This document provides an overview of acute respiratory distress syndrome (ARDS). It defines ARDS, describes its risk factors and pathophysiology. Key points include: ARDS involves fluid buildup in the lungs leading to hypoxemia; risk factors include sepsis, pneumonia and trauma; pathophysiology involves damage to the alveolar-capillary barrier allowing fluid influx; mortality has decreased to 30-40% with improved care but remains higher with greater illness severity or older age; complications can include barotrauma from mechanical ventilation.

1. Acute Respiratory Distress Syndrome
SIVA PADMANABHAN SIVAKUMAR, MD, FCCP, FACP
(aka Sivakumar Padmanabhan)
FELLOW, AMERICAN COLLEGE OF PHYSICIANS
FELLOW, AMERICAN COLLEGE OF CHEST PHYSICIANS
MEMBER , AMERICAN THORACIC SOCIETY,
MEMBER , SOCIETY OF CRITICAL CARE MEDICINE
MEMBER, AMERICAN COLLEGE OF LIFESTYLE MEDICINE
MEMBER, AMERICAN ASSOCIATION OF PHYSICIANS OF INDIAN ORIGIN
August 18, 2023

2. RUTLAND REGIONAL MEDICAL CENTER
AFFILIATION: UNIV OF VERMONT MED SCHOOL
INTENSIVIST & CHIEF,
DEPT OF CRITICAL CARE MEDICINE
RUTLAND, VERMONT, 05701
Southern New Hampshire Medical Center and
Elliot Hospital
Affiliation: Massachusetts General Hospital
Intensivist ,
Nashua and Manchester,
New Hampshire, 03060

3. OBJECTIVES
Definitions
Case based learning
Role of POCUS (Point Of Care Ultrasound)
Etiology- Pathophysiology
Course of the illness
Complications
Usual treatments &Advanced therapies
Palliative Care- when to call?
Post ICU syndrome
ICU survivor groups/ clinics
Future ?
bilateral
opacities
suggestive of
ARDS

4. Of the following, which is more commonly
recognized as a major risk factor for the
development of ARDS?
∙ Hyperthyroidism
∙ Massive transfusion
∙ Syncope
∙ Appendicitis

5. 5
correct response-Massive transfusion
Multiple risk factors exist for ARDS. These include direct lung injury (most commonly
aspiration of gastric contents), systemic illnesses, and injuries.
The most common risk factor for ARDS is sepsis.
Major risk factors associated with the development of ARDS include the following:
∙ Bacteremia, Sepsis
∙ Trauma, with or without pulmonary contusion
∙ Fractures, particularly multiple fractures and long bone fractures
∙ Fat embolism syndrome
∙ Burns, Massive transfusion
∙ Pneumonia, Aspiration
∙ Drug overdose, Near drowning
∙ Postperfusion injury after cardiopulmonary bypass
∙ Ac. Pancreatitis
( not in order of frequency)

6. Which of the following is most accurate regarding
symptoms and physical examination findings in
patients with ARDS?
∙ Findings associated with ARDS often include bradycardia
and bradypnea
∙ The absence of bilateral rales excludes a diagnosis of
ARDS
∙ Hypertension is more commonly present in patients with
ARDS than hypotension
∙ Patients with suspected ARDS should be investigated for
signs of intravascular volume overload

7. 7
correct response-
∙ Patients with suspected ARDS should be investigated for signs of
intravascular volume overload
∙ Findings associated with ARDS often include tachypnea, tachycardia
∙ The absence of bilateral rales does not exclude a diagnosis of ARDS
∙ Hypotension is more commonly present in patients with ARDS than
∙ hypertension

8. Infiltrates noted
on chest
radiography may
be interstitial,
characterized by
alveolar filling, or
both
The presence of
asymmetric
pulmonary
infiltrates on
radiography
excludes a
diagnosis of ARDS
CT is required
for diagnosis in
all patients
with ARDS
Transesophageal
echo is
contraindicated
in patients with
suspected ARDS
Which of the following is most accurate
regarding imaging studies in ARDS?

