critically ill adult patients treated in the Vanderbilt University Medical Center ED and randomized patients to receive NS or balanced crystalloids (BC), primarily lactated Ringer's (LR) based on calendar month (Figure S1).⁷ NS increased risk of major adverse kidney events and death at 30 days (i.e., MAKE30; Data S1) and in-hospital metabolic acidosis changes compared to more physiologic and balanced IV fluids like LR, which is hypotonic relative to plasma and has a more physiologic pH and osmolarity compared to NS (Table S1). In this intention-to-treat subgroup analysis of SCD patients enrolled in the study, our primary objective was to evaluate the same variables as SALT-ED specifically at the index visit (first visit). The primary aim was to determine if there were differences in length of stay (LoS) between those patients with SCD receiving NS versus BC, and secondary aims included evaluating the changes in kidney-related outcomes and suggestion of in-hospital metabolic acidosis by evaluating electrolyte status. We hypothesized that NS exposure would worsen all of these in those patients enrolled who had SCD. Exploratory aims included a per-protocol analysis of index visits and reviewing all ED visits among those with SCD and comparing all results to the overall SALT-ED cohort.

Comparisons between the overall SALT-ED cohort and those with SCD are outlined in Table S2. There were 247 ED visits among 97 unique adults with SCD during the trial period (~2.5 visits/patient), with N = 126 (51%) visits allocated to the BC group and N = 121 (49%) in the NS group (Table S3). Most documented chief complaints in the ED were VOE-related (Table S4). Patients with SCD were younger, more likely to identify as female and Black, and have a lower baseline serum creatinine (SCr) compared to the overall SALT-ED population (Tables S5 and S6). Total ED crystalloid volume and adherence to randomized IV fluid assignment were similar between all patients and those with SCD. Strikingly, patients with SCD enrolled in the SALT-ED trial had a 3.5 times higher odds of achieving a MAKE30 composite endpoint than the entire cohort. While no patients with SCD died during the study, there were 200 patient deaths in the overall study.

At the index visits, N = 58 adults with SCD were randomized to BC and N = 39 to NS (Table 1). Only one patient in the BC arm received Plasma-Lyte, and thus, we use the term LR for comparison. Groups were similar based on sex, race, total ED crystalloid volume, baseline and initial ED renal function (including SCr and eGFR), and baseline and initial serum electrolytes in the ED. Admission status and ICU transfers were similar between the two groups. No patients with SCD were on renal replacement therapy (RRT) for end-stage renal disease (ESRD). The 100% adherence to IV fluid assignment was lower in the LR group, suggesting a preference for NS in patients with SCD. Of note, prior to the SALT-ED trial, standard of care ED IV fluid at Vanderbilt was NS. Patients had evidence of hyperfiltration based on eGFR. While not statistically significant, compared to those with SCD randomized to LR, those patients who received NS had increased mean LoS (4.8 vs. 5.3 days) and more major adverse kidney events (i.e., MAKE30–17.9% vs. 12.1%). MAKE30 events were driven by the last SCr doubling from baseline and maximum in-hospital SCr at least double baseline SCr (20.5% NS vs. 13.8% LR). Maximum in-hospital SCr levels were significantly higher in patients randomized to NS in the ED compared to those receiving LR (p = .035). While last in-hospital SCr was higher in the NS group, it did not reach statistical significance. eGFR between the two groups at in-hospital maximum SCr and last SCr were similar. As was seen in the SALT-ED trial, mean electrolyte comparisons and post-hoc analyses suggested a trend toward increased in-hospital plasma BUN and sodium, as well as a trend toward metabolic acidosis in those receiving NS. Results were similar in the per-protocol analysis of the index visit and of the full data set (Tables S6 and S7).

