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Over the last couple of years septic shock has had an increase in incidence and ranges from 1.06 episodes per 1000 patient days up to 260 episodes per 1000 patient days.2 This has led to many enquires in the treatment and recognition of sepsis and specifically septic shock, leading to a consensus conference in 1990.5
In 1914, Schottmueller stated that "Septicemia is a state of microbial invasion from a portal of entry into the blood stream which causes signs of illness."2 In the last few decades many advances and changes has been made towards the treatment and definition of septic shock. To understand the numerous treatments one must know the disease process and classification for sepsis.
The term sepsis was derived from the Greek meaning of rotten flesh and putrefaction. It was only in the 1800s that the link between bacteria and infection was realized by the founders of modern microbiology and medicine.1,2,5 The term sepsis syndrome was found by Roger Bone in 1989 and stated that it was hypothermia ( < 35.5 °C) or hyperthermia ( > 38.3 °C), tachycardia (> 100 b/min), tachypnea (> 20 b/min), clinical evidence of an infection site, and at least one end-organ demonstrating inadequate perfusion or dysfunction. This term however is out of date and is now replaced be the term severe sepsis.5
In 1991 during a consensus conference by the American College of Chest Physicians and the Society of Critical Care Medicine, a framework was established to improve the early diagnosis of sepsis and thus helping in earlier therapeutic intervention.5 It was recognized that a single definition for sepsis would make it difficult in identifying patients and ongoing research. This led to the terms systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis and septic shock respectfully.5
The real modern change in understanding came from Schottmueller when he explained the release of pathogenic germs into the bloodstream would cause systemic symptoms and signs and this created the understanding of the condition we call sepsis today.1,2
2.2 CATEGORIES OF SEPSIS
There has been a wide confusion and lack of common definition of sepsis, and in 2000, 1058 intensive care unit (ICU) physicians completed a survey where only 22% gave the consensus conference definition when asked.5 This emphasized the lack of a standard definition and required a thinking shift with regards to sepsis and the evolving process around it.
The body has many mechanisms to prevent the spreading of infectious agents. When these bursts of bacteria enter the circulatory system, they are generally handled quickly and effectively by the macrophages in the monocyte-macrophage system. There is then the chance of either a large amount of bacteria release into the system or that these bacteria are resistant to the defense system in place. This creates an overwhelming amount of bacteria. This pathology is called bacteremia and produces associated symptoms of malaise, prostration, and signs of fever, chills, etc. 3
There are several conditions that can increase the exposure to the bacteremia, they are potentially:3
chronic obstructive pulmonary disease (COPD) patients
chronic liver disease
chronic renal failure
trauma and burns
previous antibiotic treatment
This exposure irrelevant of the cause produces systemic effect and leads to the development of systemic inflammatory response syndrome (SIRS) and potentially sepsis. Any of these conditions with the relevant signs and symptoms of infection must create high suspicion towards SIRS or sepsis.
It must be mentioned that SIRS and sepsis is not necessarily one entity. The same systemic response seen in patients with severe infections can sometimes occur in patients without such infections which might have been causes by other inflammatory processes in place.2,5 Sepsis on the other hand is SIRS plus evidence of infection.2,5 Therefore SIRS will always be the first pathological phase of sepsis in the presence of infections.
SIRS is defined as the presence of more than one of four clinical criteria:5
Body Temperature: Greater than 38°C or less than 36°C
Tachycardia: Heart rate greater than 90 beats/min
Tachypnea: Respiratory rate greater 20 breaths/min or a PaCO2 of less than 32 mmHg with ongoing hyperventilation.
White blood cell count less than 12000/mm3, less than 4000/mm3, or with less than 10% immature neutrophils.
Many have criticized that SIRS is too sensitive and non-specific and that most ICU patients and many general ward patients meet the SIRS criteria.5 In 2001 a conference was held again to reevaluate the term SIRS and a conclusion was made that an expanding list of signs and symptoms of sepsis should be used to reflect the clinical response to infection.5 These markers used are all for inflammation rather than infection. This has some drawbacks as none of these markers are a 100% specific for sepsis and therefore diagnosis still relies on a combination of clinical symptoms and signs, including the available markers.5
2.2.2 SEVERE SEPSIS
Severe sepsis, which is the third category mentioned in different stages of sepsis, is the pathophysiological evolution of the condition. This is defined as sepsis associated with organ dysfunction, hypoperfusion abnormality, or sepsis-induced hypotension.5 If left untreated it will quickly lead to septic shock. It is often confused to septic shock, but the treatment from severe sepsis must be just as aggressive and done in a timely manner.
