1 Introduction

Hypertonic saline solutions (HTS) are used in the acute management of severe hyponatremia, elevated intracranial pressure (ICP), and cerebral edema [1]. The osmolality of sodium chloride 3% (3% HTS) is 1026 mOsm/L, which exceeds the threshold of 900 mOsm/L suggested by American Society for Parenteral and Enteral Nutrition (ASPEN) as the maximum osmolality that can be safely infused peripherally [2]. Thus, many institutions have traditionally restricted 3% HTS to administration via central venous catheter (CVC), and relied on sodium chloride 2% (2% HTS) for patients without central venous access [1, 3]. While CVCs allow for safer administration of infusions with higher osmolality, they can be associated with complications such as thrombosis and infection [4, 5]. As there is increasing evidence that peripheral administration of 3% HTS is safe [6,7,8,9,10,11,12], the policy at our institution was revised in 2018 from “central line required” to “central line preferred”. We hypothesized that this policy would reduce time to medication administration since 3% HTS is commercially available and does not require central line placement. The objective of this study was to evaluate the infusion-related adverse events associated with peripheral administration of 3% HTS compared to 2% HTS to determine if it can provide timely and safe treatment.

2 Methods

Approval was obtained by the Icahn School of Medicine at Mount Sinai Institutional Review Board. Following Institutional Review Board approval, a single-center retrospective chart review was performed. A report was run to identify patients who received 2% HTS or 3% HTS while admitted or in the emergency department between January 1, 2016 and December 31, 2019. Patients were manually screened for eligibility. Patients of any age were included if they received 2% HTS or 3% HTS peripherally for hyponatremia or ICP/intracranial hemorrhage. Indication for HTS was determined through physician documentation. Patients were excluded if they received HTS via a CVC, received both 3% and 2% HTS within 24 h of each other, or received HTS for pseudohyponatremia (serum sodium concentration < 135 mEq/L in the setting of a normal serum osmolarity) [13].

The primary outcome was the incidence of infusion-related adverse events, a composite definition including both phlebitis and infiltration in patients receiving 2% vs 3% HTS. Events were identified via nursing and physician documentation. Unscheduled line removal and replacement during HTS administration was also collected as a surrogate for possible infusion-related adverse event. Secondary endpoints included achievement of appropriate sodium correction in patients with hyponatremia (defined as increase in serum sodium by 6–8 mEq/L in 24 h) [14, 15], incidence of over-correction (defined as an increase in serum sodium by > 12 mEq/L in 24 h or > 18 mEq/L in 48 h) [15], length of time from ordering to medication administration, and incidence of osmotic demyelination syndrome (ODS). Cases of ODS were identified through documentation in the medical record, including during subsequent encounters.

For patients receiving HTS for hyponatremia, data was collected regarding the acuity and severity of the hyponatremia, as well as the presence or absence of symptoms such as headache, lethargy, altered mental status, or seizures [14, 15]. Acute hyponatremia was defined as onset within the last 48 h of HTS administration and chronic hyponatremia was defined as onset greater than 48 h before administration. Hyponatremia was classified as mild (serum sodium level 130–134 mEq/L), moderate (serum sodium 120–129 mEq/L) or severe (serum sodium level < 120 mEq/L) [16]. Serum sodium levels were collected at baseline, 12 h, 24 h, and 48 h.

2.1 Statistical Analysis

The chi squared test was used to evaluate categorical data. The Mann–Whitney test was used to evaluate continuous data. Significance was set at an alpha of 0.05. Data were analyzed using SAS software (v9.4, SAS Institute).

3 Results

A total of 282 patients were evaluated for inclusion. Sixty-four were excluded due to documented presence of a CVC during HTS administration and 19 were excluded for receiving both 2% and 3% HTS in a 24-h period. A total of 199 patients were included in analysis. Table 1 outlines the baseline characteristics of the included patients. The median age was 60 years and only 4% were pediatric patients (< 18 years). The majority of patients included received HTS for treatment of hyponatremia (74.4%); 25.1% received HTS for management of ICP and 0.5% for overlapping indications. Significantly more patients in the 2% HTS group were treated for hyponatremia versus the 3% HTS group (92 [80.7%] vs 56 [65.9%]; p = 0.04). Significantly more patients in the 3% HTS group received intermittent administration (49 [57.6%] vs 13 [11.4%]; p < 0.001), whereas patients in the 2% HTS group were more likely to receive HTS as a continuous infusion (26 [30.6%] vs 97 [85.1%]; p < 0.001) (Table 2).

