COVID-19 and Acute Respiratory Distress Syndrome (ARDS)

Lucy Stun, PharmD, BCCCPClinical Coordinator: Critical Care, Emergency MedicineContact: lstun@kum.eduApril 9th , 2020

COVID-19 and Critical Illness

• It is estimated that 4.9-11.5% of proven COVID-19 infections will develop severe disease requiring intensive care

Murthy S, Gomersall C, Fowlder R. Care for Critically Ill Patients with COVID-19. JAMA; 3/11/2020Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 2020. CDC Website.

Risk Factors Requiring Critical CareAge ≥ 60 40% exhibit comorbidities • Diabetes

• Hypertension • Cardiac disease• Underlying pulmonary disease (ie asthma, COPD)• Obesity • CKD• Cancer

Onset of symptoms Needing ICU admission8-10 days

ARDS: Clinical Features

• 2/3 of COVID-19 ICU patients meet criteria for ARDS

Diffuse inflammatory

lung injury

Progressive dyspnea

Increased O2requirements• Mechanical

Ventilation

Bilateral infiltrates on CXR or

CT

ARDS: Clinical Diagnosis

Thompson BT et al. Acute Respiratory Distress Syndrome. N Engl J Med. 2017 Aug 10;377(6):562-572

Screen shot of ICU Rounding Report (EPIC®)

ARDS Pathogenesis Timeline

Early Exudative

StageFibroproliferative

stageFibrotic Stage

Day 7-10 Day 10-14 Day >14

Early Exudative Stage

• LEFT: Healthy Patient• RIGHT: Exudative Phase• Day 7-10• Interstitial edema• Acute and chronic

inflammation

Proliferative & Fibrotic Stages

• LEFT: Proliferative Phase • RIGHT: FIBROTIC Phase• Fibroproliferative stage

• Between 7-10 days up to 2 weeks

• Persistent hypoxemia, low lung compliance, may have progressive pulmonary HTN

• Fibrotic stage• Loss of normal lung

architecture; fibrosis and cyst formation

General ARDS Critical Care Management

Fan E, et al. American Thoracic Society Documents. Mar 2017. Murthy S, Gomersall C, Fowlder R. JAMA; 3/11/2020PETAL Network Clinical Trials. Neuromuscular Blockade in ARDS NEJM 2019http://www.ardsnet.org/files/ventilator_protocol_2008-07.pdf

ARDS Management Principles Conservative IV fluid management Consideration of ECMOEmpiric bacterial pneumonia coverage Prone positioning

• Improves oxygenation • Enhances lung recruitment• May reduce mortality

Lung protective mechanical ventilation strategies (ARDSnet trial)

Use of neuromuscular blockade• Not routinely used unless other

indications (ex: ventilator dys-synchrony and refractory hypoxemia)

Permissive Hypercapnia

General ARDS Critical Care Management

Fan E, et al. American Thoracic Society Documents. Mar 2017. Murthy S, Gomersall C, Fowlder R. JAMA; 3/11/2020PETAL Network Clinical Trials. Neuromuscular Blockade in ARDS NEJM 2019http://www.ardsnet.org/files/ventilator_protocol_2008-07.pdf

ARDS Management Principles Conservative IV fluid management Consideration of ECMOEmpiric bacterial pneumonia coverage Prone positioning

• Improves oxygenation • Enhances lung recruitment• May reduce mortality

Lung protective mechanical ventilation strategies (ARDSnet trial)

Use of neuromuscular blockade• Not routinely used unless other

indications (ex: ventilator dys-synchrony and refractory hypoxemia)

Permissive Hypercapnia

ExtraCorporeal Membrane Oxygenation

General ARDS Critical Care Management

Fan E, et al. American Thoracic Society Documents. Mar 2017. Murthy S, Gomersall C, Fowlder R. JAMA; 3/11/2020PETAL Network Clinical Trials. Neuromuscular Blockade in ARDS NEJM 2019http://www.ardsnet.org/files/ventilator_protocol_2008-07.pdf

ARDS Management Principles Conservative IV fluid management Consideration of ECMOEmpiric bacterial pneumonia coverage Prone positioning

• Improves oxygenation • Enhances lung recruitment• May reduce mortality

Lung protective mechanical ventilation strategies (ARDSnet trial)

Use of neuromuscular blockade• Not routinely used unless other

indications (ex: ventilator dys-synchrony and refractory hypoxemia)

Permissive Hypercapnia

Prone Positioning- Nursing Services & Respiratory Therapy Services (Lippincott Procedure)

General ARDS Critical Care Management

Fan E, et al. American Thoracic Society Documents. Mar 2017. Murthy S, Gomersall C, Fowlder R. JAMA; 3/11/2020PETAL Network Clinical Trials. Neuromuscular Blockade in ARDS NEJM 2019http://www.ardsnet.org/files/ventilator_protocol_2008-07.pdf

