Practical considerations and management

of Multi-organ failure of COVID-19 in Pre-

ICU setting STOP COVID - 19
SAVE LIVES

Frans JV Pangalila
Dept Internal Medicine – Tarumanagara University
ICU Royal Hospital
Jakarta
“ COVID-19 IS A HYPERCOAGULABLE
STATE “
STOP COVID - 19
SAVE LIVES
in case of COVID-19
marked D-dimer elevation is common
elevation in fibrinogen and other inflammatory markers
thrombocytopenia is less frequent and generally mild
coagulation lab profile is not consistent with DIC

D-dimer ≥ 1µg/ml was associated with higher

odds of in-hospital death!
Zhou F et al, The Lancet 2020
SEVERE ACUTE RESPIRATORY SYNDROME-2 (SARS-CoV-2)
- CORONA VIRUS DISEASE 2019 (COVID -19) -
Basic pathophysiology
“ COVID-19 shedding to ACE2 receptor “
o Hypoxemic respiratory failure
o Cytokine storm
o Coagulopathy - DIC
Clinical spectrum
o 81% were MILD status
- no pneumonia or mild pneumonia
o 5% were SEVERE status
- PaO2/FiO2 < 300 mmHg
o 14% were CRITICAL ILL status
- need ventilator, shock and MOF
Mortality predictors
o Older age
o Higher SOFA score (≥ 6)
o D-dimer > 1 µg/mL
Case report (I)….start the journey
Day 1○ o 52 year old man with known care Bronchial asthma
o Present medical condition:
- presented with fever, dry cough, feeling very tired since 2 days ago
- on exam: consciousness, Temp 38.6○C, BP 130/80 mmHg
pulse 90 bpm, RR 20 pm, pulse oxymetri 99%, no murmurs, no rales
or wheez
- lab: Hb 12.3 gdl WBC 6500 ul lymphocyte 9% platelet 215 ul
- X-ray mild infiltrate both lung
What to do next ?
- a history of contact with covid-19 was denied
o Treatment: hydoxychloroquine, azithromycine and
inhaler (beta-agonis) as needed
Day 5○ o patient getting worse: short of breath, Temp 38○C BP 140/90 mmHg
pulse 118 bpm, RR 34 pm, pulse oxymetri 90-91%
- WBC 5600 ul (NLR 6) CRP 110 mg Platelet 184.000 ul PCT 0.05 ng
- D-Dimer 1 µg/ml AST 125 ALT 110 Glucose 160 mgdl
- kidney function normal Panel rapid covid test (+)
- ct scan thorax: ground glass opacity bilateral (+)
 Pasien Dalam Pemantauan (PDP) atau konfirmasi “COVID 19”
Rawat bangsal
(PDP) “ Risiko tinggi “
o Usia lanjut (≥ 50 thn)
o laki laki Kasus
(-) • rawat HighoCare co morbid: hipertensi, diabetes
Unit (HCU) (+)
o temperatur ≥ 37.8 ○C
• suplemen O2 - High flow Nasal Cannula (HFNC)
- pemantauano lama keluhan
ketat ≥ 6jam
tiap 1-3 hari
maksimal 48 jam
• profilaksisoantikoagulan
netrofil-limfosit rasio > 5 D Dimer tiap
(pemantauan
o CRP > 50
2 atau 3 hari)
o d dimer ≥ 0.7µg/ml atau > 3 kali
standar oksigen suplemen oksigen
• nasal kanul (02 NK 2-3 l) nilai normal atas • simpel mask atau NRM
(pemantauan 2 x perhari) o CT thoraks: pneumonia (+) (pemantauan ketat)

RR > 30/menit SpO2 < 93% HR > 120/menit

Intensive Care Unit (ICU)

