The Egyptian Journal of

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Critical Care Medicine

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Original Article
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Hypertonic Saline Versus Isotonic Saline in Septic

Shock (Effects on Morbidity, Mortality, and
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Clinical Outcome)
Hassan S. Effat∗, Sayed S. Ramadan, Mohamed S. Mokhtar, Moataz M. Ibrahim
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Abstract
Introduction: Septic shock remains an impatient cause of morbidity and mortality. A cascade of inflammatory mediators
released cause misdistribution of blood flow and organ perfusion. Early restitution of the circulation by fluid administration either
crystalloid or colloid solution improve tissue oxygen delivery and increase survival.
Aim of work: This study is a prospective randomized single center study its main objective is to investigate the therapeutic value
of hypertonic saline in patients with septic shock.
Patients and methods: Forty critically ill patients admitted with septic shock divided into two groups, the first group received
isotonic saline and hydroxylthyl (control group) starch, while the second received hypertonic saline 3% in addition to isotonicsaline
and hydroyethyl starch.
Results: Our study results showed that hypertonic saline administration in septic shock patients is safe and can be used as an
adjuvant resuscitation fluid therapy as it has a rapid and prolonged effect on those patients hemodynamics or plus it showed
significant anti-inflammatory action and also it improve all cardiac functions although this improvement was transient as was the
improvement in mortality, intensive care unit stay, need for mechanical ventilator use of inotropes and vasopressors and the scoring
system evaluation.
Discussion: Hypertonic saline 3% is safe and can be used in resuscitation of septic shock patients.
Keywords: hypertonic saline 3%, septic shock

1. Introduction Sepsis is defined as confirmed or clinically suspected infection

plus 2 or more SIRS criteria.
Sepsis and the systemic inflammatory response syndrome (SIRS)
Sever sepsis defined as sepsis and one or more organ
are common and represent a major factor in morbidity and
dysfunction, while septic shock is defined as sepsis plus
mortality in intensive care units (ICUs) and the critically ill. The
hypotension ( . . . 90 mm Hg) despite fluid resuscitation.1
pathogenesis of these syndromes is becoming increasingly
As proved infusion of several liters of isotonic fluids is
understood and it is hoped that this will result in improved
associated with the adverse effects of extravasation into the
outcome.1
interstitial space. In sepsis, in particular, this may result in
SIRS is the clinical response to infection manifested by two or
peripheral and/or pulmonary edema.2
more of the following criteria.
A large number of very interesting experiments highlighted
 Temperature >38°C or <36°C. that hypertonic saline resuscitation may decrease susceptibility to
 HR > 90bpm. post-traumatic sepsis, trauma and sepsis-induced immune
 Respiration >20 breaths/min. dysfunction, inflammatory, inflammatory response and apo-
 WBC count >12,000/mL or <4000 mL or >10% immature ptosis.3
neutrophils.

2. Aim of the work

Critical Care Medicine Department, Cairo University, Cairo, Egypt
∗
Corresponding author: Hassan S. Effat, Critical Care Medicine Department,
Cairo University, Cairo, Egypt. E-mail: h.effat@hotmail.com
Conflicts of interest: The authors reported no conflicts of interest.
Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-
ND), where it is permissible to download and share the work provided it is
properly cited. The work cannot be changed in any way or used commercially
without permission from the journal.
The Egyptian Journal of Critical Care Medicine (2021) 8:2
Received 6 June 2020; Revised 26 November 2020; Accepted 22 January 2021;
Available online 1 January 2020
http://dx.doi.org/10.1097/EJ9.0000000000000023
This study is designed to compare the effects of hypertonic saline/
hydroxyl-ethyl starch (HSS/HES) and isotonic saline/hydroxyl-
ethyl starch (ISS/HES) on hemodynamic, inflammatory media-
tors, and clinical outcome in septic shock.
3. Patients and methods
All consecutive critically ill patients admitted to critical care
department in Ahmed Maher Teaching Hospital. Were screened
for patients with the diagnosis of septic shock. 40 patients were
eligible when they met the inclusion criteria for septic shock, the
40 patients divided to 2 groups: the first group received isotonic