9. 9
Infiltrates noted on chest
radiography may be interstitial,
characterized by alveolar filling,
or both

10. ARDS in 2023
10
Acute respiratory distress syndrome (ARDS) is a severe lung condition
in which fluid builds up in alveoli in the lungs. It is most often seen in
individuals who are critically ill or who have significant injuries.
Patients with severe illness related to COVID-19 may quickly progress to
ARDS.
Which of the following has been recognized as a risk factor associated with
ARDS and progression from ARDS to death in patients with COVID-19?
∙ Neutropenia
∙ Treatment with methylprednisolone
∙ Coagulation dysfunction
∙ Fever
∙ Extremes of age

11. Presentation
Title
11
, , ,
,
Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in
Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China
Chaomin Wu, MD1,2,3; Xiaoyan Chen, MD3; Yanping Cai, MD2; et
alJia’an Xia, MD4; Xing Zhou, MD2; Sha Xu, MD2; Hanping Huang, MD4; Li Zhang, MD4; Xia Zhou, MD4; Chunling Du, MD1; Yuye Zhang, BD3; Juan Song, BD3; Sijiao Wang, BD3; Yencheng Chao, MD3; Zeyong Yang, MD5; Jie Xu, MD6; X
in Zhou, MD7; Dechang Chen, MD8; Weining Xiong, MD9; Lei Xu, MD10; Feng Zhou, MD1; Jinjun Jiang, MD3; Chunxue Bai, MD3,11; Junhua Zheng, MD12; Yuanlin Song, MD1,3,11,13
JAMA Intern Med. 2020;180(7):934-943 jamainternal_wu_2020_oi_200022.pdf
Original Investigation March 13, 2020
201 patients median age was 51 years
128 (63.7%) patients were men.
Eighty-four patients (41.8%) developed ARDS, and of those 84 patients, 44 (52.4%) died.
In those who developed ARDS more patients presented with dyspnea (50 of 84 [59.5%]

12. Increased Comorbidities such as hypertension, diabetes
risk factors associated with the development of ARDS and progression from ARDS to death included
● older age
● neutrophilia
● organ and coagulation dysfunction (eg, higher lactate dehydrogenase)
● hi D-Dimer
● fever (≥39 °C) was associated with higher likelihood of ARDS development and lower likelihood of death .
● treatment with methylprednisolone decreased the risk of death
Several factors associated with the development of ARDS were not associated with death (eg, comorbidities, lymphocyte
counts, CD3 and CD4 T-cell counts, AST, prealbumin, creatinine, glucose, low-density lipoprotein, serum ferritin, PT).
Difference in median D-dimer between the death and survival groups was larger than that between the ARDS and non-
ARDS groups
Suggests that disseminated intravascular coagulation was on the pathway to death in some patients.
Interestingly, although high fever was positively associated with development of ARDS, it was negatively related to death.
Cytokine storm and viral evasion of cellular immune responses are thought to play important roles in disease severity.
Treatment with methylprednisolone decreased the risk of death.
Treatment with methylprednisolone may be beneficial for patients who develop ARDS.

13. Presentation
Title
Bilateral diffuse interstitial infiltrates
Note sparing of CP angles
High-resolution computed tomography
scan
• small right pleural effusion,
• consolidation with air-bronchograms,
• and some ground-glass-appearing
opacities.
indicate an alveolar process,
• diffuse alveolar damage.
13

14. ARDS definition –
1994 by the American-European Consensus Conference (AECC)
The term “acute respiratory distress syndrome” was used instead of
“adult respiratory distress syndrome” because the syndrome occurs in
both adults and children.
1. acute condition
2. bilateral pulmonary infiltrates and severe hypoxemia
*in the absence of evidence for cardiogenic pulmonary edema
1. Severity of hypoxemia necessary to make the diagnosis of ARDS
2. defined by the ratio of the partial pressure of oxygen in the
patient’s arterial blood (PaO2) to the fraction of oxygen in the
inspired air (FiO2).
ARDS PaO2/FiO2 ratio of less than 200,
Acute Lung Injury PaO2/FiO2 less than 300.

15. 15
Definition was further refined in 2011 by a panel of experts , termed
Berlin definition of ARDS.
● timing (within 1 week of clinical insult or onset of respiratory symptoms);
● radiographic changes (bilateral opacities not fully explained by effusions,
consolidation, or atelectasis);
● origin of edema (not fully explained by cardiac failure or fluid overload); and
● severity based on the PaO2/FiO2 ratio on 5 cm of continuous positive airway
pressure (CPAP).
3 categories:
mild (PaO2/FiO2 200-300), moderate (PaO2/FiO2 100-200), and
severe (PaO2/FiO2 ≤100).

16. Epidemiology
2005 study, the incidence of ARDS was 78.9 per 100,000 patient-years, suggesting an
estimated 200,000 cases per year in the United States alone.
A 2016 study found a 10.4% incidence of ARDS among patients admitted to ICU’s.
Approximately 25% of patients who receive mechanical ventilation for longer than 48
hours are identified as having ARDS.
ARDS rate decreased from 82.4 to 38.9 cases per 100,000 person-years from
2001 to 2008-
decline was attributed to the fall in hospital-acquired ARDS since there was no change
in the incidence of admission with ARDS.
Pneumonia, sepsis, and advanced age are the most frequently encountered
predisposing factors for ARDS.
Genetic factors may have an important role in determining individual patients’
predisposition of acquiring ARDS.

