Advances in the management of hemorrhagic and septic shock
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1. INTRODUCTION
This paper focuses on advances in the management of hemorrhagic shock and
septic shock, and is intended as a resource for surgical trainees and surgeons,
particularly those working in low resource settings around the world.
1.1 Definition of Shock
Shock is a physiologic state in which there is inadequate end-organ perfusion,
and while the causes are varied, of principal concern is the irreversible
end-organ failure and mortality that may result from even a modest imbalance
between tissue oxygen delivery and tissue oxygen requirements.
2. HEMORRHAGIC SHOCK
In this section we review the clinical assessment and initial management of
patients with hemorrhagic shock in settings of limited resources.
2.1 Case presentation
“Mrs. X died in hospital during labour. The
doctor who treated her certified her death as being due to placenta previa. The specialist obstetrician said that the hemorrhage
might not have been fatal, if she had not been anemic due to parasitic infection
and malnutrition. There was also concern because she had only been given 500
ml of blood, and because she died on the table while being sectioned by a
trainee. The hospital administrator noted that she had not arrived at the
hospital until 4 hours after the onset of severe bleeding, and that she had
bled several times during the previous month, for which she did not seek treatment.
A sociologist observed that she was 39 years old, with seven previous pregnancies
and 5 living children. She had never used contraceptives, and her last pregnancy
was unwanted. She was also poor, illiterate, and lived in a rural area.”
1
2.2 Epidemiology
Death from hemorrhage is commonplace in the world today, be it from trauma,
obstetric complications, or otherwise . Considerable
disparities impact the five million people who die yearly of traumatic injury . Persons with life-threatening but salvageable injuries
are six times more likely to die in a low-income setting (36% mortality) than
in a high-income setting (6% mortality). Also, the World Health Organization
(WHO) estimates that over 500,000 women die of obstetric causes each year.
Fully 99% of these deaths are in developing countries, and hemorrhage is the
leading cause of maternal mortality in these settings. 6
Improving access to essential and emergency surgical services at national
and district levels could certainly avert a great deal of these deaths. An
improved capacity to identify and resuscitate patients presenting with hemorrhage
could prevent much of the excessive morbidity and mortality associated with
trauma and obstetrics worldwide.7 8 Most
deaths in trauma and obstetrics are due to bleeding within the first several
hours, underscoring the need for timely assessment and intervention.
2.3 Assessment
The essential first step in the treatment of hemorrhagic
shock, regardless of its cause, is to recognize its presence. The diagnosis
of shock does not require complex lab tests, but instead relies on repeated
careful physical examination and monitoring of vital signs. Recent guidelines
from the WHO recommend that the basic equipment and personnel required for
such monitoring be considered ‘essential’ at all hospitals in
developing countries.2 Other forms of monitoring such as
continuous ECG or central venous pressure monitoring have been deemed ‘desirable’
but not essential.
2.31 Physical exam: Class I-IV Shock
The presence of shock implies a lack of tissue perfusion. Accordingly, the
physical exam signs associated with hemorrhage are an indication of the body’s
attempt to compensate for inadequate perfusion. Such signs include cool clammy
skin, altered mental status, prolonged capillary refill and decreased urinary
output. Vital signs may initially be normal, but eventual changes include
tachycardia, tachypnea, hypothermia and in due course,
hypotension.
The Advanced Trauma Life Support (ATLS) guidelines (Table
1) illustrate the progression of hemorrhage from early compensated (Class
I or II) shock to decompensated (Class III or IV)
shock with the associated development of hypotension.9 This
table, drawn largely from expert opinion, is nonetheless useful in demonstrating
that hypotension is a late sign in hemorrhagic shock and one must not await
its appearance before initiating efforts to resuscitate the patient and obtain
surgical hemostasis. Indeed, evidence from North
America has shown that the presence of hypotension at presentation in trauma
patients with hemorrhagic shock portends more than 50% mortality.10
The physical exam also entails a search for the source of bleeding. In the
trauma patient this involves a careful head to toe examination. Bleeding can
be external and obvious, or internal and hidden in the thoracic or peritoneal
cavities, retroperitoneum, pelvis or femurs. Localization
of significant internal bleeding requires early chest and pelvic x rays, abdominal ultrasound (or computed tomography in hemodynamically stable patients), and careful palpation of
the femurs. In the obstetric patient it will likely involve pelvic examination,
and in the post-operative patient this demands a careful examination of the
operative site for bleeding or hematoma and consideration
of intra-thoracic or intra-peritoneal losses.
|
Classes of hemorrhage |
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Class I |
Class II |
Class III |
Class IV |
|
Blood loss (ml) |
Up to 750 |
750-1500 |
1500-2000 |
>2000 |
|
Blood loss (% blood volume) |
Up to 15% |
15% - 30% |
30% - 40% |
> 40% |
|
Pulse rate |
<100 |
>100 |
>120 |
>140 |
|
Blood pressure |
|
|
Decreased |
Decreased |
|
Pulse pressure |
Normal or increased |
Decreased |
Decreased |
Decreased |
|
Respiratory Rate |
14-20 |
20-30 |
30-40 |
>35 |
|
Urine output (ml/hr) |
>30 |
20-30 |
15-May |
Negligible |
|
CNS/Mental status |
Slightly anxious |
Mildly anxious |
Anxious, confused |
Confused, lethargic |
|
Fluid replacement (3:1 rule) |
Crystalloid |
Crystalloid |
Crystalloid and blood |
Crystalloid and blood |
*The guidelines in Table 1 are based on the 3-for-1 rule. This rule derives
from the empiric observation that most patients in hemorrhagic shock require as
much as 300 mL of electrolyte solution for each 100 mL of blood loss. Applied blindly, these guidelines can
result in excessive or inadequate fluid administration. For example, a patient
with a crush injury to the extremity may have hypotension out of proportion to
his or her blood loss and require fluids in excess of the 3:1 guidelines. In
contrast, a patient whose ongoing blood loss is being replaced by blood
transfusion requires less than 3:1. The use of bolus therapy with careful
monitoring of the patient’s response can moderate these extremes.
*For a 70-kg man.
*From
2.32 Laboratory
Certain laboratory tests help confirm the diagnosis of hemorrhagic shock and
may help guide resuscitation. Where facilities exist, an arterial blood gas may
demonstrate metabolic acidosis, an increased base deficit and an elevated
lactate level. This is because inadequate tissue perfusion causes cells to
undergo anaerobic metabolism with the resultant products of lactic acid and
other acidic by-products.
Hemoglobin and hematocrit measurement (deemed
essential at all hospitals), while not useful in the diagnosis of shock, are
important adjuncts in identifying significant blood loss and potential need for
blood transfusion and surgical intervention. However, hemoglobin and hematocrit levels may remain normal in early acute
hemorrhage, before hemodilution from mobilized extravascular fluid or resuscitation fluid has occurred.
2.4 Initial management
The diagnosis and initial treatment of hemorrhagic
shock should occur almost simultaneously. Establishing an airway, oxygen
supplementation, obtaining IV access, taking steps to stop bleeding and
providing initial volume challenge must take place concurrently. The overall
goal of management is to stop the bleeding and replace the lost volume.11 ,12,13
2.41 ABCs
As in any patient with unstable physiology the initial evaluation includes
sequential assessment of the airway, breathing, and circulation. Establishing a
patent airway with adequate ventilation and oxygenation is the first priority.
The next goal is to obtain prompt vascular access with the minimum of two
large-caliber (minimum of #16 gauge) peripheral IV
catheters. If peripheral veins are inaccessible consideration should be given
to the insertion of a central venous catheter or saphenous
vein cutdown, depending on the skill and experience
level of the treating physician. In children younger than 6 years an intraosseous needle may be attempted. As IV lines are
inserted, appropriate blood samples are drawn. A Foley catheter is placed to monitor
urine output.