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 Effat et al. The Egyptian Journal of Critical Care Medicine (2021) 8:2
saline 0.9% and HES while the second group received 2 boluses
of hypertonic saline 3% (4 mL/kg at a rate 1 mL/kg/min) in
addition to ISS and HES.
Hypertonic solutions may be able to resuscitate critically ill
patients with septic shock better and more rapidly, than
crystalloid infusion (eg, 0.9% sodium chloride or lactated
Ringer’s solution).
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Septic shock. It denotes sepsis-induced hypotension not
corrected by fluid loading and needs inotropic and/or vasopressor
support. Perfusion abnormalities too many organs characterize
the shock state.1
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Patients who were diagnosed as having septic shock at ICU
admission and did not meet any of the exclusion criteria were
selected randomly and prospectively included into the study on
the day of ICU admission either coming from the emergency
room or already hospitalized.
3.1. Exclusion criteria
1. Trauma patients
2. Burn patients
3. Patients < 18 years
3.2. Inclusion criteria
1- Age > 18 years
2- Septic shock
a. Clinically suspected infection (or confirmed) infection
anywhere.
b. Two or more of the following: temperature >38°C
(100.4°F) or <36°C (96.8°F), heart rate (HR) > 90/min,
respiratory rate (RR) > 20/min or PaCo2 < 32 mm Hg,
white blood cell count > 12.000/mm3 or <4.000/mm3 or
>10% immature neutrophils.
3.3. Study design
Included patients with sepsis were subjected to the following:
1. Full clinical evaluation
Including history and physical examination with special
emphasis on vital signs blood pressure (BP), HR, temperature
and RR, and Glasgow coma scale (GCS), which were
evaluated at the day of admission and daily thereafter.
2. Laboratory investigations
Routine labs:
- Complete blood count: hemoglobin (PT), hematocrit, white
blood cells, and platelet count.
- Coagulation profile: prothrombin time, prothrombin con-
centration, and international normalizing ratio (INR)
- Arterial blood gases (ABGs).
- Liver Function Tests: alanine amino-transferase, aspartate
amino-transferase, bilirubin and albumin.
Kidney function Test: Na, K, urea, and creatinine.
This routine labs were done on admission and subsequently
there-after every day until ICU discharge or demise to a total of
7 days.
Labs specific for the study: C-reactive protein in day 0, 1, 2, 7.
By enzyme linked immune-sorbent assay
3. Micro-biological studies: Including Pan-cultures (sputum,
blood, urine, or biological fluid according to clinical suspicion)
44
The Egyptian Journal of Critical Care Medicine
prior to antibiotic administration or after discontinuation of
antibiotic for 48 hours.
4. Imaging studies: identify the source of sepsis (eg, abdominal
ultrasound and chest x-ray), Echo-heart measuring cardiac
output (CO), ejection fraction, and fractional shortening) in
days 0, 1, 2, and 7
5. Clinical data:
These data were evaluated up to a maximum follow period
of 7 days.
- Length of ICU stay.
- Need for and duration of mechanical ventilation.
- Need for and duration of inotropic support.
- Need for renal supportive therapy (hemo-dialysis)
- Final outcome: Eventually patients were sub-grouped into
survivors and non-survivors within 1 week follow up then
compared all studied variables.
6. Application of acute physiology and chronic healthy evalua-
tion II (APACHE II), sequential organ failure assessment
(SOFA) and multiple organ damage scores (MODs):
APACHE II score evaluated on admission while SOFA and
MOD scores were evaluated serially every day until ICU
discharge or demise or up to a total of 7 days.
1. APACHE II:
After admission of a patient to ICU, an integral score based
on several measurements; higher scores imply a more severe
disease and a higher risk of death.
2. SOFA score:
The SOFA score is a scoring system to determine the extent
of a person’s organ function or rate of failure. The score is
based in 6 different scores, one each for the respiratory,
cardiovascular, hepatic, coagulation, renal, and neurological
systems.
3. MOD score:
The MOD score is a scoring of system to determine the
extent of organ function or rate of failure.
3.4. The statistical methods
Data were statistically described in terms of range, mean ±
standard deviation (±SD), median, frequencies (number of cases)
and relative frequencies (percentages) when appropriate. Com-
parison of quantitative variables between the study groups was
done using Mann-Whitney U test for independent samples. For
comparing categorical data, chi-square (c2) test was performed.
Fisher exact test was used when the expected frequency is <5.
Receiver operator characteristic analysis was used to determine
the optimum cut off value for the studied diagnostic markers.
Correlation between various variables was done using Pearson
correlation coefficient for continuous variables.
A probability value (P) < .05 was considered statistically
significant. All statistical calculation were done using computer
programs Microsoft Excel 2010 (Microsoft Corporation, New
York, NY) and Statistical Package for the Social Science (version
17, SPSS Inc., Chicago, IL) for Microsoft Windows.
4. Results
Our study was done in Ahmed Maher teaching hospital and was
designed as prospective study that enrolled forty patients
admitted to our ICU suffering from septic shock who were
divided into two groups:
 Effat et al. The Egyptian Journal of Critical Care Medicine (2021) 8:2 The Egyptian Journal of Critical Care Medicine