ARDS Management Principles Conservative IV fluid management Consideration of ECMOEmpiric bacterial pneumonia coverage Prone positioning

• Improves oxygenation • Enhances lung recruitment• May reduce mortality

Lung protective mechanical ventilation strategies (ARDSnet trial)

Use of neuromuscular blockade• Not routinely used unless other

indications (ex: ventilator dys-synchrony and refractory hypoxemia)

Permissive Hypercapnia

Critical Care NMB Management Principles

• Most common agents• Cisatracurium

• 0.5-10 mcg/kg/min• Not affected by organ dysfunction

• Rocuronium• 3-12 mcg/kg/min• Rapid onset; short duration. Ideal for

intermittent NMB• Vecuronium

• 0.6-1.7 mcg/kg/min• Longer onset than rocuronium

• Titration parameters• Control of respiratory effort• Train-of-four (TOF)

• 4 sequential stimuli are administered to assess level of neuromuscular blockade

www.anesthesiologyhub.com

Critical Care Sedation Management Principles

• RASS • Most ICU patients will titrate sedation to a

RASS of 0 to -2 • If requiring NMB, titrate RASS to -3 to -5

• Choice of sedative• Propofol or dexmedetomidine typically first

line• Ketamine• Avoid benzodiazepines if possible

www.researchgate.netDevlin et. al. CCM 2018; 46(9);e826-873.

Critical Care Sedation Management PrinciplesDrug Typical Dosing Regimen Contraindications/Warning Common Adverse

EffectsComments

Propofol 10-100 mcg/kg/minUsual max 150 mcg/kg/min

Bolus dosing not typically used

Hypersensitivity to eggs or soy

May exacerbate pre-existing pancreatitis

Hypotension ● WIth high doses (> 60 mcg/kg/min) or prolonged use (> 48 hrs) monitor for PRIS and pancreatitis including periodic Trig. Trig > 500 should prompt consideration of alternative sedation

Dexmedetomidine 0.2-1 mcg/kg/hrMax: 1.5 mcg/kg/hr

Bolus dosing not typically used

BradycardiaHypotension

● With prolonged use consider slower titration to avoid withdrawal. Consider addition of clonidine to facilitate titration off

● Does not required MV

Ketamine 0.5-2 mg/kg/hr Hypertension/tachycardia CV disease

ArrhythmiasEmergence reactionsCan cause hypertensionHypersalivation

● Doses > 0.5 mg/kg/hr MV recommended

Midazolam 1-5 mg/hr Renal impairment Hypotension ● At sedation doses typically hemodynamically neutral● Continuous infusion requires MV● Caution in renal impairment as drug and its active

metabolite can accumulate

mcg- microgram; kg- kilogram; min- minutes; PRIS- propofol related infusion syndrome; Trig- triglycerides; hr- hour; MV- mechanical ventilation; mg- milligram; CV- cardiovascular

Critical Care Pain Management Principles

• Use of validated pain scales• 0-10 self-reported scale• CPOT - used in critically ill sedated or non-

responsive patients• Score ranges from 0-8• 0-2 : Minimal to no pain present• > 2: Unacceptable level of pain present

• Use of adjuvant therapies• Acetaminophen• Gabapentin• Ketamine• Topical agents

Devlin et. al. CCM 2018; 46(9);e826-873.

COVID-19/ARDS Critical Care Management

Murthy S, Gomersall C, Fowlder R. JAMA; 3/11/2020

COVID-19 ARDS Management Principles PPE as appropriate Glucocorticoid therapy

• Role in treating COVID-19 unknown; not routinely used for ARDS management

• Currently not part of TUKHS treatment guidance document

Primarily Supportive Septic shock and organ dysfunction (ex: AKI) occur in significant portion of critically ill patients

Avoid high-flow nasal cannula or non-invasive ventilation strategies• Increased exposure risk

TUKHS Critical Care Surge Plan • Ongoing development and subject to change• Members: Dr Williamson, Dr Flynn, Dr Satterwhite, Adam Olberding (RN-

Director), Courtney Ash (RT-Director)• Cambridge will likely house traditional MICU patients and no positive COVID

patients• Current State (as of 3/28/20):

– COVID(+) 61 then 63 then 65– COVID(-) HC9– COVID Triage 66– Future MICUs? Bell PP, CA PP

TUKHS Other Initiatives and On-Goings• Inventory Management

– http://departments.kumed.com/rx/home/COVID19%20Info/COVID-19%20Acute%20Care%20Pharmacy%20Inventory%20Tracker.xlsx

• Recurring Wednesday morning meetings to discuss:– New COVID-19 literature– New medication mgmt. options– All updates can be found on the abx sharepoint