Pasien gunakan High Flow Nasal Cannula (HFNC) ≈OPTIFLOW NHF
⓿ WHO, ESCIM/SCCM, Chinese Thoracic Society merekomendasi penggunaan
HFNC pada gagal napas COVID-19
- Non Invasive Ventilation (NIV) ≈ CPAP/BIPAP berpotensi gagal karena
pengalaman pada endemi MERS-CoV
- Australian and New Zealand Intensive Care Society (ANZICS) tidak anjur
kan penggunaan (NIV)
- Basis bukti: penelitian FLORALI (ARDS), Yang X et al Lancet Resp Med 2020
Boudma L et al Int Care Med 2020 (INTERIM)

⓿ HFNC suplai oksigen hingga 100% pada flow 60% l permenit

- flow 60 L/menit menimbulkan efek PEEP 5 - 6 cmH2O
(10 L/menit ≈ efek PEEP 1 cmH2O)
- efek dispersi aerosol tergolong kecil (< 15 cm) dengan flow ≥ 40 l/menit
(NIV efek dispersi aerosol sampai dengan 90 cm)
Whittle J et al JACEP Open 2020 ; Ischaki L et al Eur Resp Rev 2017
- HFNC tidak diberikan pada: kesadaran menurun, hiperkapnea, hemodinamik
tidak stabil atau kegagalan organ multipel
 Antikoagulan profilaksis…WHY ?

KONSENSUS PENATALAKSANAAN TROMBOEMBOLI

VENA (TEV) PADA PENYAKIT KRITIS

“ Lima langkah awal dari 10 langkah pendekatan TEV di ICU “

⓿ Langkah I : identifikasi risiko *TEV / EP melalui riwayat medis

⓿ Langkah 2 : identifikasi, adakah indikasi pemberian antikoagulasi profilaksis

⓿ Langkah 3 : identifikasi akan risiko pendarahan

⓿ Langkah 4 : pemberian sedini mungkin antikoagulan profilaksis

⓿ Langkah 5 : melakukan assessment diagnostik *TEV / EP *TEV : tromboemboli vena

*EP: emboli paru
Identifikasi indikasi pemberian Identifikasi risiko pendarahan
Antikogulan Profilaksis: akibat Antikoagulan:
Padua skor Improve skor

Risiko tinggi TEV ≥ 4

Risiko tinggi pendarahan ≥ 7

Kasus ini diberikan Enoxaparin 0.4 cc sc (dosis profilaksis)

Pemberian Antikoagulan Profilaksis se Dini mungkin !!
 Antikoagulan Profilaksis (+) diberikan

Lakukan prosedur diagnostik Tromboembolisme Vena

Alur diagnostik

Skor Padua ≥ 4

Skor Wells DVT ≥ 2

PROFILAKSIS ANTIKOAGULAN Diagnostik
Skor revisi Geneve EP
≥ 11

Skor Improve < 7

....back to the case: on HFNC (optiflow)
HFNC
• initial set flow 40 L/menit + FiO2 60% and
then adjusted….
• target: SpO2 92 – 96%
• monitoring (every 1-2 hours)
- work of breathing: RR> 35 breath/min,
thoraco-abdominal asynchrony and or
persistent accessories muscle use
- blood gas analysis if needed

….after 2 days on HFNC (IMC)

• from set flow 60 L/min + FiO2 80% and
weaning to flow 30 L/min + FiO2 40%
→ SpO2 97 - 99% , change to NC 3l/min
• clinical get improved, WOB is normal
but Covid-19 confirmed (+)
• back to the ward (isolation room)
 COVID-19
Why are they Hypoxic-Hypercoagulable ??
 Hypoxemia in COVID-19