Table 1 Table 2
Age in groups I and II Co-morbid conditions
Age Mean N SD P Group I Group II
Group I 57.65 20 20.76 .27 N % N % P
Group II 51.65 20 12.59 Smoker 4 20 7 35 .48
SD, standard deviation.
Steroid 3 15 2 10 1
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DM 10 50 10 50 1
HTN 5 25 7 35 .7
Cardiac 5 25 3 15 .69
Group I: 20 pts who received routine resuscitation fluids.
COPD 4 20 4 20 1
Group II: 20 pts who were received 2 boluses of 3% hypertonic CNS disorders 4 20 3 15 1
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saline in addition to routine resuscitation fluids. Renal 6 30 3 15 .45

Comparing the age of the 2 groups there was insignificant Hepatic 4 20 5 25 1
difference between them as shown in Table 1 (57.6 ± 20.7 years in
group 1 versus 51.6 ± 12.5 years, P: .27).
As regard gender both group showed similar ratio for
femalemale percentage. Comparing the two groups for existence As regards body temperature Respiratory rate central venous
of co. morbid conditions showed no significant difference pressure (CVP), and urine output (UO), there was insignificant
between them (Table 2). difference between the two groups throughout their ICU stay.

4.1. Glasgow coma scale 4.4. Echocardiographic parameters

GCS was matched without significant difference between the two
groups on admission and then showed transient improvement on
2nd, 3rd, and 4th days in group II then showed in-significant
difference by last follow up as shown in Figure 1.
4.2. Mean arterial blood pressure
Regarding mean arterial blood pressure (MABP) was matched on
admission for both group and showed transient nonpersistent
improvement in group II at day 2 and day 3 as shown in Figure 2.
4.3. Heart rate
The HR was not significantly different between the two groups on
admission but HR tended to improve and became significantly
lower in group II by 4th, 5th, and 6th days than group I shown
in Figure 3.
Cardiac output tended to improve significantly in group II on day
1 and 2 as shown in Table 3.
4.5. PH
Group II showed better and less acidotic mean PH readings since
admission to day 5 as shown in Table 4.
As for carbon dioxide and PO2 values there was no significant
changes between the two groups but for sodium bicarbonate
level. There was no significant difference between two groups in
day 0 and day 7 but improvement in group 2 is noticed in days 1,
2, 3, 4, 5, and 6 as shown in Table 5.
As for sodium and potassium and for hemoglobin concentra-
tion and hematocrit level there was no significant difference
between the two groups. Total leucocytic count and platelet
count showed no significant difference when the two groups were
compared.

