Journal of Clinical Neuroscience xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Journal of Clinical Neuroscience

journalhomepage:www.elsevier.com/locate/jocn

Case study

Method of Hypertonic Saline Administration: Effects on Osmolality in

Traumatic Brain Injury Patients
a b a,⇑ b,c
Kelly L. Maguigan , Bradley M. Dennis , Susan E. Hamblin , Oscar D. Guillamondegui
aDepartment of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN 1211 Medical Center Drive, B131 VUH, Nashville, TN 37232, United States
b Department of Trauma and Surgical Critical Care, Vanderbilt University Medical Center, Nashville, TN 1211 21st Avenue South, 404 Medical Arts Building, Nashville, TN 37232, United States.
cDepartment of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN 1161 21st Ave. So., T4224 Medical Center North, Nashville, TN 37232, United States

article info abstract

Article history: Hypertonic saline (HTS) is an effective therapy for reducing intracranial pressure (ICP). The ideal method of administration is
Received 4 November 2016 unknown. The purpose of this study was to evaluate the method of HTS infusion and time to goal osmolality. A retrospective
Accepted 22 January 2017 cohort analysis was conducted in severe TBI patients with ICP monitoring in place who received 2 doses of HTS. Patients
Available online xxxx
were divided into bolus versus continuous infusion HTS cohorts. The primary outcome was median time to goal osmolality.
Secondary outcomes included percentage of patients reaching goal osmolality, percent time at goal osmolality, mean cerebral
Keywords: perfusion pressure (CPP) and ICP, ICU length of stay, and mortality. Safety outcomes included rates of hyperchloremia,
Traumatic brain injury
hypernatremia, and acute kidney injury (AKI). 162 patients were included with similar baseline characteristics. Time to goal
Hypertonic saline
osmolality was similar between cohorts (bolus 9.78 h vs. continuous 11.4 h, p = 0.817). A significant difference in the
Osmolality
Intracranial pressure percentage of patients reaching goal osmolality favoring the continuous group was found (93.9% vs 73.3%, p = 0.003). The
continuous group was maintained at goal osmolality for a higher percentage of osmolality values after reaching goal (80% vs.
50%, p = 0.032). No difference was seen in CPP, ICP, length of stay and mortality. Rates of hypernatremia were similar, but
significant higher rates of hyperchloremia (0.77 vs 1.58 events per HTS days, p < 0.001) and AKI (0% vs 12.9%, p = 0.025)
were observed in the continuous cohort. Although no difference in time to goal osmolality was observed, continuous HTS was
associated with a higher percentage of patients achieving goal osmolality.

2017 Elsevier Ltd. All rights reserved.

1. Introduction
The ideal hyperosmolar agent for elevated intracranial pressure (ICP)
(>20 mmHg) and method of administration remains debated in patients with
traumatic brain injury (TBI). Hyperosmolar treat-ment is typically instituted
to optimize the cerebral blood flow and to improve tissue oxygenation of the
injured brain after non-pharmacologic treatments and sedation have been
optimized [1– 3]. This therapy reduces ICP by creating an osmotic gradient
across an intact blood brain barrier to draw water from the interstitial space to
the vascular space. It also decreases blood viscosity and cerebral blood
volume [3,4]. In patients with persistently elevated ICP readings,
hyperosmolar therapy is often repeated until a goal blood osmolality is
reached [5–8].
Mannitol and hypertonic saline (HTS) have been studied exten-sively as
hyperosmolar agents in TBI, but recent meta-analyses have favored
hypertonic saline. These studies have indicated a greater reduction of ICP
with HTS than mannitol, as well as poten-tial reduction in the rate of rebound
intracranial hypertension and acute kidney injury [9–11]. Proposed
mechanisms for these advan-tages include the reduced likelihood of HTS
crossing the blood brain barrier, its ability to improve the mean arterial
pressure by increasing circulating volume, modulation of neuroinflammatory
pathways, and improvement in blood rheology within the cerebral vasculature
[12]. Despite recommendations from the Brain Trauma Foundation for
mannitol, HTS is increasingly used as the first-line hyperosmolar agent in
severe TBI [13]. It can be administered as either an intravenous bolus,
continuous infusion, or a combination of both. The safety and efficacy of both
bolus and continuous infu-sion HTS have been demonstrated in previous
studies [14,15]. However, the efficacy of the two different methods of
administra-tion has not been directly compared. The purpose of this study was

⇑ Corresponding author. Fax: +1 (615) 343 7280.

