This tutorial looks at the diagnosis and management of the patient with septic shock. See below for a transcript of this major tutorial.

SEPSIS AND SEPTIC SHOCK

Introduction

Sepsis is defined as life threatening organ dysfunction due to a dysregulated host response to infection. In other words, normally, once we are infected with bacterial, fungi or viruses, our immune system activates, mops up the pathogens, clears away debris and returns to normal afterwards. That does not occur in systemic sepsis – either due to an overwhelming infection (e.g. bowel perforation) or an anomaly within the immune system: there is an initial massive release of inflammatory and cytotoxic material (sometimes called a “cytokine storm”) and then immunoparalysis, due to loss of inflammatory reserve. The patient is a “sitting duck” for further infection.

Septic Shock is defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities substantially increase mortality. There are anomalies of the cardiovascular system, neurohormonal system and autonomic nervous system. At the bedside, the clinical presentation is of acute organ dysfunction, the most common of which are hypotension, tachypnea and confusion. The most basic definition of septic shock is that it is an infected state characterized by persistent hypotension despite adequate fluid resuscitation and lactate levels ≥ 2 mmol/L. It requires the need for vasopressor therapy to maintain a mean arterial pressure (MAP) ≥ 65 mmHg.

Septic shock is a major cause of morbidity and mortality worldwide, especially in intensive care units. Understanding the pathogenesis of septic shock is critical to improving therapeutic interventions and outcomes.

PATHOGENESIS OF SEPSIS AND SEPTIC SHOCK

The pathogenesis of septic shock involves a series of immune, inflammatory, and metabolic responses. This intricate cascade is initiated by infection, typically from a bacterial pathogen, but can also be caused by fungi, viruses, or parasites. The resultant immune response goes haywire, leading to dysregulation of the inflammatory process, endothelial dysfunction, microcirculatory failure, metabolic derangements, and organ failure.

Initial Infection and Immune Response

Sepsis starts with the encroachment of a pathogen (usually bacteria) into the bloodstream or tissues. The immune system detects these pathogens via pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) present on immune cells like macrophages, dendritic cells, and neutrophils. These receptors recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which trigger an innate immune response.

Once the infection is recognized, a cascade of signaling events is initiated, leading to the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukins (IL-1, IL-6, IL-8), and interferons. This cytokine storm is crucial for recruiting immune cells to the site of infection, increasing vascular permeability, and amplifying the immune response. This happens in all situations when infection occurs and it is self limiting.

However, in septic shock, the initial immune activation becomes dysregulated. Massive release of proinflammatory mediators overwhelms the body’s control mechanisms, causing a systemic inflammatory response (SIRS) that causes intense collateral damage to tissues distant to the site of infection. There is widespread activation of  and damage to endothelial cells,  resulting in glycocalyx disruption and capillary leak, the coagulation system, resulting in microvascular coagulation, and the complement cascade, resulting in tissue damage.

Once of the major issues to understand in early sepsis is that due to dysregulation, much of the body’s inflammatory reserve and homeostatic mechanisms are used up early. Consequently, it may take some time to restore innate immunity (immunoparalysis), making the patient vulnerable to secondary infections, and neurohormonal reserve – particularly vasopressin and, later, cortisol.

Impact of Sepsis on the Endothelium and Microcirculation

Endothelial cells lining the blood vessels play a central role in maintaining vascular integrity, regulating blood flow, and controlling inflammation. In septic shock, the release of proinflammatory cytokines and mediators causes endothelial activation and dysfunction. This results in:

