SEPSIS

I. Be able to define Sepsis and Septic shock and discuss the pathophysiology of sepsis.
II. Be able to define qSOFA score in the management of patients with sepsis.
III. Be able to formulate a management plan for patients with sepsis.
IV. Be able to discuss the indications of enteral nutrition and TPN

Definition

Sepsis is the consequence of a dysregulated inflammatory response to an infectious insult.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host
response to infection; organ dysfunction is defined as an increase of two or more points in
the sequential (sepsis-related) organ failure assessment (SOFA) score .
Septic shock is defined as sepsis that has circulatory, cellular, and metabolic abnormalities
that are associated with a greater risk of mortality than sepsis alone; these abnormalities
can be clinically identified as patients who fulfill the criteria for sepsis who, despite
adequate fluid resuscitation, require vasopressors to maintain a mean arterial pressure
(MAP) ≥65 mmHg and have a lactate >2 mmol/L (>18 mg/dL).

Epidemiology

 Reasons for a possible increased rate of sepsis include advancing age,

immunosuppression, and multidrug-resistant infection

Etiology/ Risk Factors

 intensive care unit (ICU) admission, a nosocomial infection, bacteremia, advanced age,
immunosuppression, previous hospitalization (in particular hospitalization associated with
infection), and community-acquired pneumonia.

 The qSOFA score is easy to calculate since it only has three components,
each of which are readily identifiable at the bedside and are allocated one
point:

●Respiratory rate ≥22/minute

●Altered mentation
●Systolic blood pressure ≤100 mmHg

 Organ dysfunction: an acute change in total SOFA score ≥ 2 points

Septic shock consists of the following parameters: 

 Sepsis +
 Significant circulatory, metabolic, and cellular abnormalities  +
 Requiring vasopressor therapy  to maintain a mean blood pressure of ≥ 65
mmHg and presence of increased lactate levels > 2 mmol/L (18 mg/dL) in the
absence of hypovolemia
Pathophysiology

 Patients with suspected or documented sepsis typically present with hypotension,

tachycardia, fever, and leukocytosis. As severity worsens, signs of shock (eg, cool
skin and cyanosis) and organ dysfunction develop (eg, oliguria, acute kidney injury,
altered mental status)

Pathophysiology

 Sepsis is the state of a hyperinflammatory systemic reaction

1. Local activation of inflammatory mediators (complement system, mast

cells, macrophages) results in vessel dilation and further release of proinflammatory
cytokines (esp. TNFα, IL-1)

2. Generalized endothelial disruption → capillary leak → generalized edema due

to a shift of intravascular fluid and albumin into the surrounding tissue

3. Intravascular hypovolemia  → excessive triggering of the extrinsic

coagulation cascade → disseminated intravascular coagulation (DIC)
and microvascular thrombosis

4. Decreased oxygen utilization and tissue ischemia  → widespread cellular

injury → organ dysfunction (commonly multisystem)
An adequate immune response requires a balance between proinflammatory (anti-
infectious) and anti-inflammatory signals

Sign and symptoms

 Symptoms and signs specific to an infectious source 

 Arterial hypotension (eg, systolic blood pressure [SBP] <90 mmHg, mean arterial
pressure [MAP] <70 mmHg, an SBP decrease >40 mmHg, or less than two standard
deviations below normal for age)

 Temperature >38.3 or <36ºC.

 Heart rate >90 beats/min or more than two standard deviations above the
normal value for age.
 Tachypnea, respiratory rate >20 breaths/minute
 Signs of end-organ perfusion:
•Warm, flushed skin may be present in the early phases of sepsis. As sepsis
progresses to shock, the skin may become cool due to redirection of blood
flow to core organs. Decreased capillary refill, cyanosis, or mottling may
indicate shock.
•Additional signs of hypoperfusion include altered mental status, obtundation
or restlessness, and oliguria or anuria.
 •Ileus or absent bowel sounds are often an end-stage sign of hypoperfusion.

Investigation

Laboratory signs —

●Leukocytosis (white blood cell [WBC] count >12,000 microL–1) or leukopenia (WBC count <4000
microL–1

●Normal WBC count with greater than 10 percent immature forms.

●Hyperglycemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence of diabetes.

●Plasma C-reactive protein more than two standard deviations above the normal value.

●Arterial hypoxemia (arterial oxygen tension [PaO2]/fraction of inspired oxygen [FiO2] <300).