• Trials– Losartan (TUKHS;Dr Salathe)– Remdesivir (Gilead; looking into enrolling TUKHS into an expanded use program)– Remdesivir vs HCQ/Azithromycin vs Supportive Care (TUKHS; pending; Dr Pitts)

• Pharmacy– Staffing/Training – Standardization of Pain, Sedation, Paralysis

• Physicians: Dr Thomas, Nazir, Postigo, Spikes, Duthuluru• Pharmacists: Rose, Jace, Mikka, Lucy

What Is Our Ask of You?!• Keep informed• Ask questions• Identify patient clinical trends and share that information!• Be judicious in our resources

References• Murthy S, Gomersall C, Fowlder R. Care for Critically Ill Patients with COVID-19. JAMA; 3/11/2020.• Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak

in China. JAMA. Published online February 24, 2020. • Thompson BT et al. Acute Respiratory Distress Syndrome. N Engl J Med. 2017 Aug 10;377(6):562-572• Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–

March 16, 2020. CDC • http://www.ardsnet.org/files/ventilator_protocol_2008-07.pdf• Fan E, Del Sorbo L, Goligher E, et al. An Official American Thoracic Society/ European Society of Intensive Care

Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adults with Acute Respiratory Distress Syndrome. American Thoracic Society Documents; March 2017.

• National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, et al. Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Eng J Med 2019;380:1997.

• Artigas A, Bernard GR, Carlet J, et al. The American-European Consensus Conference on ARDS, part 2: Ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. Acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 157:1332.

• Devlin et. al. CCM 2018; 46(9);e826-873. • PETAL Network Clinical Trials. Neuromuscular Blockade in ARDS NEJM 2019• http://www.ardsnet.org/files/ventilator_protocol_2008-07.pdf

Acknowledgment• Mikka Soukup, PharmD, BCCCP• Angela Miller, PharmD, BCPS

Questions?Lucy Stun, PharmD, BCCCPClinical Coordinator: Critical Care, Emergency MedicineContact: lstun@kumc.eduApril 9th, 2020

Surviving Sepsis Campaign• Guidelines on the Management of Critically Ill Adults with Coronavirus

Disease 2019 (COVID-19)• NOT all based on COVID-19 literature

– Guidelines based on available literature to support any critically ill patient including any COVID-19 literature available.

• Final version will be published ccmjournal.org• Next few slides are summaries from the guidelines

Expansion in Treatment of COVID-19 Patients

Supportive Care Index• Hemodynamic

– Fluid Management– Vasoactive Agents– Shock

• Prevalence of 1-35%– Cardiac Injury

• Prevalence of 7-23%

• Ventilator Support

COVID-19: Hemodynamic Support

• Estimated shock prevalence: 1-35%

• Elevated cardiac markers: 7-23%

• Risk factors associated with shock development:• Older age• Co-morbidities (DM, CV disease including HTN)• Lower lymphocyte count• Elevated D-dimer level• Cardiac injury

COVID-19: Hemodynamic Support

Fluid Therapy- Crystalloids preferred- Driven by dynamic parameter evaluation

- Non-invasive cardiac output monitoring (NICOM)- Passive leg raise- Fluid bolus challenge- Fluid responsive defined as > 10% change in stroke volume

- Capillary refill time- Lactate measurement- Skin temperature

Fluid Management

• Conservative fluid management based on dynamic assessment– Reduce mortality– Reduce mechanical

ventilator support days of therapy

– Early clearance-directed therapy was associated with a reduction in mortality, shorter ICU length of stay and shorter duration of mechanical ventilation

• Buffered/balanced crystalloids over unbalances crystalloids

Vasoactive AgentsFirst Line Agent NOREPINEPHRINE Recommend against

dopamine if NE is available

First Line Alternative Vasopressin Epinephrine

Second Line (distributive shock) Vasopressin

Second Line (evidence of cardiac dysfunction) Dobutamine

Refractory Shock Add hydrocortisone 50mg IV q6h

MAP Goal= 60-65 mmHg

OR

Ventilator Support• 19% - prevalence of hypoxic respiratory failure in COVID-19• 14% - develop severe disease requiring oxygen therapy• 5% - require ICU admission and mechanical ventilation• Risk Factors for Respiratory Failure

– >60y/o– Male– Co-morbidities: DM, Malignancy, Immunocompromised

• Start oxygenation if SpO2<90-92% (NTE 96% on supplementation)

Expanded ARDS from SCCM Guideline

ARDS Management Expansion• Recommend against the use of nitric oxide • Last ditch effort: inhaled pulmonary vasodilator

– Taper off if no rapid improvement to avoid rebound pulmonary vasoconstriction

COVID-19 Therapy• Cytokine Storm in COVID-19 reminiscent in secondary hemophagocytic

lymphohistiocytosis (HLH)• Suggest AGAINST IVIG