Table 1 Baseline characteristics of study population
Full size table
Table 2 HTS administration characteristics
Full size table

For the primary outcome of infusion related adverse events, no difference was found between the two groups (0 vs 1 [0.9%]; p = 0.39), with only one patient experiencing phlebitis in the 2% HTS group. This patient was admitted to the ICU and received a continuous infusion of 2% HTS for acute mild hyponatremia. The infusion was running at 20 mL/h through a 20 gauge IV in the forearm. Site rotation was documented among 15.3% of patients in the 3% HTS group and 11.4% in the 2% HTS group (p = 0.55). For patients receiving a continuous infusion, the majority infusion rate was similar between the two groups (40 mL/h vs 50 mL/h; p = 0.197) as was the maximum infusion rate (50 mL/h in both groups). The duration of continuous infusion was significantly shorter in the 3% HTS group compared to the 2% HTS group (7.5 h vs 22.5 h; p < 0.001). For intermittent infusions, patients in both groups received on average 1 infusion per day run over 1 h. The volume was not significantly different between the two groups (100 mL vs 150 mL; p = 0.15). There were no reports of ODS in either group (Table 3).

Table 3 Outcomes for all subjects
Full size table

The rate of overcorrection at 48 h was significantly higher in the 3% HTS group (9 [16.1%] vs 2 [2.5%]; p = 0.01). However, there was no difference rates of overcorrection at 24 h (10 [17.9%] vs 10 [11.2%]; p = 0.38) (Table 3) or achievement of target correction (34 [61.8%] vs 58 [63%]; p = 0.88) (Table 4). Length of time to administration was not different between the 3% HTS and 2% HTS (53 min vs 58 min; p = 0.12). More patients in the 3% group received desmopressin after initiation of HTS for prevention of sodium overcorrection than those in the 2% group (10 [17.2%] vs 4 [4.3%]; p = 0.02). The median dose of desmopressin given was 1 mcg in the 3% group vs 1.5 mcg in the 2% group (p = 0.42) (Table 5).

Table 4 Outcomes for hyponatremia treatment subgroup
Full size table
Table 5 Baseline characteristics for hyponatremia treatment subgroup
Full size table

4 Discussion

We found an overall low rate of infusion-related adverse events and no statistically significant difference between the 3% HTS and 2% HTS groups. The rates of infusion-related adverse events in our study (0.5% overall) were lower than that of previously published studies, which are between 2.1 and 30% [6, 7, 17, 18]. Site rotation occurred at a similar rate in both groups, and while it may indicate local venous irritation, at our institution peripheral lines are replaced every 3–4 days. We did not assess peripheral line days and were unable to determine if line replacements were according to protocol or infusion-related events. It is likely that using line rotation as a surrogate for infusion-related adverse events would lead to an overestimation of adverse events.

We found no difference in rates of IRAE between patients who received 2% HTS (684 mOsm/L) and 3% HTS (1,027 mOsm/L) administered peripherally. This finding is consistent with that of a study by Meng et al. [7] who compared patients receiving 3% HTS and patients receiving routine-care solutions peripherally, essentially comparing hypertonic solutions to isotonic solutions. Of the total number of catheters evaluated, phlebitis occurred in 25%. No differences were found between the frequencies of phlebitis between the HTS group and the isotonic group. These findings, in addition to ours, suggest that the high osmolarity of 1026 mOsm/L does not confer excessive additional risk compared to isotonic solutions.

Our evaluation of infusion-related adverse effects is limited by the differences in administration methods between the 3% HTS and 2% HTS groups. The 3% HTS group was more likely to receive treatment via bolus administration, defined as an infusion of up to 1 h at our institution. Bolus administration of HTS may be less irritating than continuous infusions, potentially underestimating the risk of phlebitis with 3% HTS. This assumption is supported by data published by Pohl et al. [17] that found in pediatric patients receiving 3% HTS via peripheral IV, bolus administrations were 89.1% less likely to have a complication compared with continuous infusion.

