This paper was presented on the 6th International congress of
Serbian Society of Emergency Physicians held in Nis, from 23-25.
2020, entitled: Hemodynamic Stabilization and Adjuvant Therapy in a
Sepsis is urgent medical condition caused by inadequate immune
response to infection. Septic shock encompasses circulatory,
cellular and metabolic disorders presented as hypotension resistant
to fluid replacement with urgent need for vasopressor therapy .
Early recognition of these conditions, detailed initial estimation
and prompt therapy are of primary importance for reduction of death
rate in sepsis. Guidelines published in 2016, underlined the
importance of early fluid supplementation and control of the source
of infection. Furthermore, appropriate laboratory estimation and
hemodynamic monitoring are crucial for improvement of treatment
outcome. This literally implies lactate level measurement,
hemoculture sampling before administration of antibiotics, preferred
use of broad-spectrum antibiotics and rapid crystalloid
supplementation in the dose of 30ml/kg. In hypotensive cases
resistant to fluid replacement, vasopressors should be given within
3 - 6 hours since diagnosis was made . The latest recommendations
for treatment of sepsis from 2018 have confirmed all treatment
modalities published in 2016 with the update concerning the timing
of treatment initiation. The new recommendation stressed that
treatment should be initiated and rapidly administrated within the
first hour after diagnosis of sepsis . The shift in timing needs
reconsideration of fluid replacement intensity and dynamics,
appropriate and timely vasopressor administration as well as the use
of adjuvant therapy, which is going to be discussed in the following
FLUID REPLACEMNET, HEAMODYNAMIC STABILITY ESTIMATION, AND THE
USE OF VASOACTIVE DRUGS IN SEPTIC PATIENTS
Sepsis is a life-threatening condition associated with
generalized endothelial damage, increased capillary permeability,
decreased circulatory blood volume and decreased preload into the
right atrium. These hemodynamic effects result into decreased tissue
perfusion and organ disfunction. One of the main goals in
reanimation of septic patient is to renew circulatory blood volume
and normalize oxygen delivery to tissues that is the prerequisite
for improvement and elimination of organ damage. It is recommended
to initiate fluid supplementation with crystalloid boluses within
first hour in dose of 30 ml/kg. Dose should be completely
administered within third hour after the sepsis or septic shock
Fluid supplementation in septic patients is usually performed in
- Rescue phase: initiated within few minutes, lasting for a
few hours after diagnosis in cases with life-threatening
decompensated shock (low blood pressure, signs of decreased
tissue perfusion). The volume of given crystalloids should be 30
- Optimization phase: is applicable for a patient with sepsis
in a state of compensated shock, whose life is not immediately
endangered. Administration of additional volume of fluids is
more cautious and should be titrated until achievement of
optimal cardiac output and tissue perfusion. Undesirable
hypervolemia should be avoided in this phase.
- Stabilization phase usually occurs within 24-48 hours after
diagnosis, with patient being in good general condition. Volume
of administered fluid should be enough to compensate standard
renal, gastro-intestinal or other unclear fluid losses. Patients
are neither in the state of shock, nor in immediate danger to
develop this condition.
- De-escalation phase is characterized by absence of shock in
patient and by recovery of all organ functions. Fluids should be
given in order to provide net-neutral or slightly negative fluid
balance. In this way, iatrogenic unnecessary fluid overload is
be avoided [4,5].
For initial fluid replacement, in rescue phase, recommendations
are in favor for isotonic salt or balanced crystalloids solutions.
In the last 10 years, Ringer or Ringer-lactate solutions are
considered advanatagous. If non-balanced isotonic solutions are
administered, hyperchloremic and metabolic acidosis is more likely
to occur, with consecutive renal vasoconstriction and blood flow
reduction through the renal cortex. If balanced solutions are used,
renal insufficiency may develop less frequently with less need for
dialysis and with decreased mortality in critically ill patients
[6,7,8]. The clinical use of colloids was sometimes justified by the
need to improve low oncotic pressure or to reduce capillary leakage
or in some cases with the idea to reduce excessive fluid volume
replacement. Unfortunately, the use of colloids showed no advantage
over balanced crystalloids in sepsis and septic shock. Furthermore,
no benefit was seen when albumins were administered during initial
reanimation comparing to balanced crystalloids and the treatment
cost was higher in this group of patients . Other colloids such
as hydroxyethil starch are also not recommended in sepsis, since
their use was associated with renal insufficiency and increased
The goal of every fluid replacement strategy is to maintain median
arterial pressure (MAP) above 65 mm Hg thus providing adequate
tissue perfusion. While attempting to achieve desirable MAP, it is
often possible to cause volume overload if large volumes of fluids
are given. State of overload is manifested by pulmonary oedema,
hypoxemic respiratory insufficiency, swelling of peripheral tissue,
development of intrabdominal hypertension with prolonged duration of
stay in intensive care (ICU) and higher death rate [4,11]. For this
reason, continuous estimation of fluid volume status is mandatory
through the measurement of both static (median arterial pressure,
central-venous pressure, hourly urine output) and dynamic
parameters. Static parameters have shown considerable inferiority
comparing to dynamic measures for prediction of volume overload
[12,13,14]. Also, dynamic parameters enabled more appropriate fluid
replacement, affecting positively the cardiac output, shortening
duration of mechanical ventilation and ICU stay with the decrease in
mortality [15,16,17]. Dynamic measures are performed after
administration of bolus fluids or after passive leg elevation. The
latter maneuver may return 200 - 300 ml of blood from lower
extremities to systemic circulation. Consecutive changes in the
cardiac output may be directly measured using thermodilution or
echocardiography or by registering changes in pulse pressure.