1. Increased vascular permeability: capillaries become leaky and protein rich fluid extravascates into the interstitium, expanding and damaging its gelatinous structure (“fracking the interstitium”). This results in reduced circulating volume, tissue edema and organ dysfunction. such as nitric oxide (NO), prostacyclin, and other vasoactive substances.
2. Vasoplegia –  Pathological vasodilatation across the arteriolar and venular network is a characteristic component of septic shock. The causes are multifactorial, but include increased production of vasodilators like nitric oxide, bradykinin, and prostacyclin. This is manifest by low blood pressure, caused by increased unstressed blood volume, reduced venous return, reduced stroke volume and reduced arterial resistance.
3. Microcirculatory dysfunction: the microcirculation is characteristically disrupted in sepsis. This is characterized by clot deposition in small vessels, platelet aggregation, disruption of the glycocalyx and endothelial swelling. Blood flow is reduced, and this leads to tissue hypoxia and organ dysfunction, particularly in the lungs, kidneys, liver, bowel and heart.
4. Coagulopathy: Septic shock is associated with coagulopathy likely due to activation of the coagulation cascades following endothelial disruption, resulting in widespread microthrombosis. The platelet count falls dramatically, and then, due to loss of coagulation reserve, bleeding results.

 Metabolic Changes in Sepsis (including Lactate)

Although I don’t cover metabolic changes in the video tutorial – it is worth looking at them to develop a holistic understanding of sepsis/multi-organ dysfunction.

1. There is insulin resistance – resulting in hyperglycemia, and subsequent relative hypoinsulinemia. Increased blood glucose provides fuel for pathogens and exacerbates immune dysfunction.
2. Mitochondrial function and oxygen utilization become dysfunctional. The impact of this on outcomes is poorly understood, but it may be part of the motor behind multi-organ failure, particularly in the kidneys.
3. Principle utilization of skeletal and visceral proteins as sources of energy, principally by gluconeogesesis. The body is unable to use fat stores as a source of energy, and “autocannibalism” results. This may be a significant component of “polymyopathy” of critical illness.
4. Aerobic Glycolysis – although the body produces approximately 1.5 mol of Lactate per day, this is usually rapidly cleared by the Liver (Cori cycle) such that plasma lactate is unmeasurable. I acute critical illness including sepsis, lactate conversion to pyruvate is reduced and lactate production increased due activation of lactate dehydrogenase by epinephrine (adrenaline). Reduced or dysfunctional hepatic blood flow results in reduced lactate metabolism. The consequence is hyperlactatemia and metabolic acidosis. The degree of acidosis strongly correlates with the severity of acute critical illness. A plasma lactate in excess of 2mmol/L is considered clinically relevant.  

Organ Dysfunction and Failure (MODS – Multi-Organ Dysfunction Syndrome)

It is imperative that clinicians quantify the degree of organ failure in acute critical illness at an early stage. A useful tool for monitoring MODS is the SOFA score.

The most easily quantified systems for identifying MODS are the respiratory system, the cardiovascular system, the central nervous system, the kidneys, coagulation and the liver.

• Respiratory  – hypoxic respiratory failure that may progress to Acute Respiratory Distress Syndrome (ARDS)
• Cardiovascular – hypotension, hypoperfusion
• CNS – confusion, delirium
• Kidneys – oliguria, acute kidney injury
• GI/Liver – Ileus, hyper or hypolglycemia, hyperbilirubinemia
• Blood – coagulopathy, thrombocytopenia

The mechanisms behind each of these injuries are beyond the remit of this article. One should calculate the SOFA score on each critically ill patient each day.

SCREENING THE PATIENT FOR SEPSIS

Every hospital has its own screening tool for sepsis, and, despite 30 years of proposals, there is no universally accepted tool. Below is a summary of the options currently available.

Quick SOFA (qSOFA) Score (2016)

The qSOFA score is based on three clinical criteria:

Respiratory rate ≥ 22 breaths per minute

Altered mentation (Glasgow Coma Scale < 15)

Systolic blood pressure ≤ 100 mmHg

A qSOFA score of 2 or more points indicates a high risk of sepsis and warrants immediate further evaluation and intervention.

Although the qSOFA  score is a useful rule of thumb, it is neither sensitive nor specific and not recommended as a standalone screening tool by the Surviving Sepsis Campaign.

Systemic Inflammatory Response Syndrome (SIRS) Criteria (1992)

The Systemic Inflammatory Response Syndrome (SIRS) criteria have been widely used to identify septic patients for 30 years and remain popular in many hospitals. Again they lack both sensitivity and specificity.

