Sepsis and Septic Shock

In 2017, the WHO recognized the prevention and management of sepsis as a global health priority. It has recently been defined as a life-threatening organ dysfunction resulting from infection. Despite the best efforts in protocol-based care, mortality from septic shock remains high, almost 35% to 40%.

> Sepsis 1. Criteria for Systemic Inflammatory Response Syndrome

The term “sepsis” has been used widely for decades; However, it has been associated with multiple definitions, and the term has been loosely applied to many syndromes. In an effort to improve the ability to study sepsis, a panel of experts meeting in 1992 formalized the definition of the term. At that time, “sepsis” was defined as an inflammatory response to infection. Clinical diagnosis required compliance with ≥2 criteria for Systemic Inflammatory Response Syndrome (SIRS) along with a suspected or confirmed focus of infection. At that time, septic shock was defined as persistent hypotension or hyperlactatemia despite fluid resuscitation.

> Sepsis 2.0 and “severe sepsis”

Many criticisms arose regarding the definitions of Sepsis-1, most notably that the SIRS criteria simply reflected an adequate response to the infection. This is how a new term emerged, “severe sepsis” , which implies organic dysfunction secondary to the state of sepsis. In 2001, a second group of experts updated the Sepsis-1 definitions, which remained virtually unchanged except for the introduction of sequential organ failure assessment criteria to identify organ dysfunction, which was indicative of sepsis. serious.

> Sepsis 3.0. 2016 update.

The initial definition specified in the Sepsis-1 criteria was widely used for almost 2 decades; but was hampered by low sensitivity and specificity. An important criticism is that the physiology implicit in the SIRS criteria (tachycardia, fever, leukocytosis and hypotension) focuses on the inflammatory response , which is common to many critical diseases (trauma, pancreatitis, postsurgical inflammation).

As an example, more than 90% of patients admitted to an intensive care unit (ICU) met the criteria for sepsis. Another criticism is that the SIRS criteria failed to identify 13% of patients with similar profiles of infection, organ failure, and substantially increased mortality. Because the inflammatory response is an expected and useful response in many cases of infection, a challenge for a new definition of sepsis was to differentiate the life-threatening dysregulated response from the normal inflammatory process in response to uncomplicated infection.

Clinically, this was characterized by an acute change of ≥2 points in the SOFA Score , in the presence of suspected infection. The initial score is assumed to be 0 in patients in whom the presence of preexisting organ dysfunction is unknown. The SOFA score had good predictive validity for ICU mortality. For patients with suspected infection, the area under the receiver operating characteristic (ROC curve) (AUROC) is 0.74. This number is higher than the SIRS criterion, which has an AUROC of 0.66. According to this new definition, the term “severe sepsis” is redundant. Consequently, this term was removed from the updated definition.

Septic shock is identified clinically as persistent hypotension requiring vasopressors to maintain mean arterial pressure (MAP) above 65 mm Hg and elevated serum lactate, >18.0 mg/dL, despite adequate fluid resuscitation.

> Total screening for rapid sequential evaluation of organ failure

Although change in SOFA score is a strong tool for mortality stratification, it is difficult to calculate and requires laboratory values ​​that are not readily available for rapid screening of patients outside the ICU. For example, a serum lactate level that is routinely analyzed from a blood gas sample in the ICU may be difficult to do in a ward and serial patient.

In search of easy identification, the group of experts designed accessible screening measures and arrived at 3 criteria, called qSOFA ( Quick Sequential Organ Failure Assessment ). For non-ICU patients who had ≥2 of the following criteria: Glasgow score <13, systolic blood pressure <100, or respiratory rate 22, mortality was similar to that of patients identified using the full SOFA score.

> Performance for rapid vs sequential organ failure assessment screening evaluation of sequential vs. organ failure SIRS

Subsequent studies have highlighted the need for careful use of the tools for different patient populations. As a screening tool for emergency department patients, many studies have demonstrated poorer performance of qSOFA compared to SIRS for the identification of sepsis. As a prognostic risk stratification tool for ICU patients, the SOFA score best predicted mortality. A systematic review found similar results and the SIRS criteria had better sensitivity but worse specificity for the detection of sepsis among emergency, ICU, and hospital ward patients.

In the US there are currently approximately 1.7 million cases of sepsis annually, with an increasing trend each year.

There are almost 250,000 deaths per year due to sepsis, and it is the leading cause of death in non-cardiac ICUs.

Of septic patients admitted to ICUs worldwide, the most common sources of infection are the lungs (64%), abdomen (20%), bloodstream (15%), and urinary tract (14%).