2.42 Initial measures to stop bleeding
In the assessment area the treating team can take
effective initial measures to stop or slow hemorrhage. For example, in chest
trauma, immediate placement of a chest tube to suction helps to expand the lung
and to seal off chest-wall bleeding. Bleeding from traumatic external wounds
can usually be effectively controlled by focused manual pressure. The only
resources required for this are training and sufficient gauze bandages.
Other methods of reducing hemorrhage in trauma patients include splinting for
fractured extremities, wrapping for pelvic fractures, and deep interfascial packing or judicious application of
tourniquets for complicated wounds, such as landmine and machete wounds.14 Immediate methods for postpartum obstetric bleeding may
include bimanual uterine compression, administration of oxytocin
and uterine evacuation.
2.43 Initial fluids
According to ATLS guidelines, warmed isotonic crystalloid solutions (Ringer’s
lactate or normal saline) are used for initial resuscitation in hemorrhagic
shock. An initial fluid bolus is given rapidly with the use of a pressure bag.
Further treatment is based in part on the patient’s response to initial
fluid challenge. The usual initial dose is 1-2 liters for an adult and 20mL/kg
for a pediatric patient.9
Despite these guidelines, considerable debate has taken place in recent years
around the appropriate timing and volume of initial fluid resuscitation, as
well as the type of fluid used for resuscitation.15
(i) Crystalloid: early vs. delayed; larger vs.
smaller volume
Some surgeons are concerned that attempts to increase
blood pressure in patients with uncontrolled sources of hemorrhage may be
counterproductive and associated with increased bleeding and higher mortality.
These concerns led to a prospective, randomized clinical study comparing
delayed fluid resuscitation (upon arrival to the operating room) versus
standard fluid resuscitation (in the field by paramedics) in hypotensive patients with penetrating torso trauma. The
authors reported that delayed fluid resuscitation was associated with lower
patient mortality.16
A number of limitations with this study have prevented its universal acceptance
and subsequent studies have not shown similar benefit. A recent Cochrane
systematic review examined six prospective trials and found “insufficient
evidence for or against the use of early or larger volume fluid administration
in the treatment of uncontrolled hemorrhage.”17
Since over-aggressive crystalloid resuscitation may result in hemodilution, hypothermia and ongoing hemorrhage, the
clinician needs to avoid both extremes of too little fluid and massive fluid
resuscitation. Sufficient volume must be restored to prevent exsanguination and cardiac arrest prior to surgical control
of bleeding. Prior to hemorrhage control, it is reasonable to titrate fluid resuscitation to achieve normal mentation and a palpable radial pulse, rather than to
achieve a normal blood pressure.
On balance, we currently recommend that patients presenting in hemorrhagic
shock be given an initial volume challenge as recommended by the ATLS, while
prompt attempts are made to achieve hemostasis. In
regions where access to definitive care may be delayed, many patients with
hemorrhagic conditions are already likely to have established shock and to fit
into the ‘delayed resuscitation’ category. In such circumstances,
patients are much more likely to die of too little fluid than too much.
(ii) Colloids vs. crystalloid
Colloid solutions such as albumin, dextran, or hydroxyethyl starch are composed of a suspension of
particles with much larger molecular weight than crystalloids. They have been
studied and used in resuscitation and have the advantage of requiring less
fluid to correct hypovolemia. However, they have the
disadvantage of higher cost and there is no evidence that they are more
clinically effective.18 ,19 Authorities such as the WHO therefore
recommend that, where supply of infusion fluids is limited, isotonic
crystalloid solutions should be preferentially available.20
(iii) Hypertonic solutions
Hypertonic solutions (usually 7.5% hypertonic saline
(HS)) have also been studied and have been shown to be safe and effective in
the initial resuscitation of patients with bleeding.21, 22, 23, 24 Like colloid
solutions they have the advantage of requiring lower volume (an initial dose of
250mL of 7.5% HS in adults can expand intravascular volume by up to 1L by
mobilization of extravascular fluid) to correct hypovolemia. They can also be prepared locally and some
suggest they may reduce costs associated with larger volume isotonic infusions
in lower resource settings.23 Although early clinical trials
have shown some promise, widespread use of HS in the management of hemorrhagic
shock will depend on the results of an ongoing large multicentre
trial.
2.44 Warming – effects of hypothermia
on mortality
In clinical studies, the presence of hypothermia on
hospital admission is associated with higher mortality for traumatized
patients.25,26
Hypothermia can reduce cardiovascular performance and create coagulopathy that worsens hemorrhage. Therefore, monitoring
and normalization of body temperature is a priority in shock resuscitation.
Bottles or bags of infused fluids should be warmed to body temperature using
fluid warmers if available or alternatively they can be prewarmed
in a bucket of warmed water. Blood should not be placed in hot water as this
may lead to hemolysis and release of potassium.20 Passive external rewarming of the
patient using warm blankets or garments is also important and useful, even in
hospitals in warmer climates.
2.5 Reassessment: Response to initial fluids
Once the above resuscitative measures have been
undertaken the patient needs to be reexamined. Subsequent treatment options
depend in large part on the patient’s response to this initial
resuscitation.15 The initial fluid challenge is therefore
both therapeutic and diagnostic in that it triages bleeding patients into three
categories. This is illustrated by the WHO guidelines, 20 in Figure 1.
The first category of patients includes those who respond rapidly to fluid
challenge and regain normal vital signs. These patients are much less likely to
require blood transfusion or immediate operative intervention. Patients, who
respond to initial resuscitative efforts but then deteriorate hemodynamically, are termed ‘transient responders’
and frequently have injuries that require early operative intervention. The
duration of their response will dictate whether time allows for diagnostic
maneuvers to be performed which identify the site of bleeding.
Patients who fail to respond to initial resuscitative efforts should be assumed
to have ongoing active hemorrhage from a major diathesis and require prompt
operative intervention.9,15,20 It should be underscored that the actively bleeding patient
cannot be resuscitated until surgical control of hemorrhage is achieved. On
rare occasions, failure of patients with bleeding to respond to resuscitative
efforts may be due to other causes of shock like cardiogenic,
neurogenic, obstructive or septic shock.
2.6 Blood transfusion and other products
We acknowledge, particularly in the era of high HIV
prevalence, that blood transfusion carries the potential to transmit disease
and is also limited by donor availability and short shelf life. However, in
patients with hemorrhagic shock, blood products can be life saving.
2.61 Decision to transfuse
Though controversy exists, most published guidelines
from
Others argue that in resource-constrained settings the administration of
precious units of blood should be delayed until hemorrhage is controlled.29,30,31
In actively hemorrhaging patients and where adequate blood transfusion
capacity exists, we recommend prompt transfusion after the initial crystalloid
bolus. However, in settings where blood availability is severely limited, we
acknowledge that giving blood to a hypotensive
patient that is still actively hemorrhaging (before surgical hemostasis has been achieved) may be a misuse of precious
resources and in many of these cases the clinical situation will have passed
beyond control. Ultimately, bedside clinical judgment will determine the need
for transfusion.
2.62 Blood Products.
Various blood products are in use today, including whole blood as well as
separated blood components such as packed red cells, platelets, and plasma. The
separation of blood components is advantageous in that it allows a single blood
donation to provide treatment for two or three patients and also avoids the
transfusion of elements of the whole blood that the patient may not require.
However, the needed resources for component separation have restricted its
worldwide use.20
Whole blood transfusion is therefore the current practice in most worldwide
settings. Interestingly, whole blood transfusions have recently regained
interest among North American surgeons operating in austere military settings.32 In several recent retrospective studies, the administration
of fresh whole blood was compared to the administration of separated packed red
cells and found to have similar outcomes.33
The advantage of whole blood is that no special equipment is needed for
processing. Also, whole blood supplies plasma volume, red cells, platelets, and
stable coagulation factors, thereby potentially avoiding the coagulopathy often seen in hemorrhagic shock.
