Continuous controlled-infusion of hypertonic saline solution in traumatic brain-injured patients: a 9-year retrospective study
Roquilly et al. Critical Care
Continuous controlled-infusion of hypertonic saline solution in traumatic brain-injured patients: a 9-year retrospective study
Antoine Roquilly 0 3
Pierre Joachim Mahe 0 3
Dominique Demeure Dit Latte 0 3
Olivier Loutrel 0 3
Philippe Champin 0 3
Christelle Di Falco 0 3
Athanase Courbe 0 3
Kevin Buffenoir 2
Olivier Hamel 2
Corinne Lejus 0 3
Vronique Sebille 1
Karim Asehnoune 0 3
0 Anesthesiology and Intensive Care Unit, Hotel Dieu Nantes University Hospital , 1 place Alexis Ricordeau, Nantes, F-44093 France
1 Cellule de Biostatistique, EA 4275, UFR de Pharmacie, Nantes University , A rue Gaston Veil, Nantes, F-44000 France
2 Neurosurgery Unit, Hotel Dieu Nantes University Hospital , 1 place Alexis Ricordeau, Nantes, F-44093 France
3 Anesthesiology and Intensive Care Unit, Hotel Dieu Nantes University Hospital , 1 place Alexis Ricordeau, Nantes, F-44093 France
Introduction: Description of a continuous hypertonic saline solution (HSS) infusion using a dose-adaptation of natremia in traumatic brain injured (TBI) patients with refractory intracranial hypertension (ICH). Methods: We performed a single-center retrospective study in a surgical intensive care unit of a tertiary hospital. Fifty consecutive TBI patients with refractory ICH treated with continuous HSS infusion adapted to a target of natremia. In brief, a physician set a target of natremia adapted to the evolution of intracranial pressure (ICP). Flow of NaCl 20% was a priori calculated according to natriuresis, and the current and target natremia that were assessed every 4 hours. Results: The HSS infusion was initiated for a duration of 7 (5 to 10) (8 4) days. ICP decreased from 29 (26 to 34) (31 9) mm Hg at H0 to 20 (15 to 26) (21 8) mm Hg at H1 (P < 0.05). Cerebral perfusion pressure increased from 61 (50 to 70) (61 13) mm Hg at H0 up to 67 (60 to 79) (69 12) mm Hg at H1 (P < 0.05). No rebound of ICH was reported after stopping continuous HSS infusion. Natremia increased from 140 (138 to 143) (140 4) at H0 up to 144 (141 to 148) (144 4) mmol/L at H4 (P < 0.05). Plasma osmolarity increased from 275 (268 to 281) (279 17) mmol/L at H0 up to 290 (284 to 307) (297 17) mmol/L at H24 (P < 0.05). The main side effect observed was an increase in chloremia from 111 (107 to 119) (113 8) mmol/L at H0 up to 121 (117 to 124) (121 6) mmol/L at H24 (P < 0.05). Neither acute kidney injury nor pontine myelinolysis was recorded. Conclusions: Continuous HSS infusion adapted to close biologic monitoring enables long-lasting control of natremia in TBI patients along with a decreased ICP without any rebound on infusion discontinuation.
Refractory intracranial hypertension (ICH) is the most
frequent cause of death after traumatic brain injury (TBI)
. In brain-injured patients, hyponatremia frequently
develops, mainly caused by inappropriate antidiuretic
hormone syndrome and cerebral salt-wasting syndrome
[2,3]. Hyponatremia induces brain ischemia resulting
from the swelling of perivascular astrocytic , and also
increases the brain-contusion volume and intracranial
pressure (ICP). The control of natremia is a major goal
for prevention and treatment of ICH in an attempt to
improve the neurologic recovery after brain injury.
The first-line treatment of ICH is osmotherapy .
