Clinical trial NCT03276494
Conditions: Stroke Intracranial Hypotension Cerebral Edema
Sponsor: Ohio State University
Start date: 2017-04-21; Completion date: 2018-04-21
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Hypertonic saline is used to treat elevated intracranial pressure. Intraosseous vascular access has been used to administer fluids and medications. This study combines these to administer 3% hypertonic saline via IO.

Detailed description:
HTS is used to mitigate and temporize intracranial pressure (ICP) elevations and cerebral edema by creating an osmotic gradient across the cell wall. HTS is part of the elevated ICP algorithm in the emergency neurologic life support protocols HTS is superior to mannitol which is the alternate osmotherapy agent . HTS is typically administered via central vascular access due to the concern that if extravasation of the infusion occurs, tissue damage from cell implosion can occur

The IO route is generally accepted in resuscitation environments including the emergency department, EMS, and military settings with some authors recommending the IO as a primary method of obtaining emergency vascular access The adult advanced cardiac life support (ACLS) guidelines recommend either intravenous or IO access.

A number of studies have established the safety of IO administration of hypertonic solutions. Randomized adult pigs to IO 7.5% HTS, IO 3% HTS, and 0.9% isotonic saline and found regular tissue morphology, no necrosis or microscopic ischemic changes in the HTS groups. Several studies conducted to evaluate the efficacy of hypertonic solutions on resuscitation for hemorrhagic shock used the IO route and did not make note of problems arising from the administration of IO HTS. Another study using a canine model of hemorrhagic shock briefly mentioned transient lameness in the IO HTS group, but this resolved by 48 hours . While the majority of studies using hypertonic saline solutions did not make note of complications, one study induced hemorrhagic shock in dehydrated swine and resuscitated one group with 7.5% HTS and noted a high rate of local complications from soft tissue and bone marrow necrosis .

One study noted a subgroup of patients in which IO access was obtained on conscious patients. None of the patients received local anesthetic and none reported pain during insertion. Eighteen of the 22 conscious patients reported pain during fluid administration. Central venous catheter (CVC) placement is the current standard of care; even with local anesthesia it can be painful. Most of the potential subjects, due to the nature of their severe neurologic injury, may not be affected by the pain associated with IO fluid administration. Manufacturer literature suggests the use of lidocaine to anesthetize the bone before infusing if possible (Teleflex).

It is expected that utilizing IO for vascular access in the ICU will be safe and tolerable. If this study confirms the anticipated results, there are numerous implications. First, neurologically injured patients requiring emergent HTS may have faster access to this therapy. A study comparing IO to CVC access undergoing resuscitation in the emergency department found IO to be faster to insert (2.3 vs. 9.9 minutes) and had fewer failures to access on the first attempt. Second, serious complications from IO were absent compared with severe to life-threatening mechanical complications from CVC including pneumothorax, damage to the carotid artery, and bleeding which were cited at 0.7%-2.1% depending on site. And thirdly, central line associated blood stream infections (CLABSI) are a leading cause of hospital acquired infections in the ICU and are associated with higher mortality. CLABSI rates are measured by number of infections per 1,000 catheter days and shorter CVC dwell time is prudent. If a reliable and rapid source of vascular access could postpone or eliminate CVC insertion, risk of CLABSI may be reduced. These potential benefits outweigh the minimal expected risk.

Arms: arm 1: Administration of intraosseous hypertonic saline
Interventions: intervention 1: Intraosseous intervention 2: Hypertonic saline
Intervention descriptions: intervention 1: Intraosseous administration of hypertonic saline intervention 2: Intraosseous administration of hypertonic saline

Protocol documents:
Prot_000.pdf: 
Study Title: Safety & Tolerability of Intraosseous Access for Hypertonic Saline Administration: 
A Pilot Study 
 
NCT number: 03276494 
 
Document last updated June 11, 2019  
 
 
 
 
 
 


Safety & Tolerability of Intraosseous Access for Hypertonic Saline Administration: A Pilot 
Study 
 
I. Objectives: 
 
Question: Is it safe and tolerable to utilize intraosseous (IO) access in the ICU for hypertonic sa-
line (HTS) administration? 
Hypothesis: Utilizing the IO route for vascular access will be safe and tolerable for administra-
tion of hypertonic saline (3%) administration. 
Operational definitions. Safety will be evaluated based on absence of extravasation of the infu-
sion into the surrounding tissue and absence of tissue damage proximate to the IO infusion. Tol-
erability will be evaluated based on absence of pain severe enough that the patient requests the 
infusion be stopped or nonverbal indicators of pain such as agitation or pulling at the site. 
 