18. Early ARDS Pathophysiology
increase in the permeability of the alveolar-capillary barrier>>>> influx of fluid
into the alveoli.
alveolar-capillary barrier is formed by the microvascular endothelium and the
epithelial lining of the alveoli.
Many insults cause damage to the vascular endothelium or to the alveolar
epithelium could result in ARDS.
main site of injury may be focused on either the vascular endothelium
(eg, sepsis) or the alveolar epithelium (eg, aspiration of gastric contents).
Injury to the endothelium results in increased capillary permeability and the influx
of protein-rich fluid into the alveolar space.

19. 19
Injury to the alveolar lining cells also promotes pulmonary edema formation.
Alveolar epithelial cells - Type I cells, make up 90% of the alveolar epithelium, injured easily.
Damage to type I cells allows increased entry of fluid into the alveoli and decreased clearance of fluid
from the alveolar space.
Type II alveolar epithelial cells are relatively more resistant to injury.
>> production of surfactant, ion transport, and proliferation and differentiation into type l cells after
cellular injury.
Damage to type II cells results in decreased production of surfactant with resultant decreased
compliance and alveolar collapse.
Interference with normal repair processes in the lung may lead to the development of fibrosis.
Neutrophils play a key role in the pathogenesis , as suggested by studies of bronchoalveolar lavage
(BAL) and lung biopsy specimens in early ARDS. Despite the apparent importance of neutrophils in this
syndrome, ARDS may develop in profoundly neutropenic patients, and infusion of granulocyte
colony-stimulating factor (G-CSF) in patients with ventilator-associated pneumonia (VAP) does not
promote its development.
evidence suggests that the neutrophils observed in ARDS may be reactive rather than causative.

20. Pathophysiology
Cytokines (tumor necrosis factor [TNF], leukotrienes, macrophage inhibitory factor),
platelet sequestration and activation,
-in the development of ARDS.
An imbalance of proinflammatory and anti-inflammatory cytokines after an inciting event, -
sepsis.
Evidence from animal studies suggests that the development of ARDS may be promoted by the
positive airway pressure delivered to the lung by mechanical ventilation-ventilator-associated
lung injury (VALI).
Studies (2017) on the ARDSNet patient cohort have identified at least two major subgroups
based on immune response and physiologic presentation.
Type one -primarily acute lung injury without antecedent systemic processes like sepsis or
pancreatitis.
Type two-acute lung injury with an overwhelming systemic insult like sepsis.
note, type one patients benefit from a fluid-restrictive management strategy
while type two patients benefit from a fluid-liberal approach.

21. Pathophysiology
ARDS --inhomogeneous process------ mechanical effects on alveoli,
Relatively normal alveoli, more compliant than affected alveoli, may
become overdistended by the delivered tidal volume =volutrauma,
resulting in barotrauma (pneumothorax and interstitial air).
Alveoli already damaged by ARDS may experience further injury
from the shear forces exerted by the cycle of collapse at end-
expiration and reexpansion by positive pressure at the next
inspiration >> atelectrauma
these forces promote the secretion of proinflammatory cytokines
worsening inflammation and pulmonary edema.
The use of positive end-expiratory pressure (PEEP) to diminish
alveolar collapse ,
low tidal volumes and limited levels of inspiratory filling
pressures -beneficial in diminishing VALI.

22. 22
ARDS causes a marked increase in intrapulmonary shunting, leading to
severe hypoxemia.
Although a high FiO2 is required to maintain adequate tissue oxygenation and
life, additional measures, like lung recruitment with PEEP required.
Theoretically, high FiO2 levels may cause DAD via oxygen free radical and
related oxidative stresses, collectively called oxygen toxicity.
Generally, oxygen concentrations higher than 65% for prolonged periods
(days) can result in DAD, hyaline membrane formation, and, eventually,
fibrosis.

