Advances in the management of hemorrhagic and septic shock

1. INTRODUCTION 1.1 Definition of shock 2. HEMORRHAGIC SHOCK 2.1 Case presentation 2.2 Epidemiology 2.3 Assessment 2.31 Physical exam 2.32 Laboratory 2.4 Initial management 2.41 ABCs 2.42 Initial measures to stop bleeding 2.43 Initial fluid therapy

2.44 Warming- Effects of hypothermia on mortality

2.5 Reassessment: Response to initial fluids

2.6 Blood transfusion and other products 2.61 Decision to transfuse 2.62 Blood products 2.63 Auto-transfusion 2.64 Blood substitutes

2.7 Definitive management: timing of surgery and damage control

2.8 Specific situations 2.81 Major obstetric bleeding 2.82 Post-operative bleeding 2.9 Complications of resuscitation 2.91 Renal failure 2.10 Summary3. SEPTIC SHOCK 3.1 Case presentation

3.2 Epidemiology 3.3 Pathophysiology 3.4 Assessment & initial management 3.41 Fluid therapy 3.42 Antimicrobial therapy 3.43 Vasopressors 3.5 Additional therapies 3.51 Steroids 3.52 Glucose control

3.53 Drotrecogin alfa and recombinant human activated Protein C (rhAPC)

3.54 Intravenous immunoglobulin (IVIG)

3.55 DVT prophylaxis 3.56 Stress ulcer prophylaxis 3.57 Mechanical ventilation 3.58 Renal replacement therapy

3.6 Definitive management of surgical sepsis

3.7 Summary4. RECOMMENDATIONS

4.1 Recommendations for management of hemorrhagic shock

4.2 Recommendations for management of severe sepsis and septic shock

5. REFERENCES

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 asbeing due to placenta previa. The specialist obstetrician said that the hemorrhanot 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 bland 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 whichshe did not seek treatment. A sociologist observed that she was 39 years old, with sevenprevious pregnancies and 5 living children. She had never used contraceptives, and her la

ge might

ood,

st pregnancy was unwanted. She was also poor, illiterate, and lived in a rural area.” 1

are

re ntries, and hemorrhage is the leading cause of maternal mortality in

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 whodie yearly of traumatic injury . Persons with life-threatening but salvageable injuriessix 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 ain developing couthese 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 deathin trauma and obstetrics are due to bleeding withinth

s the first several hours, underscoring

e need for timely assessment and intervention.

to

l g

2.3 Assessment The essential first step in the treatment of hemorrhagic shock, regardless of its cause, isrecognize 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 personnerequired for such monitoring be considered ‘essential’ at all hospitals in developincountries.2 Other forms of monitoring such as continuous ECG or cenp

tral venous ressure monitoring have been deemed ‘desirable’ but not essential.

e

,

hanges include tachycardia, tachypnea, hypothermia and in due

2.31 Physical exam: Class I-IV Shock The presence of shock implies a lack of tissue perfusion. Accordingly, the physical examsigns associated with hemorrhage are an indication of the body’s attempt to compensatfor inadequate perfusion. Such signs include cool clammy skin, altered mental statusprolonged capillary refill and decreased urinary output. Vital signs may initially be normal, but eventual ccourse, 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 thhypotension 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 presein

at

ntation trauma patients with hemorrhagic shock portends more than 50% mortality.10

s, or

x

ion leeding or hematoma and consideration of intra-thoracic or

intra-peritoneal losses.

Table 1

morrhage

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 obviouinternal and hidden in the thoracic or peritoneal cavities, retroperitoneum, pelvis or femurs. Localization of significant internal bleeding requires early chest and pelvicrays, 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 examinatof the operative site for b

Classes of he Class I Class II Class III Class IV Blood loss (ml) Up to 750 750-1500 1500-2000 >2000 Blood loss (% blood Up to 15% 15% - 30% 30% - 40% > 40% volume) Pulse rate <100 >100 >120 >140 Blood pressure Normal Decreased Decreased Normal

Pulse pressure ed Decreased Decreased Decreased Normal or increas

Respiratory Rate 14-20 20-30 30-40 >35 Urine output (ml/hr) >30 20-30 15-May Negligible

CNS/Mental status Slightly anxious anxious Mildly Anxious,

confused Confused,lethargic

Fluid replacement (3:1 rule) Crystalloid Crystalloid loid and

blood loid and

blood Crystal Crystal

*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 mLof 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 loss and require fluids in excess of the 3:1 guidelines. In contrast, a patient whose

blood

ongoing blood loss is being replaced by blood transfusion requires less than 3:1. The uof bolus thextremes. *For a 70-kg man. *From American College of Surgeons Committee on Trauma. Advanced trauma life su

se erapy with careful monitoring of the patient’s response can moderate these

pport for doctors. 7th edition. Chicago (IL): American College of Surgeons; 2004

help

cause etabolism with the

sultant products of lactic acid and other acidic by-products.

lood

ore emodilution from mobilized extravascular fluid or resuscitation fluid has occurred.

