Sepsis covid 19 11.09.2020 (5) final

13th Sept 2020 - World Sepsis Day DR VIJAY K AGRAWAL 1
Sepsis in COVID-19
Manifestations to Management

13th Sept 2020 - World Sepsis Day
Disclosure Statement of Financial Interest
I DO NOT have a financial
interest / arrangement or
affiliation with one or more
organizations that could be
perceived as a real or
apparent conflict of interest
in the context of the subject
of this presentation.
NO

Will try to touch TIP OF ICEBURG
• No one is expert about Covid 19 disease in present scenario…
• Daily changing information from International & National literature
• Frequently changing government advisory and guidelines….
• Different hospitals ………… Different problems….. Different solutions………
So, will try to share information ………………………………………… what so
ever could have gathered from various sources.
Disclosure

What is sepsis and why to discuss
Covid 19 introduction
Clinical manifestations
Management of sepsis
Add on available treatment
4

1 2
3
Accounts for 25-
50% of in-hospital
total mortality…
4
Those who survive tend to have
increasing complications, morbidity,
high costs of care, and decreasing
quality of life.

Sepsis: major health problem with
increasing prevalence, high costs, and
poor outcomes

What is sepsis ?

10/19/2020 DR VIJAY K AGRAWAL 8
DEFINITIONS – from 1992 till 2016
A. Infection: Invasion of normally sterile body tissues by microorganism
B. Systemic Inflammatory Response Syndrome (SIRS):
systemic response to a variety of insults (burns, trauma, pancreatitis, infection)
SIRS: presence of 2 or more of the following criteria
1. Fever (core temperature > 38.3 C or 101.0 F) or hypothermia (core
temperature < 36 C or 96.8 F)
2. Heart rate > 90 beats/min
3. Respiratory rate > 20 breaths/min or PaCO2 < 32 or need for mechanical
ventilation for an acute respiratory process
4. WBC > 12,000/mm3, < 4,000/mm3, or band cells > 10%
C. Sepsis: patient meets the criteria for SIRS and has a suspected
or confirmed infection. Crit Care Med 2008 Vol. 36, No. 296-327

D. SEVERE SEPSIS
Patient meets sepsis definition and has at least 1 sign of
organ dysfunction*:
 SBP < 90 mmHg, MAP < 65 mmHg for at least one hour despite adequate fluid resuscitation (20 ml/kg
saline) or use of vasopressors
 Lactate > 4 mmol/L
 Urine output < 0.5 ml/kg/hr after adequate fluid resuscitation or rise in creatinine > 0.5 mg/dL over
baseline
 PaO2/FiO2 ratio < 300 or requiring > 4 liters oxygen via nasal cannula to maintain SpO2 > 90%
 Platelets < 100,000/mm3, INR > 1.5, PTT > 60s
*Organ dysfunction must be new onset
E. SEPTIC SHOCK – SEVERE SEPSIS WITH LOW
BLOOD PRESSURE

CHANGES IN YEAR
2016
Sepsis-3

JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287
Sepsis (with organ dysfunction) – “ life-threatening organ
dysfunction caused by a dys-regulated host response to
infection”. This is a clinical diagnosis.
Septic Shock – a subset of Sepsis with circulatory and
cellular/metabolic dysfunction associated with a higher risk
of mortality.

TO ASSESS organ dysfunction
SOFA SCORE

•The Sepsis-3 definitions recommend
using a change in the total SOFA
score of 2 or more points from the
baseline score to represent organ
dysfunction

Quick SOFA / q SOFA
> 22/ min SBP
≤100mmHg
• Patients with qSOFA = 2-3 are at increased risk of death
or prolonged ICU stay (> 3 days)
New onset

Sepsis (with organ dysfunction) and Septic Shock
Medical emergencies
Treatment and resuscitation should begin immediately.

COVID-19
• Coronaviruses are large group of viruses that cause illness in humans and
animals.
• Animal coronaviruses evolve and infect people -then spread between people
such as MERS and SARS (zoonotic disease)
• Outbreak COVID-19 - noticed in a seafood market in Wuhan city in Hubei
Province of China in mid Dec 2019
• On January 30th, the World Health Organization declared the 2019 Novel
Coronavirus (SARS-CoV-2*) a global health emergency.
• Spread- 214 countries worldwide.

• Till 12 Sep 2020
• Coronavirus Cases globally : 28,285,700 , Deaths: 911,255
• Coronavirus Cases in India :4,665,469, Deaths: 77,548

• Enveloped RNA beta coronavirus- SARS virus,
• Uses ACE2 receptor for cell entry.
• Source : Persons infected by the coronavirus

• Median incubation period is 5.1 days (range 2–14 days).
• Period of infectivity starts 2 days prior to onset of symptoms and
lasts up to 8-11 days.