2.2.3 SEPTIC SHOCK
Shock is a normal compensatory mechanism used by the body to maintain systolic blood pressure and brain perfusion during periods of distress. Shock in medical terms describes the state of collapse and failure of the cardiovascular system in which blood circulation slows and eventually ceases.5 If shock isn't treated appropriately in the correct time and manner it will lead to death due to under perfusion of vital organs. To make it more specific the 2008 Surviving Sepsis Campaign states that septic shock is severe sepsis plus hypotension not reversed with fluid resuscitation.1,5 Most literature states that sepsis induced hypotension is that of a systolic blood pressure of less than 90 mm Hg or a mean arterial pressure (MAP) of less than 70 mm Hg.1
Before septic shock is treated with fluid resuscitation and vasopressors it is generally characterized by intravascular volume depletion, peripheral vasodilation, myocardial depression, and hyper metabolism. This hyper metabolism has an effect on the supply and demand of oxygen to the tissue and makes the demand too high for the possible supply, causing global tissue hypoxia.2
Therefore in short sepsis is the infection with the systemic manifestations of infection. We however will be looking at septic shock and management thereof.
3. TREATMENT AND MANAGEMENT
Treatment relies heavenly on the presence of infection (sepsis) or patients with no clinical and/or bacteriological evidence of infection (SIRS).5 Septic shock is more of a focus point in the pre-hospital setting due to the nature and seriousness of the condition. Appropriate and a timely response is vital due to the high mortality rate if left untreated or if progression worsens. Several treatments and therapies are not available for the pre-hospital setting but will be mentioned in this document.
3.1 FEVER TREATMENT
As mentioned before fever is one of the major signs of sepsis and was considered to be harmful for many years. It has been treated over time primarily with antipyretic agents. Studies in 1975 in animals have indicated that improved outcomes were achieved with fever after bacterial injection. More prolonged animal experiments have shown that the control of fever may be detrimental and the release of heat shock proteins has an important protective effect.
Other short-term studies stated that by avoiding the fever may decrease the severity of acute lung injury. To add to the controversial topic is has been shown that ibuprofen was well tolerated and actually decreases oxygen consumption, but there was no data to show that it reduced mortatlity.11,12 Some new studies indicated that external cooling did help patients in ICU, but the comment was made that the study wasn't blinded and had other flaws.
3.2 VOLUME RESUSCITATION
During sepsis the inflammatory response causes an array of different processes. These processes induce vasodilation, increase micro vascular permeability, and capillary leakage of serum proteins. Each one of these lead to reduced intravascular volume, preload, cardiac output, and inadequate tissue perfusion and oxygenation.2,7,8 Hypovolaemia in sepsis can be due to vomiting, diarrhea, sweating, edema, peritonitis or other exogenous losses. It can however also be due to maldistributive defect with vasodilation, peripheral blood pooling, and extravasation of fluid into the interstitial space and increased capillary endothelial permeability.8
The human body has several compensatory mechanisms in place. Firstly blood will be shunted away from skeletal muscle beds and the splanchnic viscera to help in supporting vital organ blood flow to the heart and brain. The use of antihypertensive medications and diuretics may alter this response and treatment should therefore be considered before it is initiated.8
With regards to the capillary pressure gradients, pre-capillary vasoconstriction will decrease micro vascular blood pressure and thus promotes the net movement of fluid from the interstitial compartment into the vascular compartment. These initial compensatory mechanisms play an important role in choosing the correct fluids for administration.8
With regards to the cardiac compensatory mechanism, the myocardial contractility increases stroke volume. This will be important to remember when the patient has a pre-existing cardiac disease as more strain is placed on the myocardium. There is a sustained release of adrenocortico-medullary hormones including cortisol, aldosterone and catecholamines. Fluid retention is also increased by the release of arginine-vasopressin (AVP) from the posterior pituitary and aldosterone from the adrenal cortex.8
At a microcirculatory level there is changes such as acidosis, pyrexia, and increased red blood cell concentration and this enhances the environment for the unloading of oxygen at tissue level.8