E-mail address: Susan.hamblin@vanderbilt.edu (S.E. Hamblin).

http://dx.doi.org/10.1016/j.jocn.2017.01.025
0967-5868/ 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Maguigan KL et al. Method of Hypertonic Saline Administration: Effects on Osmolality in Traumatic Brain Injury Patients. J Clin Neurosci (2017),
http://dx.doi.org/10.1016/j.jocn.2017.01.025
2 K.L. Maguigan et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
to evaluate the effects of HTS continuous infusion on the time to goal
osmolality. We hypothesize that patients receiving bolus only HTS will reach
goal osmolality more rapidly than patients receiving continuous infusion
HTS.
2. Methods
This IRB-approved retrospective cohort analysis was conducted at an
academic Level 1 trauma center. Trauma patients included in this study were
admitted to a 14-bed trauma ICU and managed by a multidisciplinary team
led by trauma surgeons.
2.1. Hyperosmolar therapy
Hyperosmolar therapy at our institution is directed by center specific
guidelines and by the attending trauma surgeon and neu-rosurgery service. It
is initiated when an elevated ICP is suspected or documented by an ICP
monitor or external ventricular drain (EVD). The standard preparation of HTS
utilized at our institution is 3% sodium chloride. In 2011, our institution
transitioned HTS therapy from bolus only to mostly combination therapy with
a continuous infusion. However, both approaches continue to be used based
on team preference. For patients who receive bolus only therapy, HTS boluses
of 250–500 mL are typically given until both goal ICP (<20 mmHg) and
blood osmolality (>310 mOsm/kg) are reached. Patients who receive HTS
therapy as a continuous infusion will start at a rate of 30–50 mL/h with
repeatable bolus doses as needed to achieve a goal ICP. The infusion is
titrated to maintain a sodium of 150–160 mEq/L and an osmolality value
>310 mOsm/kg. ICP is monitored continuously by an EVD or ICP monitor
and laboratory values are obtained every six hours. Man-nitol is often
reserved for HTS refractory ICPs or extreme elevations in ICP if maximum
serum sodium or osmolality has not been achieved.
2.2. Study design
Patients eligible for inclusion were identified by the Trauma Registry of
the American College of Surgeons (TRACS) from January 2008 to May 2014.
Patients with a diagnosis of severe TBI (Glasgow Coma Scale score <9) who
received an ICP monitor or EVD as well as two or more doses of 3% sodium
chloride were included in the study. Patients were excluded if they underwent
a craniotomy as ICP was surgically managed in these patients. HTS cohorts
were divided into those patients who received bolus HTS only and those who
received continuous infusion HTS with ‘‘as needed” bolus HTS therapy.
Rescue mannitol administration was permitted in both groups.
The primary outcome of this study was time to goal osmolality. Goal
osmolality was defined as a serum osmolality value of P310 mOsm/kg. Time
zero was the first documented HTS dose on the medication administration
record or the first documented
Table 1
Baseline characteristics.
Characteristic
Age, median (IQR)
Male sex, No. (%)
Admission GCS, median (IQR)
Admission ISS, median (IQR)
Admission AIS Head/Neck, median (IQR)
Opening pressure, median (IQR)
Blunt trauma, No. (%)
Total HTS administered (mL), median (IQR)
Total mannitol administered (g), median (IQR)