Clinical Manifestations
Mild COVID Moderate COVID Severe COVID
Fever, Cough
Fatigue, Shortness of breath
Expectoration , Myalgia,
Rhinorrhea, sore throat,
diarrhea, anosmia, loss of
taste
Pneumonia with no
signs of severe
disease.
Severe Pneumonia alone
or leading to
ARDS,
Sepsis,
Septic shock,
MODS, Death

If Sepsisis associated
with Covid 19 ?
Signs of multi-organ injury typical of sepsis
occur in approximately 2-5% of those with
COVID-19 after approximately 8-10 days

Severe Sepsis Mortality Increases
With Number of Organ Failures
1
21%
44%
65%
76%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
One Two Three Four or More
Angus, D., Linde-Awirble, W., Lidicker, J., et al. Epidemiology of severe sepsis in the United States:
Analysis of incidence, outcome, and associated cost of care. Crit Car Med. 2001; 29:1303-1310.
Number of Organ Dysfunctions
Mortality%

Severe Sepsis Mortality Increases
With Number of Organ Failures
1
21%
44%
65%
76%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
One Two Three Four or More
1. Angus, D., Linde-Awirble, W., Lidicker, J., et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated
cost of care. Crit Car Med. 2001; 29:1303-1310.
Number of Organ Dysfunctions
Mortality%
COVID 19
PROBABLY
DOUBLE OR
MORE
MORTALITY

Common sources of sepsis seen IN SICK Covid -19 PATIENTS ?..
 Pulmonary: = 60-80%
 Abdomen/Pelvis: ~10-15 %
 Primary bacteremia: ~10%
 Urosepsis: 10%
 Skin: 5%
 Other: ~5%

Comorbidities and other conditions that have been
associated with severe illness/sepsis and mortality
include-
• Cardiovascular disease
• Diabetes mellitus
• Hypertension
• Chronic lung disease
• Cancer (in particular hematologic malignancies, lung cancer, and
metastatic disease)
• Chronic kidney disease
• Obesity, Smoking, Aged, Pregnancy

When should we suspect sepsis
in COVID -19 – symptom based
• Hypo- or Hyperthermia
• Slurred speech or confusion
• Extreme pain in the muscles or joints
• Passing no urine in a day
• Severe breathlessness
• “It feels like I’m going to die”
• Skin that’s mottled, discolored or very pale

• Particular laboratory features have also been associated with
worse outcomes / sepsis
• Lymphopenia
• Thrombocytopenia
• Elevated liver enzymes
• Elevated lactate dehydrogenase (LDH)
• Elevated inflammatory markers (eg, C-reactive protein [CRP],
ferritin)
• Elevated D-dimer (>1 mcg/mL)
• Elevated prothrombin time (PT)
• Elevated troponin
• Elevated creatine phosphokinase (CPK)
• Acute kidney injury

The Surviving Sepsis Campaign (SSC) international
guidelines were developed for early detection and
treatment of severe sepsis and septic shock
2016
2018

STEP-1 Two Clocks
3 hour
2016 GUIDELINES
TIME IS LIFE IN SEPSIS

SURVIVING SEPSIS CAMPAIGN BUNDLES
TO BE COMPLETED WITHIN 3 HOURS:
1) Measure lactate level
2) Obtain blood cultures prior to administration of antibiotics
3) Administer broad spectrum antibiotics
4) Administer 30 mL/kg crystalloid for hypotension or lactate
>4mmol/L

5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation
to maintain a mean arterial pressure [MAP] 65 mm Hg)
6) In the event of persistent arterial hypotension despite volume resuscitation (septic
shock) or initial lactate ≥ 4 mmol/L (36 mg/dL):
- Measure central venous pressure (CVP)*
- Measure central venous oxygen saturation
(ScvO2)*
7) Remeasure lactate if initial lactate was elevated*
*Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm Hg,
ScvO2 of 70%, and normalization of lactate

Why measure lactate?
 Diagnose severe sepsis with elevated lactate as a diagnosis of tissue
hypoperfusion
 Trigger for quantitative resuscitation if lactate is 4 mg/dL or more
ABG
BLOOD
SAMPLE

4) Administer 30 mL/kg crystalloid for hypotension or lactate 4mmol/L
- Measure central venous oxygen saturation (ScvO2)*
*Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm
Hg,

Blood Cultures To optimize identification of causative
organisms
At least two blood cultures be obtained
Before antimicrobial therapy is
administered
As long as such cultures do not cause
significant delay (>45 minutes) in
antimicrobial administration,
At least one drawn percutaneously and
one drawn through each vascular access
device, unless the device was recently
(<48 hr.) inserted
(Grade 1C).

