Safety of peripherally administered 23.4% sodium chloride

Safety of peripherally administered 23.4% sodium chloride | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Safety of peripherally administered 23.4% sodium chloride Christian Silva, Jessica Nagy, Andrew R. Zullo, Rebecca A Greene This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6346181/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Aug, 2025 Read the published version in Neurocritical Care → Version 1 posted 5 You are reading this latest preprint version Abstract Background/Objective For patients with increased intracranial pressure, prompt initiation of hyperosmolar therapy with 23.4% sodium chloride may minimize permanent neurological damage and prevent cerebral herniation. Placement of a central venous catheter can delay time to osmotherapy and may negatively impact patient outcomes. The objective of this study was to examine the safety of 23.4% sodium chloride administered through a peripheral intravenous (IV) catheter. Methods This was a retrospective observational cohort study conducted at a large academic health system. Patients were admitted to one 719-bed academic medical center and level 1 trauma center or one 247-bed academic community hospital. Subjects were 18 years or older, admitted between March 29, 2015 and October 21, 2023, and received 23.4% sodium chloride through a peripheral IV. Patients who expired or were discharged less than 24 hours after hypertonic saline administration were excluded. All subjects received at least one 30 milliliter bolus of 23.4% sodium chloride administered through a peripheral IV catheter. Measurements and Main Results The primary outcome, defined as extravasation of peripherally administered 23.4% sodium chloride, was assessed using the Naranjo Adverse Drug Reaction Probability Scale and occurred in 56 out of 863 administrations (6.4%). Secondary outcomes included incidence of tissue necrosis, interventions used to treat extravasations, and attributable risk factors for extravasation. There were no cases of tissue necrosis, no surgical interventions performed, and one case of medical intervention using hyaluronidase. Patients with a history of diabetes had a 2.39 times higher risk of experiencing a 23.4% sodium chloride extravasation event (95% CI 1.41–4.05 [p = 0.001]). Conclusions Peripheral administration of 23.4% sodium chloride was associated with a low rate of extravasation and no significant injury in patients that did experience a possible or probable extravasation event. Diabetes mellitus was a possible risk factor for extravasation. Intracranial pressure cerebral edema hypertonic saline solutions peripheral catheterization traumatic brain injury Figures Figure 1 Introduction Increased intracranial pressure (ICP) may result from a variety of potentially fatal conditions, including intracranial hemorrhage (ICH), seizure, stroke, malignancy, or infection. 1 Severe increases in ICP can result in irreversible brain damage by reducing cerebral perfusion pressure (CPP) and causing cerebral herniation, an event with a mortality rate greater than 60% in cases of traumatic brain injury (TBI). 2 Elevated ICP must therefore be treated expeditiously to reduce morbidity and mortality. In order to achieve rapid reductions in ICP, guidelines pertaining to the acute treatment of cerebral edema and management of severe traumatic brain injury recommend administration of mannitol or hypertonic saline. 3 – 5 Mannitol and hypertonic saline both reduce ICP, however mannitol produces an osmotic diuresis that may lower mean arterial pressure (MAP), decrease CPP, and cause acute kidney injury. 6 Additionally, current data show superior brain tissue oxygenation and greater benefit in the presence of cerebral ischemia with hypertonic saline. 7 – 8 Intravenous (IV) sodium chloride has been studied in a variety of concentrations, most commonly 3% and 23.4%. 3 Sodium chloride 23.4% is logistically advantageous as it is available in 30 milliliter vials that are more compact than 500 milliliter 3% sodium chloride bags and may conserve space in a medical supply bag. Notably, the smaller volume of 23.4% compared to 3% allows administration over a shorter timeframe (2–5 minutes vs. 10–15 minutes), decreasing the time to treatment. 9 Disadvantages of 23.4% sodium chloride are similar to those associated with 3% sodium chloride and include transient hypotension, pulmonary edema, and hyperchloremic acidosis. 10 – 11 One area of concern specific to 23.4% sodium chloride is its osmolarity of 8010 mOsm/L which exceeds the 900 mOsm/L threshold recommendation for peripheral line administration making it more likely to cause pain and vascular inflammation. 12 Prior data supporting the use of 23.4% sodium chloride given peripherally is limited to two observational studies (n = 74 peripheral administrations), which reported only one extravasation event. 9 , 13 Studies examining lower concentrations of peripheral hypertonic saline (3%) had a low risk of complications and infrequent infusion related adverse events (IRAEs). 14 – 17 Nevertheless, there is currently little data to support the safety of peripherally administered 23.4% sodium chloride and many institutions require administration through a central venous catheter to minimize the risk of extravasation and tissue injury. Central line insertion is more time consuming and awaiting placement can result in a delay in treatment that may be detrimental to patients with an elevated ICP or impending cerebral herniation. Thus, determining the safety of peripheral administration of 23.4% sodium chloride to provide expeditious treatment is essential. This study investigated the safety of 23.4% sodium chloride administration through a peripheral IV catheter and examined potential risk factors for extravasation. Methods Study Design and Setting This was a retrospective observational cohort study conducted at a large academic health system. Patients were admitted to one 719-bed academic medical center and level 1 trauma center or one 247-bed academic community hospital. This study was approved by the institutional review board and patient consent was not required due to the retrospective design. Selection of Participants Subjects included in this study were identified through the electronic medical record (EMR) and were admitted between March 29, 2015 and October 31, 2023. Patients were included if they were age 18 years or older and received at least one 30 milliliter bolus of 23.4% sodium chloride at any time during the hospital admission. Patients were excluded if the hypertonic saline was given through a central venous catheter, if the method of administration could not be determined, or if the patient was incarcerated or pregnant at the time of admission. Those who expired or were discharged less than 24 hours after the dose of 23.4% sodium chloride were also excluded to ensure an adequate observation window for identification of extravasations. Exposure Sodium chloride 23.4% was administered in a dose of 30 mL (120 mEq) intravenously via an infusion pump over 2–5 minutes. Institutional procedure at both study sites required the administering nurse to link the medication administration to the intravenous catheter utilized in the EMR. Our study utilized documentation of these “linked IV lines” to ascertain the site of medication administration (peripheral vs. central and exact location of IV-line insertion [antecubital, wrist, hand, etc.]). Per institutional policy, nursing staff assessed IV lines at 4-hour intervals and documented a description of site appearance as well as ability or inability to properly flush the catheter. Site assessments were conducted for the entire duration an IV line was in place and this information was permanently stored in the EMR. Outcome Measures, Follow-up, and Data Collection The primary outcome was the incidence of extravasation events with peripheral administration. The follow-up period for the outcome was 24 hours after a dose of 23.4% sodium chloride. An algorithm was created to identify any IV line that had a documented descriptor that could indicate an extravasation had taken place. To compile the correct site descriptors to be used for this algorithm, the researchers (CS, RG) reviewed a list of all words