,

verall goal of management is to stop the bleeding and replace the lost olume.11

2.32 Laboratory Certain laboratory tests help confirm the diagnosis of hemorrhagic shock and mayguide resuscitation. Where facilities exist, an arterial blood gas may demonstrate metabolic acidosis, an increased base deficit and an elevated lactate level. This is beinadequate tissue perfusion causes cells to undergo anaerobic mre Hemoglobin and hematocrit measurement (deemed essential at all hospitals), while not useful in the diagnosis of shock, are important adjuncts in identifying significant bloss and potential need for blood transfusion and surgical intervention. However, hemoglobin and hematocrit levels may remain normal in early acute hemorrhage, befh 2.4 Initial management The diagnosis and initial treatment of hemorrhagic shock should occur almost simultaneously. Establishing an airway, oxygen supplementation, obtaining IV accesstaking steps to stop bleeding and providing initial volume challenge must take place concurrently. The ov ,12,13

th

e s an

iate blood mples are drawn. A Foley catheter is placed to monitor urine output.

r slow

ressure. The only resources required for this are training and sufficient gauze bandages.

ed

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 wiadequate 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 thskill and experience level of the treating physician. In children younger than 6 yearintraosseous needle may be attempted. As IV lines are inserted, approprsa 2.42 Initial measures to stop bleeding In the assessment area the treating team can take effective initial measures to stop ohemorrhage. 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 p Other methods of reducing hemorrhage in trauma patients include splinting for fractur

extremities, wrapping for pelvic fractures, and deep interfascial packing or judiciouapplication of tourniquets for complicated wounds, such as landmine and machete wounds.

s

14 Immediate methods for postpartum obstetric bleeding may incu

lude bimanual terine compression, administration of oxytocin and uterine evacuation.

or

e. The usual initial dose is 1-2 liters for an

dult and 20mL/kg for a pediatric patient.9

2.43 Initial fluids According to ATLS guidelines, warmed isotonic crystalloid solutions (Ringer’s lactatenormal 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 onthe patient’s response to initial fluid challenga

ume of initial fluid resuscitation, as well as the type of fluid

sed for resuscitation.15

Despite these guidelines, considerable debate has taken place in recent years around theappropriate timing and volu

th

)

ssociated with lower patient mortality.16

(i) Crystalloid: early vs. delayed; larger vs. smaller volume Some surgeons are concerned that attempts to increase blood pressure in patients wiuncontrolled sources of hemorrhage may be counterproductive and associated with increased bleeding and higher mortality. These concerns led to a prospective, randomizedclinical study comparing delayed fluid resuscitation (upon arrival to the operating roomversus standard fluid resuscitation (in the field by paramedics) in hypotensive patients with penetrating torso trauma. The authors reported that delayed fluid resuscitation was a

st the use of ume fluid administration in the treatment of uncontrolled

emorrhage.”17

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 againearly or larger volh

al mentation and a palpable radial

mpts

uch circumstances, patients

re much more likely to die of too little fluid than too much.

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 exsanguinationand cardiac arrest prior to surgical control of bleeding. Prior to hemorrhage control, it is reasonable to titrate fluid resuscitation to achieve normpulse, 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 atteare made to achieve hemostasis. In regions where access to definitive care may be delayed, many patients with hemorrhagic conditions are already likely to have establishedshock and to fit into the ‘delayed resuscitation’ category. In sa (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 ievidence that they are more clinically effective.

s no 18 ,19 Authorities such as the WHO

therefore recommend that, where supply of infuso

sion fluids is limited, isotonic crystalloid lutions should be preferentially available.20

nd

(iii) Hypertonic solutions Hypertonic solutions (usually 7.5% hypertonic saline (HS)) have also been studied ahave 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 cabe prepared locally and some suggest they may reduce costs associated with larger volume isotonic infusions in lower resource settings.

n also

23 Although early clinical trials hashown some promise, widespread use of HS in the management ow

ve f hemorrhagic shock

ill 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, ma 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 wBlood should not be placed in hot water as this may lead to hemolysis and release of potassium.

onitoring nd normalization of body temperature is a priority in shock resuscitation.

ater.