●Acute oliguria (urine output <0.5 mL/kg/hour for at least two hours despite adequate fluid
resuscitation).

●Creatinine increase >0.5 mg/dL or 44.2 micromol/L.

●Coagulation abnormalities (international normalized ratio [INR] >1.5 or activated partial

thromboplastin time [aPTT] >60 seconds).

●Thrombocytopenia (platelet count <100,000 microL–1).

●Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 micromol/L).

●Adrenal insufficiency (eg, hyponatremia, hyperkalemia), and the euthyroid sick syndrome can also
be found in sepsis.

●Hyperlactatemia (higher than the laboratory upper limit of normal) – An elevated serum lactate
(eg, >2 mmol/L) can be a manifestation of organ hypoperfusion in the presence or absence of
hypotension and is an important component of the initial evaluation, since elevated lactate is
associated with poor prognosis [44,67-69]. A serum lactate level ≥4 mmol/L is consistent with, but
not diagnostic of, septic shock. Additional laboratory studies that help characterize the severity of
sepsis include a low platelet count, and elevated international normalized ratio, creatinine, and
bilirubin. Although arterial and venous lactate correlate, arterial lactate measurements are more
accurate and preferred

●Plasma procalcitonin more than two standard deviations above the normal value (not routinely
performed in many centers) – Elevated serum procalcitonin levels are associated with bacterial
infection and sepsis].
●Mid-regional pro-Adrenomedullin (MR-proADM) has been used to predict occurrence and
worsening of organ failure in critically ill patients.

Treatment

Treatment

 Immediate resuscitation (respiratory and circulatory support)

 Intubation and mechanical ventilation may be required if the following is
present: respiratory insufficiency, dyspnea, persistent hypotension, or poor
peripheral perfusion
 Fluid resuscitation  (hypotension and hypoperfusion)
 Vasopressors (catecholamines) may be necessary when patients
remain hypotensive despite fluid resuscitation (e.g., norepinephrine) 
 Empiric antibiotic treatment: begin immediately after blood cultures have been
drawn, preferably within 1 hour after recognition 
 Treat for MRSA until ruled out: vancomycin or linezolid/daptomycin in
combination with either:
 Piperacillin/tazobactam, cefepime,
or carbapenems if Pseudomonas infection is likely
 3rd generation cephalosporin (e.g., ceftriaxone or cefotaxime) if Pseud
omonas infection is unlikely
 Antifungal treatment in cases of documented fungemia (presence of a fungus
in the bloodstream)
 Control infectious source
 Remove any foreign bodies
 Surgically drain abscesses or perform debridement on infectious wounds
 Manage any complications of surgery (e.g., ileus, peritonitis, anastomotic
insufficiency, osteomyelitis)
 Reassess the success of the therapeutic management every 48–72 hours
 Other therapy considerations
 Glucocorticoids (e.g., prednisone or dexamethasone): if there is an increased
risk of cerebral edema 
 Insulin-based control of blood glucose levels: control of stress-
induced hyperglycemia results in a shorter length of stay in the ICU, even in non-
diabetic patients. 

In addition to immediate resuscitation and empiric therapy, the infectious focus must be

identified and treated!

Complications

 Critical illness polyneuropathy

 Definition: axonal injury, particularly to the motor neurons, as a sequela of
sepsis and multiple organ dysfunction
  Clinical features
 Predominantly distal, symmetrical, flaccid paralysis of the
extremities with muscle atrophy; may affect the diaphragm
 Absent or reduced reflexes
 Dysesthesias in a glove-and-stocking distribution may be present
 Preservation of cranial nerve function
 May be associated with critical illness myopathy : flaccid quadriparesis
(proximal > distal); facial muscle weakness, sensation normal, tendon
reflexes normal or ↑
 Diagnosis: typical clinical features, sepsis, and electrophysiological evidence
of motor and sensory neuropathy
 Electromyography (EMG): spontaneous activity (e.g., fibrillations)
 Nerve conduction studies: normal velocity, reduced amplitude
 Treatment: no specific treatment available, usually gradual spontaneous
resolution (weeks to months)

Critical illness polyneuropathy is a common cause of prolonged weaning from mechanical

ventilation in a patient with sepsis!