Changes of cardiac output during inspiratory and expiratory phase of
mechanical ventilation could be estimated through the variations of
the pulse pressure, stroke volume and diameters of v. cava inferior
Apart from dynamic measurements, fluid replacement during rescue
phase can beassessed through an analysis of lactate levels and
central venous oxygen saturation (ScvO2). Increase in lactate levels
during sepsis may result from tissue hypoxia, increased aerobic
glycolysis induced by β-adrenergic stimulation, but the increase may
also be the result of effects of certain drugs (epinephrine, β2
agonists) or hepatic insufficiency. Lactate follow up, may
objectively estimate response to resuscitation attempts and predict
its inferior outcome. This was particularly evidenced in septic
patients with lactate levels above 4 mmol/l [18,19]. If serum
lactate levels as markers of tissue hypoperfusion are above 2 mmol/l
during initial assessment, measurements should be repeted every 2-4
hours until normalization . Therapy driven by the levels of this
biomarker, may significantly reduce mortality in septic patients
[20,21]. Therapeutic effects of fluid supplementation may also be
followed byScvO2and capillary refill assessment, although their
follow up was not found to be advantageous,comparing to lactate
level analysis [20,22].
Response to supplemented fluid in septic patients is considered
adequate if systolic pressure rises above 90 mmHg, in case of
hypotension reversion or when MAP reaches levels above 65 mmHg
without vasopressor influence. Yet, certain number of patients
(36.2%) remains refractory to fluid administration, as seen in a
retrospective study done on 3686 patients . These patients often
need prolonged mechanical ventilation and longer stay at ICU with
higher death rate. The most common causes of refractoriness to fluid
supplementation are: delay in fluid administration after making
diagnosis of sepsis (longer than 2 hours), the presence of heart
failure as a comorbidity, hypothermia, coagulopathy,
immunocompromised patients and serum lactate above 4 mmol/l at
initial assessment of patients .
Rapid fluid renewal with satisfactory perfusion of vital organs
aiming to correct MAP above the 65 mmHg, is essential for
reanimation of critically ill patients and should not be delayed. If
restoration of adequate tissue perfusion fails after initial fluid
administration, vasopressor therapy, isolated orcombined with
inotropic drugs should be initiated. Physiological effects of both
vasopressor and inotropic drugs are the rise of blood pressure and
cardiac output and improvement of oxygen delivery to tissues.
Vasopressor dose should be carefully titrated until desirable MAP
level, having in mind potential risks for development of arrythmiaor
cardiac, mesenteric, cerebrovascular and peripheral ischemia caused
by these drugs . Failure of vasopressors to correct blood
pressure above desirable threshold (MAP>65 mmHg), induces linear
decline of tissue perfusion with significant reduction of hourly
output of urine, with detrimental effect to mental status and
lactate clearance . Norepinephrine is the vasopressor of choice
due to potent agonistic α-adrenergic effects and less potent
β-adrenergic effects. Early administration of norepinephrine showed
greater benefit in the treatment of septic shock due to better organ
perfusion and reduced incidence of arrhythmias and mortality in
these patients, compared to other vasopressors [26,27,28]. Immediate
administration of norepinephrine (93 vs 192 minutes) after diagnosis
of septic shock, was associated with better control of shock in the
first 6 hours with reduced incidence of cardiogenic pulmonary oedema
and newly arrhythmias compared to late administration of
norepinephrine . In order to implement this experience in
everyday clinical practice, new studies with a higher degree of
evidence are needed. Vasopressors other than norepinephrine such as:
epinephrine, vasopressin, terlipresine or phenylephrine, may also be
used [29,30]. Combined use of norepinephrine with any additional
vasopressor may be applied if the isolated norepinephrine therapy
was not able to achieve satisfactory MAP levels or if there is a
risk for norepinephrine overdose (40 to 50 μg/min) in septic
patients. In spite of these recommendations, combined treatment
showed no efficacy in a study of Zhou et al. . Combination of
norepinephrine and vasopressin in septic patients with preexisting
cardiac insufficiency was associated with inferior survival of these
patients due to occurrence of malignant arrhythmia compared to
monotherapy with either norepinephrine or dopamine . Considering
these data, the choice of proper vasopressor for the treatment of
septic shock, requires obtaining additional information about
preexisting heart problems, before reaching the final decision.