Therefore, when separated packed red blood cells (PRBC) are used for
resuscitation, additional blood components such as fresh frozen plasma (FFP),
platelets, and fibrinogen should be considered when providing large volume
resuscitation. In these settings of massive transfusion the patient is more
likely to develop coagulopathy and further bleeding
because of the loss of clotting factors and platelets.34 Once
the patient has lost the equivalent of one blood volume or required five or
more units of PRBC, FFP should be given in an empiric FFP:PRBC
ratio of 1:1 while awaiting laboratory results.35, 36 In settings where resources permit,
the hemoglobin, platelet count and coagulation studies should be repeated often
during the massive transfusion. Fresh frozen plasma should be given to keep INR
<1.5 times normal; platelets should be given to keep platelet count above
80,000/ml; and cryoprecipitate to keep fibrinogen level within normal limits if
it is low despite transfusion of FFP.34
2.63 Autotransfusion
Salvage autotransfusion of the patient’s
recovered blood can be a very useful adjunct in the resuscitation of bleeding
patients. This intervention has been shown to be safe and efficacious and can
be very useful in settings where donated blood is scarce and transfusion
capabilities limited.37,38
The techniques of autotranfusion are well described
elsewhere (see WHO: Clinical Use of Blood) but essentially this method can be
carried out even if a dedicated disposable apparatus is not available. One
caveat with this method is the possibility of contamination with bowel
contents, pus, amniotic or pancreatic fluid and if any of these are suspected
the blood should not be transfused.
2.64 Blood substitutes
The search for blood substitutes has been a matter of
intense research lately because of the afore-mentioned problems with
transfusion as well as the coagulopathy associated
with major trauma. However, so far, trials of hemoglobin based oxygen carriers
have demonstrated some adverse consequences and have not been shown to improve
survival. A proposed method of reversing the coagulopathy
of trauma is the use of antifibrinolytic agents, such
as aprotinin and tranexamic
acid (TXA). To date there is no support for the use of aprotinin
although further trials are ongoing.39 Even if effective, its
high cost is prohibitive in most settings. A worldwide multi-centre randomized,
controlled trial of TXA in hemorrhagic shock is currently underway.40
Although TXA is much cheaper than aprotinin and the
trial does include several hospitals in sub-Saharan
2.7 Definitive management: Timing of surgery
and damage control
The most important aspect in the successful treatment
of patients in hemorrhagic shock is to stop bleeding. We acknowledge that much
bleeding stops without surgical intervention (e.g. femur fracture, minor spleen
injuries). However, most severe hemorrhages require surgical intervention.
Efforts to resuscitate a patient endlessly in the emergency department or on
the ward are fruitless in the setting of active hemorrhage.
In these cases the patient is best served by having immediate surgery to
control bleeding while the anesthesia team continues resuscitation. Radiologic tests are useful to identify the source of
bleeding so as to focus operative efforts but these should not delay effective
treatment, particularly in those patients with ongoing hypotension and hypoperfusion despite volume resuscitation.12,15
The recognition of coagulopathy, acidosis and
hypothermia (the “triad of death”) as major contributors to
mortality, has led to the concept of damage control surgery, where achievement
of hemostasis and control of contamination are
prioritized, while definitive reconstruction of injuries is left for subsequent
operations. Once bleeding and contamination are controlled by the most
expeditious techniques (including packing of solid organ injuries or ligation or shunting of vascular injuries), patients are
transferred to high dependency units for aggressive treatment to interrupt the
cycle of coagulopathy, acidosis and hypothermia.
Definitive repair of injuries and abdominal closure are deferred until
homeostasis has been restored. We have a very low threshold to employ a damage
control strategy, and often decide on this approach for unstable patients even
before the incision is made. Ideally, surgical procedures should be abbreviated
immediately after the achievement of hemostasis, and
before the onset of the triad of death. Even with aggressive approaches, once
these processes have set in, it is very difficult to salvage the patient.
2.8 Specific situations
The approach to the bleeding patient will vary
considerably given the clinical context. The above guidelines are targeted
primarily to the trauma patient but the principles of early recognition, early
resuscitation and early surgery apply in other scenarios of major hemorrhage.
The management of these patients, such as those with major obstetric or
post-operative hemorrhage is well described elsewhere and beyond the scope of
this discussion. However several specific situations are briefly considered
here.
2.81 Major obstetric bleeding
Surgery for obstetrics in
The causes of obstetric hemorrhage can briefly be categorized in the following
manner.20,41 If
bleeding occurs during the first 22 weeks of pregnancy, abortion, ectopic or molar pregnancy should be suspected. If bleeding
occurs after 22 weeks or during labour but before
delivery, suspect placenta previa, placental
abruption or ruptured uterus. If bleeding occurs after childbirth, suspect one
of the four ‘T’s’ of postpartum hemorrhage: loss of uterine
tone (atony), tears of the genital tract, retained
placental tissue, or thrombin abnormalities (or DIC).
In addition, pregnant women should be given Group O negative, and/or group
specific blood until fully crossmatched blood is
available. In areas where the population contains extremely low numbers of
women who are Rhesus D negative, Group O blood may be used.20
Once resuscitation measures have been initiated the clinician should search for
the cause of hemorrhage using cervical and vaginal examination (except when
placenta previa is suspected).
The incidence of, and mortality from, postpartum hemorrhage (PPH) is much
greater than from antepartum hemorrhage and uterine atony is far and away the most common cause of postpartum
hemorrhage. If conservative measures for uterine atony
such as uterine massage or oxytocics are
insufficient, surgery with uterine artery ligation,
or hysterectomy should be considered sooner rather than later. See SIA Review
March 2008
http://www.ptolemy.ca/members/current/antenatal/ . If retained
products of conception are present and there is uncontrolled hemorrhage, the
possibility of disseminated intravascular coagulation should be considered.
2.82 Post-operative bleeding
One anesthetist with many years experience working in Sub-Saharan African
hospitals had this to say about post-operative hemorrhage:
“In [my] experience, by far the commonest time of death for all patients
is during the postoperative period because of hemorrhage and inadequate
intravenous fluid . . . it is mandatory to check every major case, obstetric and
general surgical – several times – in the postoperative period,
assess volume status, ensure adequacy of intravenous infusion and institute
proactive measures, such as a return to the operating theater for investigation
of bleeding.” Paul Fenton, Managing situations of acute
blood loss with limited resources.30
Postoperative bleeding is often concealed and therefore the diagnosis is often
delayed. Blood loss and hypovolemia often develop in
the postoperative period and vigilant monitoring of vital signs and the
surgical site is an essential part of patient management. The clinician should
look for the signs of tachypnea, thirst, tachycardia,
hypotension, cold extremities, reduced urine output and decreased conscious
level. Ensuring normovolemia in the postoperative
patient is essential. Intravenous fluid replacement should address both
measured losses occurring after surgery and the maintenance requirements of the
patient. Where significant blood loss continues to occur postoperatively and
there is no treatable disturbance of the coagulation status of the patient,
early surgical re-exploration should be considered.
2.9 Complications of resuscitation
Most of the ‘complications of resuscitation’ of patients in
hemorrhagic shock are in fact complications of the hemorrhage itself and its
impact on end-organ perfusion.42 A period of prolonged hypoperfusion can injure the lungs, heart, liver and
kidneys. These patients may require ventilation and intensive support in a high
dependency area if such facilities exist. Morbidity and mortality is high in
this group of patients.
