CHAPTER 1

INTRODUCTION
Septic shock is a subclass of distributive shock, a condition in which abnormal
distribution of blood flow in the smallest blood vessels results in inadequate blood supply to
the body's tissues, resulting in ischemia and organ dysfunction. Septic shock refers
specifically to distributive shock due to sepsis as a result of infection

2,5

. Septic shock can be

defined as sepsis-induced hypotension that persists despite treatment with intravenous

fluids. Low blood pressure reduces tissue perfusion pressure, causing the tissue hypoxia that
is characteristic of shock. For septic shock there is an additional of systolic blood pressure is
less than 90mm Hg, a mean arterial pressure(MAP) is less than 70 mm Hg, or a systolic
blood pressure decreases 40 mm Hg or more without other causes for hypotension 7,9.
The pathophysiology of septic shock is played by an immune and coagulation response to an
infection. Both pro-inflammatory and anti-inflammatory responses play a role in septic
shock. Most cases of septic shock are caused by gram-positive bacteria,[8] followed by
endotoxin-producing gram-negative bacteria, though fungal infections are an increasingly
prevalent cause of septic shock. Toxins produced by pathogens cause an immune response; in
gram-negative

bacteria

lipopolysaccharides

these

are endotoxins,

which

are

bacterial

membrane

2,3

. In gram-positive bacteria, these are exotoxins or enterotoxins, which

may vary depending on the species of bacteria. These are divided into three types. In gramnegative sepsis, free LPS attaches to a circulating LPS-binding protein, and the complex then
binds to the CD14 receptor on monocytes, macrophages, and neutrophils. In response to
inflammation,a compensatory reaction of production of anti-inflammatory substances occurs
5,6

Globally, there were 18 million people die each year from sepsis 1. Thus, sepsis is now a
global problem. Hence, early resuscitation of septic shock patients reduces the sepsis-related
morbidity and mortality. The main goals of septic shock resuscitation include volemic
expansion, maintenance of adequate tissue perfusion and oxygen delivery, guided by central
venous pressure, mean arterial pressure, mixed or central venous oxygen saturation and
arterial lactate levels within 6 hours in emergency department

8,9,12,13

. As the patient is

transferred to the intensive care unit, the early goal directed therapy (EGDT) is continued and
in the intensive care unit phase fluid resuscitation plays a very important. Until today, there is
no any definitive types of fluids that is said to be suitable in septic shock patients 10,15.
1

CHAPTER II
LITERATURE REVIEW

2.1 Fluid Responsiveness

The rationale fluid resuscitation is normally done in septic shock patients is normally to
improve cardiac output and organ perfusion and therefore limiting any types of organ
dysfunction. Hence, the only reason to resuscitate a patient with fluid (give a fluid bolus)
would be to cause a clinically significant increase in stroke volume. A patient whose stroke
volume increases by 1015% after a fluid challenge (250500 ml) is considered to be a fluid
responder

2,4,5

. Based on Frank-Starling principle, as the preload increases, stroke volume

increases until the optimal preload is achieved, at which point the stroke volume remains
relatively constant. If the fluid challenge does not increase stroke volume, volume loading is
not beneficial for the patient but might be harmful. The adverse effects of fluid loading when
a patient is on the flat portion of the Frank-Starling curve, is related to the curvilinear shape
of the left ventricular pressure volume curve, resulting from altered diastolic compliance at
higher filing pressures 4,7,8.
As the patient reaches the plateau of his/her Frank-Starling curve, atrial pressures increase,
increasing venous and pulmonary hydrostatic pressures which combined with the increased
release of natriuretic peptides, causes a shift of fluid into the interstitial space, with an
increase in pulmonary and tissue oedema. Hence, tissue oedema impairs oxygen and
metabolite diffusion, distorts tissue architecture, impedes capillary blood flow and lymphatic
drainage and disturbs cell-cell interactions

9,10,11

. Increased right atrial pressure (CVP) is

transmitted backwards increasing venous pressure in vital organs, with a profound effect on
microcirculatory flow and organ function. The kidney is particularly affected by increased
venous pressure, which leads to increased renal subcapsular pressure and reduced renal blood
flow and glomerular filtration rate. A research done by Michard et al., in 2002, around 50%
of patients who received a fluid bolus based on clinical signs and static haemodynamic
measurements turned out to be not fluid responsive 1,2.