HSS draws fluid from interstitial space, improves
intracranial compliance, and decreases ICP, notably by
counteracting the brain accumulation of extracellular
osmolytes observed within blood-brain barrier
dysfunction [6,7]. In this setting, a bolus of mannitol or of
hypertonic saline solution (HSS) efficiently decrease the ICP
[5,8]. Several reports suggested that a bolus infusion of
HSS is more effective than mannitol for the treatment of
elevated ICP, but mannitol is still the mainstay of
hyperosmolar therapy [9,10]. A bolus of either mannitol or
HSS encounters the same limits that are a time-limited
effect as well as the risk of a rebound of ICH [5,8,9]. As
the time-limited effect of a bolus of HSS is still an issue,
several studies have evaluated the use of continuous HSS
infusion after TBI. In adult patients, continuous HSS
infusion has been tested prophylactically in the
prevention of ICH, but no data are available in the setting of
refractory ICH [11-14]. Continuous HSS infusion
increased natremia and osmolarity, decreased the risk of
ICH, and improved the cerebral perfusion pressure (CPP)
in TBI patients without ICH [11-14]. To date, no clear
conclusion can be drawn regarding potential side effects
. The HSS continuous infusion induced severe
hypernatremia [12-14]. In this setting, dose adjustment of HSS
is critical for preventing potential side effects of severe
acute hypernatremia (osmotic demyelination syndrome
or central pontine myelinolysis , renal failure ,
phlebitis ). Issues regarding side effects have not been
addressed in the current literature. Moreover, data
regarding the ending of the infusion are sparse, despite
the risk of a rebound of ICP . We present the report
of our 9-years experience with the use of an algorithm
for dose adaptation of prolonged continuous HSS
infusion in patients with refractory ICH. The aims of this
descriptive study were therefore to describe a continuous
infusion of HSS adapted to a target of natremia and to
investigate its potential ability to decrease ICP without
inducing severe hypernatremia and rebound in ICP in
TBI patients with refractory ICH.
Materials and methods
This retrospective descriptive study was performed from
1 January 2001 to 31 December 2009 in a surgical ICU
of a tertiary hospital. No change in our current clinical
practice and no randomization were performed. As it
was an observational retrospective study, according to
the French legislation (articles L.1121-1 paragraph 1 and
R1121-2, Public Health Code), neither informed consent
nor approval of the ethics committee was needed to use
data for an epidemiologic study.
Patients were identified from an electronic registry
prospectively recorded. Inclusion criteria were as follows:
(a) traumatic brain-injured patients defined as having a
Glasgow Coma Score (GCS) 8 after initial care; (b)
ICP monitored with an intraparenchymal probe; (c)
treated with a continuous HSS infusion adapted to a
target of natremia; and (d) in the purpose of refractory
ICH. ICH was defined as an ICP > 20 mm Hg for more
than 15 minutes [5,18]. Refractory ICH was considered
when ICP remained > 20 mm Hg despite general care,
control of capnia (< 5.8 kPa), as well as body
temperature (< 38.0C), and mannitol, and barbiturate injections
. Exclusion criteria were as follows: (a) continuous
HSS infusion for < 8 hours, (b) or hyponatremia without
General care of severe head-trauma patients
All patients were sedated with a continuous intravenous
infusion of fentanyl (2 to 5 g.kg-1.hr-1) and midazolam
(0.2 to 0.5 mg.kg-1.hr-1) and were mechanically
ventilated. Apart from counterindications, sedated patients
were kept in a semirecumbent position. Secondary brain
injuries were prevented by keeping the body
temperature between 36.0C and 37.0C, ensuring
normoglycemia and normocapnia, and by avoiding hypoxemia. In
severe TBI patients, natremia and blood gases were
assessed at least twice a day, and expiratory end-tidal
(Et) CO2 was continuously monitored. Patients were
monitored with invasive arterial pressure, and mean
arterial pressure was measured up to the brain for the
calculation of the CPP. For patients with severe TBI and
with an abnormal computed tomography (hematomas,
contusions, swelling, herniation, or compressed basal
cisterns), the ICP was monitored [5,19] with an
intraparenchymal probe placed in the most affected side
(Codman, Johnson and Johnson Company, Raynham, MA,
USA.). CPP was maintained > 65 mm Hg with isotonic
fluids (NaCl, 0.9%) and vasopressor (norepinephrine).