To investigate the relationship of maximum in-hospital SCr with randomized IV fluid in the ED during the index visit, relationship with other covariates and potential confounders were assessed. The variables age, sex, race, study month, study day, randomized ED fluid type (NS vs. LR), total crystalloids in ED, baseline SCr, and ED SCr were first assessed using univariate linear regression estimates with maximum in-hospital SCr as the outcome. Multivariate linear regression was then used and the model was iteratively reduced until the final model was derived (Table S8). The final model found that age, randomized ED IV fluid type, and ED SCr levels had the largest effect on maximum in-hospital SCr results. For patients receiving LR in the ED, their maximum in-hospital SCr was likely to be 0.086 mg/dL (95% CI 0.027–0.15; p = .005) less than those participants who were randomized to receive NS in the ED (Table 1).

Fluid replacement therapy in the ED for adults with SCD and its impact on clinical outcomes remains woefully understudied. Improving care and mitigating negative side effects of the care delivered in the ED are often cited as an area of great need by adult patients with SCD and their clinical practitioners.^{3, 4, 6} In a retrospective pediatric cohort study among patients 3–21 years old, we found IV fluid use varied among ED providers during VOE management but that NS was used 65% of the time and increased the likelihood of hospitalization, more time spent in the ED, and worse pain control.⁶ This SALT-ED sub-analysis is the first investigation of prospectively recruited adult patients with SCD randomized to NS or LR in the ED. The results from this large RCT sub-analysis further support recent evidence suggesting NS is not an ideal resuscitation IV fluid for adults or children with SCD presenting to the ED with pain and other complications. Further, a recent target trial emulation analysis comparing in-hospital use of NS to LR found that use of NS may increase hospital LoS during VOE.⁸ Of note, type of IV fluids administered in the ED was not included in the analysis.

In our analysis, patients with SCD had an approximate 3.5 times higher odds of suffering an acute kidney injury (AKI) event during hospitalization as compared to the entire SALT-ED cohort. This further supports other evidence that this patient population deserves special attention during ED care. In addition to in-hospital development of AKI, SCD patients may present with AKI, defined by a rise in serum SCr, or subclinical AKI, defined by a rise in other biomarkers of kidney injury. Further, the development of AKI is a well-established model for the progression of CKD in other populations as well as in SCD. Pre-clinical models simulating sRBC biomechanical interactions with the microvasculature have also demonstrated that low-sodium, hypotonic fluids can hydrate sRBCs and reduce endothelial adhesion, whereas fluids high in sodium chloride may do the opposite. This suggests IV fluids with higher sodium and chloride content may uniquely increase risk of vaso-occlusion under physiologic conditions.⁵

Results from this sub-analysis further support prior evidence suggesting NS is not an ideal resuscitation IV fluid for patients with SCD presenting to the ED with pain and other complications and that less acidotic, more balanced crystalloids like LR may be a better option for IV fluid resuscitation among adults with SCD presenting to the ED. Further research is needed to confirm these findings. To adequately determine the optimal IV fluid regimen for adults with SCD presenting to the ED with VOE or other complications, a well-controlled and powered RCT is needed.

血浆酸中毒和张力增加可介导镰状红细胞 （sRBC） 膜和细胞质的病理变化。这些变化导致血管内溶血、内皮损伤和内皮粘附，并倾向于微血管闭塞，导致血管闭塞发作 （VOE） 和终末器官损伤。¹ 肾功能障碍尤其常见于患有镰状细胞病 （SCD） 的成人患者，并且是导致早期死亡的主要原因。^1、2虽然患有 SCD 的成年人因 VOE 和其他可能导致住院的并发症寻求急诊科 （ED） 护理，但选择最合适的干预措施，例如哪种晶体液进行补液，仍然是一个挑战，并且仍在研究中。³ 这些干预措施如何影响终末器官损伤也仍然未知。急诊科 SCD 最佳治疗的循证指南不推荐特定的液体类型，⁴ 但最近的临床前模型表明，细胞外液张力增加（即钠和氯化物升高）会增加 sRBC 刚度和内皮粘附，从而在生理条件下增加 VOE 的风险。⁵ 此外，生理盐水 （NS） 是 ED 中最常见的静脉内 （IV） 液体，可导致高氯血症性代谢性酸中毒，这可能导致 SCD 患者的不良结局。^6、7