Of the isolated organisms , 62% were gram-negative bacteria ; 47% gram-positive bacteria and 19% fungi . The most common gram-positive organism is Staphylococcus aureus (20%), and the most common gram-negative isolates are Pseudomonas (20%) and Escherichia coli (16%).

Many factors are associated with increased risk of mortality in patients with sepsis and septic shock: emergency surgery, trauma, transfer from the hospital floor, presence of chronic obstructive pulmonary disease, cancer, heart failure, immunosuppression, cirrhosis, previous mechanical ventilation or hemodialysis .

The pathophysiology underlying the septic state is complex. It is unclear why some patients have a productive immune response to fight infection while others deteriorate and reach a dysregulated state. The role of several cellular mediators has been investigated, especially tumor necrosis factor-α and interleukin-1, which can reproduce the symptoms of sepsis when administered exogenously.

It was previously thought that sepsis was the result of a “cytokine storm” of these mediators, but it has been shown that the release of pro-inflammatory mediators is also accompanied by anti-inflammatory mediators . It is also known that exogenous administration of lipopolysaccharide causes endothelial damage and detachment of the endothelial glycocalyx. This mechanism leads to the hyperpermeability and edema formation observed in sepsis.

Lipopolysaccharides also cause the release of nitric oxide from damaged endothelial cells, leading to pathological arterial dilation and hypoperfusion. In contrast, exogenous inhibitors of inducible nitric oxide synthase appear to reverse pathological vasodilation in animal models.

The signs and symptoms that appear in sepsis usually involve multiple organ systems.

The profound release of several inflammatory mediators during sepsis leads to systemic multiorgan failure. Therefore, sepsis should be managed as a systemic disorder .

> Cardiovascular

Pathological arterial dilation and venous dilation lead to hypotension, which can be profound. On the other hand, myocardial depression is observed in up to 60% of septic patients. The exact mechanism of this septic cardiomyopathy is unclear. Slightly elevated serum troponin levels are frequently observed and may be linked to the severity of sepsis.

> Pulmonary

Cytokine-mediated lung injury results in increased permeability of the endothelium of alveolar and capillary vessels, causing non-cardiogenic pulmonary edema, which impairs oxygenation and ventilation. The development of hypoxia and metabolic acidosis results in significant tachypnea. The incidence of acute respiratory distress syndrome (ARDS) in patients with sepsis is 7%. Careful monitoring of respiratory parameters is very important to identify patients who require mechanical ventilation due to respiratory muscle fatigue.

> Kidney

Sepsis-related acute kidney injury (AKI) contributes significantly to the morbidity and mortality of sepsis. Risk factors for developing AKI are advanced age, chronic kidney disease, and cardiovascular disease. The pathophysiology is multifactorial, including hemodynamic changes, endothelial dysfunction, renal parenchymal inflammation, and obstruction of the tubules with necrotic cells and debris.

Prompt volume resuscitation to prevent hypotension and avoidance of nephrotoxic agents, such as intravenous contrast substances, may help mitigate the risk of developing AKI. Once AKI develops, proper dosage of medications, avoidance of volume overload through the use of diuretics, and careful management of electrolytes are necessary and important. In patients requiring renal replacement therapy, early initiation of this therapy appears to be beneficial.

> Hematological

The primary hematologic manifestations are anemia, leukocytosis, neutropenia, thrombocytopenia, and disseminated intravascular coagulation (DIC). Inhibition of thrombopoiesis and immune platelet damage are responsible for the thrombocytopenia observed in the absence of DIC. Anemia is secondary to inflammation, there is shortening of blood cell survival and hemolysis in the context of DIC.

DIC is diagnosed by thrombocytopenia and prolongation of the prothrombin time or activated partial thromboplastin time. DIC in sepsis may present as bleeding from multiple sites or thrombosis of small and medium-sized blood vessels. In the absence of bleeding, coagulopathy can be controlled along with treatment of the underlying disorder. Platelet and clotting factor replacement should be considered in patients with bleeding from multiple sites.

> Gastrointestinal

Liver failure is a rare but significant complication of septic shock, occurring in less than 2% of septic patients, with a marked impact on morbidity and mortality. Septic liver dysfunction is diagnosed by an increase in bilirubin concentration, >2 mg/dl, and coagulopathy with an international normalized ratio (INR) >1.5. Pathophysiologically, it is attributed to hemodynamic, cellular, molecular factors and immunological changes that lead to parenchymal hypoxia.

Clinical manifestations include hypoxic hepatitis, sepsis-induced cholestasis, coagulopathies, and hyperammonemia, causing hepatic encephalopathy.

> Endocrine

Hyperglycemia is common in septic patients and is attributed to stress-induced elevation of glucagon, catecholamines, cortisol, and insulin, combined with growth hormone resistance-induced cytokine release.