Long-term prognosis — Following discharge from the hospital, sepsis carries an increased

risk of death (up to 20 percent) as well as an increased risk of further sepsis and recurrent
hospital admissions (up to 10 percent are readmitted). Most deaths occur within the first six
months but the risk remains elevated at two years 

Septic shock — Septic shock is a type of vasodilatory or distributive shock. Septic shock is defined
as sepsis that has circulatory, cellular, and metabolic abnormalities that are associated with a
greater risk of mortality than sepsis alone [29]. Clinically, this includes patients who fulfill the
criteria for sepsis (see 'Sepsis' above) who, despite adequate fluid resuscitation, require
vasopressors to maintain a mean arterial pressure (MAP) ≥65 mmHg and have a lactate >2 mmol/L
(>18 mg/dL). Per predictions from the SOFA score (calculator 2), patients who fulfill these criteria
for septic shock have a higher mortality than those who do not (≥40 versus ≥10 percent).
(See "Predictive scoring systems in the intensive care unit", section on 'Sequential (sepsis-related)
Organ Failure Assessment (SOFA)'.)

Others — Multiple organ dysfunction syndrome (MODS) and systemic inflammatory response

syndrome (SIRS) are terms frequently used in practice that need to be distinguished from sepsis.

Multiple organ dysfunction syndrome — Multiple organ dysfunction syndrome (MODS) refers to

progressive organ dysfunction in an acutely ill patient, such that homeostasis cannot be
maintained without intervention. It is at the severe end of the severity of illness spectrum of both
infectious (sepsis, septic shock) and noninfectious conditions (eg, SIRS from pancreatitis). MODS
can be classified as primary or secondary:

●Primary MODS is the result of a well-defined insult in which organ dysfunction occurs early and
can be directly attributable to the insult itself (eg, renal failure due to rhabdomyolysis).
●Secondary MODS is organ failure that is not in direct response to the insult itself, but is a
consequence of the host's response (eg, acute respiratory distress syndrome in patients with
pancreatitis).

There are no universally accepted criteria for individual organ dysfunction in MODS. However,
progressive abnormalities of the following organ-specific parameters are commonly used to
diagnose MODS and are also used in scoring systems (eg, SOFA (calculator 2) or LODS) to predict
ICU mortality [45-47] (see "Predictive scoring systems in the intensive care unit"):

●Respiratory – Partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio

●Hematology – Platelet count

●Liver – Serum bilirubin

●Renal – Serum creatinine (or urine output)

●Brain – Glasgow coma score

●Cardiovascular – Hypotension and vasopressor requirement

In general, the greater the number of organ failures, the higher the mortality, with the greatest
risk being associated with respiratory failure requiring mechanical ventilation. (See "Acute
respiratory distress syndrome: Prognosis and outcomes in adults".)

Systemic inflammatory response syndrome — The use of systemic inflammatory response

syndrome (SIRS) criteria to identify those with sepsis has fallen out of favor since it is considered
by many experts that SIRS criteria are present in many hospitalized patients who do not develop
infection, and their ability to predict death is poor when compared with other scores such as the
SOFA score [31,48,49]. SIRS is considered a clinical syndrome that is a form of dysregulated
inflammation. It was previously defined as two or more abnormalities in temperature, heart rate,
respiration, or white blood cell count [27]. SIRS may occur in several conditions related, or not, to
infection. Noninfectious conditions classically associated with SIRS include autoimmune disorders,
pancreatitis, vasculitis, thromboembolism, burns, or surgery.

Enteral nutrition and TPN

 Contraindications to parenteral nutrition include hyperosmolality, severe

hyperglycemia, severe electrolyte abnormalities, volume overload, inadequate IV
access, and inadequate attempts to feed enterally
 Relative contraindications to parenteral nutrition are not well defined. However,
parenteral nutrition is often avoided in sepsis, systemic inflammatory response
syndrome, minor vomiting, gastrointestinal bleeding, short-term mechanical
ventilation, and conditions expected to reverse quickly that temporarily preclude
enteral feeding.
 Enteral feeding