Volume resuscitation thus plays a vital role in the initial treatment modalities and crystalloids are the most common used fluid of choice. There however have been reports of colloids helping in reducing micro vascular permeability and capillary leakage.2 These colloids are however artificial colloids (Dextran, Hespan, Gelofusion, etc.) and can be found in the prehospital setting. The benefit versus risk does indicate that there is however an increased risk of mortality with colloid administration.2
The rate of fluid administration is that of 1000 ml over 30 min with an initial 20ml/kg bolus, but more rapid and larger volumes may be required.1
The goal for fluid resuscitation treatment is:1
Central venous pressure (CVP): 8-12 mmHg (the higher range if patient is mechanically ventilated)
Mean arterial pressure (MAP): â‰¥ 65 mmHg
Urine output â‰¥ 0.5 mL.kg-1.hr-1
Central venous (superior vena cava) or mixed venous oxygen saturation â‰¥ 70% or â‰¥ 65%, respectively (Grade 1C)
Balsol is also a good alternative due to its neutral pH, which would help in large volume administration. The first 24 hours of fluid resuscitation must be done aggressively due to input/output differences.1
3.3 INOTROPIC/VASOPRESSOR THERAPY
This line of therapy usually follows the fluid resuscitation and is done by using one or more short acting sympathomimetic including norepinephrine, dopamine, phenylephrine, dobutamine, and epinephrine.2
There has been an array of studies done on these different sympathomimetic and most indicate norepinephrine to be more superior compared with dopamine.2 Other literature mentions that either norepinephrine or dopamine is the initial vasopressors of choice.1 The physiological response that epinephrine has is that of increase in heart rate, mean arterial pressure and cardiac output.9 All of these are well known factors in the pathophysiology of sepsis. It also induces hyperglycaemia and hyperlactaemia; it however does not have an effect on splanchnic circulation in dopamine-sensitive septic shock.9
There are several reasons dopamine and epinephrine is mentioned more than the other sympathomimetic in this document. Firstly they are more widely available in the hospital and pre-hospital setting. They are broad spectrum catecholamines compared to pure ¡-adrenergic agonist. Pure ¡-adrenergic agonist can cause substantial reductions in cardiac output. On the other spectrum the pure ¢-agonist like dobutamine can cause exacerbate vasodilation and hypotension.9 If norepinephrine or dopamine cannot be use or is not available the use of epinephrine as first line alternative is recommended.1 This is the common case for pre-hospital practitioners in South Africa.
Epinephrine does have its drawbacks and due to increased lactate levels and the slight enhancement of the lactate/pyruvate ratio, it does decrease global splanchnic flow. Due to this the American College of Critical Care Medicine and the Society of Critical Care Medicine recommends the use of norepinephrine only in patients who fail to respond to the traditional therapies.9 This is why it was mentioned in the beginning that this line of therapy usually follows fluid resuscitation. In the South African pre-hospital setting this is done with a 2-10 µg/min infusion titrated to effect.10 Dopamine must also be used selectively and low-dose dopamine is not recommended for renal protection.1,2
3.4 INTENSIVE INSULIN THERAPY
This type of therapy is more related to ICU and in-hospital treatment of septic patients. Hyperglycaemia and insulin resistance is common in any critically ill patient. These two conditions increase the risk of complications like severe infections, critical illness polyneuropathy, Multi Organ Failure (MOF), and death. MOF is the leading cause of ICU deaths and doesn't require sepsis but SIRS is a necessary precursor, it involves 2 or more organ systems that are remote from the injured site to be involved. Many risk factors exist like burns, ischaemia, transfusion, renal failure, invasive devices, etc.13
In one prospective, randomized, controlled trial the normalization effect of intensive insulin therapy among critically ill patients was captured. It showed that in the intensive insulin therapy group the blood glucose levels was maintained between 4.4 to 6.1 mmol/L which compared to the conventional therapy group was 10 to 11.1 mmol/L.2
3.5 ADRENAL REPLACEMENT THERAPY
Corticosteroid usage is another controversial agent in the management of severe sepsis. It has been shown that it doesn't offer a survival advantage and in one study resulted in a higher mortality rate. In more recent studies however it has been shown that septic patients either develop a relative adrenal insufficiency or SIRS-induced glucocorticoid receptor resistance. This however is where the use of an intravenous stress dose of hydrocortisone helps to improve vasopressor activity in septic shock and is recommended when epinephrine doesn't produce wanted effect.2 It has also been shown that a high number of patients receiving corticosteroid therapy had their vasopressor therapy withdrawn within 28 days compared to a placebo group.