Antibiotic Therapy
 Intravenous antibiotic therapy be started
as early as possible and within the first
hour of recognition of septic shock and
severe sepsis without septic shock .

Antibiotic Therapy
 Initial empiric anti-infective therapy – activity against all
likely pathogens and adequate concentrations into
suspected or potential sources of infection
 Reassess antibiotic regimen daily for de-escalation

Appropriate Antibiotic
Matching antibiotic sensitivities of the organism to the
antibiotic used.
Adequate Antibiotic
Appropriate PLUS correct dose, penetration to site of
infection, correct route and combination therapy (if needed)
THERAPY PRINCIPLES

Factors in Selecting Initial Appropriate Therapy
• Patient features: Choose empiric therapy based on site and
severity of infection, and physician assessment of the likelihood
for deterioration and mortality.
• Local susceptibility and epidemiology: Choose empiric therapy
to cover the likely infecting pathogens based on patterns while
considering prior antibiotic therapy.
• Initial antibiotic therapy dosing and duration: Choose initial empiric
therapy that will deliver enough antibiotic to the site of infection and
be well-tolerated (consider antibiotic penetration).
• Combination vs. monotherapy: Initial antibiotic choice should give
broad enough coverage, avoid emergence of resistance, and have the
potential for synergy if necessary.

Fluid therapy
Initial fluid challenge in sepsis-induced tissue
hypoperfusion (hypotension or elevated lactate) with
suspicion of hypovolemia to be a minimum of 30
ml/kg of crystalloids
A portion of this may be albumin equivalent.
More rapid administration and greater amounts of
fluid, may be needed in some patients
Without Covid 19

For the acute resuscitation of adults with COVID-
19 and shock, use a conservative over a liberal
fluid strategy.
With Covid 19
In adults with COVID-19 and shock, using
dynamic parameters skin temperature,
capillary refilling time, stroke volume variation
(SVV), pulse pressure variation (PPV), passive
leg raise test and/or serum lactate
measurement over static parameters in order
to assess fluid responsiveness are preferred.

CHOICE OF FLUIDS
Crystalloids Colloids
Ringers
Lactate
Normal
Saline
AlbuminGelatins
Hetastarch

IV FLUID COMPOSITIONS
Na+ Cl- Lactate Acetate
0.9% NaCl 154 154 0 0
Lactated Ringer's (LR) 130 111 29 0
Hartman's 131 109 29 0
Ringer's Acetate (RA) 130 112 0 27
Plasma-Lyte®/Normosol-R ® 140 98 0 27
Crystalloids
mEq/L
using buffered/ balanced crystalloids over
unbalanced crystalloids is preferred

SOURCE CONTROL
AS PER PRIMARY SOURCE

5) Apply vasopressors (for hypotension that does not respond to initial fluid
resuscitation

Apply vasopressors (for
hypotension that does not
respond to initial fluid
resuscitation to maintain a
mean arterial pressure
(MAP) ≥65mmHg)

Choice of Vasopressors'
First
Line
Second
Line
Niche
Drugs
Norepinephrine
Epinephrine Low Dose
Vasopressin
(.01-.03 units/min)
Dopamine
(sinus
bradycardia)
Phenylephrine
(high cardiac output
or serious
tachyarrhythmias
and salvage)

Vasopressors
• In general avoid
• Dopamine, unless
• Relative or absolute bradycardia and low risk of
tachyarrhythmias
• Phenylephrine, unless
• Norepinephrine associated with serious
arrhythmias
• Cardiac output is known to be high and blood
pressure target difficult to achieve
• As salvage therapy

6) In the event of persistent arterial hypotension despite
volume resuscitation (septic

Initial Resuscitation of Sepsis Induced Tissue
Hypoperfusion
Recommend
Insertion central venous catheter
Recommended goals :
• Central venous pressure: 8–12 mm Hg
• Higher with altered ventricular compliance
or increased intrathoracic pressure
• ScvO2 saturation (SVC)  70%

Lactate Clearance
In patients with elevated lactate levels as a
marker of tissue hypoperfusion
Targeting resuscitation to normalize lactate as
rapidly as possible
High Lactate levels does not always indicate hypovolemia. May be due to
mitochondrial dysfunction, liver failure, beta agonists, mesenteric ischemia or
epinephrine use.

• Suggestion against using IV hydrocortisone to treat septic shock patients if adequate
fluid resuscitation and vasopressor therapy are able to restore hemodynamic
stability.
• If this is not achievable, we suggest IV hydrocortisone at a dose of 200
mg per day
• Steroids are of no benefit in the treatment of severe sepsis in the absence
of shock.
Use of steroids in moderate to severe covid 19
cases is recommended

The new guidelines try to push back the
recently-invented sepsis clock to start the
moment a patient is first seen in the ED

"Time zero” or “time of presentation” is defined as the
time of triage in the emergency department or, if
referred from another care location, from the earliest
chart annotation consistent with all elements of sepsis
(formerly severe sepsis) or septic shock ascertained
through chart review."