23. Pathophysiology
ARDS is uniformly associated with pulmonary hypertension.
Pulmonary artery vasoconstriction likely contributes to ventilation-perfusion
mismatch -one of the mechanisms of hypoxemia in ARDS.
Normalization of pulmonary artery pressures occurs as the syndrome resolves.
The development of progressive pulmonary hypertension is associated with a poor
prognosis.
The acute phase of ARDS usually resolves completely.
Less commonly, residual pulmonary fibrosis occurs, in which the alveolar spaces are
filled with mesenchymal cells and new blood vessels--facilitated by interleukin (IL)-1.
Progression to fibrosis may be predicted early in the course by the finding of
increased levels of procollagen peptide III (PCP-III) in the fluid obtained by BAL.
fibrosis on biopsy correlates with an increased mortality rate.

24. mortality rate
Until the 1990s, 40-70%
However, 2 reports in the 1990s, one from a large county hospital in Seattle and one from the United Kingdom-
lower mortality rates, in the range of 30-40%.
• better understanding and treatment of sepsis,
• recent changes in the application of mechanical ventilation,
• and better overall supportive care of critically ill patients.
most deaths in ARDS patients are attributable to sepsis (a poor prognostic factor) or multi-organ failure rather than
to a primary pulmonary cause, although the recent success of mechanical ventilation using smaller tidal volumes
may suggest a role of lung injury as a direct cause of death.
Mortality in ARDS increases with advancing age.
King County, Washington-mortality rates of 24%- teens---15 and 19 years
and 60% in patients 85 years and older.
The adverse effect of age may be related to underlying health status.
Indices of oxygenation and ventilation, including the PaO2/FiO2 ratio, may predict the outcome or risk of death.
2016 -multicenter study including 50 countries found an increasing hospital mortality rate with ARDS severity:
34.9% -mild, 40.3% -moderate, and 46.1-severe ARDS

25. barotrauma
Patients with ARDS often require high-intensity mechanical ventilation, including high levels of
positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) and,
possibly, high mean airway pressures;
1. pneumomediastinum , pneumothorax
2. Other potential complications
3. accidental extubation, right mainstem intubation.
**prolonged mechanical ventilation eventually requires tracheostomy.
1. prolonged intubation and tracheostomy >>upper airway complications
2. post extubation laryngeal edema , subglottic stenosis.
patients with ARDS often require prolonged mechanical ventilation and invasive
hemodynamic monitoring,
1. risk for serious nosocomial infections, including ventilator-associated pneumonia (VAP) and
line sepsis. incidence of VAP in ARDS as high as 55%
higher than that in other populations requiring mechanical ventilation.
Preventive strategies
1. elevation of head of the bed
2. use of subglottic suction endotracheal tubes
3. oral decontamination.

26. infections in ARDS
• urinary tract infection (UTI) related to the use of urinary catheters
• sinusitis & pneumonia due to the use of nasal feeding, endotracheal and
gastric drainage tubes
• Clostridium difficile colitis -> a complication of broad-spectrum antibiotic
therapy.
Patients with ARDS, because of the extended intensive care unit (ICU) stay and
treatment with multiple antibiotics, >>infections with drug-resistant organisms such
as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-
resistant Enterococcus (VRE), or gram-negative organisms with extended-
spectrum beta-lactamases.
survivors of ARDS, significant functional impairment was noted at 1 year,
primarily related to muscle wasting and weakness
Corticosteroid treatment and use of neuromuscular blockade are risk factors for
muscle weakness and poor functional recovery.

27. ARDS--complications
difficulty weaning from mechanical ventilation.
Strategies to facilitate weaning,
• daily sedation vacation,
• early institution of physical therapy,
• attention to nutrition,
• use of weaning protocols, may decrease the duration of mechanical ventilation and facilitate
recovery.
Acute ( on chronic) Renal failure is a frequent complication of ARDS,
hypotension, nephrotoxic drugs, underlying illness.
Fluid management is complicated, especially if the patient is oliguric.
• ileus- due to sepsis, narcotics, benzos, electrolyte imbalance
• stress gastritis,
• anemia due to
○ critical illness, marrow suppression,
• E’poetin deficiency in AKI/CKD), blood loss due to GI bleeding,
○ hemolysis, phlebotomy, (iatrogenic blood loss)
○ ****Stress ulcer prophylaxis is indicated for these patients.
Multisystem organ failure is usually the cause of death

28. ARDS--complications
survivors of ARDS often suffer from posttraumatic stress disorder (PTSD),
prolonged myopathy limiting activities of daily living,
increased long-term mortality after apparent recovery.
major post icu complications linger a minimum of 3 months,
several patients have persistent neurocognitive dysfunction for upto 1-2
years independent of physiologic status and cardiopulmonary reserve.
management is primarily supportive and aided by the clinician having a
keen awareness that such PTSD symptoms persist.
Post icu- survivor clinic Multidisciplinary team