II. Background and rationale: 
 
HTS is used to mitigate and temporize intracranial pressure (ICP) elevations and cerebral edema 
by creating an osmotic gradient across the cell wall. HTS is part of the elevated ICP algorithm in 
the emergency neurologic life support protocols (NCS, 2014). HTS is superior to mannitol which 
is the alternate osmotherapy agent (Kamel et al., 2011 & Ricard, et al., 2014). HTS is typically 
administered via central vascular access due to the concern that if extravasation of the infusion 
occurs, tissue damage from cell implosion can occur (Goutos, et al., 2014) 
 
The IO route is generally accepted in resuscitation environments including the emergency de-
partment, EMS, and military settings with some authors recommending the IO as a primary 
method of obtaining emergency vascular access (Lewis & Wright, 2014). The adult advanced 
cardiac life support (ACLS) guidelines recommend either intravenous or IO access (Link, et al, 
2015).  
 
A number of studies have established the safety of IO administration of hypertonic solutions. 
Bebarta, et al. (2014) randomized adult pigs to IO 7.5% HTS, IO 3% HTS, and 0.9% isotonic 
saline and found regular tissue morphology, no necrosis or microscopic ischemic changes in the 
HTS groups. Several studies conducted to evaluate the efficacy of hypertonic solutions on resus-
citation for hemorrhagic shock used the IO route and did not make note of problems arising from 
the administration of IO HTS (Dubick, et al, 1992; Runyon et al., 1994). Another study using a 
canine model of hemorrhagic shock briefly mentioned transient lameness in the IO HTS group, 
but this resolved by 48 hours (Orasinski, Krahwinkel, & Sanders, 1992). While the majority of 
studies using hypertonic saline solutions did not make note of complications, one study induced 
hemorrhagic shock in dehydrated swine and resuscitated one group with 7.5% HTS and noted a 
high rate of local complications from soft tissue and bone marrow necrosis (Alam et al., 2002).   
 
One study noted a subgroup of patients in which IO access was obtained on conscious patients 
(Schalk, et al., 2011). None of the patients received local anesthetic and none reported pain dur-
ing insertion. Eighteen of the 22 conscious patients reported pain during fluid administration. 
Gazin, et al., reported all 5 conscious patients in their study reported pain with fluid administra-
tion (2001). Central venous catheter (CVC) placement is the current standard of care; even with 


local anesthesia it can be painful. Most of the potential subjects, due to the nature of their severe 
neurologic injury, may not be affected by the pain associated with IO fluid administration. Man-
ufacturer literature suggests the use of lidocaine to anesthetize the bone before infusing if possi-
ble (Teleflex).  
 
It is expected that utilizing IO for vascular access in the ICU will be safe and tolerable. If this 
study confirms the anticipated results, there are numerous implications. First, neurologically in-
jured patients requiring emergent HTS may have faster access to this therapy. A study comparing 
IO to CVC access undergoing resuscitation in the emergency department found IO to be faster to 
insert (2.3 vs. 9.9 minutes) and had fewer failures to access on the first attempt (Leidel, et al., 
2009). Second, serious complications from IO were absent (Lewis & Wright, 2014) compared 
with severe to life-threatening mechanical complications from CVC including pneumothorax, 
damage to the carotid artery, and bleeding which were cited at 0.7%-2.1% depending on site 
(Parienti, et al., 2015). And thirdly, central line associated blood stream infections (CLABSI) are 
a leading cause of hospital acquired infections in the ICU and are associated with higher mortali-
ty (Lin, et al., 2015). CLABSI rates are measured by number of infections per 1,000 catheter 
days and shorter CVC dwell time is prudent. If a reliable and rapid source of vascular access 
could postpone or eliminate CVC insertion, risk of CLABSI may be reduced. These potential 
benefits outweigh the minimal expected risk.  
 