that had been used by nursing staff to describe the IV sites and identified which ones would indicate a potential problem (i.e., erythema, bleeding, tender, etc.) and which ones would not (Table 1 in supplementary material). Patients with a problematic site descriptor were then manually reviewed using searchable terms in the EMR (Table 2 in supplementary material) to confirm whether an extravasation event occurred. Administrations flagged in the alternative primary outcome analysis (described below) were also manually reviewed. Table 1 Patient Demographics Variable Study Cohort (N = 863) Age, years – median (Q1, Q3) 62 (48, 75) < 40 153 (17.7) 40–64 320 (37.1) ≥ 65 390 (45.2) Sex Male 511 (59.2) Female 352 (40.8) Ethnicity Hispanic or Latino 115 (13.3) Not Hispanic or Latino 727 (84.2) Unknown 21 (2.4) Race Asian 17 (2.0) Black 75 (8.7) White 638 (73.9) Other or Unknown 133 (15.4) Body Mass Index, kg/m 2 – median (Q1, Q3) 26.23 (22.68, 30.36) < 18.5 35 (4.1) 18.5–24.9 285 (33.3) 25–29.9 248 (28.9) 30–34.9 119 (13.9) ≥ 35 90 (10.5) Unknown 80 (9.3) Weight, kg – median (Q1, Q3) 75.50 (64.50, 88.95) Diabetes Mellitus 152 (17.6) Peripheral Artery Disease 28 (3.2) Raynaud’s Phenomenon 0 (0) Hospital Department Emergency Department 661 (76.6) ICU 169 (19.6) Other (not ICU or ED) 33 (3.8) Glasgow Coma Scale on Admission – median (Q1, Q3) 8 (5, 14) Emergency Department Length of Stay, Days – median (Q1, Q3) 0.22 (0.14, 0.33) ICU Length of Stay, Days – median (Q1, Q3) 4.53 (2.02, 11.29) Hospital Length of Stay, Days – median (Q1, Q3) 7.90 (3.26, 16.95) Admission Diagnosis Traumatic 87 (10.1) Non-traumatic 18 (2.1) Unknown 758 (87.8) Discharge Disposition Expired 248 (28.5) Hospice 119 (13.8) Care Facility 317 (36.7) Home 170 (19.7) Left against medical advice 9 (1.0) Time from Administration to Documented Extravasation, hours – mean (SD) 9.9 (7.3) Time from Administration to Documented Extravasation, hours – median (Q1, Q3) 7.3 (3.7, 18.0) Time from IV Placement to 23.4% NaCl Administration, hours – mean (SD) 4.3 (5.6) Time from IV Placement to 23.4% NaCl Administration, hours – median (Q1, Q3) 1.5 (0.5, 6.3) *All values are shown as n (%) unless otherwise specified **Abbreviations: Q1, first quartile; Q3, third quartile; SD, standard deviation; kg, kilogram; m 2 , square meters; ICU, intensive care unit; ED, emergency department; IV, intravenous; NaCl, sodium chloride. Table 2 Outcomes Variable Study Cohort Primary Outcome HTS Extravasation None 807 (93.5) Possible 47 (5.4) Probable 9 (1.0) Naranjo Score of Potential Extravasations 1–4 (Possible) 47/56 (84) 5–8 (Probable) 9/56 (16) ≥ 9 (Definite) 0/56 (0) Naranjo Score – mean (SD) 4.30 (0.81) Naranjo Score – median (Q1, Q3) 4 (4, 4) Other Potential Problematic Medications Noted Neither irritant nor vesicant 4 (7.1) Irritant 37 (66.1) Vesicant 5 (8.9) Irritant and vesicant 10 (17.9) Secondary Outcomes Medical Intervention Required Hyaluronidase 1 (0.12) Phentolamine 0 (0) Terbutaline 0 (0) Surgical Intervention Required 0 (0) Documented Necrosis 0 (0) *All values are shown as n (%) unless otherwise specified In recognition of the limitations of EMR documentation, an alternative primary outcome analysis was conducted to account for extravasations not otherwise identified by the algorithm outlined above. In this analysis, patients with peripheral IV lines removed within 24 hours of 23.4% sodium chloride administration were manually reviewed. This was considered a catch-all analysis because extravasation of a vesicant such as 23.4% sodium chloride would presumably be noticed within 24 hours by either the patient and/or staff prompting immediate IV catheter removal. We additionally cross-referenced our cohort with a utilization report of extravasation antidotes (phentolamine, terbutaline, hyaluronidase) and a query of institutional safety reporting software. Each suspected event was assessed using the Naranjo Adverse Drug Reaction Probability Scale to determine the likelihood that 23.4% sodium chloride caused the extravasation event in question 18 . Using this scoring tool, extravasation injuries were classified as unlikely, possible, probable, or definite. Event adjudication was conducted by 2 investigators (CS, RG), and accounted for other irritants and vesicants given during the 24-hour post-dose timeframe. Secondary outcomes included the incidence of tissue necrosis and interventions used to treat extravasation injuries such as surgical procedures or administration of hyaluronidase, phentolamine, or terbutaline. Risk Factors In secondary analyses, we assessed potential risk factors for extravasation. Variables that were considered as possible risk factors included age, sex, ethnicity, race, BMI, site of IV placement, needle gauge, Glasgow Coma Scale (GCS) on arrival, hospital department where 23.4% sodium chloride was administered, number of 23.4% doses received through the same IV line, and history of diabetes, peripheral artery disease, or Raynaud’s phenomenon. These potential risk factors were also used to describe the study cohort. Statistical Analyses Continuous data were presented as medians with an interquartile range while categorical data were included with a simple count and percentage for the entire cohort. Outcomes were reported using mean values when applicable. A between group comparison was conducted between individuals found to have a potential extravasation and those who did not. For the analyses in this comparison, a Wilcoxon rank-sum test was performed for continuous data and Pearson’s chi-squared test for categorical data. An alpha = 0.05 level was used to assess statistical significance. Using a least absolute shrinkage and selection operator (LASSO) regression to select the most important predictors, we fit a modified multivariable Poisson regression model to estimate risk ratios (RR) with 95% confidence intervals for the relationships between possible risk factors and potential extravasation. The LASSO employs shrinkage, which is the principle of reducing the regression coefficients to improve the quality of predictions. Model reduction is achieved since the LASSO regression reduces some regression coefficients to zero, thereby eliminating independent variables from the model that are not predictive. This approach was necessary given the high levels of multicollinearity (i.e., fairly high correlation) that would have likely been present between some variables. This type of statistical analysis allowed for a more accurate representation of how each individual variable independently impacted the outcome of extravasation. Statistical tests were performed using STATA software. Results Study Cohort A total of 1,567 administrations of 23.4% sodium chloride were identified between March 29, 2015 and October 31, 2023. Of these, 704 administrations were excluded with the most common reasons being administration of hypertonic saline via a central line (n = 397) and death or discharge within 24 hours of the dose (n = 295). This resulted in a total of 863 peripheral administrations that met study criteria (Fig. 1). The 863 administrations occurred in 822 unique patients; 41 (4.75%) were repeat doses that were administered via the same IV catheter as a prior dose. Patient demographics are described in Table 1 . Primary Outcome The primary outcome, defined as incidence of extravasation with peripherally administered 23.4% sodium chloride, occurred in 56 of 863 administrations (6.4%; Table 2 ). Of the administrations that were associated with extravasation injury, 47 patients (5.4%) experienced a possible hypertonic saline extravasation and 9 patients (1.0%) experienced a probable hypertonic saline extravasation according to the Naranjo Adverse Drug Reaction Probability Scale. In total, 93% of the extravasation events were also associated with administration of an irritant, vesicant, or both during the 24-hour observation window after a dose of 23.4% sodium chloride was administered. Alternative Primary Outcome Analysis Of the 56 extravasation events observed in this study, 12 were identified based on our algorithm that searched IV site descriptors. Our alternative primary outcome analysis investigating all patients with peripheral IV catheters discontinued within 24 hours of 23.4% sodium chloride administration identified