Please cite this article in press as: Maguigan KL et al. Method of Hypertonic Saline Administration: Effects on Osmolality in Traumatic Brain Injury Patients. J Clin Neurosci (2017),
http://dx.doi.org/10.1016/j.jocn.2017.01.025
HTS flow rate in the nursing flowsheet. Secondary outcomes included
percentage of patients reaching goal osmolality, percent of osmolality values
at goal while on HTS, mean CPP and ICP, ICU length of stay, and ICU
mortality. Safety outcomes included the incidence of AKI, hypernatremia (Na
>160 mEq/L), and hyper-chloremia (Cl >120 mEq/L). Acute kidney injury
was defined as an increase in serum creatinine of 1.5 times baseline serum
crea-tinine value, according to the RIFLE criteria [16]. The incidence and
indication for hemodialysis and continuous renal replacement therapy
(CRRT) in the ICU was collected as well as requirements for long-term
dialysis at discharge. The incidence of electrolyte abnor-malities was
normalized to total patient days on HTS per cohort since more patients
received continuous infusion instead of bolus only HTS.
Demographic data, including age, gender, admission Glasgow Coma Scale
score (GCS), Injury Severity score (ISS), and head/neck Abbreviated Injury
Scale score (AIS) were collected through TRACS. Medication administration
record, laboratory values and vital signs were extracted from the electronic
medical record. From this data, time to goal osmolality and ICP were
calculated, along with per-centage of osmolality values at goal range while on
HTS.
2.3. Statistical analysis
Statistical analysis was performed using SPSS Statistics Version
22. Due to the retrospective nature of the study, a power calcula-tion was not
performed. Medians were utilized to analyze non-normally distributed data
and means were used to analyze nor-mally distributed data. Non-parametric
categorical data was ana-lyzed with the Fisher’s Exact Test. The Mann–
Whitney U test was used for non-parametric continuous data.
3. Results
Two hundred sixteen patients were identified for inclusion. Reasons for
exclusion included less than 2 doses of HTS (n = 36), ICP monitoring not
available during HTS administration (n = 14), craniotomy (n = 2), and
administration of HTS outside of the trauma ICU (n = 2). Thus, a total of 162
patients were included with 132 in the continuous infusion HTS arm and 30 in
the bolus only HTS arm.
Patient demographics were relatively similar between the two groups.
Baseline characteristics are summarized in Table 1. The majority of patients
included were young males without comor-bidities who were admitted after
blunt trauma. More HTS was administered in the continuous infusion cohort
compared to the bolus only cohort (1250 mL vs. 2735 mL, p < 0.001).
Mannitol administration was greater in the continuous infusion cohort, but
this did not reach statistical significance (127.5 g vs. 87.5 g, p = 0.181).
For the primary outcome, no difference was observed in time to goal
osmolality. Patients receiving continuous infusion HTS
Continuous infusion HTS (n = 132) Bolus only HTS (n = 30)
29.4 (22.4–46.2) 29.1 (19.3–51.6)
101 (76.5%) 20 (66.7%)
3 (3–3) 3 (3–3)
37 (29–45) 33.5 (26–42.8)
5 (4–5) 5 (4–5)
15 (9–23) 15 (8.3–21.5)
126 (95.4%) 29 (96.7%)
2735 (1790–4395) 1250 (750–1937.5)
127.5 (50–250) 87.5 (6.25–193.75)
 K.L. Maguigan et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx 3