Extraventricular drainage was used in case of
hydrocephalus. Neuromuscular nondepolarizing agents were not
used for ICH management. Mannitol (a bolus of 0.5 g/
kg, repeatable once in case of poor ICP control, ICP >
20 mm Hg, after 30 minutes; maximal dose, 1 g/kg) was
used to control episodes of ICH. When control of ICH
was poor, midazolam infusion was continued, and
barbiturate (sodium thiopental) was used (loading dose of 2
to 3 mg/kg) followed by a continuous infusion (starting
dose of 2 to 3 mg/kg/h) adapted to the ICP evolution
and, once per day, to a serum-level monitoring
(thiopental blood level targets, 20 to 30 g/ml) . For each
patient, continuous HSS infusion was started when the
ICP remained > 20 mm Hg 30 minutes after the
initiation of barbiturate infusion (refractory ICH). When the
continuous osmotherapy failed (persistent refractory
ICH), a decompressive craniectomy was discussed with
the neurosurgical team, and HSS infusion was pursued.
Adjustment of the target of natremia
The attending physician set a target of natremia (from
145 to 155 mmol/L) adapted to the evolution of ICP.
When ICP was > 20 mm Hg, the target of natremia was
increased by an increment of 5 mmol/L every 4 hours,
and a bolus of HSS was infused (natremia below the
new target, left side of Figure 1). The infusion of HSS
was prolonged for as long as required to control the
ICP. When the ICP was 20 mm Hg for at least 24
hours, the target of natremia was left unchanged until
Figure 1 Dose-adaptation of continuous hypertonic saline solution infusion. The attending physician set the targets of natremia according
to the intracranial pressure (ICP). The target could be modified by a step of 5 mmol/L from 145 to 155 mmol/L. Natremia and natriuresis were
assessed every 4 hours. Target was considered achieved if -2 mmol/L < Delta < +2 mmol/L; otherwise, the flow of NaCl infusion was adapted.
On infusion initiation or when natremia was below the target (left side), a 1-hour bolus was performed. When the target of natremia was
reached (middle), the flow of a continuous infusion of HSS (NaCl 20%) was adapted to the urinary excretion of sodium, and the extraurinary
sodium loss was neglected. If natremia was above the target (right side), the infusion of NaCl (20%) was discontinued for 1 hour. Except in case
of intracranial pressure > 20 mm Hg. Natriuresis, urinary sodium concentration (mmol/L); kaliuresis, urinary potassium concentration (mmol/L);
dieresis, urinary output (ml/h); Delta, natremia - target).
barbiturate infusion could be stopped. When barbiturate
could be stopped (progressively) without increasing the
ICP, the target of natremia was gradually decreased to
145 mmol/L (by decrements of 5 mmol/L) in an attempt
to maintain the CPP and to prevent hyponatremia.
Dose adaptation of a continuous HSS
To limit the risk of fluid overload observed with other
saline solutions , we used a 20% chloride sodium solution
infusion (adapted from [2,21,22]; see Figure 1 and
Addition File 1 for an example). Dose-adaptation of HSS
infusion was performed by nurses according to an algorithm
(Figure 1). Biologic monitoring (blood and urinary
electrolyte concentrations, osmolarity) was performed every 4
hours. For calculation, three situations were available:
1. On infusion initiation or when natremia was
below the target, a bolus of chloride sodium was
administered. The dose of sodium was calculated
according to the natremia measured in the previous
12 hours (natremia below the target, Figure 1).
Considering that a bolus of chloride sodium only
fills the extracellular fluid compartment (one fourth
of the body weight), the required volume of NaCl
20% was calculated as follows:
Volume (NaCl 20%) = Delta weight/11.
The bolus was administered in 1 hour.
2. When the target of natremia was reached, the
flow of continuous infusion of HSS (NaCl 20%) was
adapted to the urinary excretion of sodium, and the
extraurinary sodium loss was neglected. The flow of
NaCl 20% was calculated as follows:
Dose NaCl 20% ml/h = Natriuresis Diuresis 0.3
3. When the natremia was above the target, the infusion of NaCl (20%) was discontinued for 1 hour. Then the continuous infusion of NaCl was resumed for the remaining 3 hours.
A polyuria has been described with the intravenous
infusion of HSS . In an attempt to prevent severe
dehydration, a compensation of the volume loss due to
excessive diuresis should be performed. Replacement for
volume loss was performed in 1 hour when diuresis
exceed 120 ml/h (corresponding to basal hydration
excluding HSS infusion) with a solution composed as
follows: 1,000 ml Glucose (2.5%) + NaCl (natriuresis/17)
grams + KCl (kaliuresis/13) g.