The surviving sepsis guidelines suggest that intravenous hydrocortisone only be given to adult septic shock patients if blood pressure doesn't respond to fluid resuscitation or vasopressor therapy.1 It also recommends that corticosteroids doses of > 300 mg daily should not be administered in severe sepsis or septic shock for the purpose of treating septic shock (Grade 1A)
3.6 MEDIATOR-DIRECTED THERAPY
There is several proinflammatory cytokines release in severe sepsis and they create many biological effects. These vary from activation of coagulation to the enhancement of the formation of thrombin and fibrin clots. It has been shown that the administration of drotrecogin alfa activated reduced coagulopathy and inflammation.2
The use of low-molecular weight heparin is also recommended in the prophylaxis of DVT. If heparin is contra-indicated other devices like compression stockings can be used.
3.7 RENAL REPLACEMENT AND BLOOD PURIFICATION THERAPIES
The renal replacement therapy is associated with intermittent haemodialysis with an adequate dose of maintenance haemodialysis. Due to the high incidence of extra renal complications which may lead to MOF and high mortality this form of treatment is the current standard.
The replacement of blood products is also a practice that is recommended. The optimum heamoglobin for patients with severe sepsis hasn't been specifically investigated, but is suggested to be of 7-9 g/dl. The transfusion of red blood cell product increases the oxygen delivery potential and usually doesn't increase the oxygen consumption. The transfusion of these products is however recommended to occur only once tissue hypoperfusion has been resolved and when other clinical conditions have been resolved such as myocardial ischemia, severe hypoxaemia, acute haemorrhage, cyanotic heart disease, or lactic acidosis. Platelet replacement is recommended when platelet counts are < 5000/mm3.1
The use of erythropoietin in severe sepsis to specifically treat anaemia is not recommended. This line of therapy can be used in specific septic patients where other acceptable pathological reasons are in place (renal failure-induced compromise of red blood cell production). The use of anti-thrombin administration is also not recommended due to no beneficial effect in 28-days.1
3.8 BICARBONATE THERAPY
The usage of sodium bicarbonate is not recommended. The theory is that it is used in hypoperfusion-induced lactic acidaemia associated with sepsis, but no evidence supports this.
3.9 ARDS IN SEPSIS
Acute Respiratory Distress Syndrome (ARDS) is found to be a common problem in the ICU setting and is associated with sepsis. These two pathological processes are closely linked in terms of pathophysiology. ARDS is commonly seen as a disease of the lung but in reality is like sepsis, a systemic condition that has an effect widespread on multiple organs and tissues.14
It is diagnosed clinically by the association of several conditions namely severe hypoxaemia, bilateral infiltrates on chest radiograph and the absence of any evidence of increased hydrostatic pressure. It is induced either by direct injuries, pneumonia to the lungs, or secondary by a distant event like sepsis from elsewhere. The location of this injury however doesn't affect the lungs reaction and it is similar in either way.
It has been found that between 40 - 60% of ARDS cases will be due to sepsis. Mortality rates are still high at 30 - 50% and are due to MOF in 80% of cases, indicating the systemic nature of the disease.14 Therefore it is a condition that can be found during sepsis and is vital to be treated accordingly as in the case of sepsis.
Most of these patients get intubated and set on a ventilator due to the nature of the pathophysiology and low threshold, but noninvasive Continues Positive Airway Pressure (CPAP) by mask can be administered.1,14 This is however only to be considered in the minority of ARDS patients with specific criteria of ARDS condition. They should be presenting with mild-moderate hypoxemic respiratory failure and have a stable haemodynamic profile and that is comfortable and easily arousable. It is also important that they can clear their own airway and protect it and recover rapidly from the precipitating insult. It has been found that low volume ventilation has much better outcomes and a 6 ml/kg predicted body weight tidal volume is recommended.1,14 The reason for the better outcome is uncertain but may be partly due to rapid reduction in inflammatory mediators' levels in pateints.14
With regards to plateau pressures on the ventilator it is said that the limit for the upper goal in a passively inflated patient should be â‰¤ 30 cm H20. Therefore high tidal volumes with high plateau pressures should be avoided in ARDS and tidal volumes should be kept at the lowest possible or steadily brought down over 1-2 hrs to the 6 ml/kg goal. No single mode of ventilation was shown to be more beneficial than the other.1 If hypercapnia (above pre-morbid baseline PaCO2) is required to keep the plateau pressures and tidal volumes as low as possible then it can be pursued, as long as it is modest.1
Positive End-Expiratory Pressure should be set to avoid extensive lung collapse. It is also suggested that PEEP should be titrated based on severity of oxygenation deficit and then guided by the FIO2 required to maintain adequate oxygenation. PEEP should be set at > than 5 cm H2O as this is the requirement to avoid lung collapse.1
The position the patient is situated can also have an effect in oxygenation. There have been several small studies and one larger study that showed improved oxygenation in patient in the prone position. This is especially true with patients with severe hypoxaemia and those exposed to high tidal volume and those that show a improvement on CO2 exchange due to proning.1 This prone positioning does have risk factor that can be life threatening like accidental endotracheal tube dislodgement and/or central venous catheter dislodgement, but can be avoided with standard operational procedure in place.1
Elevation of the bed is also recommended although this will not have such a high impact in the pre-hospital setting. The raising of the bed to 30-45 degrees is recommended due to its ability to decrease aspiration risk and ventilator-associated pneumonia.