100 93.9%
Percentage of Paents and Osmolality 90
Values 80%
80 73.3%
70
60
50%
50 Con nuous Infusion
40
Bolus Only
30
20
10 p=0.003 p=0.032
0
Pa ents Reaching Goal Osmolality Values at Goal on
Osmolality HTS

Fig. 1. Percentage of patients reaching goal osmolality and osmolality values at goal while on HTS.

Table 2
Secondary outcomes.

Outcome Continuous infusion HTS (n = 132) Bolus only HTS (n = 30) P value
Mean ICP, median (IQR) 13.9 (10.2–18.1) 15.5 (12.9–17.8) 0.157
Mean CPP, median (IQR) 72.8 (66.9–78.6) 71.8 (67.7–75) 0.312
ICU length of stay, median (IQR) 9 (6–15) 10 (5.3–13.8) 0.782
Hospital length of stay, median (IQR) 12.5 (7–21) 14 (6–22) 0.962
ICU mortality, No. (%) 60 (45.5%) 12 (40%) 0.685

Table 3

Electrolyte abnormalities per days on HTS and rates of acute kidney injury per days on HTS.

Outcome Continuous infusion HTS Bolus only HTS P value

Acute kidney injury (P1.5 increase in baseline SCr) 17 (12.9%) 0 (0%) 0.025
Hypernatremia (P160 mEq/L) 0.04 0.01 0.231
Hyperchloremia (P120 mEq/L) 1.58 0.77 <0.001

reached goal in 11.4 h compared to 9.78 h in the bolus only group (p = 0.817).
However, as seen in Fig. 1, a greater percentage of patients receiving
continuous HTS reached goal osmolality [93.9% (n = 124) vs 73.3% (n = 22),
p = 0.003] and were maintained at goal osmolality for a higher percentage of
osmolality values (80% vs 50%, p = 0.032). As summarized in Table 2, no
differences were observed in any additional secondary outcomes. Finally,
Table 3 shows the incidence of electrolyte abnormalities normalized to days
on HTS, which is notable for a higher rate of hyperchloremia in the
continuous infusion cohort. Rates of acute kidney injury were notable for a
significant increase in the continuous infusion cohort (12.9% vs 0%, p =
0.025) Only one patient with AKI required continuous renal replacement
(CRRT) therapy for hyperkalemia and acidosis, which was likely unrelated to
the hyperosmolar therapy.
Theoretically, patients who are maintained at goal osmolality will be able to
maintain the osmotic gradient to decrease intravascular volume and ICP for a
longer period of time [17]. Preserving osmo-lality is also key in sustaining
ICP reduction. The brain has the abil-ity to counteract the effects of HTS by
raising intracellular solute concentrations if the osmolality gradient is not
maintained [18]. Specifically, astrocytes compensate for the decrease in brain
con-tent water induced by HTS by increasing solute concentrations thus
returning brain water to a normal volume and increasing intracellular
osmolarity [19]. This physiological response can be blunted by reaching and
maintaining goal osmolality, which in our study, was achieved more
frequently in the continuous infu-sion cohort. Lastly, in patients with
refractory intracranial hyper-tension, osmolality must be maintained prior to
further escalation of medical management. At our institution, pentobarbi-tal
coma therapy can only be considered if hyperosmolar therapy has been
optimized [20].

4. Discussion
In this study, we report the effects of different methods of HTS
administration in patients with severe TBI. To our knowledge, this is the first
study to compare continuous infusion HTS and bolus only HTS. The primary
outcome demonstrated that both methods of administration are effective in
achieving goal serum osmolality within a similar period of time. Interestingly,
a higher percentage of patients receiving continuous infusion HTS reached
goal osmo-lality and were maintained at goal a higher percentage of time
compared to patients only receiving bolus therapy.
HTS is used preferentially over mannitol as our first-line hyper-osmolar
agent as meta-analyses have demonstrated superior ICP reduction and control
with HTS [9,10,21]. A goal osmolality of P310 mOsm/kg was chosen in this
study because previous studies have demonstrated improved outcomes when
targeting a range of 310–320 mOsm/kg [22]. Wagner et al. examined the
effects of con-tinuous HTS in patients with spontaneous intracerebral hemor-
rhage when targeting an osmolality range of 310–320 mOsm/kg. A significant
reduction in ICP crises (ICP >20 mmHg for 20 min) was noted in those
patients treated with HTS who were main-tained at goal osmolality [22].

This study is notable for two important findings: a higher pro-portion of

patients in the continuous infusion HTS group reached goal osmolality and The administration of HTS is not without its risks as its admin-istration
those in the continuous infusion HTS group were maintained at goal can cause both neurological and systemic complications. Neurological
osmolality for a higher percentage of time. complications of HTS administration include central