20 Passive external rewarming of the patient using warmis

blankets or garments 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 anddiagnostic in that it triages bleeding p

atients into three categories. This is illustrated by

the WHO guidelines, 20 in Figure 1.

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 North America and the WHO agree that transfusion should be provided to patients with hemorrhage if hemodynamic instability persists after approximately 2 L of crystalloid infusion.9,20 Hypoperfusion (e.g. anuria) in the absence of hypotension should also be considered a possible indication for transfusion. No absolute laboratory threshold for transfusion exists, but patients with hemoglobin levels less than 70g/dL whose bleeding has stopped or 100mg/dL in patients with ongoing bleeding should be considered for transfusion.27,28

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 Africa, such a therapy will only be useful if it is shown to be effective, affordable and widely available. 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 Africa far outweighs that of general surgery and therefore surgeons working in settings where obstetric coverage is lacking should be well versed in the management of obstetric hemorrhage. Obstetric bleeding may be unpredictable and massive. Because of the physiologic changes of pregnancy the pregnant woman may demonstrate few signs of hypovolemia until cardiovascular collapse occurs. For those women who do make it to a hospital with surgical capacity, an aggressive response to obstetric hemorrhage will reduce needless maternal deaths. 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.

Table 2

Systemic Inflammatory Response Syndrome (SIRS): 2 or more of - Temperature >38 C or <36 C

- Heart rate >90 in the absence of rate lowering medications or cardiac pacing

- Respiratory rate > 20 (or PaCO2 <32, or mechanically ventilated)

- 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 dysfunctionOrgan hypoperfusion: examples - decreased urine output (<0.5cc/kg/hr) - decreased peripheral circulation: abnormal capillary refill - altered or decreased level of consciousness Organ dysfunction: examples -Coagulopathy -Respiratory Failure -Acute Renal Failure -Acute Hepatic Failure ("Shock Liver") Septic Shock Sepsis plus:

Refractory Hypotension: -systolic blood pressure < 90 mm Hg -unresponsive to fluid bolus of >20cc/kg

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 Africa, as many patients will never have access to hospitalized medical care, let alone ICU admission. Thus, it is difficult to accurately estimate the incidence, outcome, and cost of sepsis and septic shock in underserviced African nations. In the United States, Angus and colleagues estimate that there are 751,000 cases of severe sepsis per year, for a rate of 3.0 per 1,000 persons, or 2.26 per 100 hospital discharges.45 Of these, 51.1% (383,000) are admitted to ICU, and 130,000 more require ventilation in an intermediate care unit or coronary care unit. The mortality is significant, with 215,000 (28.6%) patients dying each year as a result of severe sepsis. This is equivalent to the number of deaths from acute myocardial infarction. Severe sepsis is also extremely costly, with an average cost of $22,000 (U.S.) per patient, making for a U.S. annual cost of $16.7 billion. Worldwide, it is estimated that sepsis affects 18 million people each year. Severe sepsis is a disease process with an increasing incidence, a high mortality, and a large financial cost. Given the comparative lack of per capita ICU resources in underserviced African nations, the mortality rate of severe sepsis in Africa is likely significantly higher than that seen in the U.S.

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 American College of Surgery’s Advanced Trauma Life Support, the goal is to identify immediately life-threatening situations and then appropriately intervene, allowing for rapid resuscitation of the patient. Rivers and colleagues demonstrated decreased mortality with early resuscitation and hemodynamic optimization of patients with severe sepsis and septic shock.48 In response to the mortality benefit seen with early resuscitation, the Surviving Sepsis Campaign similarly structures its recommendations around the concept of early identification and resuscitation of patients with severe sepsis and septic shock.49 These guidelines for the assessment and resuscitation of patients with severe sepsis and septic shock may not be applicable in all locales due to the availability of laboratory facilities, invasive monitoring equipment, and intensive care units. However, this should not prevent physicians from implementing those elements of the

guidelines that are practicable in their centre. 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 Africa, the prevalence of functional adrenal insufficiency is almost 20% in critically ill patients with stage IV HIV, and is positively predicted by Rifampicin use and eosinophilia.59 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. A CT scan of the abdomen is highly sensitive in determining an intraabdominal source of sepsis, but is unfortunately unavailable in many centres. In the setting of possible intra-abdominal sepsis, in which suitable imaging is unavailable or indeterminate, consideration should be given to surgical exploration, whether via laparoscopy or exploratory laparotomy 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 Bogota bag style closure, allowing for relaparotomy and irrigation and debridement. 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, University of British Columbia

Corresponding author: SM Hameed, Trauma Services VGH, 855 W 12th Avenue Vancouver, BC, Canada V5Z 1M9 morad.hameed@vch.ca

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