2.91 Renal failure
Acute tubular necrosis is a major complication of
hemorrhagic shock. The more severe the hypovolemia
and the longer it lasts, the more likely are the kidneys to suffer ischemic
injury and shed their tubular cells. If they do, days or weeks may elapse
before they recover. During this time the patient can die from uremia,
potassium intoxication, or infection. This complication can be difficult to
treat and the patient should be referred for specialist care if at all
possible. This again underscores the importance of early resuscitation and
surgical control of bleeding in patients presenting with hemorrhage.43
2.92 Over resuscitation
Our capacity to increase the volume and rate of
resuscitation has led to the recognition of late complications of resuscitation
fluid administration, including dilutional coagulopathy, hypothermia, pulmonary edema, and the
abdominal compartment syndrome. Prompt achievement of hemostasis
and judicious fluid administration with discrete boluses and careful evaluation
of hemodynamic and end organ responses may reduce
fluid volumes and limit some of the adverse consequences of fluid overload.
2.10 Summary
Bleeding patients should be rapidly assessed and resuscitated according to the
severity of their hemorrhage while simultaneous strategies are initiated to
control bleeding. The human resources, equipment and supplies necessary for
monitoring, resuscitation and intervention should be available at all
hospitals. Much can be done even with limited resources to salvage many
patients who present with bleeding after trauma, obstetric complication or
surgery.
3. SEPTIC SHOCK-DEFINITION
Septic shock is the most serious end of a continuum that ranges from Systemic
Inflammatory Response Syndrome (SIRS), to sepsis, to severe sepsis, to septic
shock. It is worth reviewing the definitions of each of these terms, which are
detailed in Table 2. Clinically, septic shock is defined as
persistent and refractory hypotension in the setting of a proven or presumed
infection with evidence of SIRS.
|
Systemic Inflammatory Response Syndrome (SIRS): 2 or more of |
|
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- Temperature >38 C or <36 C |
|
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- Heart rate >90 in the absence of rate lowering medications or cardiac pacing |
|
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- Respiratory rate > 20 (or PaCO2 <32, or mechanically ventilated) |
|
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- Leukocytosis >12,000 /microL or Leukopenia <4,000 /microL or left shift (>10% immature neutrophils) |
|
Sepsis |
Proven or presumed infection in setting of SIRS |
|
Severe Sepsis |
Sepsis plus organ hypoperfusion or dysfunction |
|
Organ hypoperfusion: examples |
|
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- decreased urine output (<0.5cc/kg/hr) |
|
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- decreased peripheral circulation: abnormal capillary refill |
|
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- altered or decreased level of consciousness |
|
Organ dysfunction: examples |
|
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-Coagulopathy |
|
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-Respiratory Failure |
|
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-Acute Renal Failure |
|
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-Acute Hepatic Failure ("Shock Liver") |
|
Septic Shock |
Sepsis plus: |
|
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Refractory Hypotension: |
|
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Vasopressor dependency following adequate fluid resuscitation. |
Table 2 from Rivers et al. 2005,46
and
2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.80
3.1 Case Presentation
A 32-year-old man is brought to hospital by family members with a history of
worsening fever, occasional cough, and increasing abdominal pain. He began to
be unwell two weeks ago, and over the past week he has been delirious with a
high fever. He has had some loose green stools.
On physical examination, the man looks toxic. His airway is patent, he is tachypneic with mildly decreased air entry on the right
base, and he is febrile with a temperature of 40.5 degrees Celsius. Pulses are thready and his extremities are cool. There is peritonism. He is taken to the operating theatre for laparotomy 10 hours after presentation, having only
received 1 Litre of normal saline intravenously, and
he becomes profoundly hypotensive on induction of
anesthesia.
Laparotomy shows evidence of inflammation of the
terminal ileum and perforation. The perforation is repaired, and the abdomen
irrigated and closed primarily. Antibiotic therapy for presumed Salmonella Typhi infection is started 17 hours after presentation to
hospital.
In the following two days the patient deteriorates further with ongoing high
fevers, and renal failure and hypotension not responsive to fluid therapy. He
dies on the second post-operative day from multi-organ failure.
3.2 Epidemiology
Comparisons of epidemiological studies of severe sepsis in European and North
American countries are difficult given variations in study methodology,44 and no comparisons with African
nations have been reported in the literature. Even with consensus guidelines on
the definition of severe sepsis and septic shock, there are difficulties with
evaluating reporting practices in different studies, and many studies rely on
ICU admission data and discharge data. However, with a lack of adequate medical
resources in many African nations, there is undoubtedly an underreporting bias
in severe sepsis in
In the
Given the comparative lack of per capita ICU resources in underserviced
African nations, the mortality rate of severe sepsis in
3.3. Pathophysiology
of Septic Shock
In response to infection, the body mounts a complex inflammatory reaction
involving humoral, cellular, and neuroendocrine
pathways. These result in systemic vasodilation,
increased capillary permeability with intravascular volume depletion, and, in
many cases, depression of myocardial function. In septic shock, oxygen delivery
to the tissues is compromised by distributive, hypovolemic
and cardiogenic mechanisms. The key to treating
septic shock is to understand that at a microvascular
level there is impairment of perfusion, with tissue ischemia and hypoxia
– efforts must therefore be simultaneously devoted to both control of the
infectious source and rapid reversal of the hemodynamic
consequences of inflammation.46 Tissue hypoxia itself leads
to further inflammation and further discrepancies between oxygen delivery and
oxygen utilization. This impaired perfusion and tissue hypoxia may be present
despite normal vital signs, and in the absence of hypotension.47
The discrepancy between oxygen transport and utilization underscores the
utility of measuring both serum lactate and the central venous oxygen
concentration (ScvO2), as proposed by both Rivers et al. and subsequently in
the Surviving Sepsis Guidelines. In combination with an elevated lactate, a low
ScvO2 indicates high extraction of oxygen from circulating blood, reflecting
poor perfusion and/or increased metabolic demands. Correction of the ScvO2 to a
value >70% is accomplished by improving perfusion of tissues and delivery of
oxygen, through a combination of fluids, erythrocytes, and vasoactive
substances. Failure to correct serum lactate and ScvO2 within the first 6 hours
is associated with worsened outcomes.
In the context of an African medical centre that does not have the monitoring
or laboratory facilities to conduct serial ScvO2 measurements, it should be
noted that the principles of management remain the same: early and adequate
resuscitation to maintain end organ perfusion and oxygenation and expeditious
control of the infectious source. The caveat to this is to reiterate that
normal vital signs and a lack of hypotension do not rule out tissue hypoperfusion and hypoxia.
3.4 Assessment and Initial Resuscitation
The assessment of shock should begin with a rapid assessment of the
patient’s airway, breathing, and circulation. As with the
“ABC” approach standardized in algorithms such as the
On initial assessment of the patient, signs of systemic inflammatory response
syndrome (SIRS) should be readily apparent: the presence of tachypnea
(respiratory rate >20), tachycardia (heart rate > 90), and fever or
hypothermia (>38 or <36 degrees Celsius). Hypotension, as defined by a
systolic blood pressure <90 or mean arterial pressure <65, may not be
present despite significant organ hypoperfusion.
Attention should also be paid to the patient’s mental status, and to
other signs of organ hypoperfusion such as poor
capillary refill and mottled skin, in order to evaluate the severity of the
illness. While the history may suggest a possible source of infection, a
thorough physical examination should attempt to identify sources such as soft
tissue abscess, intraabdominal sepsis and
peritonitis, which may require drainage or surgical intervention in order to
provide source control. All of the above physical findings require no invasive
or expensive investigations.