In septic shock, glucose should be monitored frequently to maintain blood glucose <180 mg/dl while avoiding overly aggressive control and associated hypoglycemic episodes.

In addition to metabolic dysregulation, 8-9% of patients with severe sepsis have signs of adrenal insufficiency, which may further contribute to catecholamine insensitivity.

Septic patients also have vasopressin deficiency due to depletion of stores, increased vasopressinase activity, and inhibition of nitric oxide-mediated vasopressin production. The hypothalamic-pituitary-thyroid axis may also be affected during sepsis, leading to apparent clinical hypothyroidism. However, there is no evidence in favor of treating septic hypothyroidism.

> Neurological

Septic encephalopathy is a common manifestation of severe sepsis and septic shock. Symptoms may include mental status changes, altered sleep/wake cycle, disorientation, agitation, and hallucinations. Altered mental status may be the only presenting sign in geriatric patients. Focal deficits are not typical of septic encephalopathy and should be evaluated with neuroimaging and stroke studies.

Seizure is a rare complication of septic encephalopathy and can be diagnosed by electroencephalographic monitoring. In the event of significant alterations in mental status, some patients may require endotracheal intubation to protect the airway. Other reversible causes of encephalopathy—hypoxemia, hypercapnia, hypoglycemia, hyponatremia or hypernatremia, drug toxicity, hyperammonemia, and thyroid insufficiency—must be promptly evaluated and ruled out.

> Era of early goal-directed therapy

In 2001, a landmark trial was published that demonstrated a mortality benefit from "the first goal-directed therapy (GDT) ," which used an algorithm of fluid resuscitation, blood transfusion, vasopressors, and inotropes, directed by specific hemodynamic goals. MAP, central venous pressure, and mixed venous oxygen saturation. This trial ushered in an era of sepsis care in which pulmonary artery catheters were routinely placed in the majority of septic patients to monitor these parameters. .

More recent trials have failed to replicate the results of PTDO, and the practice of algorithmic resuscitation has largely fallen into disuse. However, many of the principles of fluid resuscitation and hemodynamic goals remain in place, reflected in the Surviving Sepsis Campin guidelines.

> Detection and diagnosis

If the suspicion of sepsis is high based on screening criteria (qSOFA or SIRS) and clinical presentation, initial management should not be delayed while awaiting the results of diagnostic studies.

Blood cultures should be drawn promptly and specimens collected for urine cultures if a urinary tract infection is suspected. Imaging usually includes a chest x-ray to rule out the development of pneumonia. Additional imaging, such as abdominal CT, may be required if an intra-abdominal process is suspected (eg, diverticulitis, abscess). Procalcitonin levels can be measured early, not to be used as a diagnostic criterion but to later guide the discontinuation of antibiotics for certain infections.

> Antibiotics and focus control

Observational studies have suggested that early initiation of antibiotic therapy may achieve better outcomes, and this idea has been incorporated into the Surviving Sepsis Guide for sepsis, aiming to initiate antibiotics within the first hour of presentation. There is concern that these data are not robust and that this guidance will lead to widespread inappropriate use of antibiotics.

When there is a strong suspicion of sepsis, cultures should be obtained and broad-spectrum antibiotic therapy initiated to empirically cover a range of likely pathogens, depending on the patient’s comorbidities and presentation.

In most patients, antibiotics should target both gram-positive and gram-negative bacteria.

In those with an intra-abdominal process , anaerobic organisms must also be covered. In patients with immunodeficiencies or immunosuppression , antifungals and/or antiviral therapies may be indicated. Antimicrobial therapy should be based on culture results. Serial measurements of procalcitonin have been shown to successfully guide cessation of antibiotic therapy to reduce cumulative exposure.

If possible, the source of the infection must be addressed. The patient should be examined for a localized focus (e.g., infected pressure ulcer or erythematous vascular catheter site. Management may include removal of invasive devices (e.g., dialysis catheters, infected orthotic devices, or pacemakers). ) or surgical evacuation of intra-abdominal abscesses.

> Fluid resuscitation

Observational studies have shown that reducing the duration of hypotension in septic patients is associated with decreased mortality in septic shock.

The premise of fluid resuscitation is to increase cardiac output and MAP to combat pathological vasodilation. The Surviving Sepsis Campaign recommends an initial fluid bolus of 30 ml/kg. For most patients, this amount is probably adequate. However, there were concerns that this volume may be excessive for many patients.

Observational studies have shown that the administration of an excessive volume is associated with increased mortality, which could be due to the associated pulmonary edema, with the requirement for prolonged mechanical ventilation and worsening of kidney injury. In an effort to avoid excessive resuscitation, several measures have been used to predict volume response, defined as the increase in a patient’s cardiac output with additional fluid.