Hour-1 bundle
The most important change in the revision of the SSC
bundles is that the 3-h and 6-h bundles have been
combined into a single “hour-1 bundle” with the explicit
intention of beginning resuscitation and management
immediately.

KEY FACTORS
TO SAVE LIVES
FROM SEPSIS .....
Early fluid resuscitation
Early identification
Early antibiotics

Starting supplemental
oxygen if the peripheral
oxygen saturation (Spo2)
is < 92-94 %
Ventilation:
Spo2 be
maintained no
higher than 96%.
using HFNC over
conventional
oxygen therapy &
NIV
close monitoring for worsening of respiratory
status, and early intubation in a controlled
setting if worsening occurs.
low tidal volume (Vt) ventilation (Vt 4-8mL/kg
of predicted body weight), over higher tidal
volumes (Vt>8mL/kg).
Target plateau
pressures < 30cm
H2O
higher PEEP
strategy, over a
lower PEEP strategy.
Early prone
ventilation
Intermittent boluses of neuromuscular blocking agents, except In the
event of persistent ventilator dys-synchrony, the need for ongoing deep
sedation, prone ventilation, or persistently high plateau pressures
In refractory hypoxemia despite optimizing ventilation, use of rescue
therapies, and proning, ……. using venovenous (VV) ECMO if available

Off- label Medications

Remdesivir
• Nucleoside analogue- will inhibit the replication of SARS-CoV-2
• Patients with moderate disease (those on oxygen)
Contraindications:
• AST/ALT > 5 times ULN
• Severe renal impairment (i.e., eGFR < 30ml/min/m2 or need for
hemodialysis)
• Pregnancy or lactating females
• Children (< 12 years of age)
• Dose: 200 mg IV on day 1 followed by 100 mg IV daily for 5 days

Favipiravir
• Favipiravir is a viral RNA polymerase inhibitor
• 3200 mg (1600 mg 12 hourly) loading dose on day-1 followed by 1200 mg
maintenance dose (600 mg 12 hourly daily) on day-2 to day-10
• Indication: Mild to moderate COVID

Convalescent plasma
• Patients with moderate disease who are not improving (oxygen
requirement is progressively increasing despite steroid therapy
Requisites:
• ABO compatability and cross matching with donor plasma
• Neutralizing antibody titre above specific threshold
• Close monitoring –post transfusion
• Dose:4-13ml/kg (total dose not more than 200ml over 2hrs)

Tocilizumab
Monoclonal antibody to IL-6 receptor
• Moderate disease with progressive increase in requirement of O2
• Mechanically ventilated pts. Not improving with steroids
• Presence of inflammatory marker(IL-6, ferritin , CRP)
• Rule out active infection and TB
• Monitor for infection post therapy
Dose: 8mg/kg slow IV with 100 ml NS over 1 hr,
Repeat if needed after12-24 hrs

Vitamin C
• Vitamin C - beneficial effects in patients with severe and critical illnesses.
• Anti-oxidant, free radical scavenger that has anti-inflammatory
properties, influences cellular immunity and vascular integrity,
• Cofactor in the generation of endogenous Catecholamines.
• Vitamin C high dose: Will Overcome Oxidative stress in serious COVID-19
causing sepsis and ARDS.
• Dose: 100-200 mg/kg/d- IV for 4 -5 days

Methylene Blue
• Nitric oxide – Mediator of hemodynamic changes in sepsis
• Methylene blue- antagonize NO by inhibiting guanylate cyclase
• Releases the cAMP pathway
• Facilitating the vasoconstrictor effect of epinephrine
• Antioxidant effect
• 2 mg/kg in IV bolus, 2mg/kg hourly infusion

The Role of Procalcitonin for Risk Assessment and
Treatment of COVID-19 Patients
• Procalcitonin (PCT) is a widely used biomarker to assess the risk of bacterial
infection and disease progression.
• Early evidence suggests that PCT may also be a valuable tool in identifying
COVID-19 patients at high risk for clinical deterioration or patients at risk for
bacterial co-infection.
• PCT helps to discriminate between milder cases and more severe cases.
• PCT also helps to distinguish between severe bacterial pneumonia and mild viral
pneumonia.
• If a patient has bacterial co-infection, his prognosis and his mortality risk
increases if early antibiotic treatment is not initiated.
• Recent clinical findings show that unnecessary antibiotic use can be safely
reduced in patients with low likelihood of bacterial co-infection indicated by low
PCT values.

Thank you…!

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Sepsis covid 19 11.09.2020 (5) final