The Surviving Sepsis Guidelines suggest the following goals for the first 6
hours of resuscitation:49
Central Venous Pressure (CVP): 8-12
Mean Arterial Pressure (MAP): >=65mmHg*
Urine Output >= 0.5mL/kg/hr
Central Venous Oxygen Saturation >= 70% or
Mixed Venous oxygen saturation >=65%
*MAP= 2/3 DIASTOLIC PRESSURE + 1/3 SYSTOLIC PRESSURE
In order to meet these goals, intravenous access is required, with central
venous access preferable as it provides a means of obtaining CVP and CvO2
measurements. A Foley catheter should be placed to monitor urine output.
3.41 Fluid Therapy
Early resuscitation of the septic patient involves fluid bolus challenges of
crystalloids or colloids. The Surviving Sepsis guidelines suggest 1000ml of
crystalloid or 300-500ml of colloid over 30 minutes, with more rapid infusions
given in the setting of sepsis-induced tissue hypoperfusion.
The goal is to ensure adequate cardiac preload, and in a monitored setting the
goal Central Venous Pressure is >8mmHg in an unintubated
patient (>12mmHg if mechanically ventilated).48,49,50 It may require
several litres of isotonic crystalloids to achieve
this target and to restore perfusion.
As detailed above in the section on hemorrhagic shock, in a meta-analysis
examining crystalloids versus colloids in critically ill patients, colloids
were not shown to reduce the risk of death in patients with trauma, burns, or
in the post-operative period.18 Additionally, a Cochrane
systematic review of resuscitation with colloid found no evidence to support
the superiority of one colloid being superior to another between albumin, PPF, hydroxyethyl starch, dextran, and
gelatin.51 Given the increased cost of colloids versus
crystalloids, and the lack of superiority in critically ill patients, it is
advisable to use crystalloids (normal saline or Ringer’s lactate
solution) in the context of an African medical centre.
The use of blood transfusion, in order to increase the oxygen carrying capacity
of the circulating volume and the oxygen delivery to end organs, was used in
Rivers’ study protocol.48 Packed red blood cells were transfused
to a hematocrit of >30% in the setting of a ScvO2
<70% in patients that did not respond to fluid resuscitation and use of vasopressors. In the absence of an ability to measure a
ScvO2, a hematocrit <30% in a patient with septic
shock may indicate a role for transfusion. However, the local availability and
safety of the blood supply with regards to infectious risks associated with
transfusion would need to be taken into account.
With fluid resuscitation come the attendant risks and complications of
pulmonary edema and abdominal compartment syndrome. It can be a delicate
balance between under- and over-resuscitation and signs of pulmonary edema must
be watched for.52 This is particularly true in settings where
there are no resources to initiate mechanical ventilation. In general, our
approach has been to restore perfusion rapidly through the aggressive use of
intravenous normal saline. Enough volume should be given to normalize the CVP,
MAP, urine output, and central venous oxygenation if available. Beyond 6-12
hours after presentation (once intravascular volume has been restored), we use
a more judicious approach to fluid management with with
a maintenance i.v fluid rate of 100-200mL/hr and
0.5-1L fluid boluses as needed to respond to evidence of hypovolemia
or hypoperfusion.
3.42 Antimicrobial Therapy
Delays in the initiation of appropriate antibiotic therapy are known to
increase mortality in septic shock. The Surviving Sepsis Guidelines advise
initiating broad spectrum antimicrobial therapy that covers suspected
infectious organisms and takes into account local antimicrobial resistance
patterns, within the first hour of resuscitation. When possible, cultures from
blood, urine, and respiratory sources should be obtained, but this must not
delay initiating treatment.81 The guidelines also suggest
that in the setting of pseudomonas infections, double coverage should be
considered.
In the neutropenic patient, combination empiric
therapy should be considered. Prophylaxis with fluconazole
or ketoconazole in immunocompromised
critically ill patients at increased risk of invasive fungal infections may
decrease their risk of fungal infection by 50% and the total mortality by 25%.53
The addition of aminoglycosides should be undertaken
with some caution. In a meta-analysis of beta-lactam monotherapy versus beta lactam-aminoglycoside
combination therapy, no difference was found in all-cause fatality rates
between groups. However a significant increase in nephrotoxicity
was seen in the aminoglycoside group.54
Therapy should be reassessed daily, with consideration given to whether the
patient is improving on the implemented regimen. If cultures show susceptibility
to more narrow-spectrum antimicrobial agents, therapy should be adjusted
accordingly. Duration of therapy should be limited to 7-10 days unless the
patient is immunocompromised or there are undrainable sources of infection.
3.43 Vasopressors
One of the goals of resuscitation in severe sepsis and
septic shock is the maintenance of a mean arterial pressure greater than
65mmHg. Patients who do not respond to initial fluid boluses, or who remain hypotensive despite adequate fluid volume resuscitation,
will require vasopressor support. In the setting of
using vasopressors, the Surviving Sepsis guidelines
suggest prompt insertion of an arterial catheter in order to allow titration to
effect.
While a meta-analysis performed by Mullner55 and colleagues
failed to find enough evidence to support the use of one vasopressor
over another, the Surviving Sepsis Guidelines support the use of norepinephrine or dopamine as the initial vasopressors of choice in septic shock.49
In the event of poor response to norepinephrine,
epinephrine is the alternative agent of choice in septic shock. There is no
role for renal-protective low-dose dopamine in septic shock.
Vasopressin, otherwise known as antidiuretic hormone,
has been studied in the treatment of septic shock, as there is an association
between septic shock and vasopressin deficiency. A randomized controlled trial
comparing patients who received only norepinephrine
to those who received both norepinephrine and
vasopressin found that short-term vasopressin infusion spared norepinephrine use and increased urine output.56
A subsequent randomized control trial of 778 patients again found that low dose
administration of vasopressin decreased norepinephrine
use, but no difference in 28-day mortality was found between patients who
received vasopressin and norepinephrine and patients
who received norepinephrine alone.57
The use of inotropes in septic shock is indicated in
patients with myocardial dysfunction as indicated by low cental
venous oxygen saturation (or other indicators of organ hypoperfusion)
in the setting of adequate central venous pressure (CVP > 12 mmHg). The
agent of choice is dobutamine.49
3.5 Additional Therapies
3.51 Steroids
Patients in septic shock and other critical illnesses can have a functional
adrenal insufficiency with resultant increased morbidity and mortality.58 Of particular relevance to surgeons in HIV endemic regions of
Benefits have been seen with early administration of low-dose hydrocortisone in
patients who remain hypotensive despite adequate
volume and use of vasopressors.60 A meta-analysis of 15
trials, incorporating 2023 patients, showed decreased ICU mortality, increased
proportion of shock reversal by day 7, and no increased rate of
gastrointestinal bleeding, infection, or hyperglycemia.61
However, steroid therapy in septic shock remains controversial, as there was
considerable heterogeneity in the studies included in the meta-analysis.
Furthermore, a recent clinical trial by the CORTICUS study group, found both an
increased risk of new episodes of sepsis and septic shock, as well as
hyperglycemia, among septic shock patients treated with hydrocortisone.62 Use of hydrocortisone in this study did not affect mortality,
regardless of adrenal function as reflected by response to corticotropin
stimulation. The authors suggested that there was no role for hydrocortisone as
a general adjuvant therapy for septic shock, nor any role for corticotropin stimulation testing. There was an allowance
that there may be a role for early treatment with hydrocortisone in patients in
septic shock who remain hypotensive and fail to respond
to fluid and vasopressor therapy, as demonstrated by Annane et al.60
3.52 Glucose Control
The metabolic response to critical illness, which includes the release of cortisol and catecholamines,
promotes hyperglycemia. Hyperglycemia is known to alter neutrophil
function and to be associated with increased susceptibility to infection. In a
landmark clinical trial, 82 found that intensive insulin
therapy (maintaining glucose levels between 4.4 and 6.1mmol/L) in a population
of critically ill surgical patients was associated with decreased mortality.65 Other studies have shown that an algorithm approach to
treatment of blood sugars in critically ill patients is administrable by nursing
staff without physician input,66 and
that adherence to an algorithm such as the SPRINT protocol results in better glycemic control and a reduction in hospital mortality of
26-32%.67 However, despite showing overall benefical effects of intensive insulin therapy, a follow up
trial in critically ill medical patients demonstrated increased mortality in
patients who stayed in ICU for less than 3 days, raising concerns about the
timing of initiation of intensive insulin therapy. Questions also remain about
the potential neurologic consequences of undetected
episodes of hypoglycemia in patients receiving intensive insulin therapy. An
ongoing multicentre trial should help to clarify
these considerations.