the additional 44 events. We did not identify any unique events when cross-referencing our cohort with a utilization report of extravasation antidotes (terbutaline, phentolamine, hyaluronidase). A query of institution safety reporting software did not return additional unique events. Secondary Outcomes No patient had documented tissue necrosis in their medical record. There were no cases of terbutaline or phentolamine use. There was one case of hyaluronidase used to treat a 23.4% sodium chloride extravasation. There were no other medical or surgical interventions recorded in the EMR for the 55 remaining possible or probable extravasations. Potential Extravasation Risk Factors To determine attributable risk factors, a comparison was conducted between patients who experienced a possible or probable extravasation and those who did not (Table 3 in supplementary material). This analysis revealed that age, ethnicity, history of diabetes, duration of IV line, and location of IV line placement were significantly different between patients who experienced an extravasation event compared to those who did not. However, after using a multivariable LASSO regression model to estimate the independent associations between each individual variable and the outcome of extravasation, we observed that only history of diabetes had a statistically significant association (Table 3 ). The risk ratio (RR) of extravasation injury for patients with diabetes was 2.39 (95% CI 1.41–4.05 [p = 0.001]). Table 3 Results from the LASSO regression estimating the relationships between potential risk factors and the occurrence of hypertonic saline extravasation. Potential Risk Factor RR 95% CI P-value Age 40–64 1.00 0.37–2.70 1.00 ≥ 65 1.83 0.73–4.62 0.20 Not Hispanic or Latino 3.40 0.81–14.28 0.10 BMI 0.78 0.24–2.56 0.69 18.5–24.9 25–29.9 0.45 0.13–1.5 0.21 30–34.9 0.75 0.22–2.60 0.65 ≥ 35 0.66 0.18–2.51 0.55 Diabetes Mellitus 2.39 1.41–4.05 0.001 *Abbreviations: RR; Risk Ratio, CI; confidence interval. Discussion In this retrospective cohort study, we observed a 6.4% incidence of possible or probable extravasation with peripheral administration of 23.4% hypertonic saline and identified diabetes mellitus as a possible risk factor. Among the 56 patients who experienced an extravasation event, there were no surgical interventions performed, no documented tissue necrosis, and one case of medical treatment using hyaluronidase suggesting a low injury severity. To our knowledge, this is the largest study investigating the safety of peripheral administration of 23.4% sodium chloride. These findings suggest that peripheral administration of 23.4% NaCl is reasonably safe and can be considered in all patients that may be at risk for cerebral herniation and do not have central venous access. Analysis of baseline demographics for the entire cohort (Table 1 ) show the study population had a median age of 62 years old with a median body mass index of 26.23 kg/m 2 . Regarding conditions that may increase the risk of extravasation, it was found that 17.6% of patients had a past medical history that included diabetes mellitus, 3.2% had peripheral artery disease, and no patients had a diagnosis of Raynaud’s phenomenon. As expected, most (76.6%) peripheral administrations of 23.4% hypertonic saline took place in the emergency department and only a small fraction took place in an ICU (19.6%) or non-ICU floor (3.8%). The extravasation incidence rate was overall low, but higher than 2 prior studies. Faiver et al. found 1 event out of 57 peripheral administrations of 23.4% hypertonic saline (1.75%), no patients with tissue necrosis, and 1 administration with pain that resulted in the injection being stopped (1.75%). 13 O’Brien et al. found no events out of 17 peripheral administrations and only 1 patient (5.9%) that experienced pain, erythema, and/or edema. 9 Although Faiver et al. looked at tissue complications for the duration of the hospital stay, O’Brien et al. limited their window for infusion site reactions to 60 minutes after administration. 9 , 13 The median (Q1, Q3) time to a documented event in our study was 7.3 hours (3.7–18.0 hours), which demonstrates that a 60-minute period may not be ideal because many extravasation events could be missed in retrospective evaluation. Incidence may have been higher in our study due to the 24-hour observation window and the potential for over-reporting with the Naranjo Adverse Drug Reaction Probability Scale. For example, the event described by Faiver et al. in which a patient experienced pain may have been determined to be a possible or probable event in our study depending on other alternative causes and objective evidence. The absence of severe injury, necrosis, or surgical intervention could be due to the overall acuity of those likely to receive 23.4% sodium chloride. In an emergency department setting, where 76.6% of administrations in this study took place, there exists a large multidisciplinary team and likely multiple subspecialties involved in a patient’s care who are monitoring the patient during the entirety of the bolus and the hours following. Therefore, it is likely that any problem with an IV catheter or insertion site abnormalities such as leaking or erythema would have been noticed early before serious injury could occur. This would be especially true in the case of a patient who is coherent and can inform providers of their pain or discomfort. Despite the high likelihood of observing a vesicant extravasation quickly, our study still required a 24-hour observation window. This would provide the most conservative estimate in case the area of extravasation was covered in a sterile field, unobserved, the patient was not conscious enough to inform providers of pain, and/or if there was a delay in documenting an event. The lack of extravasation and documented complications could also be due to the rapidity of administration since 23.4% may be safely given in as little as 2–5 minutes. 9 This reduces the timeframe for an extravasation event to occur compared to a less concentrated 3% sodium chloride bolus or continuous infusion, which may be running for hours with less supervision. One of the largest studies conducted regarding the safety of peripherally administered 3% sodium chloride concluded that the duration of infusion was the only variable associated with an increased risk of an infusion-related adverse event. 17 In terms of potential predictors of extravasations, we identified diabetes as an independent predictor of a possible or probable extravasation. Patients with a past medical history that included diabetes had a 2.39 times higher risk for extravasation (p = 0.001). The underlying mechanism for this is not known but may be related to vascular changes such as narrowing and/or hardening of blood vessels, that occurs in the setting of long-standing uncontrolled hyperglycemia. 19 Providers should exercise caution when considering administration of irritants or vesicants in this patient population. Our alternative primary outcome analysis identified the majority (78.6%) of extravasation events highlighting the limitations of retrospective study design on determining the safety of peripheral 23.4% sodium chloride administration. Future prospective studies in which each potential event is analyzed, described, and scored as it occurs should be considered to provide a higher degree of specificity for extravasation occurrences. Additionally, when reviewing other medications given through the same IV catheter as the 23.4% sodium chloride, some medications did not have a linked IV line documented and could not be included as an alternative causative agent for extravasation. Similarly, because this study used a 24-hour post-dose observation window, it is possible that the extravasations identified were caused by a different medication given within that time frame and may have affected the overall Naranjo score. Lastly, because we used a 24-hour observation window for determining whether an extravasation event occurred and for our alternative primary outcome analyses, patients who died or were discharged prior to 24 hours were excluded, which could have introduced selection bias. 20 Conclusion Peripheral administration of 23.4% sodium chloride was associated with a low rate of extravasation and no significant injury in patients that did experience a possible or probable extravasation event. Diabetes mellitus was a possible risk factor for extravasation. References Canac N, Jalaleddini K, Thorpe SG, Thibeault CM, Hamilton RB. Review: pathophysiology of intracranial hypertension and noninvasive intracranial pressure monitoring. Fluids Barriers CNS. 2020;17(1):40. 