Local normal ranges for natremia were 137 to 145
mmol/L. Acute kidney injury was defined by a 200%
increase in serum creatinine concentration as compared
with a previous assessment of renal function . Severe
central pontine myelinolysis was considered if clinical
symptoms (prolonged alteration of consciousness,
quadriplegia, and dysarthria) were associated with the
appearance of a central pons lesion on magnetic
The following data were recorded in the electronic
medical file prospectively completed: age, sex, GCS, ICH
management, continuous infusion of HSS (duration,
target natremia, biologic monitoring, blood osmolarity
measured with an osmometer, quantity of infused
sodium), and evolution of ICP and CPP during the
infusion. Serum creatinine concentration, coagulation tests,
and central pontine myelinolysis were also recorded, as
well as the Glasgow Outcome Scale (GOS) and death at
To account for the correlation between measurements
from the same individual, repeated measures analysis of
variance (ANOVA) using linear mixed models, allowing
random effects with restricted maximum-likelihood
estimation, was used to examine changes in variables over
time. Time effect was included in the models along with
baseline measurements. Several covariance structures
among the repeated measurements (autoregressive,
unstructured, Toeplitz, and so on) were compared by
using Akaikes Information Criterion . Residual
analysis was used to evaluate the validity of the models
assumptions, including normality and homoscedasticity.
Mixed models post hoc tests based on estimated
marginal means were performed for comparing the levels of
the studied variables at different times. Skewed variables
were log-transformed, and statistical analyses were
performed with SAS 9.1 statistical software (SAS Institute,
Cary, NC, USA). Continuous variables were expressed
as median (percentiles 25 to 75; mean SD). The P
values for each variable tested are presented in
Additional file 1, Table S1. P values < 0.05 were considered
to be statistically significant.
During the 9-year study period, 780 patients with TBI
were admitted into the ICU. Among the 243 (31.2%)
patients with a severe TBI monitored with an ICP, 50
(20.6%) patients developed a refractory ICH and were
treated with a continuous HSS infusion (Figure 2).
Patients were aged 40 (range, 25 to 45 years) (36 13)
years, and 46 (92%) were men. The GCS on the scene
was 6 (5 to 8; 6 2), and the first measured ICP was
28 (25 to 34; 31 9) mm Hg (Table 1). Traumatic
lesions observed on the initial cerebral
tomodensitometry were 24 (48%) subarachnoid haemorrhage, 19
(38%) epidural haemorrhage, 40 (80%) cerebral
contusions, and no patient had hydrocephalus (multiple
lesions could be observed in the same patient). Of 50
patients, 29 (58%) required neurosurgery for hematoma
evacuation. Barbiturate infusion was started on day 2
(1 to 3; 3 2) for a duration of 5 (4 to 8; 6 3) days.
Over the period of infusion, the dose of barbiturate
was 2.7 (1.4 to 5.5; 3.1 2.5) mg/kg/h. The length of
stay in the ICU was 25 (9 to 36; 27 19) days. Of 50
patients, three (6%) died in the ICU of intractable ICH,
and 10 (20%) of care withdrawal. The GCS at
discharge from the ICU (for surviving patients) was 14
(8 to 15; 13 7), and the GOS evaluated at 1 year was
4 (1 to 5; 3 2; Table 1).
The continuous HSS infusion was started on day 2 (1
to 4; 3 2) for a duration of 7 (5 to 10; 8 4) days.
After the first 96 hours, the number of patients still
receiving continuous HSS decreased considerably
(discontinuation of HSS infusion or death); see Additional
File 1, Figure S1. In an attempt to preserve the statistical
power of the study, we provide the results for the first
96 hours of infusion (H0 to H96).
Figure 2 Flow chart. ICHT, intracranial hypertension; ICP,
intracranial pressure; TBI, traumatic brain injury.
Table 1 Population description
ISS, Injury Severity Score; SAPS, simplified acute physiology score; Cerebral perfusion pressure, (Mean arterial pressure - Intracranial pressure); ICU, intensive care
unit; HSS, hypertonic saline solution; Glasgow Outcome Scale ranges: 1, dead; 2, vegetative state (meaning the patient is unresponsive, but alive); 3. severely
disabled (conscious, but the patient requires others for daily support because of disability); 4, moderately disabled (the patient is independent but disabled); 5,
good recovery (the patient has resumed most normal activities but may have minor residual problems).