 Definition: administration of nutrients directly into the stomach, duodenum, or

jejunum with the help of feeding tubes
 Contraindications
 Mechanical ileus, bowel obstruction
 Acute abdomen (e.g., severe pancreatitis, peritonitis)
 Upper GI bleeding
 Mucositis
 Severe substrate malabsorption
 Congenital GI anomalies
 High-output fistulas
 Nonfunctional GI tract (e.g., gastroschisis, short bowel syndromes)
 Routes
 Short-term: nasogastric tube
 Long-term (> 2–3 weeks):
 Gastrostomy tube: gastric feeding tube inserted endoscopically
through a small incision through the abdomen into the stomach or
 Jejunostomy tube: feeding tube inserted through a
small incision through the abdomen into the jejunum to bypass the distal small
bowel and/or colon
 Complications
 Feeding-tube-related:
 Blockage of the feeding tube
 Nasogastric tube:
 Accidental placement of the tube inside the trachea 
 Injury to, or perforation of the stomach wall
 Gastrostomy or jejunostomy:
 Peristomal infection
 High-output fistulas
 Diarrhea 
 Gastroesophageal reflux
 Metabolic complications of specialized nutrition support
Open

 CLINICAL SCIENCE

Specialized nutrition support

Summary

Specialized nutrition support (SNS) is required when oral intake is either limited or not
possible for a prolonged period of time. Common indications for SNS include patients in
critical care, those with dysphagia, unconscious patients who cannot be fed,
severely malnourished patients, and those with intestinal malabsorption. The two forms
of SNS are enteral nutrition and parenteral nutrition. Enteral feeding is always preferred
whenever possible, but parenteral feeding may be instituted if the patient has a
nonfunctional GI tract (e.g., gastroschisis, short bowel syndromes), and/or if enteral
feeding is contraindicated. Patients who are on SNS may develop several complications
related to feeding tubes or intravenous catheters, as well as additional metabolic
complications such as electrolyte imbalances, hyperglycemia, refeeding
syndrome, gallstone disease, and nonalcoholic fatty liver disease.

Indications

 Dysphagia (e.g., post-stroke state, multiple sclerosis, esophageal carcinoma)

 Patients with a low GCS who cannot be fed
 Difficulty with oral intake in the early postoperative state
 Severe anorexia (e.g., terminally ill cancer patients, anorexia nervosa)
 Severe malnutrition
 Critically-ill patients
 Intestinal malabsorption

Types

 First-line: enteral feeding
 Advantages
 Easier to perform
 Metabolic complications occur less often
 Intestinal motility is stimulated, preventing mucosal atrophy
 Lower risk of blood stream infection
 Second-line: parenteral feeding

The following principle applies in most situations: oral before enteral, enteral before
parenteral!

Enteral feeding

 Definition: administration of nutrients directly into the stomach, duodenum, or

jejunum with the help of feeding tubes
 Contraindications
 Mechanical ileus, bowel obstruction
 Acute abdomen (e.g., severe pancreatitis, peritonitis)
 Upper GI bleeding
 Mucositis
 Severe substrate malabsorption
 Congenital GI anomalies
 High-output fistulas
  Nonfunctional GI tract (e.g., gastroschisis, short bowel syndromes)
 Routes
 Short-term: nasogastric tube
 Long-term (> 2–3 weeks):
 Gastrostomy tube: gastric feeding tube inserted endoscopically
through a small incision through the abdomen into the stomach or
 Jejunostomy tube: feeding tube inserted through a
small incision through the abdomen into the jejunum to bypass the distal small
bowel and/or colon
 Complications
 Feeding-tube-related:
 Blockage of the feeding tube
 Nasogastric tube:
 Accidental placement of the tube inside the trachea 
 Injury to, or perforation of the stomach wall
 Gastrostomy or jejunostomy:
 Peristomal infection
 High-output fistulas
 Diarrhea 
 Gastroesophageal reflux
 Metabolic complications of specialized nutrition support

Parenteral nutrition

 Definition: intravenous administration of nutrients that bypasses the gastrointestinal

tract
 Total parenteral nutrition: provision of all nutritional requirements
intravenously without using the gastrointestinal tract
 Contraindications
 Enteral nutrition is feasible
 Serum hyperosmolality
 Severe hyperglycemia
 Severe electrolyte abnormalities
 Volume overload
 Routes
 Parenteral nutrition is required for < 2 weeks: peripheral venous line,
or peripherally inserted central catheter
 Parenteral nutrition is required for > 2 weeks: tunneled central venous
catheter or a port 
 Complications
 Venous catheter-related:
 Catheter displacement
 Thrombosis and/or embolism
 Catheter-related blood stream infection
 Fluid overload
 Metabolic complications of specialized nutrition support