In resource poor settings, it may not be feasible to readily implement such glycemic control strategies given the need for intensive
monitoring and frequent therapeutic adjustments. However, given the reduction
in mortality seen in initial studies, it would be reasonable to follow glucose
levels, avoid hyperglycemia where possible and to evaluate whether glycemic control strategies are practicable.
3.53 Drotrecogin
alfa (recombinant human Activated Protein C)
Recombinant Activated Protein C (rhAPC) is an
anticoagulant with anti-inflammatory properties that has been studied as a
specific therapy for the treatment of sepsis. It is an understatement to say
that there has been controversy surrounding the findings of the PROWESS and
ADDRESS trials that investigate adult therapy, and the RESOLVE trial in
children.68,69,70,71,72
While a thorough evaluation of the risks and benefits of administration of this
therapy is beyond the scope of this article, it is important to note that there
has been no consistent benefit seen with the use of rhAPC,
and that there is some risk of hemorrhage even when used properly.73
While the Surviving Sepsis 46 guidelines suggest the use of rhAPC in patients at high risk of death (as assessed by an
APACHE score greater than/equal to 25) based on the results of the PROWESS
trial, it is doubtful that rhAPC is a viable therapy
in the setting of a resource limited setting in Africa given the high cost of
therapy and limited benefit.
3.54 IVIG
Meta-analyses of the use of Intravenous Immunoglobulin (IVIG) in the setting of
severe sepsis and septic shock have shown a survival benefit of approximately
25% with use of polyclonal IVIG.74,75 The therapies used varied, but in order to see a benefit, a
total IVIG dose of greater than 1 gram per kilogram of body weight was needed.
In addition, the duration of therapy needed to be greater than 2 days to see a
survival benefit.74 Currently IVIG is not widely used as a
standard therapy for septic shock.
3.55 DVT prophylaxis
Patients without contraindication to anticoagulation should be given
prophylaxis against deep vein thrombosis with either heparin or low molecular
weight heparin.49
3.56 Stress Ulcer Prophylaxis
Particularly in those patients treated with steroids for severe sepsis and
septic shock, the use of H2 receptor antagonists or proton pump inhibitors is
advised for stress ulcer prophylaxis.49
3.57 Mechanical Ventilation
The strong association of septic shock with acute lung injury (ALI) frequently
necessitates the use of mechanical ventilation to ensure adequate oxygen
delivery. Physicians with access to mechanical ventilation for their patients
should review the lung protective strategies detailed in the Surviving Sepsis
guidelines, as significant advances have been made in the prevention of
ventilator associated morbidity and mortality.49
3.58 Renal Replacement Therapy
Sepsis frequently results in acute kidney injury through a variety of
mechanisms. Early and aggressive resuscitation, prompt control of the
infectious source and avoidance of nephrotoxins can
reduce the incidence, severity and duration of renal dysfunction. Maintenance
of renal function and the prevention of irreversible renal failure is a critical
priority in the management of septic patients, especially where access to
continuous and intermittent renal replacement therapies is limited.
3.6 Definitive Management: Source
Identification and Control
Within the first six hours of presentation with sepsis, an anatomical source
should be determined. In some cases, history and physical alone will provide
the most likely etiology. On physical exam, a careful inspection for skin and
soft tissue infections such as cellulitis and abscess
should be made. Early debridement and drainage of any
abscess should be considered after initial resuscitation. The use of the least
invasive means of drainage or debridement that
achieves source control should be encouraged; ie: percutaneous drainage rather than operative, when
appropriate.49,76
The use of imaging will clearly be limited by locally available resources. A
chest radiograph may show evidence of pneumonia, or it may show bilateral
infiltrates consistent with Acute Respiratory Distress Syndrome without giving
an indication of the etiology of the sepsis. Abdominal radiographs may prove to
be unhelpful except in the setting of findings of gross obstruction or
perforation. The finding of free air on abdominal plain films will nearly
always require prompt surgical exploration. An ultrasound is useful in ruling
out biliary and renal pathology.
In the setting of severe secondary peritonitis, surgical intervention is
necessary in order to remove the source of infection, reduce bacterial
contamination, and prevent recurrent infections. For example, in the case
presentation of perforated typhoid fever above, the key to treating the
patient’s sepsis is irrigating and decontaminating the peritoneal cavity,
and identifying and repairing or removing the site of perforation. Even in
doing so, there is a risk that the patient will develop intraabdominal
abscesses, recurrent perforations, or other complications requiring reoperation. This has led some surgeons to advocate the
“open-abdomen” strategies, which leave the abdomen temporarily open
but contained by a vacuum system or
Two recent randomized controlled trials comparing closed management of the
abdomen following surgery for secondary peritonitis with open management, with
a total of 262 patients, had similar findings favouring
closed management.77,78
While mortality rates were not significantly different between the open and
closed management groups, there was a significant reduction in health care
utilization, and decreased costs associated with closed management. No benefit
was found that would support a generalized approach to secondary peritonitis of
open-management with planned relaparotomy.
3.7 Septic Shock Summary
Severe sepsis and septic shock are life threatening conditions that require
early recognition and initiation of treatment in order to decrease mortality.
The change in approach to septic shock in the past decade, particularly the
implementation of early goal-directed therapy, has decreased mortality. While
not all aspects of early goal-directed therapy are immediately available in
African medical centres, this should not prevent the
implementation of those principles of resuscitation that are practicable, such
as early fluid and antibiotic administration.
4. RECOMMENDATIONS
4.1 Recommendations for Management of
Hemorrhagic Shock
1. Resources for the assessment and management of hemorrhagic shock should be
made available at all hospitals.
2. Patients with hemorrhagic shock should be given an initial volume challenge
of crystalloid (usually 2L in average adult)
3. Patients with ongoing signs of bleeding after this volume infusion should be
prepared for urgent surgery/control of hemorrhage
4. Patients with ongoing signs of bleeding require transfusion with whole
blood, but the timing of initial transfusion is controversial in low-resource
settings (i.e. before/after hemorrhage control). When possible, use blood as
part of pre-operative resuscitation.
5. Ongoing assessment/resuscitation is required in the post-operative period.
4.2 Recommendations for Management of
Septic Shock
1. Patients must be promptly evaluated for signs of Severe Sepsis and Septic
Shock and resuscitation initiated as soon as the diagnosis is considered.
2. Broad-spectrum antimicrobial therapy, including antifungal prophylaxis in at
risk individuals, must be initiated within 1 hour of the commencement of
resuscitation, and must not be delayed by acquisition of appropriate cultures.
3. Source identification and control should occur within 6 hours if possible,
with consideration given to surgical drainage and debridement
of infected collections when applicable.
4. Laboratory and monitoring facilities should be upgraded where possible to
allow for the timely collection and determination of serum lactate and central
venous oxygen saturation (ScvO2), and to allow for measurement of CVP as part
of early-goal directed therapy; tissue hypoperfusion
and hypoxemia may be present in the absence of hypotension, and following early
goal directed therapy algorithms decreases mortality.
5. Complications of resuscitation, including pulmonary edema requiring intubation, and abdominal compartment syndrome requiring laparotomy, need to be weighed more heavily in those centres that cannot provide mechanical ventilation or
surgical intervention.