10.1186/s12987-020-00201-8 . Published 2020 Jun 23. Lan Z, Richard SA, Li Q, et al. 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Diabetic vascular diseases: molecular mechanisms and therapeutic strategies. Signal Transduct Target Ther . 2023;8(1):152. Published 2023 Apr 10. 10.1038/s41392-023-01400-z Lesko CR, Fox MP, Edwards JK. A Framework for Descriptive Epidemiology. Am J Epidemiol. 2022;191(12):2063–70. 10.1093/aje/kwac115 . Supplementary Files HTSManuscriptSupplementaryMaterial.docx Cite Share Download PDF Status: Published Journal Publication published 21 Aug, 2025 Read the published version in Neurocritical Care → Version 1 posted Reviewers agreed at journal 04 Apr, 2025 Reviewers invited by journal 03 Apr, 2025 Editor invited by journal 02 Apr, 2025 Editor assigned by journal 01 Apr, 2025 First submitted to journal 31 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6346181","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":438118053,"identity":"a87c8920-9b5f-4a3f-b957-b45834b87119","order_by":0,"name":"Christian Silva","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0007-7587-0798","institution":"Rhode Island Hospital","correspondingAuthor":true,"prefix":"","firstName":"Christian","middleName":"","lastName":"Silva","suffix":""},{"id":438118054,"identity":"b7c7edbb-87fe-4a65-a3bb-e0a1684cc6a6","order_by":1,"name":"Jessica Nagy","email":"","orcid":"","institution":"Rhode Island Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jessica","middleName":"","lastName":"Nagy","suffix":""},{"id":438118055,"identity":"ada4bc10-743b-4a75-b4c4-032c4d13f3ae","order_by":2,"name":"Andrew R. Zullo","email":"","orcid":"","institution":"Brown University Public Health Program: Brown University School of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"R.","lastName":"Zullo","suffix":""},{"id":438118056,"identity":"0b01d40f-1ca7-4a1f-b4ac-57ed931cfffe","order_by":3,"name":"Rebecca A Greene","email":"","orcid":"","institution":"Rhode Island Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"A","lastName":"Greene","suffix":""}],"badges":[],"createdAt":"2025-03-31 15:30:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6346181/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6346181/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12028-025-02342-w","type":"published","date":"2025-08-21T16:29:43+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82132220,"identity":"f89e23ec-cdc0-436a-a7ce-c5cb93177a30","added_by":"auto","created_at":"2025-05-07 05:42:06","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":234402,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure1ConsortDiagram.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6346181/v1/4072ebe60c88a10b8901e053.jpg"},{"id":82134764,"identity":"ea1972fd-2720-4072-9e26-84639a5017b8","added_by":"auto","created_at":"2025-05-07 06:06:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":859083,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6346181/v1/9c319b4c-d04d-4894-bf0c-0cfa3acbff0e.pdf"},{"id":82131112,"identity":"2ef969e6-d491-44c8-b4d4-c9bf203a9f2b","added_by":"auto","created_at":"2025-05-07 05:34:06","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":52987,"visible":true,"origin":"","legend":"","description":"","filename":"HTSManuscriptSupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-6346181/v1/0ace846f19da25f65901ea0e.docx"}],"financialInterests":"","formattedTitle":"Safety of peripherally administered 23.4% sodium chloride","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIncreased intracranial pressure (ICP) may result from a variety of potentially fatal conditions, including intracranial hemorrhage (ICH), seizure, stroke, malignancy, or infection.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Severe increases in ICP can result in irreversible brain damage by reducing cerebral perfusion pressure (CPP) and causing cerebral herniation, an event with a mortality rate greater than 60% in cases of traumatic brain injury (TBI).\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Elevated ICP must therefore be treated expeditiously to reduce morbidity and mortality.\u003c/p\u003e \u003cp\u003eIn order to achieve rapid reductions in ICP, guidelines pertaining to the acute treatment of cerebral edema and management of severe traumatic brain injury recommend administration of mannitol or hypertonic saline.\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Mannitol and hypertonic saline both reduce ICP, however mannitol produces an osmotic diuresis that may lower mean arterial pressure (MAP), decrease CPP, and cause acute kidney injury.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Additionally, current data show superior brain tissue oxygenation and greater benefit in the presence of cerebral ischemia with hypertonic saline.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIntravenous (IV) sodium chloride has been studied in a variety of concentrations, most commonly 3% and 23.4%.\u003csup\u003e3\u003c/sup\u003e Sodium chloride 23.4% is logistically advantageous as it is available in 30 milliliter vials that are more compact than 500 milliliter 3% sodium chloride bags and may conserve space in a medical supply bag. Notably, the smaller volume of 23.4% compared to 3% allows administration over a shorter timeframe (2\u0026ndash;5 minutes vs. 10\u0026ndash;15 minutes), decreasing the time to treatment.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Disadvantages of 23.4% sodium chloride are similar to those associated with 3% sodium chloride and include transient hypotension, pulmonary edema, and hyperchloremic acidosis.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOne area of concern specific to 23.4% sodium chloride is its osmolarity of 8010 mOsm/L which exceeds the 900 mOsm/L threshold recommendation for peripheral line administration making it more likely to cause pain and vascular inflammation.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Prior data supporting the use of 23.4% sodium chloride given peripherally is limited to two observational studies (n\u0026thinsp;=\u0026thinsp;74 peripheral administrations), which reported only one extravasation event.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Studies examining lower concentrations of peripheral hypertonic saline (3%) had a low risk of complications and infrequent infusion related adverse events (IRAEs).\u003csup\u003e\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Nevertheless, there is currently little data to support the safety of peripherally administered 23.4% sodium chloride and many institutions require administration through a central venous catheter to minimize the risk of extravasation and tissue injury. Central line insertion is more time consuming and awaiting placement can result in a delay in treatment that may be detrimental to patients with an elevated ICP or impending cerebral herniation. Thus, determining the safety of peripheral administration of 23.4% sodium chloride to provide expeditious treatment is essential.\u003c/p\u003e \u003cp\u003eThis study investigated the safety of 23.4% sodium chloride administration through a peripheral IV catheter and examined potential risk factors for extravasation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Setting\u003c/h2\u003e \u003cp\u003eThis was a retrospective observational cohort study conducted at a large academic health system. Patients were admitted to one 719-bed academic medical center and level 1 trauma center or one 247-bed academic community hospital. This study was approved by the institutional review board and patient consent was not required due to the retrospective design.