The SIRS criteria are:

Temperature: >38°C or <36°C

Heart rate: >90 beats per minute

Respiratory rate: >20 breaths per minute or PaCO2 < 32 mmHg

White blood cell count: >12,000/mm³, <4,000/mm³, or >10% immature bands

Patients who meet 2 or more criteria are considered to have SIRS, and if the cause is infection, it may progress to sepsis.

Early Warning Scores

Most hospitals use Early Warning Scores (EWS) to identify the deteriorating patient on the ward, but these are now commonly combined with SIRS and other criteria for identifying sepsis. EWS looks at common bedside observations and categorizes the variation from normal. These include heart rate, respiratory rate, need for oxygen, blood pressure, level of awakeness (AVPU) and temperature. The more systems that are abnormal the higher the score and the more likely that an intervention (e.g. consulting the critical care team) will take place. I am a big fan of EWS.

If medical review determines that the patient indeed is likely to have sepsis, a “bundle” of care (such as “sepsis-6”) is activated and the patient follows a sepsis pathway. Although such pathways are used worldwide, I am going to follow a slightly different 10 point therapeutic route that mirrors the Surviving Sepsis Guidelines and is more applicable to critical care.

MANAGING THE PATIENT WITH SEPTIC SHOCK

Step 1 Put in an IV line

TAKE BLOOD IMMEDIATELY FOR:

1. Blood Cultures

2. CRP or Procalcitonin/ FBC (WCC) / Lactate

This will give us an idea of the level of inflammation (WCC, CRP and Lactate) over the next hour or two and, hopefully will help us guide antibiotic therapy

Step 2 Through that IV line

ADMINISTER

1. Broad Spectrum Antibiotics (e.g. co-amoxyclav) based on your best guess source.
2. Upto 30ml/kg of intravenous fluid, preferably a balanced solution such as Hartmann’s, Lactated Ringers, or Plasmalyte-148.

Step 3 Vasopressors

If the MAP (or adjusted MAP target) does not reach 65mmHg after fluid resuscitation (do NOT give more than 5L of iv fluid) then the patient requires VASOPRESSORS.

The vasopressor of choice is norepinephrine (noradrenaline -NAD). This is an extremely effective agent: it restores the stressed blood volume, increases diastolic blood pressure – improving coronary blood flow, has inotropic effects – thus maintains stroke volume, and preferentially perfuses the midline structures, rather than the extremities. The major benefit of norepinephrine versus epinephrine in this setting is NAD’s lack of B2 adrenoceptor effect – it does not raise blood glucose or lactate.

Norepinephrine should be administered relatively early, and it does not require a central line: NAD can be safely delivered by a proximal peripheral cannula.

Step 4: Hormone Replacement Therapy

If the dose of norepinephrine is rising (the exact level is unclear – I turn to this drug early) then an ultra low dose infusion of arginine vasopressin is indicated. Vasopressin works via V1 receptors to increase vascular tone, and V2 receptors to maintain vascular volume. The dose is typically 0.03 units per minute – this will have no physiological impact on normal patients – in the setting of sepsis or severe blood loss vasopressin (as hormone replacement therapy) restores vascular tone, improves the effectiveness of norepinephrine and improves renal blood flow and urinary output. There is no downside, and I typically wean norepinephrine off before stopping vasopressin.

If High Dose Vasopressors are Not Working – consider Corticosteroids

Corticosteroids in this setting may have 2 benefits: 1. Damping down the initial hyperinflammatory response (some evidence in community acquired pneumonia), 2. As hormone replacement therapy (glucocorticoids are co-factors for catecholamine function).

Step 5 Identify and Control the Source of the Infection

The source is either medical or surgical. Medical sources are commonly – urinary tract, respiratory, intracranial (meningitis) or catheter related bloodstream infections.

As part of the workup, various cultures should be sent: blood culture, sputum culture, urine culture. A chest x-ray should be performed and tailored imaging to confirm the suspected source of the problem (CT abdomen, pelvis, chest, spine, brain)

Surgical sources are medley – they range from necrotizing soft tissue infections, to retained products of conception, perforated bowel or viscus, pilonidal abscess, intra-abdominal abscess, pancreatitis, spinal abscess, wound infection or wound dehiscence. Your cannot medically manage a surgical problem.