Low V/Q High V/Q Very low V/Q

• suplemen oksigen • TV 4 - 6ml/kg

(HFNC/CPAP/BiPAP) • PEEP <16
• TVAlveoli
8ml/kg • recruitment
Alveoli
Alveoli
• PEEP 8 - 10 Anticoagulation ? • proning
• proning awake • APRV
ACE2
• conservative fluid • conservative fluid
Bilateral pulmonary
• NO/PG
Focal ?
opacities infiltrare,•Consolidation
ECMO and
vasodilatation thromb
No specific i finding
CXR
Peripheral distribution Atelectasis

o inflammation o macro-micro thrombosis o alveolar injury

o lung vasoplegia: vasodilatation o DEAD SPACE o lung vasoplegia: vasodilatation
(ACE2 ↑↑) Sepsis coagulopathy o patient self-inflicted lung injury
(P – SILI)
↑trans pulmonary
pressure (strain ↑)
Hypoxemia

Work of breathing ↑
Covid-19 on the Brain ↑ Respiratory drive
(Neuropism))
 RELATIONSHIP HYPOXEMIA and COAGULOPATHY IN COVID-19
COVID-19

ACE 2

Excessive local-systemic immune response → cytokine storm

↑↑↑ IL 1, IL2, IL6, G-SCF, TNFα, IFNγ and others

HYPERCOAGULABILITY ENDOTHELIOPATY
o activated coagulation DAMP (alarmin)
o fibrinolytic suppresion Damage Associated Molecular Pattern
o endothelial damage
Low blood flow o thrombocytosis and platelet
activation
THROMBUS FORMATION HIFs*
HYPOXIA
“ Co-morbid “

Macrothrombosis Microthrombosis
(venous-arterial thromboembolic event)
MOF - microangiopathy

MOF: multi-organ failure *HIFs: hypoxia inducible transcription factors

o The pathological features in lungs greatly resemble those seen in
SARS and MERS infection
o bilateral diffuse alveolar damage + cellular fibromyxoid exudates

Hyaline membrane formation Interstitial mononuclear Thrombus in pulmonary

(blue arrow) inflammatory infiltrate arterioles (black arrow)

Xiaohong Y et al. Chinese Journal of Pathology 2020

Evidence from autopsies
Annals of Internal Medicine STOP COVID - 19
SAVE LIVES

Autopsy Findings and Venous Thromboembolism in

Patients with COVID-19
A Prospective Cohort Study

Findings:
Autopsy revealed deep venous thrombosis in 7 of 12 patients
(58%) in whom venous thromboembolism was not suspected
before Death; pulmonary embolism was the direct cause of
death in 4 patients

Wichmann D et al Ann Intern Med 2020

 COVID-19 and Coagulopathy
Abnormal coagulation paremeters are associated with
poor prognosis in patients with Novel Coronavirus
Pneumonia
o significantly ↑ d Dimer and FDP associated
Tangwith poor
N et al. prognosis
J Thromb Haemost 2020
*d Dimer > 1µg/ml was independent risk factor of in-hospital death
o vascular endothelium inflammation extensive intravascular micro -
thrombosis on autopsy
o vascular endothelial cells express high levels ACE-2

Anticoagulation therapy should be initiated for severe

COVID-19 patients if otherwise contraindicated
Anticoagulant Treatment and COVID-19 Mortality
In-Hospital Median Mayor
mortality survival bleeding

Anticoagulation
22.5% 21 days 3%
N = 786
No anticoagulation
22.8% 14 days 1.9%
N = 1987

Required Mechanical Ventilation (N = 395)

In-Hospital Median Mayor
mortality survival bleeding
Anticoagulation
29,1% 21 days
N = 119
No anticoagulation
62.7% 9 days
N = 276

Paranjpe et al. J Am Coll Cardiol 2020

Does Heparin treatment work ?
Helmst J et al J Thromb Haemost 2020

use heparin
not use heparin

LMWH and Heparin users in COVID-19 is significantly related to lower mortality rate