Please cite this article in press as: Maguigan KL et al. Method of Hypertonic Saline Administration: Effects on Osmolality in Traumatic Brain Injury Patients. J Clin Neurosci (2017),
http://dx.doi.org/10.1016/j.jocn.2017.01.025
4 K.L. Maguigan et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
pontine myelinolysis and seizures, but these effects are usually only observed
with correction of severe hyponatremia. The most common systemic side
effects observed include electrolyte abnor-malities such as hypernatremia and
hyperchloremia that can potentiate hyperchloremic acidosis and acute kidney
injury [14]. We chose to examine the electrolyte abnormalities related to the
two types of HTS administration. An increased rate of hyper-chloremia was
observed with continuous HTS, which could possi-bly be attributed to an
overall increase in the volume of HTS administered for this cohort. However,
this hypothesis was not replicable with hypernatremia. This is an interesting
finding as recently more interest is being devoted to exploring the adverse
effects of hyperchloremia [23,24]. In a single center multidisci-plinary ICU,
administration of chloride-liberal therapy, which only included a small
percentage of patients admitted with a primary neurological diagnosis, was
associated with higher incidence of acute kidney injury and need for renal
replacement therapy [23]. However, these results were not replicated in a
larger multicenter study which did not show a difference in rates of acute
kidney injury or need for renal replacement [24]. The mechanism of chlo-ride
induced acute kidney injury is poorly understood, but it is hypothesized that
chloride causes a decrease in glomerular filtra-tion rate through
vasoconstriction of the renal vessels, which is directly related to tubular
chloride reabsorption [25]. Because the continuous HTS cohort received a
significantly higher volume of HTS and thus a higher chloride load, this could
explain why there was a higher incidence of acute kidney injury observed.
However, only one patient required CRRT, so the difference in rates of AKI
may not be clinically significant.
Because HTS is increasingly used in the treatment of intracra-nial
hypertension, it is important to determine if there is an opti-mal method of
administration in order to optimize patient outcomes, and our study does offer
several strengths. We used both the medication administration record and the
nursing flow-sheet to determine the initial timing of the first dose of HTS.
This allowed us to identify the most accurate time of the initial admin-
istration of the HTS, which is often difficult to discern retrospec-tively,
especially during medical emergencies like intracranial hypertension. Lastly,
we targeted a narrow population with a diag-nosis of severe TBI, in which
hyperosmolar therapy was indicated based on confirmed elevations in ICP.
There are a few limitations of this study. First, even though the total
amount of mannitol was collected, the specific timing of man-nitol
administration was not analyzed. Like HTS, mannitol can increase osmolality
and decrease ICP, which could have affected our primary and secondary
outcomes if more mannitol was given earlier after injury since it can be
administered peripherally. Also, the type of sedation utilized was collected
including propofol, midazolam, pentobarbital and fentanyl. However because
these therapies were often used concurrently, it is difficult to discern whether
or not the type of sedation influenced primary and sec-ondary outcomes.
Another limitation is the uneven distribution of patients in each cohort.
Because our institution transitioned to primarily using continuous infusion
HTS in 2011, there was a much smaller number of bolus only patients
included in the analysis. This may limit the applicability of our results until a
larger study can be performed to validate these findings. Lastly, due to the ret-
rospective nature of the study it is impossible to eliminate the pos-sibility of
potential biases and confounders.
5. Conclusions
No difference in time to goal osmolality was observed when comparing
bolus or continuous infusion HTS in severe TBI patients.
Please cite this article in press as: Maguigan KL et al. Method of Hypertonic Saline Administration: Effects on Osmolality in Traumatic Brain Injury Patients. J Clin Neurosci (2017),
http://dx.doi.org/10.1016/j.jocn.2017.01.025