Echocardiography and bedside ultrasound have emerged as the most reliable tools, with an increase in carbon monoxide before and after a 100-250 ml “minibolus” serving as a reliable indicator.

Variation in the diameter of the inferior vena cava during inspiration is an accurate predictor of volume response in mechanically ventilated patients, although there is conflicting evidence in spontaneously breathing patients. Similarly, in mechanically ventilated patients under specific conditions, pulse pressure variation (PPV) can be used in arterial line tracing. For those in sinus rhythm and mechanically ventilated with tidal volumes >8 mL/kg (ideal body weight), a PPV of 12% is predictive of fluid responsiveness.

> Target blood pressure

Retrospective data have suggested an association between MAP <85 and progressively increased risk of mortality and kidney damage. The only large randomized trial of 2 blood pressure targets in patients with septic shock attempted to compare the effect of a lower target MAP (65–70) compared with a higher target (80–85) and found no benefit on mortality of one vs. the other. However, a prespecified post hoc analysis of the same trial demonstrated a significant increase in kidney injury in those with pre-existing chronic hypertension and maintenance at the lower target MAP.

On the other hand, there were more cardiac arrhythmias in the higher MAP group, largely due to the likely use of high-dose catecholamines in that arm of the clinical trial. Therefore, it may be prudent to maintain a relatively higher target MAP in patients with septic shock, although retrospective observations are limiting and a specific threshold that fits all patients cannot be recommended.

Furthermore, randomized trials addressing this issue are urgently needed. Of note, guidelines for sepsis survivors recommend a target MAP of at least 65 mm Hg to titrate vasopressor support.

> Choice of vasopressor

In septic shock, vasopressors should be used to maintain blood pressure during and after fluid resuscitation.

Historically, it was recommended that vasopressors be used as the initial agent of choice for blood pressure management in septic shock. However, randomized trials comparing dopamine with norepinephrine as an initial agent showed a higher incidence of tachyarrhythmia and higher mortality with dopamine compared to norepinephrine. Therefore, the Surviving Sepsis Campaign has recommended the use of norepinephrine as a first-line agent.

Epinephrine was compared with norepinephrine as the initial agent and did not reveal a difference in mortality; however, epinephrine was associated with greater tachycardia and lactic acidosis. Specifically, in a septic patient with hypotension and signs of cardiomyopathy and right heart dysfunction, epinephrine can be added for inotropic benefit and, if cardiac output is insufficient, to maintain perfusion.

Vasopressin is a non - catecholamine molecule that acts directly on V1 and V2 receptors. It was also compared with norepinephrine and did not show a benefit in overall mortality; However, the subgroup of patients with “less severe” septic shock showed slightly lower mortality.

In addition to the catecholamine and vasopressin pathways, modulation of the renin -angiotensin-aldosterone pathway has been demonstrated as a means to synergistically increase blood pressure and reduce catecholamine requirements. Exogenous angiotensin II has been shown to increase MAP and decrease catecholamine requirements in patients with septic shock, with high doses of vasopressors, and demonstrated a good safety profile.

Taking into account the current data available, norepinephrine remains the first-line agent for initial blood pressure control in septic shock .

However, high-dose vasopressors, especially catecholamines at norepinephrine equivalents of ≥0.8 mg/kg/min, have been associated with 50% mortality at 30 days and almost 80% at 90 days. Therefore, there is a much-needed push for early use of multimodal catecholamine-sparing supplements along with vasopressors (both vasopressin and angiotensin II) in this regard.

> Complementary therapies: steroids, vitamin C and thiamine

Several complementary therapies have been investigated to combat the body’s dysregulated response to sepsis. Systemic steroids have been evaluated in several randomized trials; but the results of these trials have not been consistently beneficial in mortality. More recently, the ADRENAL trial evaluated the effect of continuous infusion of hydrocortisone in patients with septic shock and found no benefit compared with placebo.

The APROCCHSS trial showed little mortality benefit from bolus hydrocortisone every 6 hours combined with daily oral fludrocortisone.

Ascorbic acid ( vitamin C) has attracted attention as an antioxidant that may improve the dysregulated response to sepsis. A small retrospective before-and-after study evaluated the effect of a cocktail of ascorbic acid with thiamine and hydrocortisone and found promising results.

A prospective randomized trial demonstrated decreased vasopressor requirements and mortality in patients receiving boluses of ascorbic acid. The CITRIS-ALI trial investigated the role of ascorbic acid on organ dysfunction scores in patients with sepsis and ARDS and did not show a significant difference.