Fig 1 Superimposition of the Frank-Starling and Marik-Phillips curves demonstrating the

effects of increasing preload on stroke volume and lungwater in a patient who is pre-load
responsive (a) and non-responsive (b). With sepsis the EVLW curve is shifted to the left.
EVLW=extra-vascular lung water; CO=cardiac output; SV=stroke volume. MCFP=mean
circulating filling pressure. 4
2.2 Fluid Challenge
Critically ill patients and septic shock patients frequently require fluids that are administered
to reverse the hypovolemia. However, many times the quantity given is insufficient or
excessive, which leads to adverse effects. The fluid challenge (FC) allows the physician to
give fluids and at the same time evaluate the cardiovascular response, which allows for
identification of those patients who probably would benefit from an increase in the
intravenous volume. The difference with respect to the fluid load is that it consists of giving
volume without evaluating the real-time response. It must be emphasized that if a septic
patient responds to a fluid test, it does not necessarily mean that a fluid bolus is
necessary. It is necessary to first determine if the patient needs fluid intake or not. It is thus
concluded that the response to fluids should not be confused with need for fluids. This
test is reserved for hemodynamically unstable patients and offers three advantages:
1. Quantify the cardiovascular response during fluid infusion
2. Allow for the correction of fluid deficits
3. Utilize a small quantity of fluids, minimizing the risk of overload and its p potential
3

adverse effects, especially at the pulmonary level.

The FC is done with the intent to increase the SV or CO.47 To evaluate the cardiovascular
response generated by the FC, there are multiple indicators available that are used both as
guides for the administration, as predictors, goals and limits of safety. To choose one or the
other depends on the clinical situation or on the availability of the particular monitoring of
each ICU. For the FC, colloids as well as crystalloids can be used as there are no
demonstrated advantages of one over the other. It was recently reported that the use of
colloids does not reduce the risk of death, compared with the crystalloids. Therefore, the need
for the type of fluid used will depend on the clinical condition.48 However, more important
than the type and amount of fluid administered is the rate of administration. Small amounts
are provided, usually 3 ml/kg (maximum 250 mL) in 5 to 10 min. A patient will be
considered to be responsive when the SV increases by 10-15%. Despite using small aliquots,
these should be sufficient to increase end-diastolic volume of the right ventricle. If these are
insuffi cient, the SV cannot increase and there is the risk of a false negative. In conclusion,
the FC is neither new nor complex. It allows evaluation of the cardiovascular response at the
patients bedside and, simultaneously, prevents fluid overload.
2.2 Fluid resuscitation
Crystalloid solutions have been recommended as a first choice to resuscitate septic shock
patients and nowadays they are the most used type of fluids in the Unites States.
Crystalloid is the most popular term used to refer to solutions containing water, inorganic
ions and small organic molecules. Crystalloids are composed of glucose or sodium chloride
solutions, and can be hypotonic, isotonic or hypertonic. Some of them can have other
components, such as potassium or calcium, and can use some buffers as lactate or acetate to
become plasma-like 2,4,6.
The most common used balance solutions include Ringers injection, Ringer Lactate, Ringer
Acetate and Plasma-Lyte. The Ringer Lactate was developed during early 1930s, by adding
sodium lactate to Ringer solution as a buffer, reducing its chloride concentration (109mEq/L)
when compared to Ringers injection solution. Ringer Lactate is a mild hypotonic solution
(273mOsm/kg) and has potassium and calcium in its composition. Concerns that large
amounts of Ringer Lactate infusion could increase plasma lactate levels in critically ill