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSelection of Participants\u003c/h3\u003e\n\u003cp\u003eSubjects included in this study were identified through the electronic medical record (EMR) and were admitted between March 29, 2015 and October 31, 2023. Patients were included if they were age 18 years or older and received at least one 30 milliliter bolus of 23.4% sodium chloride at any time during the hospital admission. Patients were excluded if the hypertonic saline was given through a central venous catheter, if the method of administration could not be determined, or if the patient was incarcerated or pregnant at the time of admission. Those who expired or were discharged less than 24 hours after the dose of 23.4% sodium chloride were also excluded to ensure an adequate observation window for identification of extravasations.\u003c/p\u003e\n\u003ch3\u003eExposure\u003c/h3\u003e\n\u003cp\u003eSodium chloride 23.4% was administered in a dose of 30 mL (120 mEq) intravenously via an infusion pump over 2\u0026ndash;5 minutes. Institutional procedure at both study sites required the administering nurse to link the medication administration to the intravenous catheter utilized in the EMR. Our study utilized documentation of these \u0026ldquo;linked IV lines\u0026rdquo; to ascertain the site of medication administration (peripheral vs. central and exact location of IV-line insertion [antecubital, wrist, hand, etc.]). Per institutional policy, nursing staff assessed IV lines at 4-hour intervals and documented a description of site appearance as well as ability or inability to properly flush the catheter. Site assessments were conducted for the entire duration an IV line was in place and this information was permanently stored in the EMR.\u003c/p\u003e\n\u003ch3\u003eOutcome Measures, Follow-up, and Data Collection\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was the incidence of extravasation events with peripheral administration. The follow-up period for the outcome was 24 hours after a dose of 23.4% sodium chloride. An algorithm was created to identify any IV line that had a documented descriptor that could indicate an extravasation had taken place. To compile the correct site descriptors to be used for this algorithm, the researchers (CS, RG) reviewed a list of all words that had been used by nursing staff to describe the IV sites and identified which ones would indicate a potential problem (i.e., erythema, bleeding, tender, etc.) and which ones would not (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e in supplementary material). Patients with a problematic site descriptor were then manually reviewed using searchable terms in the EMR (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e in supplementary material) to confirm whether an extravasation event occurred. Administrations flagged in the alternative primary outcome analysis (described below) were also manually reviewed.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Demographics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e Variable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy Cohort (N\u0026thinsp;=\u0026thinsp;863)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years \u0026ndash; median (Q1, Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (48, 75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e153 (17.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u0026ndash;64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e320 (37.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e390 (45.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e511 (59.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e352 (40.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEthnicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHispanic or Latino\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e115 (13.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot Hispanic or Latino\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e727 (84.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (2.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRace\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (2.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlack\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75 (8.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e638 (73.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther or Unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e133 (15.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody Mass Index, kg/m\u003csup\u003e2\u003c/sup\u003e \u0026ndash; median (Q1, Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.23 (22.68, 30.36)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (4.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18.5\u0026ndash;24.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e285 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u0026ndash;29.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e248 (28.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u0026ndash;34.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119 (13.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90 (10.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (9.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, kg \u0026ndash; median (Q1, Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75.50 (64.50, 88.95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes Mellitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e152 (17.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral Artery Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (3.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRaynaud\u0026rsquo;s Phenomenon\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospital Department\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmergency Department\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e661 (76.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e169 (19.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther (not ICU or ED)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlasgow Coma Scale on Admission \u0026ndash; median (Q1, Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (5, 14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmergency Department Length of Stay, Days \u0026ndash; median (Q1, Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.22 (0.14, 0.33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU Length of Stay, Days \u0026ndash; median (Q1, Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.53 (2.02, 11.29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospital Length of Stay, Days \u0026ndash; median (Q1, Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.90 (3.26, 16.95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdmission Diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTraumatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87 (10.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-traumatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (2.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e758 (87.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDischarge Disposition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExpired\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e248 (28.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119 (13.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCare Facility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e317 (36.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e170 (19.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft against medical advice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (1.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from Administration to Documented Extravasation, hours \u0026ndash; mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.9 (7.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from Administration to Documented Extravasation, hours \u0026ndash; median (Q1, Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.3 (3.7, 18.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from IV Placement to 23.4% NaCl Administration, hours \u0026ndash; mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3 (5.