Our results may be further limited by the shorter duration of continuous infusion in the 3% HTS compared to the 2% HTS group, which is also shorter compared to published literature, although infusion rates are comparable. Deveau et al. [18], through evaluating IRAE associated with the peripheral administration of 3% HTS, proved that a higher infusion rate is associated with increased odds of an IRAE. Studies by both Perez et al. [8] and Dillon et al. [9] found rates of IRAE higher than our study at about 6% and both had longer infusion rates at 36 h and 14 h, respectively. An evaluation by Jones et al. compared two centers with differing maximum HTS infusion rates, 75 mL/h versus 30 mL/h. Amongst the 73.7% of patients receiving HTS via peripheral IV, the median duration of infusion was 44.72 h. Infusion-related reactions were identified in 15 patients (7%) with an average infusion rate of 33 mL/h. Interestingly higher infusion rates did not appear to contribute to a higher frequency of events. This differs from Meng et al.’s evaluation which observed a higher frequency of events when infusions exceeded 30 mL/h. Perez et al. and Dillon et al. both found an event rate of about 6% in adult ICU patients receiving HTS via peripheral line, with average infusion rates similar to or lower than ours (39 mL/h and 34 mL/h respectively). These two studies also had infusion rates longer than ours at 36 h in Perez et al. and 14 h in Dillon et al.

Studies in the pediatric population similarly suggest the safety of peripheral administration of 3% HTS. Luu et al.’s [10] retrospective review of pediatric patients receiving 3% HTS during critical care transport reported no local infusion reactions, although infusion durations averaged only 47 min. Brenkert et al. [11] retrospectively evaluated pediatric patients receiving HTS in the emergency department, similarly documenting no incidences of phlebitis or tissue injury with bolus administration. Pohl et al. [17] evaluated pediatric patients receiving 3% HTS peripherally and demonstrated a low rate of infiltration (2.1%). As only 4% of patients in our study were < 18 years old, specific conclusions about pediatric patients in our study are limited.

We did not find a significant difference in rates of overcorrection with 3% HTS compared to 2% HTS except for at the 48-h mark (9 [16.1%] vs 2 [2.5%]; p = 0.01). When evaluating the absolute value of sodium increase in both groups at baseline and at 48 h, we saw a similar increase (from 126 to 134 mEq/L in the 3% HTS group and from 127 to 134 mEq/L in the 2% HTS group) (Fig. 1). Additionally, the time to achieve sodium > 130 mEq/L was similar in both groups. This suggests that there is no clinical relevancy to the difference in overcorrection seen at the 48-h mark. In addition, the SALSA trial by Baek et al. [12] found that overcorrection occurred at a numerically lower rate with bolus administration compared to continuous infusion (17.2% vs 24.2%), although the difference was not statistically significant. As in the SALSA trial, we found no difference between the groups for rate of achievement of target correction or ODS, although the latter was limited by our small sample size. While Baek et al. did not record data regarding relowering treatment, we did see that 14 patients total received desmopressin in our study.

Fig. 1
figure 1

Hyponatremia treatment response. Median serum sodium level at baseline, 12 h, 24 h, and 48 h after initiation of hypertonic saline treatment by group. HTS, hypertonic saline solution

Full size image

Despite commercial availability of 3% HTS, we did not find a reduction in time to administration of 3% HTS as hypothesized. This may have been due to lack of familiarity with the updated policy as this study evaluated a period of time soon after the policy was enacted. Despite the lack of improvement in time to administration, commercially available 3% HTS may provide operational benefits and optimize nursing and pharmacy workflow, an outcome our study did not evaluate. We expect as 3% HTS is more routinely used, time to administration would likely improve over 2% HTS.

Our study is limited by its retrospective design as this restricts our results to what was documented in the medical record. This could have introduced misclassification bias and impacted the rates of infusion-related adverse events and cases of ODS, as these outcomes were determined through nurse/physician documentation. Some outcomes such as overcorrection at 48 h were not available for all patients due to discharge prior. Lastly, while we did collect data on desmopressin use, we did not analyze doses used or the timing of administration. We also did not record use of other interventions to manage rapid correction or overcorrection, such as dextrose 5%. Additionally, the use of adjunctive venous irritants was not collected.

5 Conclusion

Our study is one of the largest to evaluate the peripheral administration of 3% HTS, showing that it is not associated with an increase in infusion related adverse events or sodium overcorrection when compared to 2% HTS. In addition to adding to existing literature supporting the peripheral administration of 3% HTS, our study adds information about sodium correction rates, showing no difference in overcorrection between 3% HTS and 2% HTS. Despite not finding an improvement in time to administration, there are operational benefits to using 3% HTS that may translate to improved time to treatment, reduction in labor, and reduced central line utilization. Lack of central access should not be considered an obstacle to administration of 3% HTS and peripheral administration should be recommended in order to provide timely treatment for patients requiring HTS.