M Goodwin, M Robinson, SM Hameed
Department of Surgery,
Corresponding author:
SM Hameed, Trauma Services VGH,
morad.hameed@vch.ca
5. REFERENCE LIST
1. King M, Cairns J, Thornton J, Bayley A, editors. Primary Surgery
- Non Trauma.
2. Mock C, Lormand JD, Goosen J, Joshipura M, Peden M. Guidelines for Essential
Trauma Care.
3. Sasser S,Varghese M, Kellermann A, Lormand JD. Prehospital trauma care systems.
4. Mock CN et al. Trauma mortality patterns in three
nations at different economic levels: implications for global trauma system
development. Journal of Trauma, 1998, 44:804–814. http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50460
5. Mock CN et al. Trauma outcomes in the rural developing
world: comparison with an urban level I trauma center. Journal of Trauma, 1993,
35:518–523.
6. World Health Organization. Maternal mortality in 2005 : estimates developed by WHO, UNICEF, UNFPA, and the
World Bank.
7. Debas HT, Gosselin R, McCord C, Thind A.
Surgery. In Disease Control Priorities in Developing Countries,
Jamison et al (Eds). 2006;
8. Debas HT, McCord C. Disease
Control Priorities: Essential Surgical Services in
9.
10. Heckbert SR,
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50461
11. Krausz M. Initial
resuscitation of hemorrhagic shock. World Journal of
Emergency Surgery. 2006;
12. Cocchi MN, Kimlin E, Walsh M, Donnino MW. Identification and resuscitation of the trauma patient in shock.
Emergency Medicine Clinics of
13. Gutierrez G, Reines HD, Wulf-Gutierrez ME. Clinical review: Hemorrhagic shock. Critical Care. 2004; 8(5): 373–381
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50462
14. Dufour D, Kromann-Jensen S, Owen-Smith M, Salmela
J, Stening GF, Zetterstrom
B. Surgery for victims of war.
15. Harbrecht BG, Alarcon LH, Peitzman AB.
Management of shock. In Trauma 5th Edition.
16. Bickell WH, Wall MJ Jr,
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50463
17. Kwan I, Bunn F, Roberts I,
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50464
18. Perel P, Roberts I.
Colloids versus crystalloids for fluid resuscitation in critically ill
patients. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.:
CD000567.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50465
19. The Albumin Reviewers (Alderson P, Bunn F, Li Wan
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50466
20. World Health Organization. The
clinical use of blood in medicine, obstetrics, pediatrics, surgery &
anesthesia, trauma & burns.
21. Bunn F, Roberts I, Tasker
R, Trivedi D. Hypertonic versus near isotonic crystalloid
for fluid resuscitation in critically ill patients. Cochrane Database of
Systematic Reviews 2004, Issue 2. Art. No.: CD002045.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50467
22. Mattox KL, Maningas PA,
Moore EE, Mateer JR, Marx JA, Aprahamian
C, et al. Pre-hospital hypertonic saline/dextran
infusion for post-traumatic hypotension. Annals of Surgery.
1991; 213 (5): 482-491.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50468
23. Sakwari V, Mkony C, Mwafongo V. Rapid
resuscitation with small volume hypertonic saline solution for patients in
traumatic haemorrhagic shock. East
and Central African Journal of Surgery. 2007; 12 (1): 131-138
24. Wade CE, Grady JJ, Kramer GC. Efficacy
of hypertonic saline dextran fluid resuscitation for
patients with hypotension from penetrating trauma. Journal
of Trauma. 2003;Suppl:S144–148
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50469
25. Jurkovich
GJ, Greiser WB, Luterman A,
Curreri PW. Hypothermia in trauma victims: an
ominous predictor of survival. Journal of Trauma.1987;27:1019–1024
26. Luna GK, Maier RV, Pavlin
EG, et al. Incidence and effect of hypothermia in seriously injured patients. Journal of Trauma. 1987;27:1014–1018
27. Hill SR, Carless PA,
Henry DA, Carson JL, Hebert PC, McClelland DBL, Henderson KM. Transfusion
thresholds and other strategies for guiding allogeneic
red blood cell transfusion. Cochrane Database of Systematic Reviews 2002, Issue
2. Art. No.: CD002042
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50470
28. Hebert PC, Wells G, Blajchman
MA, et al: A multicenter, randomized, controlled
clinical trial of transfusion requirements in critical care.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50471
29. Fenton P. Resuscitation and anesthesia. In Surgical care at the district hospital.
30. Fenton P. Managing situations of
acute blood loss with limited resources. Transfusion
alternatives in transfusion medicine. 2008; 10: 82-89.
31. Hardy JF, Fenton PM. Effectiveness of blood
transfusion in
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50472
32. Kauvar DS, Holcomb
JB, Norris GC, Hess JR. Fresh whole blood transfusion: a controversial military
practice. Journal of Trauma. 2006;61:181–184
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50473
33. Spinella PC, Perkins JG, Grathwohl K, Repine T, Beekley
AC, Sebesta J et al. Risks
associated with fresh whole blood and red blood cell transfusions in a combat
support hospital. Critical Care Medicine 2007; 35: 2576-2581
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50474
34. Hardy JF, de Moerloose P,
Samama M. Massive transfusion and coagulopathy:
pathophysiology and implications for clinical
management. Canadian Journal of Anesthesia. 2004;
51(4): 293-310.
35. Gonzalez EA, Moore FA, Holcomb JB, Miller CC, Kozar RA, Todd SR, et al. Fresh frozen plasma should be
given earlier to patients requiring massive transfusion. Journal
of Trauma. 2007; 62(1): 112-9.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/51078
36. Borgman MA, Spinella PC, Perkins JG, Grathwohl
KW, Repine T, Beekley AC, et al. The ratio of blood
products transfused affects mortality in patients receiving massive transfusions
at a combat support hospital. Journal of Trauma. 2007;
63(4): 805-13.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/51079
37. Carless PA, Henry DA,Moxey AJ, O’Connell DL,
Brown T, Fergusson DA. Cell salvage for minimizing perioperative allogeneic blood
transfusion. Cochrane Database of Systematic Reviews 2006, Issue 4. Art.
No.: CD001888
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50475
38. Selo-Ojeme DO, Feyi-Waboso PA. Salvage autotransfusion versus homologous blood transfusion for
ruptured ectopic pregnancy. International
Journal of Gynecology and Obstetrics. 2007; 96(2): 108-111
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50477
39. Stanworth SJ, Birchall J, Doree CJ, Hyde C. Recombinant factor VIIa
for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database of Systematic Reviews 2007,
Issue 2. Art. No.: CD005011
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50478
40. Multicentre Trial;
41. World Health Organization. Managing
Complications in Pregnancy and Childbirth.
42. King M, Cairns J, Thornton J, Bayley
A, editors. Primary Surgery - Trauma. Vol II.
43. World Health Organization. Surgical
care at the district hospital.