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from IV Placement to 23.4% NaCl Administration, hours \u0026ndash; median (Q1, Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.5 (0.5, 6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e*All values are shown as n (%) unless otherwise specified\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e**Abbreviations: Q1, first quartile; Q3, third quartile; SD, standard deviation; kg, kilogram; m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, square meters; ICU, intensive care unit; ED, emergency department; IV, intravenous; NaCl, sodium chloride.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy Cohort\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePrimary Outcome\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHTS Extravasation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e807 (93.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePossible\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (5.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProbable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (1.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNaranjo Score of Potential Extravasations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;4 (Possible)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47/56 (84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u0026ndash;8 (Probable)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9/56 (16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;9 (Definite)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0/56 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNaranjo Score \u0026ndash; mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.30 (0.81)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNaranjo Score \u0026ndash; median (Q1, Q3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (4, 4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther Potential Problematic Medications Noted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeither irritant nor vesicant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (7.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIrritant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (66.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVesicant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (8.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIrritant and vesicant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (17.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSecondary Outcomes\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedical Intervention Required\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyaluronidase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhentolamine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTerbutaline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical Intervention Required\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDocumented Necrosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e*All values are shown as n (%) unless otherwise specified\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn recognition of the limitations of EMR documentation, an alternative primary outcome analysis was conducted to account for extravasations not otherwise identified by the algorithm outlined above. In this analysis, patients with peripheral IV lines removed within 24 hours of 23.4% sodium chloride administration were manually reviewed. This was considered a catch-all analysis because extravasation of a vesicant such as 23.4% sodium chloride would presumably be noticed within 24 hours by either the patient and/or staff prompting immediate IV catheter removal. We additionally cross-referenced our cohort with a utilization report of extravasation antidotes (phentolamine, terbutaline, hyaluronidase) and a query of institutional safety reporting software.\u003c/p\u003e \u003cp\u003eEach suspected event was assessed using the Naranjo Adverse Drug Reaction Probability Scale to determine the likelihood that 23.4% sodium chloride caused the extravasation event in question\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Using this scoring tool, extravasation injuries were classified as unlikely, possible, probable, or definite. Event adjudication was conducted by 2 investigators (CS, RG), and accounted for other irritants and vesicants given during the 24-hour post-dose timeframe.\u003c/p\u003e \u003cp\u003eSecondary outcomes included the incidence of tissue necrosis and interventions used to treat extravasation injuries such as surgical procedures or administration of hyaluronidase, phentolamine, or terbutaline.\u003c/p\u003e\n\u003ch3\u003eRisk Factors\u003c/h3\u003e\n\u003cp\u003eIn secondary analyses, we assessed potential risk factors for extravasation. Variables that were considered as possible risk factors included age, sex, ethnicity, race, BMI, site of IV placement, needle gauge, Glasgow Coma Scale (GCS) on arrival, hospital department where 23.4% sodium chloride was administered, number of 23.4% doses received through the same IV line, and history of diabetes, peripheral artery disease, or Raynaud\u0026rsquo;s phenomenon. These potential risk factors were also used to describe the study cohort.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analyses\u003c/h2\u003e \u003cp\u003eContinuous data were presented as medians with an interquartile range while categorical data were included with a simple count and percentage for the entire cohort. Outcomes were reported using mean values when applicable. A between group comparison was conducted between individuals found to have a potential extravasation and those who did not. For the analyses in this comparison, a Wilcoxon rank-sum test was performed for continuous data and Pearson\u0026rsquo;s chi-squared test for categorical data. An alpha\u0026thinsp;=\u0026thinsp;0.05 level was used to assess statistical significance.\u003c/p\u003e \u003cp\u003eUsing a least absolute shrinkage and selection operator (LASSO) regression to select the most important predictors, we fit a modified multivariable Poisson regression model to estimate risk ratios (RR) with 95% confidence intervals for the relationships between possible risk factors and potential extravasation. The LASSO employs shrinkage, which is the principle of reducing the regression coefficients to improve the quality of predictions. Model reduction is achieved since the LASSO regression reduces some regression coefficients to zero, thereby eliminating independent variables from the model that are not predictive. This approach was necessary given the high levels of multicollinearity (i.e., fairly high correlation) that would have likely been present between some variables. This type of statistical analysis allowed for a more accurate representation of how each individual variable independently impacted the outcome of extravasation. Statistical tests were performed using STATA software.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStudy Cohort\u003c/h2\u003e \u003cp\u003eA total of 1,567 administrations of 23.4% sodium chloride were identified between March 29, 2015 and October 31, 2023. Of these, 704 administrations were excluded with the most common reasons being administration of hypertonic saline via a central line (n\u0026thinsp;=\u0026thinsp;397) and death or discharge within 24 hours of the dose (n\u0026thinsp;=\u0026thinsp;295). This resulted in a total of 863 peripheral administrations that met study criteria (Fig.\u0026nbsp;1). The 863 administrations occurred in 822 unique patients; 41 (4.75%) were repeat doses that were administered via the same IV catheter as a prior dose. Patient demographics are described in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePrimary Outcome\u003c/h2\u003e \u003cp\u003eThe primary outcome, defined as incidence of extravasation with peripherally administered 23.4% sodium chloride, occurred in 56 of 863 administrations (6.4%; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Of the administrations that were associated with extravasation injury, 47 patients (5.4%) experienced a possible hypertonic saline extravasation and 9 patients (1.0%) experienced a probable hypertonic saline extravasation according to the Naranjo Adverse Drug Reaction Probability Scale. In total, 93% of the extravasation events were also associated with administration of an irritant, vesicant, or both during the 24-hour observation window after a dose of 23.4% sodium chloride was administered.