patients led the lactate buffer to be replaced by acetate in order to create Ringer Acetate. The
composition of Ringer Lactate and acetate is almost identical with the exception of the added
buffer (lactate or acetate). Plasma-Lyte is another balanced solution with osmolality of
295mOsm/L, sodium concentration of 140mEq/L and chloride concentration of 98mEq/L.
Other electrolytes and buffers making up this solution are potassium, magnesium, acetate and
gluconate. In patients with impaired kidney function, this kind of solution should be avoided
due to the risk of hyperkalemia4,8,9,11.
Crystalloids that are balanced have the presence of an organic anion (such as lactate) and a
lower chloride content that more closely resembles the composition of plasma. The difference
between the strong cations and the strong anions (the positives and the negatives) in
balanced fluids is 24-28. In plasma, the actual difference between the sodium (Na) (142
mEq/L) and chloride (Cl) (103 mEq/L) is approximately 39. However by using 24-28 instead
of 38-42, you also account for the dilutional effect of the fluid that you are infusing, which
dilutes the patients albumin and alters the acid-base status.
It was demonstrated a large retrospective cohort study involving 53,448 septic patients
showed that resuscitation with balanced fluids, in comparison to non-balanced solutions,
decreases the risk of in-hospital death (relative risk RR=0.86; 95% confidence interval
95%CI: 0.78-0.94; p=0.001). However, no significant differences in the incidence of acute
renal failure, the need of renal replacement therapy, and hospital and intensive care unit
(ICU) lengths of stay were reported. Nevertheless the level of evidence to support the use of
balanced solutions in clinical practice is weak. A recent meta-analysis suggested that
resuscitation with balanced crystalloids in comparison to unbalanced solution (normal saline
0.9%) may be associated with lower mortality rate (odds ratio OR=0.78; 95%CI: 0.58
1.05). In this context, a large randomized trial comparing balanced and unbalanced solutions
for septic shock resuscitation is still needed 1,3,9.
2.4 Hemodynamic monitoring
Fundamentally, the only reason for providing fluids to a septic shock patient is to increase the
systolic volume (SV) and, in this manner, the cardiac output (CO).5 However, taking into
consideration that only 50% of septic shock respond to fluid expansion, due to myocardial
dysfunction and altered adrenergic sensibility, the hemodynamic parameters for deciding on
administration of these fluids should identify those patients (responsive patients) who would
benefit and at the same time avoid useless and potentially harmful treatments for those who
5

would not respond. The risk of an insufficient dose of fluids is tissue hypoperfusion which,
in an uncorrected picture of hypovolemia, In contrast, an excessive amount of fluids may
alter oxygen delivery (DO2) and also be associated with a series of complications that will
result in a longer stay in the ICU or in the hospital and in an increase in mortality. 3,7,16
In order to decide on the amount of fluids to administer, it is essential to determine whether
or not there are signs of hypoperfusion. This is occasionally easy due to the presence of
evident signs of shock. However, on other occasions there are more subtle signs of
hypoperfusion. Thus, on the face of signs of inadequate tissue perfusion, usually a first step in
the resuscitation process is fluid administration. The expected result of the expansion would
be an increase in SV and CO because as the preload is greater, the SV is greater (FrankStarling Law). It should be remembered that, physiologically, the preload is understood as all
the factors that contribute to the passive stress (tension) of the ventricular wall at the end of
the diastole and is one of the main determinants of CO. In turn, the optimal preload is defined
as the degree of maximal stretching or tension of the myocardial fibers before the start of the
ventricular contraction 4,5.
During states of hypoperfusion, the positive response will be an increase of the SV. However,
this will only occur if both ventricles are operating on the ascending part of the curve. When
a positive response is observed, the patient will be categorized as fluid responsive;
however, if there is no response the fluid load may be harmful. Therefore, repetitive fluid
boluses should be discontinued if the patient does not respond or if there is a significant
increase of the extravascular lung water observed if there is a possibility of monitoring the
latter. Nevertheless, the increase of the SV as a result of a fluid test depends not only on the
increase in the preload, but also on the ventricular function and ventricular afterload.
Reduction of the contractility decreases the degree of the slope of the relationship between
the preload and the SV (Frank-Starling curve) 3.
Static parameters such as central venous pressure (CVP), which is most frequently used, are
traditionally used to guide fluid therapy. Based on the mistaken principle that the CVP
reflects the intravascular volume, it is widely assumed that patients with low CVP are
volume depleted, whereas patients with high CVP have volume overload. CVP is a good
approximation of the right atrial pressure (RAP), which in turn, is a major determinant of
right ventricular (RV) filling. As the stroke volume of the RV determines the filling of the left
ventricle (LV), it is assumed as an indirect measure of the preload of the LV. The normal
value of CVP is 2-8mmHg while in septic shock patient the CVP value that is recommended
is 8-12mmHg 7,11.
6