Figure 1. Comparing group I and II as regard (GCS) for 7 days.

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 Effat et al. The Egyptian Journal of Critical Care Medicine (2021) 8:2 The Egyptian Journal of Critical Care Medicine

Table 4
PH in HTS vs ISS
Group I Group II
Mean ± SD N Mean ± SD N P
Day 0 7.21 ± 0.13 20 7.31 ± 0.10 20 .010
Day 1 7.23 ± 0.09 20 7.33 ± 0.12 20 .002
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Day 2 7.23 ± 0.17 20 7.31 ± 0.12 20 .070

Day 3 7.20 ± 0.13 18 7.36 ± 0.14 18 .003
Day 4 7.27 ± 0.09 15 7.37 ± 0.16 17 .055
Day 5 7.25 ± 0.15 15 7.41 ± 0.08 10 .007
Day 6 7.24 ± 0.17 11 7.37 ± 0.10 6 .124
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Day 7 7.37 ± 0.09 8 7.35 ± 0.13 6 .737

ISS, isotonic saline; SD, standard deviation.

Figure 2. MABP in both groups compared for 7 days.

Table 5
Sodium bicarbonate in HTS vs ISS
Group I Group II
Mean ± SD N Mean ± SD N P
Day 0 12.29 ± 5.75 20 14.64 ± 4.96 20 .174
Day 1 11.10 ± 4.09 20 15.99 ± 5.90 20 .004
Day 2 11.71 ± 4.99 20 15.87 ± 5.79 20 .020
Day 3 11.56 ± 4.88 18 15.69 ± 6.00 18 .030
Day 4 12.99 ± 5.62 15 17.95 ± 6.03 17 .023
Day 5 14.53 ± 4.76 15 19.10 ± 2.64 10 .011
Day 6 12.74 ± 3.90 11 17.50 ± 3.56 6 .026
Day 7 18.37 ± 4.50 8 17.88 ± 4.15 6 .838
ISS, isotonic saline; SD, standard deviation.

Figure 3. Heart rate in Group I vs Group II. Table 6

Urea in HTS vs ISS
Group I Group II
4.6. Renal function Mean ± SD N Mean ± SD N P
Day 0 138.85 ± 94.56 20 90.15 ± 32.52 20 .60
Urea and creatinine showed insignificant difference between the
Day 2 132.60 ± 81.52 20 84.85 ± 28.76 20 .18
two groups through-out their ICU stay as shown in Tables 6 Day 4 111.80 ± 68.51 15 817.65 ± 34.26 17 .12
and 7. Day 6 101.18 ± 59.77 11 72.67 ± 43.32 6 .32
4.7. Creatinine ISS, isotonic saline; SD, standard deviation.

Liver function test (liver enzymes level and total bilirubin level)
showed insignificant difference between the two group B and so
albumin level and coagulation profile for example INR valves.
4.7.1. C-reactive protein. There was no difference between the
two groups in day 0, but day 1 and day 2 showed improvement
with decrease in C-reactive protein (CRP) levels in group II. With
P value .017 and .009, respectively.
Arterial oxygen concentration showed slight improvement in
the second group in day 2 and 4 but there was no significant
changes between the two groups in the other days as shown in
Figure 4.
Mixed venous oxygen concentration showed definite improve-
ment in second groups from day 1 to day 6 with no significant

Table 3 Table 7
Cardiac output in HTS vs ISS Creatinine in HTS vs ISS
Group I Group II Group I Group II
Mean ± SD N Mean ± SD N P Mean ± SD N Mean ± SD N P
Day 0 5.53 ± 1.61 20 5.87 ± 1.29 20 .296 Day 0 4.84 ± 4.61 20 2.80 ± 2.15 20 .080
Day 1 5.31 ± 1.10 20 5.95 ± 0.83 20 .042 Day 2 4.63 ± 3.76 20 2.68 ± 2.24 20 .054
Day 2 4.65 ± 1.21 20 5.74 ± 0.87 19 .003 Day 4 3.83 ± 3.14 14 2.66 ± 2.24 17 .239
Day 7 4.91 ± 1.26 8 4.90 ± 0.37 6 .982 Day 6 3.65 ± 2.82 11 1.92 ± 1.30 6 .179
ISS, isotonic saline; SD, standard deviation. ISS, isotonic saline; SD, standard deviation.