Apart from vasopressors, inotropic drugs are recommended especially
in patients with inadequate cardiac output after fluid
supplementation due to sepsis -induced cardiomyopathy or existence
of a combined shock. Most commonlyused inotropic drugs are
dobutamine and epinephrine [32,33]. Inotropic drugs may be given
individually or in combination with vasopressors. It is worth saying
that combined use of dobutamine with norepinephrine showed neither
decrease in mortality nor influenced shock duration compared to sole
administration of epinephrine . Effects of inotropic drugs
treatment must be checked through cardiac output, ScvO2 or through
mesurments of other tissue perfusion parameters.
ADJUVANT THERAPY IN SEPTIC PATIENTS
Corticosteroids regulate inadequate inflammatory response that
may be seen in sepsis and also may cause suprarenal gland
insufficiency or may increase tissue resistance to glucocorticoids
. It is believed that in patients with septic shock, steroids
may decrease the need for vasopressors and reduce the duration of a
shock, the length of stay at ICU and duration of mechanical
ventilatory support. So far, obtained results failed to prove any
clinical benefit of corticosteroids on survival outcome for patients
with sepsis or septic shock. For this reason, corticosteroids should
not be given to septic patients, particularly if they achieve
hemodynamic stability to fluid supplementation and vasopressors
[35,36,37]. Corticosteroids are more frequently added as adjuvant
therapy when there is a necessity for higher doses of vasopressors
. If the decision to use corticosteroids is made, recommended
dose of hydrocortisone should be 200mg within 24 hours continusly or
divided to 50mg every 6 hours through first three days . With
the administration of corticosteroids, the ICU and hospitalization
stay was significantly reduced, while the 28-day and overall
mortality of septic patients were reduced with moderate level of
evidence. The risk of major complications occurrence, after
corticosteroid use, was very low. Following its administration, one
may also expect undesirable effects such as: muscle weakness,
hypernatremia, and probably risk for hyperglycemia . New studies
are necessary in order to define proper timing and duration of
corticosteroid treatment related to the beginning of septic shock,
with close analysis of the patient’s outcome.
With the administration of intravenous immunoglobulins in septic
patients, the effects of antigen neutralization, blockade of Fc
receptors on phagocytes and immunomodulation of the cytokine and
cellular response can be achieved . Although reduction of
hospital mortality in septic patients after high doses (1.5-2 g/kg)
of intravenous immunoglobulins, was observed in some studies, there
are considerable limitations concerning these data, urging for
stronger evidence before their use [41,42]. In order to get more
adequate estimation of intravenous immunoglobulins efficacy in
sepsis and septic shock, some authors suggest the need for analysis
of additional parameters such as: the estimation of the amount of
immunoglobulins present in administered drugs, timing of their
administration related to sepsis onset (effects are better if
immunoglobulins were given within 24 hours after sepsis onset),
correlation between administeredimmunoglobulin dose and the degree
of inflammation during infection . Numerous contradictions and
insufficient evidence about immunoglobulin efficacy in septic
patients require further studies for the purpose of shedding light
on immunoglobulin effects.
Even though numerous trials have shown efficacy of anticoagulant
drugs in adjuvant treatment of septic patients, there is not much
evidence about their benefit to mortality reduction in of septic
patients. The greatest benefit in anticoagulant use was noticed in
patients with sepsis-induced disseminated intravascular coagulopathy
Statin drugs administration has been associated with significant
reduction in mortality of septic patients in certain observational
studies compared to randomized studies. For this reason, further
studies should answer the questions concerning efficacy, safety and
finding the adequate dose of statins in septic patients . Many
other aspects of adjuvant therapy in septic patients need
clarifications. This is the case of the usefulness of early
administration of intravenous vitamin C and B1 considering the
registered deficiency of these vitamins in these patients. Although
the early administration of these vitamins had no impact on overall
survival of septic patients, it is considered that along with
standard therapy vitamin supplementation may be beneficial in septic
Treatment of patients with sepsis and septic shock is extremely
complex, considering that sepsis is multifactorial. Good
understanding of pathophysiological processes, early diagnosis of
sepsis and septic shock, urgent and adequate fluid supplementationis
initiated within the first hour after the diagnosis with
administration of vasoactive drugs aiming to achieve hemodynamic
stability, may be crucial for better outcome of these patients.
Adjuvant therapy like corticosteroids, immunoglobulins,
anticoagulants or administration of vitamins C and B1, has some
benefit in septic patients’ treatment, but final decision about
their use might be reached after collecting firm evidence from
further clinical studies.
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