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eAlternative Primary Outcome Analysis\u003c/h2\u003e \u003cp\u003eOf the 56 extravasation events observed in this study, 12 were identified based on our algorithm that searched IV site descriptors. Our alternative primary outcome analysis investigating all patients with peripheral IV catheters discontinued within 24 hours of 23.4% sodium chloride administration identified the additional 44 events. We did not identify any unique events when cross-referencing our cohort with a utilization report of extravasation antidotes (terbutaline, phentolamine, hyaluronidase). A query of institution safety reporting software did not return additional unique events.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Outcomes\u003c/h2\u003e \u003cp\u003eNo patient had documented tissue necrosis in their medical record. There were no cases of terbutaline or phentolamine use. There was one case of hyaluronidase used to treat a 23.4% sodium chloride extravasation. There were no other medical or surgical interventions recorded in the EMR for the 55 remaining possible or probable extravasations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePotential Extravasation Risk Factors\u003c/h2\u003e \u003cp\u003eTo determine attributable risk factors, a comparison was conducted between patients who experienced a possible or probable extravasation and those who did not (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e in supplementary material). This analysis revealed that age, ethnicity, history of diabetes, duration of IV line, and location of IV line placement were significantly different between patients who experienced an extravasation event compared to those who did not. However, after using a multivariable LASSO regression model to estimate the independent associations between each individual variable and the outcome of extravasation, we observed that only history of diabetes had a statistically significant association (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The risk ratio (RR) of extravasation injury for patients with diabetes was 2.39 (95% CI 1.41\u0026ndash;4.05 [p\u0026thinsp;=\u0026thinsp;0.001]).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults from the LASSO regression estimating the relationships between potential risk factors and the occurrence of hypertonic saline extravasation.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePotential Risk Factor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u0026ndash;64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.37\u0026ndash;2.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.73\u0026ndash;4.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot Hispanic or Latino\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.81\u0026ndash;14.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.24\u0026ndash;2.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18.5\u0026ndash;24.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u0026ndash;29.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.13\u0026ndash;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u0026ndash;34.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.22\u0026ndash;2.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.18\u0026ndash;2.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes Mellitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.41\u0026ndash;4.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*Abbreviations: RR; Risk Ratio, CI; confidence interval.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective cohort study, we observed a 6.4% incidence of possible or probable extravasation with peripheral administration of 23.4% hypertonic saline and identified diabetes mellitus as a possible risk factor. Among the 56 patients who experienced an extravasation event, there were no surgical interventions performed, no documented tissue necrosis, and one case of medical treatment using hyaluronidase suggesting a low injury severity. To our knowledge, this is the largest study investigating the safety of peripheral administration of 23.4% sodium chloride. These findings suggest that peripheral administration of 23.4% NaCl is reasonably safe and can be considered in all patients that may be at risk for cerebral herniation and do not have central venous access.\u003c/p\u003e \u003cp\u003eAnalysis of baseline demographics for the entire cohort (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) show the study population had a median age of 62 years old with a median body mass index of 26.23 kg/m\u003csup\u003e2\u003c/sup\u003e. Regarding conditions that may increase the risk of extravasation, it was found that 17.6% of patients had a past medical history that included diabetes mellitus, 3.2% had peripheral artery disease, and no patients had a diagnosis of Raynaud\u0026rsquo;s phenomenon. As expected, most (76.6%) peripheral administrations of 23.4% hypertonic saline took place in the emergency department and only a small fraction took place in an ICU (19.6%) or non-ICU floor (3.8%).\u003c/p\u003e \u003cp\u003eThe extravasation incidence rate was overall low, but higher than 2 prior studies. Faiver et al. found 1 event out of 57 peripheral administrations of 23.4% hypertonic saline (1.75%), no patients with tissue necrosis, and 1 administration with pain that resulted in the injection being stopped (1.75%).\u003csup\u003e13\u003c/sup\u003e O\u0026rsquo;Brien et al. found no events out of 17 peripheral administrations and only 1 patient (5.9%) that experienced pain, erythema, and/or edema.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Although Faiver et al. looked at tissue complications for the duration of the hospital stay, O\u0026rsquo;Brien et al. limited their window for infusion site reactions to 60 minutes after administration.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e The median (Q1, Q3) time to a documented event in our study was 7.3 hours (3.7\u0026ndash;18.0 hours), which demonstrates that a 60-minute period may not be ideal because many extravasation events could be missed in retrospective evaluation. Incidence may have been higher in our study due to the 24-hour observation window and the potential for over-reporting with the Naranjo Adverse Drug Reaction Probability Scale. For example, the event described by Faiver et al. in which a patient experienced pain may have been determined to be a possible or probable event in our study depending on other alternative causes and objective evidence.\u003c/p\u003e \u003cp\u003eThe absence of severe injury, necrosis, or surgical intervention could be due to the overall acuity of those likely to receive 23.4% sodium chloride. In an emergency department setting, where 76.6% of administrations in this study took place, there exists a large multidisciplinary team and likely multiple subspecialties involved in a patient\u0026rsquo;s care who are monitoring the patient during the entirety of the bolus and the hours following. Therefore, it is likely that any problem with an IV catheter or insertion site abnormalities such as leaking or erythema would have been noticed early before serious injury could occur. This would be especially true in the case of a patient who is coherent and can inform providers of their pain or discomfort. Despite the high likelihood of observing a vesicant extravasation quickly, our study still required a 24-hour observation window. This would provide the most conservative estimate in case the area of extravasation was covered in a sterile field, unobserved, the patient was not conscious enough to inform providers of pain, and/or if there was a delay in documenting an event.\u003c/p\u003e \u003cp\u003eThe lack of extravasation and documented complications could also be due to the rapidity of administration since 23.4% may be safely given in as little as 2\u0026ndash;5 minutes.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e This reduces the timeframe for an extravasation event to occur compared to a less concentrated 3% sodium chloride bolus or continuous infusion, which may be running for hours with less supervision. One of the largest studies conducted regarding the safety of peripherally administered 3% sodium chloride concluded that the duration of infusion was the only variable associated with an increased risk of an infusion-related adverse event.