Evolution of ICP and CPP
ICP significantly diminished from 29 (26 to 34; 31 9)
mm Hg at H0 down to 20 (15 to 26; 21 8) mm Hg at
H1 (P < 0.05 versus H0), and from 22 (15 to 28; 22
9) mm Hg at H4 to 20 (15 to 24; 19 7) mm Hg at
H8 (P < 0.05 versus H4). Afterward, ICP was stable
until H96 (Figure 3a). When the HSS infusion was
stopped, the ICP remained unchanged from 11 (8 to
14) (12 5) mm Hg at H-24, to 13 (10 to 17) (14 4)
mm Hg at H-48 (non significant, NS; Figure 3a).
Cerebral perfusion pressure (CPP) increased from 61 (50 to
70) (61 13) mm Hg at H0 up to 67 (60 to 79) (69
12) mm Hg at H1 (P < 0.05). CPP was stable until H96
(Figure 3b). When stopping the HSS infusion, CPP
remained unchanged from 72 (64 to 86) (74 10) mm
Hg at H-24, to 74 (68 to 83) (76 8) mm Hg at H-48
(NS; Figure 3b). A decompressive craniectomy was
performed for five patients (10%) for a persistent ICH (one
patient died in the ICU, and GOS at 1 year was equal
to 3 for one, to 4 for two, and to 5 for one patient).
Capnia, body temperature, vasoactive drugs were not
Evolution of natremia and osmolarity
Natremia increased from 140 (138 to 143) (140 4) at
H0 to 144 (141 to 148) (144 4) mmol/L at H4 (P <
0.05; Figure 4a). Afterward, natremia continuously
increased until the 20th hour of HSS infusion, and
remained stable until the 96th hour (Figure 4a). When
we stopped the HSS infusion, natremia decreased from
146 (142 to 151) (146 7) mmol/L at H-24, to 141 (139
to 148) (142 7) mmol/L at H-48 (P < 0.05, Figure 4a).
Osmolarity increased from 275 (268 to 281) (279 16)
mmol/L at H0 up to 290 (284 to 307) (297 17) mmol/
L at H24 (P < 0.05), and remained stable until H96
(Figure 4b). Osmolarity decreased from 292 (283 to 303)
(293 13) mmol/L at H-24 after the infusion ended, to
281 (276 to 287) (282 10) mmol/L at H-48 (P < 0.05;
Figure 4b). The target of natremia was reached as soon
as H8, and natremia remained in the target range until
H96 (Figure 4c).
Figure 3 Time evolution of (a) intracranial pressure and (b)
cerebral perfusion pressure during and after the continuous
HSS infusion. Cerebral perfusion pressure was calculated as follows:
Mean arterial pressure - Intracranial pressure. Results were provided
for the first 96 hours of HSS infusion (from H0 to H96; white boxes)
and 2 days after the stop of infusion (from day 1 to day 2; gray
boxes). *P < 0.05.
Time evolution of the quantity of infused-sodium
The amount of sodium administered was not
significantly different during the study period: 32 (17 to 46)
(36 23) g in the first 24 hours, and 25 (11 to 45) (32
28) g from H72 to H96 (NS). After we stopped the
HSS infusion, a bolus of 7 (5 to 11) (7 4) g of sodium
(flow, 1 g/hour) was administered at H-24, and a bolus
of 1 (0 to 4) g (2 3) was administered at H-24 (P <
0.05). Natriuresis increased from 25 (20 to 40) g (30
18) in the first 24 hours up to 31 (24 to 45) (38 25) g
from H24 to H48 (P < 0.05) and remained unchanged
afterward (NS). Natriuresis decreased from 18 (13 to 20)
(17 5) g/day at H-24 after the infusion ended, down
to 12 (9 to 16) (12 4) g/day at H-48 (P < 0.05).
Chloremia increased from 111 (107 to 119) (113 8)
mmol/L at H0 to 121 (117 to 124) (121 5) mmol/L at
H96 (P < 0.001; Figure 5a). Kaliemia, creatininemia, and
pH remained unchanged within the study intervention
Figure 4 Time evolution of (a) natremia, (b) blood osmolarity,
and (c) delta of natremia during and after the continuous HSS
infusion. (a) Natremia was assessed every 4 hours. (b) Osmolarity
was assessed once per day. Results are given for the first 96 hours
of HSS infusion (white boxes) and 2 days after the stop of infusion
(gray boxes). (c) Delta between assessed natremia and target of
natremia was calculated every 4 hours. Target was considered as
achieved if -2 mmol/L < Delta 2 mmol/L. Results are given for the
first 96 hours of HSS infusion (white boxes). *P < 0.05.