急诊科针对乳酸林格氏液或血浆溶血剂的开创性盐水 （SALT-ED） 试验是一项单中心、实用、非盲、多交叉前瞻性随机对照试验 （RCT），该试验招募了在范德堡大学医学中心 ED 接受治疗的非危重症成年患者，并将患者随机分配接受 NS 或平衡晶体液 （BC），主要是基于日历月的乳酸林格氏液 （LR）（图 S1）。⁷ NS 在 30 天时发生主要不良肾脏事件和死亡的风险增加（即 MAKE30;数据 S1）和院内代谢性酸中毒的变化与更生理和平衡的静脉输液（如 LR）相比，LR 相对于血浆是低渗的，并且与 NS 相比具有更生理的 pH 值和渗透压（表 S1）。在对参加研究的 SCD 患者的意向治疗亚组分析中，我们的主要目标是在指数访视（首次访视）时专门评估与 SALT-ED 相同的变量。主要目的是确定接受 NS 与 BC 的 SCD 患者之间的住院时间 （LoS） 是否存在差异，次要目标包括评估肾脏相关结局的变化，并通过评估电解质状态提示院内代谢性酸中毒。我们假设 NS 暴露会使入组的 SCD 患者的所有这些情况恶化。探索性目标包括对指数就诊进行按方案分析，审查 SCD 患者的所有 ED 就诊，并将所有结果与整个 SALT-ED 队列进行比较。

表 S2 概述了整个 SALT-ED 队列与 SCD 队列之间的比较。在试验期间，97 名独特的 SCD 成人患者中有 247 次 ED 就诊 （~2.5 次/患者），其中 N = 126 （51%） 分配给 BC 组，N = 121 （49%） 分配给 NS 组（表 S3）。急诊科记录在案的大多数主诉与 VOE 相关（表 S4）。与整个 SALT-ED 人群相比，SCD 患者更年轻，更有可能被认定为女性和黑人，并且基线血清肌酐 （SCr） 较低（表 S5 和 S6）。所有患者和 SCD 患者的总 ED 晶体液体积和对随机 IV 液体分配的依从性相似。引人注目的是，参加 SALT-ED 试验的 SCD 患者达到 MAKE30 复合终点的几率是整个队列的 3.5 倍。虽然在研究期间没有 SCD 患者死亡，但整个研究中有 200 名患者死亡。

在索引访问时，N = 58 名患有 SCD 的成年人被随机分配到 BC 组，N = 39 名被随机分配到 NS 组（表 1）。BC 组中只有一名患者接受了 Plasma-Lyte，因此，我们使用术语 LR 进行比较。根据性别、种族、ED 晶体液总体积、基线和初始 ED 肾功能 （包括 SCr 和 eGFR） 以及 ED 中的基线和初始血清电解质，各组相似。两组之间的入院状态和 ICU 转移相似。没有 SCD 患者因终末期肾病 （ESRD） 接受肾脏替代治疗 （RRT）。LR 组对 IV 液体分配的 100% 依从性较低，表明 SCD 患者更倾向于 NS。值得注意的是，在 SALT-ED 试验之前，范德比尔特医院的标准护理 ED IV 液体为 NS。患者有基于 eGFR 的高滤过证据。虽然没有统计学意义，但与随机分配到 LR 的 SCD 患者相比，接受 NS 的患者平均 LoS 增加（4.8 天对 5.3 天）和更多主要不良肾脏事件（即 MAKE30-17.9% 对 12.1%）。MAKE30 事件是由最后一次 SCr 相对于基线的两倍和最大院内 SCr 至少是基线 SCr 的两倍（20.5% NS 对 13.8% LR）驱动的。与接受 LR 的患者相比，在 ED 中随机分配到 NS 的患者的最大院内 SCr 水平显着更高 （p = .035）。虽然 NS 组最后一次住院 SCr 较高，但未达到统计学意义。两组在院内最大 SCr 和最后一次 SCr 的 eGFR 相似。正如在 SALT-ED 试验中所看到的，平均电解质比较和事后分析表明，接受 NS 的患者有增加院内血浆 BUN 和钠增加的趋势，以及代谢性酸中毒的趋势。 在指数访问和完整数据集的按方案分析中，结果相似（表 S6 和 S7）。