3.10 RSI AND SEDATION
As previously mentioned, many sepsis patients due to ARDS need intubation and advance airway support. In some cases Rapid Sequence Induction (RSI) followed by intubation is required for the protection and maintenance of the airway. These patient then get placed on a ventilator and after a period of time needs some sedation to keep them in this compliant phase.
RSI is a process with multiple steps that needs to be followed and this includes the intravenous (IV) administration of a sedative and a paralytic.15 The process of RSI and intubation is well known and established and is not going to be described in this assignment but we will have a look at the medications used and which will be the best in a septic patient.
To choose the induction agent in any RSI scenario is based on the clinical assessment of the patient and evaluation of risks versus benefits. These benefits can include time of onset, predictable dose-response relationship, duration of action and the effects it would have on the cardiovascular and neurological systems. The most commonly used sedative drug used in RSI in the US and Canada is that of etomidate and was used up to 70 - 80% of emergent intubations.15
There are several factors that make this sedative ideal for the septic patients. Firstly it has a good predictable dose-response relationship with a onset of action between 5 - 15 seconds.15 It also has a rapid redistribution into inactive tissues and is not cleared by the hepatic or renal system giving it a duration of action of approximately 5 - 10 minutes.15 It does get rapidly hydrolyzed by plasma esterases and hepatic enzymes to an inactive metabolite which make is superior than midazolam which can accumulate in the elderly and in patients with renal failure.15 Etomidates neutral haemodynamic effects and its ability to maintain cardiac blood flow without increasing cardiac oxygen demand makes it ideal in the sepsis picture.15
Etomidate however does have some negatives. In 1985 a warning of adrenal suppression was added to etomidate package inserts. This adrenal suppression can last up to anywhere from 6 to 48 hours. It decreases the circulatory cortisol levels at around 30 minutes of the single dose. One large, multi-center, placebo-controlled trial of hydrocortisone use in septic shock indicated that in 499 patients, 96 (19.2%) received etomidate within 72 hours of study initiation and the mortality rates were higher in those patients (42.7% compared to non-etomidate of 30.5%).In Scotland a retrospective study indicated that etomidate had a 69% mortality rate compared to propofol- 56%, Thiopental- 46%, other- 67% and no agent- 81%.15
The Low dose of 0.1 -0.3 mg/kg should be used for RSI.15
The other alternative to etomidate is that of ketamine. Ketamine has been recommended to be considered in septic patients above etomidate.16 Although other reviews have stated that there is no preferred sedative or analgesic agent for use in the critically ill septic patient.17
Sepsis is a serious system condition that needs rapid initial treatment. These early goal directed therapies have become world standard. This is definitely true in the pre-hospital setting where these patients are found in remote site settings or clinics not capable of proper treatment. Due to its systemic effect many organ systems need to be treated at one time, making it very challenging.
The pre-hospital setting has some of its own challenges. Due to the nature of the disease process the required information is not always available making certain treatment decision difficult or impossible. Even some of the available treatments can sometimes not be the gold standard, but in the emergent setting becomes appropriate. Other more advanced treatments are left for receiving hospitals and proper monitoring. That said what is done in the pre-hospital field is vital for patient survival and makes big difference in patient stay in hospital.
There have been several new ideas and concepts and some seem to be here to stay, others have had some critique. Will certain treatment modalities be the same in 10 years' time or will we have found new data to support otherwise. This is why research in this field is vital for patient survival and outcome.