(NS; Figure 5b-d). No pulmonary edema was recorded.
Severe-form centropontine myelinolysis was neither
clinically suspected nor confirmed by magnetic
The use of a continuous HSS controlled infusion
adapted to a target of natremia for treating
post-traumatic refractory ICH allowed us to decrease ICP and to
Figure 5 Time evolution of (a) chloremia, (b) kaliemia, (c)
creatininemia, and (d) pH during the continuous HSS infusion.
Results of (a) chloremia, (b) kaliemia, (c) creatininemia, and (d) pH
were collected every 24 hours. Results were provided for the first 96
hours of HSS infusion (unchanged for longer duration). *P < 0.05.
rapidly improve CPP without any severe acute
Hyponatremia and hypo-osmolarity are frequent in
TBI patients and induce an increase in ICP as well as in
the volume of intracranial lesions . Hyperosmolar
therapy with either mannitol or HSS reduces ICP
[8-11,25] and is recommended for the treatment of ICH
. Boli of hyperosmolar solutions decrease ICP for less
than 6 hours and expose patients to a rebound of ICH
[8,9,26]. After a bolus of osmotherapy, the increase in
cerebrospinal fluid osmolarity may participate in the risk
of rebound of ICP . During osmotherapy, a decrease
in extracellular volume contributes to the fast control of
ICP , but an accumulation of organic osmolytes
(slow adaptation)  may limit the decrease in brain
volume and may expose the patient to a rebound of
ICP. In this setting, continuous osmotherapy was
proposed in the 1990s but is still not recommended. Side
effects reported in case of improper use of mannitol
(dehydration, renal failure, hypotension) may have
limited its use as a continuous therapy, and to date, only
HSS infusion has been tested for continuous
osmotherapy. Moreover, HSS has a higher reflection coefficient
than mannitol that may decrease the risk for rebound.
In a randomized study in TBI patients, continuous
infusion of HSS for 5 days increased both natremia and
osmolarity but did not decrease ICP, as compared with
hypotonic infusion . In this study, the HSS-treated
group had a significantly worse neurologic status with
higher ICP on inclusion than did the hypotonic-treated
group. Interestingly, no side effects were reported. In
two other studies [12,13], a continuous infusion of 3%
saline in TBI patients without a priori dose adaptation
decreased ICP but did not alter outcomes. In patients
with severe cerebrovascular disease and at high risk for
ICH, the preventive continuous infusion of HSS (3%)
may reduce the frequency of ICP crises and the
mortality rate . In patients with posttraumatic/operative
edema and treated with a continuous 3% HSS infusion
to a target natremia of 145 to 155 mmol/L , an
inverse relation between natremia and reduction of both
ICP and brain edema was found. Finally, continuous
infusion of HSS is an attractive treatment in an attempt
to achieve long-lasting control of ICP (for a review see
), but few data were available in patients with
refractory ICH. Consistent with a previous report, the current
protocol of continuous infusion of HSS (NaCl 20%) was
associated with a rapid and prolonged decrease of ICP
values in patients with ICH refractory to barbiturate.
In this study, a 20% saline infusion was used to
decrease the risk of fluid overload, and no pulmonary
edema or acute kidney injury was recorded. However,
because of the retrospective design of our study, the
potential side effects of HSS were recorded from the
ICU report. The risk of uncontrolled metabolic disorder
associated with HSS infusion remains problematic,
poorly described, and has probably limited the
widespread use of HSS . In two studies [12,13],
continuous infusion of 3% saline in TBI patients without a
priori dose adaptation decreased ICP but induced severe
hypernatremia that reached up to 180 mmol/L, and
concerns regarding neurologic complications and kidney
failure have been raised. In the study by Qureshi et al.
, risks of fluid overload (pulmonary edema) and of
metabolic complications (kidney failure, polyuria) with a
continuous infusion of saline, 3%, have resulted in poor
outcomes. According to previous reports [11-14,30], in
no patient did a severe form of pontine myelinolysis
develop. The cases of pontine myelinolysis reported
linked to a fast increase in natremia were observed in
patients with chronic hyponatremia  but not with
infusion of HSS for posttraumatic ICH. In a description
of HSS infusion in TBI children, no osmotic
demyelination syndrome was seen on magnetic resonance imaging,
even for natremia reaching 171 mmol/L .