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Table 9
MODs score in HTS vs ISS
Group I Group II
Mean ± SD N Mean ± SD N P
Day 0 8.45 ± 3.23 20 7.25 ± 2.61 20 .205
Day 1 9.05 ± 3.46 20 7.70 ± 2.70 20 .177
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Day 2 10.00 ± 4.49 20 7.40 ± 3.23 20 .042

Day 3 9.78 ± 4.50 18 6.83 ± 3.11 18 .029
Day 4 9.80 ± 4.77 15 6.23 ± 3.27 17 .018
ISS, isotonic saline; MODs, multiple organ damages; SD, standard deviation.
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4.9. Complication of therapys

Figure 4. SaO2 in HTS vs ISS. There was insignificant difference regarding frequency of hyper
or hypo-natremia or anaphylaxis or disturbed conscious level as
shown in Table 10.

change between the two groups in the other 2 days (day 0 and day
7) as shown in Figure 5. 4.10. Ventilatory support and MV duration

4.7.2. Sequential organ failure assessment score. Regarding
SOFA score improvement is noticed in the second group in days
2, 3, and 4 with no significant difference between the two group
in the other days as shown in Table 8.
4.8. Multiple organ damage score
MODS score improved in the second group in days 2, 3, and 4
with no significant change between the two groups in the other
days as shown in Table 9.
There was a higher frequency of mechanical ventilation in group I
than in group II (85% versus 50%) as shown in Table 11.
Table 12 shows the duration of mechanical ventilation (in
days) of group I compared to group II.
Mortality: There was a higher frequency of mortality in group I
than in group II (55% versus 20%) as shown in Table 13, with a P
value of .04.
5. Discussion
5.1. Background and rationale
The fundamental derangement in sepsis is maldistribution of
blood flow. An inciting event results in a local inflammatory
response, which is characterized by vasodilation, increased
capillary permeability, and inflammatory cell migration into the
tissues. Neutrophil activation leads to the release of vaso-
regulatory mediators (eg, nitric oxide and arachidonic acid
metabolites) and proteases (eg, elastase and matrix metallo-

Table 10
Complications of therapy in HTS vs ISS
Group I Group II
N % N % P
Figure 5. SvO2 in HTS vs ISS.
Hypernatremia 4 20 5 25 1
Hypervolemia 4 20 4 20 1
Anaphylaxis 0 0 4 20 .1
Table 8 Disturbed conscious level 0 0 4 20 .1
SOFA score in HTS vs ISS ISS, isotonic saline.
Group I Group II
Mean ± SD N Mean ± SD N P
Day 0 12.00 ± 3.11 20 10.85 ± 2.94 20 .237 Table 11
Day 1 11.70 ± 4.23 20 10.00 ± 3.52 20 .175 Ventilator support in HTS vs ISS
Day 2 11.95 ± 4.74 20 8.65 ± 4.36 20 .028 Group I Group II
Day 3 11.22 ± 5.51 18 7.22 ± 3.64 18 .015
N % N % P
Day 4 10.33 ± 6.09 15 6.35 ± 4.23 17 .038
Day 5 10.73 ± 6.42 11 7.83 ± 4.62 6 .106 M. Ventilation 17 85 10 50 .04
Day 6 9.91 ± 6.42 11 7.83 ± 6.01 6 .525 Tracheostomy 3 15 2 10 1
Day 7 6.25 ± 4.92 8 8.00 ± 7.13 6 .595 Weaning 6 30 6 30 .2
ISS, isotonic saline; SD, standard deviation; SOFA, sequential organ failure organ assessment. ISS, isotonic saline.