The usage of the pulmonary artery catheter (PAC), it is still utilized and when used
appropriately it can provide important information to assist in choosing hemodynamic
interventions in patients with sepsis. The PAC allows measurements of intracardiac pressures,
determination of cardiac output (CO; through thermodilution), and mixed venous oxygen
saturation (SvO2). Information obtained from the PAC can be useful in diagnosing different
causes of shock as well as monitoring disease progression and response to therapeutic
interventions. The pulmonary artery occlusion pressure (PAOP), as a reflection of left
ventricular end-diastolic pressure, is presumed to correlate with left ventricular end-diastolic
volume. Although clinicians assume that a high PAOP represents a high intravascular volume,
many patients with elevated PAOP may still require higher intravascular volumes to ensure
that there is adequate CO (e.g. in a patient with decreased ventricular compliance). Changes
in PAOP in relation to intravascular volume are strongly influenced by myocardial
compliance. It is important to recognize this relationship and appreciate that myocardial
compliance may be different from patient to patient and may also change in an individual
patient through the course of critical illness. It is useful to utilize the information provided by
the PAC in a dynamic way, assessing changes in PAOP and their impact on CO as
hemodynamic interventions are instituted. Current PACs offer the capability to monitor
continuous CO and continuous SvO2 1,3,9,16.
SvO2 can be measured in patients using a PAC. The determinants of SvO 2 include CO,
oxygen demand, hemoglobin, and arterial oxygen saturation. Normal SvO 2 is 7075%. In
sepsis SvO2 may be elevated secondary to maldistribution of flow (blood returning to the
venous circulation without opportunity for oxygen transfer). However, patients with sepsis
may also present with a low or normal SvO2. Values of SvO2 must be interpreted within the
overall context of the hemodynamic profile. Following SvO 2 in patients with sepsis is useful
because a low SvO2 is often associated with inadequate CO. Although a normal or high
SvO2 does not always indicate adequate resuscitation, a low SvO 2 should trigger aggressive
interventions to increase oxygen delivery to the tissues and minimize sepsis-induced tissue
hypoperfusion 2,3.
Blood flow to vital organs is usually preserved at a relatively constant rate by autoregulatory
mechanisms when mean arterial pressure (MAP) is maintained between 60 and 120 mmHg.
When MAP drops below 60 mmHg hypoperfusion can occur. It is important to appreciate that
in patients with chronic hypertension the relationship between MAP and organ perfusion
might be shifted to the right. This means that patients with chronic hypertension might need a
higher MAP to ensure that there is adequate organ flow to vital organs. There is a paucity of
data to indicate what MAP threshold should be used in patients with sepsis-induced
7

hypoperfusion. One study demonstrated that raising the MAP from 65 to 75 to 85 mmHg was
not associated with significant differences in measurements of oxygen delivery, or global or
regional perfusion. Current guidelines recommend the maintenance of a MAP of 65 mmHg or
greater as an end-point for resuscitation. It is important to supplement this end-point with
other markers of perfusion as well as clinical considerations that may apply to individual
patients 7,8,13.
Serial lactate measures also help assess response to therapy. The half-life of lactate is around
20 minutes, even in septic patients. If the lactate is persistently elevated, it's not because the
body can't get rid of it, but because the body continues producing it, shifting to anaerobic
metabolism. Hence, as the fluid resuscitation is done, in order to evaluate the responsiveness
blood lactate levels can be evaluated. The normal value of lactate 4 mmol/L. As the patient is
in the phase of septic shock there would be very less urine production in the patient which
leads to oligouria. Hence, if the production is more than 0,5cc/kgBB/hour it is considered as a
good fluid resuscitation is obtained 4,8.

CHAPTER III
8

CONCLUSION
Balanced crystalloids such as Ringer Lactate has been said to be best fluid used in order to
resuscitate patients with septic shock. In order to evaluate the benefit and responsiveness of
the patient towards fluid resuscitation, hemodynamic monitoring can be done. The parameters
that can be evaluated such as MAP > 65mmHg, serum lactate < 4mmol/L, CVP 8-12mmHg,
urine production > 0,5cc/kgBB/hour, Sv02 > 70%.

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11