 
III. Procedures. 
 
A. Research Design.  
Prospective case series 
 
B. Sample. 
Potential subjects will be recruited when the determination by the neuroscience critical care unit 
(NCCU) care team is made to initiate HTS on a patient without a CVC/PICC. This pilot study 
will include 5 subjects. Potential subjects or their surrogate decision-makers will be approached 
by an investigator or assistant to request consent. Recruitment will be open to all NCCU patients 
fitting the above criteria regardless of primary diagnosis.  
 
C. Measurements. 
Outcomes 
Primary outcome: safety 
Secondary outcomes: tolerability  
 
Data points 
Absence of extravasation of the infusion into the surrounding tissue and absence of tissue dam-
age proximate to the IO infusion 
Pain scale (critical care pain observation scale) during insertion  
Able to complete infusion without stopping for pain 
Absence of nonverbal indicators of pain (CPOT) 
Sodium:  
 
Baseline serum sodium 


 
2 & 6-hour post infusion serum sodium  
Timing:  
 
Time of order for HTS 
 
Time of affirmative consent 
 
Time of start of IO procedure 
 
Time of successful IO placement (or failure to achieve access)  
 
Time until IO removed 
 
D. Detailed study procedures 
Pre-study Training. Use of the EZ-IO device is already established at OSUWMC & The James. 
Key NCCU nurse practitioners and physicians will receive a standard one-hour hands-on training 
session from the device manufacturer. Potential subjects will be identified by the NCCU physi-
cians and nurse practitioners based on the below inclusion and exclusion criteria.  
 
The NCCU team will identify potential subjects:  
Inclusion criteria:  
NCCU patients in which osmotherapy with HTS is planned (standard of care 
Does not already have a CVC or PICC. 
Exclusion criteria:  
 
<18 years old 
 
Known pregnancy 
 
Long bone fracture in the targeted site  
 
Proximity to prosthetic joint 
 
Excessive tissue/absence of anatomical landmarks 
 
Cellulitis over potential insertion site 
 
History of osteopetrosis 
 
 
Investigators or assistants will request written or verbal telephone consent from the patient or 
surrogate decision maker if the patient is unable to consent. An IO will be inserted and place-
ment confirmed by an inability to tilt the hub of the needle and the ease of flushing through the 
needle. 40 mg lidocaine will be slowly infused into the IO over 120 seconds, and then allowed to 
dwell for 60 seconds before infusing HTS. Repeat doses of 20 mg dose of lidocaine may be used 
as needed for pain to a cumulative maximum dose of 1mg/kg over the 24 hour study period. 3% 
HTS will be bolused through the IO in doses as prescribed per the NCCU team. Serum sodium 
level will be sent at 2 and 6 hours following the HTS bolus and every 6 hours. Repeat HTS bo-
luses and/or continuous infusion may ordered per the NCCU team. Placement will be confirmed 
before and at the end of each bolus as above. 
 
If at any time during the study period the patient has intolerable pain, a CVC or PICC will be 
placed and the infusion moved to the CVC/PICC. The IO will be removed. 
 
If serum sodium is not appropriately rising following IO boluses, a CVC or PICC will be placed 
and further infusions will be moved to the CVC/PICC.  
 
If extravasation occurs, a new IO will be placed at an alternate site and further monitoring and 
treatment will be determined.  


 
The IO will be removed at or before 24 hours. If continued vascular access is required, a CVC or 
PICC will be placed. 
 
Data collection and storage procedure 
This study will utilize REDCap (Research Electronic Data Capture), a software toolset and work-
flow methodology for electronic collection and management of clinical and research data, to col-
lect and store data. The OSU Center for Clinical and Translational Science (CCTS) Research In-
formatics Services will be used as a central location for data processing and management. RED-
Cap provides a secure, web-based application that provides an intuitive data manipulation inter-
face, custom reporting capabilities, audit trail functionality, real-time data monitoring/querying 
of participant records, and variations of data exporting/importing. REDCap is hosted by 
OSUWMC IT in the Ackerman Datacenter (640 Ackerman Road; Room 345) 
 
 
 
 


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