为了调查指数访视期间 ED 中最大院内 SCr 与随机 IV 液体的关系，评估了与其他协变量和潜在混杂因素的关系。变量年龄、性别、种族、研究月份、研究日、随机 ED 液体类型 （NS vs. LR）、ED 总晶体液、基线 SCr 和 ED SCr 首先使用单变量线性回归估计进行评估，以最大院内 SCr 作为结局。然后使用多变量线性回归，并迭代简化模型，直到推导出最终模型（表 S8）。最终模型发现，年龄、随机 ED IV 液体类型和 ED SCr 水平对最大院内 SCr 结果的影响最大。对于在急诊室接受 LR 的患者，他们的最大院内 SCr 可能为 0.086 mg/dL（95% CI 0.027-0.15;p = .005） 小于那些在 ED 中随机接受 NS 的参与者（表 1）。

遗憾的是，成人 SCD 患者的 ED 补液治疗及其对临床结果的影响仍未得到充分研究。改善护理和减轻急诊科提供的护理的负面副作用经常被成年 SCD 患者及其临床从业者视为非常需要的领域。^3、4、6在一项针对 3-21 岁患者的回顾性儿科队列研究中，我们发现在 VOE 管理期间，急诊科提供者的静脉输液使用量各不相同，但 NS 的使用时间为 65%，并增加了住院的可能性、在 ED 花费的时间更多和疼痛控制更差。⁶ 该 SALT-ED 子分析是对前瞻性招募的成年 SCD 患者的首次调查，这些患者在 ED 中随机分配到 NS 或 LR。这项大型 RCT 亚分析的结果进一步支持了最近的证据表明，NS 不是因疼痛和其他并发症而就诊的 SCD 成人或儿童的理想复苏静脉输液。此外，最近的一项目标试验模拟分析将院内使用 NS 与 LR 进行比较，发现使用 NS 可能会增加 VOE 期间的医院 LoS。⁸ 值得注意的是，在 ED 中给药的 IV 液体类型不包括在分析中。

在我们的分析中，与整个 SALT-ED 队列相比，SCD 患者在住院期间发生急性肾损伤 （AKI） 事件的几率大约高 3.5 倍。这进一步支持了其他证据，即在 ED 护理期间，该患者群体值得特别关注。除了 AKI 的院内发展外，SCD 患者还可能出现 AKI，定义为血清 SCr 升高，或亚临床 AKI，定义为肾损伤的其他生物标志物增加。此外，AKI 的发展是其他人群和 SCD 中 CKD 进展的成熟模型。模拟 sRBC 与微血管系统生物力学相互作用的临床前模型也表明，低钠、低渗液体可以水合 sRBC 并减少内皮粘附，而氯化钠含量高的液体可能起到相反的作用。这表明在生理条件下，钠和氯含量较高的静脉输液可能会独特地增加血管阻塞的风险。⁵

该子分析的结果进一步支持先前的证据，表明 NS 不是因疼痛和其他并发症而就诊的 SCD 患者的理想复苏静脉输液，并且酸中毒少、更平衡的晶体液（如 LR）可能是在门诊就诊的 SCD 成人患者中静脉输液复苏的更好选择。需要进一步的研究来证实这些发现。为了充分确定因 VOE 或其他并发症而就诊于 ED 的 SCD 成人患者的最佳静脉输液方案，需要一项控制良好且有把握度的 RCT。