Step 6 Be Careful of the Search Satisficing Error

If the patient is persistently hypotensive despite multiple high dose pressors you need to expand your search for the problem. Is this cardiogenic shock (consider and echocardiogram) or a missed head or spinal injury (neurogenic shock or raised ICP). Does the patient have abdominal compartment syndrome (hypotension, oliguria, high airway pressures and intra-abdominal pressure of >20mmHg) or another compartment syndrome – cardiac tamponade, too much PEEP, tension pneumothorax etc.

If the lactate does not fall, you have a continued problem: there is still splanchnic hypoperfusion (the patient is under-resuscitated), the bowel or splanchnic circulation are ischemic, or the source is not controlled. Be careful of overvaluing hyperlactatemia in patients on epinephrine (adrenaline) infusions – this directly drives up lactate levels.

If there is severe mottling – there is no flow to the microcirculation – and that is what you can see on the skin – you cannot see the lungs, bowel and liver which are also suffering. Two things should be considered – is norepinephrine doing more harm than good (lower your MAP target and reduce the NAD) and is the patient still under-resuscitated. In this setting it is reasonable to “empty the kitchen sink” into the patient – giving plasma, 20% albumin and even 8.4% NaHCO₃ to expand the plasma volume and restore blood flow.

Step 7 Prevent Further Complications

Once the patient is in the ICU and relatively stable you need to back off on therapeutic interventions, and take measures to prevent iatrogenic complications. These include:

1. Stopping further crystalloid resuscitation – NO maintenance fluids – to avoid both fluid and solute overload.
2. Wake the patient up and avoid over sedation, give the patient a day-night cycle and proper sleep hygiene to ensure that they don’t develop deliriu,
3. Avoid intubation if at all possible, if not – carefully watch the tidal volumes and airway pressures to avoid ventilator induced lung injury.
4. Sit the patient up and sterilize the mouth to avoid ventilator associated pneumonia.
5. Remove central lines when no longer needed.
6. Give stress ulcer prophylaxis (if indicated).
7. Watch carefully for bed sores – turn and mobilize the patient.
8. Address nutrition, bowel hygiene and the microbiome at an early stage.

Step 8 Deresuscitate and Normalize the Patient

After 7 days one should be aiming to return the patient to their baseline weight – and that means deresuscitating the crystalloids from the patients body, either spontaneously, using diuretics or using continuous kidney replacement therapy (CKRT). The fluid balance should be even by day 7. In addition, nutrition should be started by day 3 and the patient should be receiving full nutrition by day 7. Sedation and other “consciousness clouding” drugs should be discontinued. Antibiotics should be de-escalated and stopped.

Step 9: Start Rehab Early

The multidisciplinary team are an essential component of modern critical care – a patient lying sedated in a bed, endlessly, develops medley complications. Sleep hygiene is imperative. Early mobilization and assessment by physiotherapy, occupational therapy, speech therapy etc. is essential. The microbiology team should assess the need for antimicrobials on a daily basis and care taken to avoid hospital acquired infections. Finally, critical illness takes a massive psychological toll – intensive care units should have a staff psychologist to deal with the patients mental health needs, to prevent PTSD.

Step 10: If the Patient is Not Getting Better They Are Getting Worse

If the patient does not recover rapidly within 7 days then they are likely to enter phase of chronic critical illness, where the body’s vital systems seem to go into a state of hibernation. Often they develop severe muscle weakness, resulting in difficulty liberating from mechanical ventilation (a tracheostomy may be required), the autonomic nervous system may become dysfunctional – manifest by rapid swings in blood pressure and heart rate, the neuroendocrine system may be burnt out and the patient may develop immunoparalysis.

There is no magic bullet to restart the body in chronic critical illness. The majority of patients will eventually recover. Unfortunately, many don’t – multiple infectious and iatrogenic hits results in progressive multi-organ failure and ultimately death. Although in hospital sepsis outcomes have improved dramatically since the turn of the century, little progress has been made on chronic critical illness; unfortunately.