D Dimer plasma concentration

SIC: sepsis induced coagulopathy D-D:D-Dimer ULN: upper limit normal

D-dimer: non-specific but useful in COVID-19

Zhou F et al. Lancet 2020

⓿ indicate:
cell injury/damage and prognosis
⓿ can we use D-dimer for diagnosis and clinical decision ?
- normal level: out patient or early discharge
- mild or moderate increase: VTE risk assessment
- high level increased: VTE suspect or other possibilities
⓿ can we use D-dimer to guide therapy?
- mild elevation + clinical risk of VTE: prophylaxis dosage LMWH
- moderate elevation + clinical risk of VTE: treatment dosage
- high elevation + clinical risk of VTE: aggressive treatment
Two additional important approach should
be done Pre-ICU

⓿ Conservative fluid administration

⓿ Awake prone position

 Fluid Overload and Spontaneous Breathing
Lung vasoplegia
Low V/Q

Baby lung
Hypoxemia
shrinkage
Power ↑work of
Conservative
Concentration
fluid administration
breathing
o maintaining adequate mean -arterial
(stress-strain↑) pressure and organ
Patient Self Fluid overload
perfusion (keep MAP ≥ 65 mmHg and CVP
Inflicted Lung as low as
(fluid
possible)
balances ++)
Lung Edema
o avoiding fluid resuscitation or bolus
Injury unless hypovolemia and
(P-SILI)
or hypoperfusion persist (intra thoracic
Capillary Leak pressure ↓)
Central venous
pressure (CVP) ↑
Venous return (preload ↑)
Vessel strech ↑↑↑
 Management of COVID-19 Coagulopathy
(a proporsal)
PDP/COVID-19 (+)

Padua score ≥ 4 Give anticoagulant prophylactic tight monitoring and

Improve score < 7 dose: LMWH (preferred) regular assessment

If, related to SIC*score ≥ 4 or Consider anticoagulant tight monitoring and

d Dimer> 6 upper normal limit therapeutic dose regular assessment

If bleeding (although rarely)

Minor bleeding: adjusted dose / stop
anticoagulant
Mayor bleeding
systole < 90 and or
Assessment
heart rate 110 x/min:
Thrombocytopenia
stop anticoagulant
after day > 5
DIC score ≥ 5 (+)
- treat as a DIC
HIT# ?

Phenotype F Phenotype T
(ratio FDP/d Dimer >> 1) (ratio FDP/d Dimer close to 1) and No *SIC: sepsis induced coagulopathy
#HIT: heparin induced thrombocytopenia
give antifibrinolytic mayor bleeding -anticoagulant continued
 Perjalanan penyakit COVID 19: gejala-tanda, laboratorium dan modalitas terapi
Stadium I Stadium II Stadium III
(awal penyakit) (pneumoni) (hiperinflamasi)

ODP ( hari 1 - 7 ) PDP ( hari 8 - 11 ) PDP-konfirmasi

( hari >11 )
Replikasi
virus
Respon inflamasi

“ flu like symptoms “ demam menetap ARDS

Gejala klinis demam, nyeri kepala, batuk sesak napas - hipoksemia SYOK – MOF
kering, myalgia, mual, diare P/f rasio ≤ 300 mmHg Defek hemostasis
lekopeni / limfopeni CRP ↑ LDH ↑
NLR > 3.13 Transaminitis
Petanda PCT normal / ↓ Ferritin ↑
CRP ↑ LDH ↑ D Dimer ↑↑
klinis Prothrombin ↑ Temuan kelainan
radiologi Ig M + Ig G +
D Dimer ↑, PCR/Ag+
IgM + IgG - “ Ground Glass Opacity “ Crazy paving-consolidation

Prophylactic
Antiviral anticoagulant
(Remedisivir), Kloroquin, transfusi plasma konvalesen
Potensi Simptomatik Standar - suplemen O2 Restriksi cairan HFNC- NIV / MV CVVH/ECMO
terapi Hindari obat
bersifat imunosupresi Prophylactic ANTICOAGULANT Therapeutic
antibiotik kortikosteroid imunoglobulin