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 Effat et al. The Egyptian Journal of Critical Care Medicine (2021) 8:2
Table 12
MV duration in HTS vs ISS
Group binary N Mean ± SD
MV. duration (in day) Group I 17 4.18 ± 1.73
Group II 10 2.50 ± 1.18
ISS, isotonic saline; SD, standard deviation.
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proteinases), which in turn lead to the increased endothelial
permeability.
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In an attempt to overcome this complex cascade of events
resulting in these hemodynamic derangements, high volume
resuscitation with crystalloid solutions (ranging from 6 to 10 L) is
often used during the initial resuscitation of a patient with sepsis.
Early volume resuscitation of a patient with sepsis and septic
shock shown to reduce morbidity, mortality, and health care
resource consumption. Hyper tonic saline (HTS) offers a
theoretically viable option for volume resuscitation.4 However,
potential alterations in hemodynamic stability can result.4
The expansion of plasma volume results in decreased plasma
levels of various neuro-hormones (eg, ACTH, cortisol, and
aldosterone) and endogenous pressers (eg, nor-epinephrine,
epinephrine, cortisol, vasopressin, and rennin) contributing to
the alterations in hemodynamic stability.4
Our study is designed to evaluate the advantages of
administration of hypertonic saline 3% in addition to routine
resuscitation fluids as isotonic saline 0.9 and Hydroxyl Ethyl
Starch (HES) on adequacy of resuscitation, progression of
inflammation and outcome of critically ill septic patients.
It is consisted of randomized 40 patients admitted to our ICU
with septic shock divided into two groups: group I consisted of20
patients received routine resuscitation fluids, compared to group
II which consisted of 20 patients received 2 boluses of hypertonic
saline 3% in addition to routine resuscitation fluids. It aims at
assessment of the potential benefits of hypertonic saline if used in
addition to isotonic saline (ISS) and HS if used alone in fluid
resuscitation in critically ill patients with septic shock regarding
effects on:
1. Fluid status and hemodynamics
2. Cardiovascular functions
3. Inflammatory mediators
4. Survival benefits and mortality
5. Expected side effects.
All included septic patients were subjected to the measurements
of hemodynamic parameters including MAP, HR, R, R, UO,
CVP at the start of the study (base line), and then every day for 7
days. Measurements of respiratory parameters including ABG,
internal jugular venous oxygen saturation at the start, then every
day for 7 days. Measurements of full laboratory parameters as
(renal and liver functions) day after day > echocardiographic
parameters as (CO, ejection fraction, and fractional shortening)
Table 13
Mortality in HTS vs ISS
Group I Group II
N % N %
Death 11 55 4 20
ISS, isotonic saline.
The Egyptian Journal of Critical Care Medicine
days 0, 1, 2, 7; scoring system done as APACHE II on admission
and SOFA and MODS daily throughout their ICU stay.
In our study, the use of small boluses of hypertonic saline in
P
addition to normal saline shown rapid optimization of fluid state
.015 and hemodynamics compared to isotonic saline where a large
volume are needed and their effect is transient.
Recent studies, it has shown to have (HTS) the ability for rapid
plasma volume expansion by mobilization of fluids from the
intra-cellular compartment through the extra-vascular fluid
space. This results in increase in plasma volume up to 4 folds
that of the actual infused volume, yet short-lived effects.4
The addition of colloids to HTS prolongs the duration of
volume expansion, therefore accentuates these effects on central
and regional circulation. HTS admixed with dextran has been
studied in the fluid resuscitation of experimental animals and
humans with hemorrhagic or traumatic shock.5
The mechanisms behind the resultant improvement in
hemodynamic status are likely multi-factorial. Rapid increase
in the intra-vascular volume through the mobilization of water
(from the intra-cellular space, micro-vascular endothelium, and
red blood cell [RBC]) into the interstitial and intra-vascular
spaces occurs.
A reduction in the endothelial edema and a decrease in
hydraulic resistance occur, all of which promote tissue perfusion.
Cardiac contractility may also improve through a direct
hyperosmolar effect and through the decrease in myocardial