44. Angus DC,
45. Angus DC, Linde-Zwirble
WT, Lidicker J, Clermont G, Carcillo
J, Pinsky MR. Epidemiology of severe sepsis in the
United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001 Jul;29(7)
1303-1310
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50479
46. Rivers EP, McIntyre L, Morro
DC, Rivers KK. Early and innovative interventions for severe sepsis and septic
shock: taking advantage of a window of opportunity. CMAJ 173(9):1054-1065, 2005
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50480
47. Donnino M, Nguyen H,
Jacobsen G, Tomlanovich M, Rivers E. Cryptic septic
shock: a sub-analysis of early, goal-directed therapy (abstract). Chest 2003;124:90S
48. Rivers E, Nguyen B, Havstad
S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed
therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50481
49. Dellinger RP, Levy MM, Carlet
JM, Bion J, Parker MM, Jaeschke
R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ,
Marshall J, Ranieri M, Ramsay G, Sevransky
J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL. Surviving
Sepsis Campaign: International guidelines for management of severe sepsis and
septic shock: 2008. Intensive Care Med (2008) 34:17-60
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50482
50. Rivers EP, McIntyre L, Morro
DC, Rivers KK. Early and innovative interventions for severe sepsis and septic
shock: taking advantage of a window of opportunity. CMAJ 173(9):1054-1065,
2005.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50480
51. Bunn F, Trivedi D, Ashraf S. Colloid solutions for fluid resuscitation. Cochrane Database of Systematic Reviews. 1,
2008.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50483
52. Vincent JL, Gerlach H.
Fluid Resuscitation in severe sepsis and septic shock: An evidence base review.
Crit Care Med 2004; 32[Suppl.]:S451-S454
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50484
53. Playford EG, Webster AC,
Sorrell TC, Craig JC. Antifungal agents for preventing fungal
infections in non-neutropenic critically ill
patients. Cochrane Database of Systematic Reviews.
1, 2008.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50485
54. Paul M, Silbiger I, Grozinsky S, Soares-Weiser K, Leibovici L. Beta Lactam
antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for
sepsis. Cochrane Database of Systematic Reviews. 1, 2008.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50487
55. Mullner M, Urbanek B, Havel C, Losert H, Waechter F, Gamper G. Vasopressors for shock.
Cochrane Database of Systematic Reviews. 1, 2008.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50489
56. Patel BM, Chittock DR,
Russell JA, Walley KR. Beneficial Effects of short
term vasopressin infusion during severe septic shock. Anesthesiology 2002 Mar;96(3):576-82
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50491
57. Russell JA, Walley KR,
Singer J, Gordon AC, Hebert PC, Cooper DJ et al. VASST Investigators. Vasopressin versus norepinephrine
infusion in patients with septic shock. N Engl
J Med 2008 Feb 28;358(9):877-87
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50492
58. Cooper MS, Stewart PM. Corticosteroid Insufficiency
in Acutely Ill patients. N Engl J Med 2003;348:727-734
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50493
59. Meya DB, Katabira E, Otim M, Ronald A, Colebunders R, Njama D, et al.
Functional adrenal insufficiency among critically ill patients with human
immunodeficiency virus in a resource-limited setting. African Health Sciences
2007;7(2):101-107
60. Annane D, Sebille V, Charpentier C, et al.
Effect of treatment with low doses of hydrocortisone and fludrocortisone
on mortality in patients with septic shock. JAMA 2002;288:862-871
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50495
61. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids fro treating severe sepsis and
septic shock. Cochrane Database of Systematic Reviews.
1, 2008.
62. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel
K et al. for the CORTICUS study group. Hydrocortisone Therapy
for patients with Septic Shock. N Engl J Med
2008;358:111-24
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50497
63. Loisa P, Parvainen I, Tenhunen J, Hovilehto S, Ruokonen E. Effect
of mode of hydrocortisone administration on glycemic
control in patients with septic shock: a prospective randomized trial. Crit Care 2007;11(1):R21.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50498
64. Weber-Carstens S, Deja M, Bercker S, Dimroth A, Ahlers OKaisers U et al. Impact of bolus application of low-dose
hydrocortisone on glycemic control in septic shock
patients. Intensive Care Med 2007 Apr;33(4):730-3
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50499
65. Chase JG, Hann CE, Shaw
GM, Wong XW, Lin J, Lotz T et al. An
overview of glycemic control in critical care –
relating performance and clinical results. Journal of
Diabetes Science and Technology 2007. 1:82-91
66. Lonergan T, Compte AL, Willacy M, Chase JG, Shaw GM, Hann CE et al. A pilot study of the
SPRINT protocol for tight glycemic control in
critically ill patients. Diabetes Technol Ther 2006 Aug;8(4)449-62
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50501
67. Chase JG, Shaw G, Le Compte
A, Lonergan T, Willacy M, Wong XW. Implementation and
evaluation of the SPRINT protocol for tight glycemic
control in critically ill patients: a clinical practice change. Crit Care 2008;12(2):R49
68. Bernard GR, Vincent JL, Laterre
PF, LaRosa S, Dhainaut JF,
Lopez-Rodriguez A, et al. for the PROWESS study group. Efficacy
and Safety of Recombinant Human Activated Protein C for Severe Sepsis. N
Engl J Med 2001;344:699-709
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50504
69. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL et al. for the ADDRESS study group. Drotrecogin Alfa (Activated) for Adults with Severe Sepsis
and a low Risk of Death. N Engl J Med 2005;353:1332-41
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50505
70. Friedrich JO, Adhikari NKJ,
O Meade M. Drotrecogin alfa
(activated): does current evidence support treatment for any patients with
severe sepsis? Critical Care 2006, 10:145
71. Agarwal R, Nath A. Activated protein C in sepsis: down but not out,
yet. Critical Care 2006, 10:416
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50506
72. Nadel S, Goldstein B,
Williams MD, Dalton H, Peters M, Macias WL et al. for the RESOLVE study group. Drotrecogin alfa (activated) in
children with severe sepsis: a multicentre phase III
randomized controlled trial. The Lancet 2007; 369:836-843
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50507
73. Marti-Carvajal A, Salanti G, Cardona AF. Human recombinant activated protein
C for severe sepsis. Cochrane Database of Systematic Reviews.
1, 2008.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50509
74. Turgeon AF, Hutton B,
Fergusson DA, McIntyre L, Tinmouth AA, Cameron DW et
al. Meta-analysis: Intravenous Immunoglobulin in Critically Ill Adult Patients
with Sepsis. Ann Intern Med. 2007;146:193-203
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50510
75. Alejandria MM, Lansang MA, Dans LF, Mantaring JBV. Intravenous immunoglobulin
for treating sepsis and septic shock. Cochrane
Database of Systematic Reviews. 1, 2008.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50511
76. Marshall JC, Maier RV, Jiminez
M, Dellinger EP. Source control in the management of severe sepsis and septic
shock: An evidence based review. Crit Care Med 2004;
32[Suppl.]:S513-S526]
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50512
77. Robledo FA, Luque-de-Leon E, Suarez R, Sanchez P, de-la-Fuente M, Vargas A et al. Open versus closed management of
the abdomen in the surgical treatment of severe secondary peritonitis: a
randomized clinical trial. Surg Infect (larchmt). 2007 Feb;8(1):63-72
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50513
78. van Ruler O, Mahler CW, Boer KR, Reuland EA, Gooszen HG,
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50514
79. Slade E, Tamber PS,
Vincent JL. The Surviving Sepsis Campaign: raising awareness to reduce
mortality. Critical Care 2003, 7:1-2 http://ccforum.com/content/7/1/1
80. Levy MM, Marshall JC, Abraham E, Angus D, Cook D,
Cohen J, Opal SM, Vincent JL, Ramsay G. 2001 SCCM/ESICM/ACCP/ATS/SIS
International Sepsis Definitions Conference. Intensive Care Med (2003),
29:530-538
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/50515
81. Kumar A, Haery C, Paladugu B, Kumar A, Symeonides
S, Taiberg L et al. The duration of hypotension
before the initiation of antibiotic treatment is a critical determinant of
survival in a murine model of Escheria
coli septic shock: association with serum lactate and inflammatory cytokine
levels. J Infect Dis. 2006 Jan 15:193(2):251-8.
http://simplelink.library.utoronto.ca.myaccess.library.utoronto.ca/url.cfm/51080
82. Van den Berghe GH. Role of intravenous insulin therapy in critcally ill patients. Endocr Pract. 2004 Mar-Apr: 10 Suppl 2:17-20
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