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn terms of potential predictors of extravasations, we identified diabetes as an independent predictor of a possible or probable extravasation. Patients with a past medical history that included diabetes had a 2.39 times higher risk for extravasation (p\u0026thinsp;=\u0026thinsp;0.001). The underlying mechanism for this is not known but may be related to vascular changes such as narrowing and/or hardening of blood vessels, that occurs in the setting of long-standing uncontrolled hyperglycemia.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Providers should exercise caution when considering administration of irritants or vesicants in this patient population.\u003c/p\u003e \u003cp\u003eOur alternative primary outcome analysis identified the majority (78.6%) of extravasation events highlighting the limitations of retrospective study design on determining the safety of peripheral 23.4% sodium chloride administration. Future prospective studies in which each potential event is analyzed, described, and scored as it occurs should be considered to provide a higher degree of specificity for extravasation occurrences. Additionally, when reviewing other medications given through the same IV catheter as the 23.4% sodium chloride, some medications did not have a linked IV line documented and could not be included as an alternative causative agent for extravasation. Similarly, because this study used a 24-hour post-dose observation window, it is possible that the extravasations identified were caused by a different medication given within that time frame and may have affected the overall Naranjo score. Lastly, because we used a 24-hour observation window for determining whether an extravasation event occurred and for our alternative primary outcome analyses, patients who died or were discharged prior to 24 hours were excluded, which could have introduced selection bias.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePeripheral administration of 23.4% sodium chloride was associated with a low rate of extravasation and no significant injury in patients that did experience a possible or probable extravasation event. Diabetes mellitus was a possible risk factor for extravasation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCanac N, Jalaleddini K, Thorpe SG, Thibeault CM, Hamilton RB. Review: pathophysiology of intracranial hypertension and noninvasive intracranial pressure monitoring. 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Am J Emerg Med. 2023;63:127\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ajem.2022.10.051\u003c/span\u003e\u003cspan address=\"10.1016/j.ajem.2022.10.051\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNaranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239\u0026ndash;45. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/clpt.1981.154\u003c/span\u003e\u003cspan address=\"10.1038/clpt.1981.154\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi Y, Liu Y, Liu S et al. Diabetic vascular diseases: molecular mechanisms and therapeutic strategies. \u003cem\u003eSignal Transduct Target Ther\u003c/em\u003e. 2023;8(1):152. Published 2023 Apr 10. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41392-023-01400-z\u003c/span\u003e\u003cspan address=\"10.1038/s41392-023-01400-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLesko CR, Fox MP, Edwards JK. A Framework for Descriptive Epidemiology. Am J Epidemiol. 2022;191(12):2063\u0026ndash;70. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/aje/kwac115\u003c/span\u003e\u003cspan address=\"10.1093/aje/kwac115\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"neurocritical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neca","sideBox":"Learn more about [Neurocritical Care](http://link.springer.com/journal/12028)","snPcode":"12028","submissionUrl":"https://www.editorialmanager.com/neca/default2.aspx","title":"Neurocritical Care","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Intracranial pressure, cerebral edema, hypertonic saline solutions, peripheral catheterization, traumatic brain injury","lastPublishedDoi":"10.21203/rs.3.rs-6346181/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6346181/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground/Objective\u003c/h2\u003e \u003cp\u003eFor patients with increased intracranial pressure, prompt initiation of hyperosmolar therapy with 23.4% sodium chloride may minimize permanent neurological damage and prevent cerebral herniation. Placement of a central venous catheter can delay time to osmotherapy and may negatively impact patient outcomes. The objective of this study was to examine the safety of 23.4% sodium chloride administered through a peripheral intravenous (IV) catheter.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis was a retrospective observational cohort study conducted at a large academic health system. Patients were admitted to one 719-bed academic medical center and level 1 trauma center or one 247-bed academic community hospital. Subjects were 18 years or older, admitted between March 29, 2015 and October 21, 2023, and received 23.4% sodium chloride through a peripheral IV. Patients who expired or were discharged less than 24 hours after hypertonic saline administration were excluded. All subjects received at least one 30 milliliter bolus of 23.4% sodium chloride administered through a peripheral IV catheter.\u003c/p\u003e\u003ch2\u003eMeasurements and Main Results\u003c/h2\u003e \u003cp\u003eThe primary outcome, defined as extravasation of peripherally administered 23.4% sodium chloride, was assessed using the Naranjo Adverse Drug Reaction Probability Scale and occurred in 56 out of 863 administrations (6.4%). Secondary outcomes included incidence of tissue necrosis, interventions used to treat extravasations, and attributable risk factors for extravasation. There were no cases of tissue necrosis, no surgical interventions performed, and one case of medical intervention using hyaluronidase. Patients with a history of diabetes had a 2.39 times higher risk of experiencing a 23.4% sodium chloride extravasation event (95% CI 1.41\u0026ndash;4.05 [p\u0026thinsp;=\u0026thinsp;0.001]).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePeripheral administration of 23.4% sodium chloride was associated with a low rate of extravasation and no significant injury in patients that did experience a possible or probable extravasation event. Diabetes mellitus was a possible risk factor for extravasation.\u003c/p\u003e","manuscriptTitle":"Safety of peripherally administered 23.4% sodium chloride","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 05:34:02","doi":"10.21203/rs.3.rs-6346181/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-04-04T12:21:38+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-03T19:12:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Neurocritical Care","date":"2025-04-02T16:24:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-01T17:31:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"Neurocritical Care","date":"2025-03-31T11:27:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"neurocritical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neca","sideBox":"Learn more about [Neurocritical Care](http://link.springer.com/journal/12028)","snPcode":"12028","submissionUrl":"https://www.editorialmanager.com/neca/default2.aspx","title":"Neurocritical Care","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"03d4a17a-859f-4080-aff8-6429b8e45867","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-25T16:37:55+00:00","versionOfRecord":{"articleIdentity":"rs-6346181","link":"https://doi.org/10.1007/s12028-025-02342-w","journal":{"identity":"neurocritical-care","isVorOnly":false,"title":"Neurocritical Care"},"publishedOn":"2025-08-21 16:29:43","publishedOnDateReadable":"August 21st, 2025"},"versionCreatedAt":"2025-05-07 05:34:02","video":"","vorDoi":"10.1007/s12028-025-02342-w","vorDoiUrl":"https://doi.org/10.1007/s12028-025-02342-w","workflowStages":[]},"version":"v1","identity":"rs-6346181","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6346181","identity":"rs-6346181","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}