However, continuous HTS was associated with a higher percentage of patients
achieving and maintaining goal osmolality. Patients receiving continuous
HTS experienced higher rates of hyper-chloremia and acute kidney injury, but
continuous infusion HTS was not associated with any difference in CPP and
ICP, ICU length of stay, and ICU mortality when compared to bolus HTS
therapy. Further studies are needed to definitively assess these methods of
HTS administration.
Conflicts of interest
All authors have no conflicts of interest to declare. This research did not
receive any specific grant from funding agencies in the public, commercial, or
not-for-profit sectors.
References
[1] Scalfani MT et al. Effect of osmotic agents on regional cerebral blood flow in traumatic
brain injury. J Crit Care 2012;27(5):526.e7–526.e12.
[2] Sakowitz OW et al. Effects of mannitol bolus administration on intracranial pressure,
cerebral extracellular metabolites, and tissue oxygenation in severely head-injured
patients. J Trauma 2007;62(2):292–8.
[3] Forsyth LL et al. Role of hypertonic saline for the management of intracranial
hypertension after stroke and traumatic brain injury. Pharmacotherapy 2008;28(4):469–84.
[4] Stocchetti N, Maas AI. Traumatic intracranial hypertension. N Engl J Med
2014;370(22):2121–30.
[5] Donkin JJ, Vink R. Mechanisms of cerebral edema in traumatic brain injury: therapeutic
developments. Curr Opin Neurol 2010;23(3):293–9.
[6] Unterberg AW et al. Edema and brain trauma. Neuroscience 2004;129
(4):1021–9.
[7] Treggiari MM et al. Role of intracranial pressure values and patterns in predicting
outcome in traumatic brain injury: a systematic review. Neurocrit Care 2007;6(2):104–12.
[8] Rosner MJ, Rosner SD, Johnson AH. Cerebral perfusion pressure: management protocol
and clinical results. J Neurosurg 1995;83(6):949–62.
[9] Li M et al. Comparison of equimolar doses of mannitol and hypertonic saline for the
treatment of elevated intracranial pressure after traumatic brain injury: a systematic review
and meta-analysis. Medicine (Baltimore) 2015;94(17):
e736.
[10] Mortazavi MM et al. Hypertonic saline for treating raised intracranial pressure: literature
review with meta-analysis. J Neurosurg 2012;116
(1):210–21.
[11] Fink ME. Osmotherapy for intracranial hypertension: mannitol versus hypertonic saline.
Continuum (Minneap Minn) 2012;18(3):640–54.
[12] Muizelaar JP, Shahlaie K. Hypertonic saline in neurocritical care: is continuous infusion
appropriate? Crit Care Med 2009;37(4):1521–3.
[13] Bratton SL et al. II. Hyperosmolar therapy. J Neurotrauma 2007;24(Suppl 1):S- 14–20.
[14] Huang SJ et al. Efficacy and safety of hypertonic saline solutions in the treatment of
severe head injury. Surg Neurol 2006;65(6):539–46 [discussion 546].
[15] Froelich M et al. Continuous hypertonic saline therapy and the occurrence of
complications in neurocritically ill patients. Crit Care Med 2009;37
(4):1433–41.
[16] Luo X et al. A comparison of different diagnostic criteria of acute kidney injury in
critically ill patients. Crit Care 2014;18(4):R144.
[17] Harukuni I, Kirsch JR, Bhardwaj A. Cerebral resuscitation: role of osmotherapy. J Anesth
2002;16(3):229–37.
[18] Ropper AH. Hyperosmolar therapy for raised intracranial pressure. N Engl J Med
2012;367(8):746–52.
[19] Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000;342(20):1493–9.
[20] Marshall GT et al. Pentobarbital coma for refractory intra-cranial hypertension after
severe traumatic brain injury: mortality predictions and one-year outcomes in 55 patients.
J Trauma 2010;69(2):275–83.
[21] Kamel H et al. Hypertonic saline versus mannitol for the treatment of elevated intracranial
pressure: a meta-analysis of randomized clinical trials. Crit Care Med 2011;39(3):554–9.
[22] Wagner I et al. Effects of continuous hypertonic saline infusion on perihemorrhagic edema
evolution. Stroke 2011;42(6):1540–5.
[23] Yunos NM et al. Association between a chloride-liberal vs chloride-restrictive intravenous
fluid administration strategy and kidney injury in critically ill adults. JAMA
2012;308(15):1566–72.
[24] Young P et al. Effect of a buffered crystalloid solution vs saline on acute kidney injury
among patients in the intensive care unit: the SPLIT randomized clinical trial. JAMA
2015;314(16):1701–10.
[25] Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest
1983;71(3):726–35.