The main side effect reported in the present report
was hyperchloremia. Excessive chloride infusion is a
major factor with hyperchloremic acidosis. Thus, it is
likely that hyperchloremic acidosis developed in TBI
patients treated with continuous HSS infusion.
Hyperchloremic acidosis increases the symptoms of
postoperative ileus and induces biologic hemostasis perturbation
. To date, these complications are not evidence
based in the ICU setting.
Finally, a dose adaptation of HSS infusion with
rigorous biologic monitoring may explain the lack of an
uncontrolled metabolic disorder, except for a probable
hyperchloremic acidosis, in our results.
How to stop the infusion is of major importance to
prevent a rebound of ICH, and few data are available. In
the study by Qureshi et al. , half of the study
population experienced a relapse of ICH at the end of the
infusion. Interestingly, even with a likely residual
barbiturate blood level, we did not report any rebound in
ICP after stopping the infusion. In the current
algorithm, the slow tapering of continuous HSS treatment
could have restored a normal brain osmolality without
inducing a cerebral edema, as the dissipation of
accumulated electrolytes and organic osmolytes takes place
along with water repletion [6,28,32]. Finally, a slow
reduction of the flow may be recommended in case of
continuous HSS infusion.
Several therapeutics have been tested for decreasing
ICP in case of refractory ICH. Despite an improvement
of the neurologic recovery in patients with moderate to
severe TBI , moderate hypothermia may expose
patients to intracranial bleeding as well as secondary
infections  and is not currently recommended in
patients with refractory ICH . Surgical craniotomy is
another option, but the optimal timing to perform this
procedure remains controversial, and its efficiency to
enhance neurologic recovery is still debated [18,35].
Regarding the absence of severe side effects with the
current protocol, continuous controlled infusion of HSS
may thus be an interesting alternative for the treatment
of refractory ICH.
Our study encountered limitations. First, the study
had a retrospective design, and a randomized trial is
necessary to confirm these results. Second, the external
validity of this single-center study may be limited.
However, our findings may be relevant to the vast majority
of level I trauma centers routinely practicing TBI
management. We did not report any significant adverse
events related to the use of continuous HSS infusion,
but this study is not powered to confirm its safety.
Finally, a comparison with an untreated group would
have strengthened our conclusions, and a larger study
with a prospective randomized design is required.
We describe for the first time a well-tolerated and
reproducible adaptation of continuous HSS infusion for
refractory ICH that relies on a closed biologic control of
natremia. An increased CPP together with a decrease in
ICP was observed during continuous HSS infusion
without any development of severe hypernatremia or
rebound of ICP. Continuous infusion of HSS with a
dose adaptation to a target natremia could therefore be
an attractive alternative for patients treated with
barbiturates for refractory ICH. Prospective studies are
required to confirm the effects and safety of the current
dose adaptation of HSS infusion.
Continuous hypertonic saline infusion may
decrease intracranial pressure in traumatic
braininjured patients with refractory intracranial
The current dose adaptation of hypertonic saline
infusion, based on a target of natremia, is reliable
and well tolerated
Close biologic monitoring within continuous
hypertonic saline infusion prevents severe
No rebound of intracranial pressure was observed
after the infusion ended
Continuous infusion of hypertonic saline infusion
could be an attractive alternative to treating patients
with refractory intracranial hypertension
Additional file 1: Table S1. Linear mixed-models analyses of the
evolution of intracranial pressure, cerebral perfusion pressure, delta
natremia, osmolarity, kaliemia, chloremia, creatininemia, and natriuresis
with time. Figure S1. Kaplan-Meier curve for the number of patients
treated with continuous HSS.
AR, PJM, DD, OL, PC, CL, and KA designed the study. AR, PJM, DD, CDF, AC,
OL, and PC collected the clinical information. VS analyzed the raw data,
performed statistical analysis, and drafted and contributed to the writing of
the article. AR, PJM, DD, OL, PC, CDL, AC, KB, OH, and KA included patients,
and drafted and contributed to the writing of the article. CL participated in
the interpretation of all data, revising the manuscript critically for important
intellectual content. All the authors contributed to the final approval of the
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