edema that is unrelated to changes in coronary blood flow.6
Silvestein and colleagues calculated efficiency ratios to represent
the change in plasma volume relative to the volume infused and
found that HSS resulted in the greatest plasma volume expansion in
(30 minutes post-infusion) with an efficiency ratio 2-3 folds greater
than any of other fluid used immediate post-infusion. They
concluded that HTS had the highest blood volume expansion
(almost three times the volume infused), explained by recruitment
of fluids from other compartments to intra-vascular space. The
volume expanding effects of HTS were short lived and lasted for 30
minutes, whereas synthetic colloids when added had significant
plasma volume expansion for 240 minutes.7
The plasma volume expansion appears to be dose related as a 6
mL/kg dose resulted in greater volume expansion than a 4 mL/kg
dose.7
In our study, hypertonic saline is our study induced rapid
transient improvement of all cardiovascular functions from days
1 and 2 as measured by left ventricular ejection fraction and CO,
also parallel improvement of tissue perfusion as measured by
mixed venous saturation, compared to isotonic saline.
An improvement in cardiovascular function and tissue
perfusion as indexed by splanchnic perfusion was also noted
in a model of Escherichia coli-induced sepsis in dogs. Comparing
lactated Ringer’s solution and hypertonic saline, both were
shown to transiently improve both systemic and regional blood
flow.
Hypertonic saline, however, was associated with a significant
(and sustained) reduction in systemic and mesenteric oxygen
extraction without worsening of other markers of perfusion.8
The improvement of CO could be related to volume
replenishment or as shown in an isolated, perfused rat heart
preparation, perfusion with HTS/dextran solution improved
P myocardial contractility unrelated to changes in coronary blood
flow, and myocardial oxygen consumption.9
.04
Other studies explained the positive inotropic effect by the
volume-expanding effects (increase preload) and the vascular
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 Effat et al. The Egyptian Journal of Critical Care Medicine (2021) 8:2
effects (decrease after-load, reduction in pulmonary, and systemic
vascular resistance), the latter effect may transiently induce
hypotension following bolus doses of hypertonic saline.
Myocardial performance may be directly improved through a
reduction in myocyte edema, or by increased myocardial uptake
of calcium with restoration of trans-membrane potential.10
In our study, CRP as an inflammatory marker tended a
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significant decline by using hypertonic saline in day 1, 2. This
might be explained by its reported immune-modulatory effects,
compared to isotonic saline.
Various immune-modulatory effects have also been described
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following the use of HTS in the treatment of sepsis.11 Significantly
reduced bacterial colony counts along with an enhancement of
both intra-cellular bacterial killing and superoxide generation
were noted in those animals resuscitated with HSS compared
with an controls resuscitated with ISS.11
A recent study in 2011 by Frank et al. showed that in septic
shock, hypertonic saline solutions compared with isotonic fluid,
may modulate expression of several but not all measured genes
that are implicated in neutrophil endothelial interaction and
capillary leakage. That was the first study to report the effects of
hypertonic saline on inflammatory gene expression in septic
shock patients.12
In our study, APACHE II score was done only on admission
showing no difference between the two groups, Regarding SOFA
and MODs scores there was significant improvement in days 2, 3,
4 in the group using hypertonic saline which reflect improvement
in their clinical course throughout their ICU stay, we noticed also
that there was significant decrease in need for mechanical
ventilation, peripheral vasopressors, hemodialysis in the group
used hypertonic saline, compared to isotonic saline.
Regarding mortality in our study, there was a significantly
lower mortality in septic patients who received 3% hypertonic
saline, compared to those who received 0.9% normal saline
without statistically significant side effects.
Up-to-date, 4 meta-analyses of HTS (alone or in conjunction
with dextran) have been performed in which the primary
outcome was survival, these include most of the original papers
reviewed thus far.
Bunn et al.13 published in The Cochrance Database a study
about hypertonic versus near isotonic crystalloid for fluid
resuscitation in critically ill patients which showed no improve-
ment in relative risk of death for hypertonic saline patients.
Colloids versus crystalloids a study was performed in 1999,
and more recently has been updated by Perel and Roberts.14 A
subsection of the meta-analysis looked at the same question by
Wade Does et al.,15 hypertonic saline in combination with
dextran provide a survival benefit in trauma? The conclusion
was no, with a relative risk of death of 0.88 (95% CI 0.74-
1.05).
In our study, some side effects appeared by use of hypertonic
saline as (disturbed conscious level, hyper-natremia, hyper-
volaemia, and anaphylaxis), compared to isotonic saline but
these side effects was benign and statistically insignificant.
Very few studies have considered the adverse effects of hypertonic
saline as a primary outcome measure. With the use of hypertonic
saline the consequences of an acute hyper-osmolar state (the most
feared complication) is central pontine myelinolysis, also known as
ODS (osmotic demyelination syndrome),16 this condition has been
reported in malnourished and those with hyponatremic states when
sodium levels have been corrected rapidly.
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The Egyptian Journal of Critical Care Medicine
Hypotension has been reported with the administration of
HTS in animal and a number of human studies bolus dose HTS
should thus be administered as a slow intravenous dose over 5
min. Further potential side effects include hyper-chloraemic
acidosis and hyperosmolar renal failure.17
Vassar and colleagues evaluated the potential side effects of
rapidly infusing 7.5% hypertonic saline with and without dextran;
8 patients of 166 had significant hyper-chloraemic acidosis.18
However, it was felt that their moribund condition accounted
for their acidosis rather than the chloride load. There were no
significant major side effects. The vast majority of trials with
bolus dose infusions of hypertonic saline have reported on
adverse effects, no significant side effects have been declared, a
number of studies have included autopsies performed on
nonsurvivors, and have not found any evidence of osmotic
demyelination syndrome.19
6. Conclusion
Hypertonic saline could be used as an adjuvant resuscitation
therapy with concurrent routine resuscitation protocols in
critically ill patients with septic shock as it has rapid and
prolonged effect in improvement of patients hemodynamic.
Hypertonic saline showed significant anti-inflammatory action
as measured by significant decline of CRP in septic shock as
compared to routine resuscitation fluids.
In addition to the previous mentioned values of hypertonic use
significant improvement of all cardiac functions as ejection
fraction, fractional shortening and CO but this improvement is
transient coinciding with hypertonic saline use.
Clinical improvement of critically patients with septic shock
was significantly higher in the group resuscitated by use of HTS as
traced by significant improvement of scoring systems as well as
decrease in ICU stay, decrease patients need for MV, peripheral
vasopressors or hemo-dialysis without occurrence of significant
side effects, compared to ordinary routine resuscitation fluids.
Future studies should be conducted as a large scale trials to
analyze this clinical improvement an anti-inflammatory effects
and their implementation on term mortality.
7. Recommendation
In the view of our study results, we recommend to use the
hypertonic saline 3% with isotonic saline 0.9% and HES as a
fluid therapy during resuscitation of patients admitted in ICU
with septic shock due to its persistent immune-modulatory effects
and relative decrease in mortality, need for inotropes and MV
and ICU stay more than isotonic saline if used alone.
A larger number of patient more than the number in our study
may improve validity and also only two boluses of hypertonic
saline were used on admission and 12 hours later it might prove to
be a better outcome if hypertonic saline is used throughout their
ICU stay. And assessment for the patients should not be for 7 days
only but more accurate results may be reached if the assessment is
for longer than 7 days.
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