29. Lung injury prediction score
identifies patients who are unlikely to develop ALI/ARDS
■ shock (2 points),
■ aspiration (2 points),
■ sepsis (1 point),
■ pneumonia (1.5 points),
■ orthopedic spine surgery (1.5 points),
■ acute abdominal surgery (2 points),
■ cardiac surgery (2.5 points),
■ aortic vascular surgery (3.5 points),
■ traumatic brain injury (2 points),
■ smoke inhalation (2 points),
■ near drowning (2 points),
■ lung contusion (1.5 points),
■ multiple fractures (1.5 points),
■ alcohol abuse (1 point),
■ obesity (BMI >30, 1 point),
■ hypoalbuminemia (1 point),
■ chemotherapy (1 point),
■ fraction of inspired oxygen >0.35 or >4
L/min (2 points),
■ tachypnea >30 breaths/min (1.5 points),
■ oxyhemoglobin saturation <95 percent (1
point),
■ acidosis (pH <7.35, 1.5 points),
■ diabetes mellitus (-1 point).

30. Diagnostic Considerations
∙ Pulmonary hemorrhage
∙ Near drowning
∙ Drug reaction
∙ Acute hypersensitivity pneumonitis
∙ Transfusion-related acute lung injury (TRALI)
∙ Acute eosinophilic pneumonia
∙ Reperfusion injury
∙ Leukemic infiltration
∙ Fat embolism syndrome

31. Differential Diagnoses
1. Aspiration Pneumonitis/Pneumonia
2. Pneumonia-
3. Community acquired- Bacterial,Viral, Fungal, Parasitic,Mycobacterial
4. Hospital acquired/ Ventilator-Associated Pneumonia
5. Severe Sepsis/ Septic Shock
6. Toxic Shock Syndrome
7. Hemorrhagic Shock
8. Transfusion Reactions-
9. Massive transfusions, TRALI (Transfusion Associated Acute lung Injury)
10.Opiate Toxicity
11.Hypersensitivity Pneumonitis
12.Mechanical Ventilation
13.Multiple Organ Dysfunction Syndrome in Sepsis
14.Pneumocystis jiroveci Pneumonia (PJP)
15.Salicylate Toxicity
16.Placental abruption,
17.Amniotic fluid embolism,
18.Fat embolism syndrome

32. Fluid Management
initial fluid resuscitation and maintenance fluid therapy
Early aggressive resuscitation for associated circulatory shock and
its associated organ injury are key aspects ;
small trials demonstrated improved outcome for ARDS in patients
treated with diuretics or dialysis to promote a negative fluid balance in
the first few days.
***Distinguish between primary ARDS due to aspiration, pneumonia,
or inhalational injury, which usually can be treated with fluid
restriction,
from secondary ARDS due to remote infection or inflammation that
requires initial fluid and potential vasoactive drug therapy

33. 33
Fluid Management
An ARDS Clinical Trials Network study of a fluid-conservative strategy versus a fluid-liberal
strategy in the management of patients with ARDS or acute lung injury (ALI) found no
statistically significant difference in 60-day mortality between the two groups 72 hours after
presentation with ARDS.
However, patients treated with the fluid-conservative strategy had an improved oxygenation
index and lung injury score and an increase in ventilator-free days, without an increase in non
pulmonary organ failures.
Patients whose fluids were managed conservatively did not have an increased need for
vasopressors or dialysis
ARDS clinical trials network of pulmonary artery catheter versus CVP to guide fluid management in
ARDS showed no difference in mortality or ventilator-free days, regardless of whether fluid status was
monitored by pulmonary artery catheter or CVP.
Closely monitor urine output and administer diuretics to facilitate a negative fluid balance.
In oliguric patients, hemodialysis with ultrafiltration or continuous veno-venous hemofiltration/dialysis
(CVVHD) may be required.

34. Noninvasive Ventilation and High-Flow Nasal Cannula
intubation and mechanical ventilation may be associated with an increased incidence of complications,
barotrauma and nosocomial infections;
used in conjunction with an oxygen blender, allowing delivery of precise inspired oxygen concentrations.
High-flow nasal cannula is usually well tolerated and allows the patient to talk, eat, and move around.
NIPPV is usually given by full face mask.
Sometimes, continuous positive airway pressure (CPAP) alone may be sufficient to improve oxygenation.
2015 study
hypoxemic, non hypercapnic patients comparing
standard oxygen, high-flow nasal cannula, and NIPPV,
all three modes had the same incidence of need for intubation/mechanical ventilation,
but high-flow nasal cannula resulted in improved 90-day mortality.
alternatives to mechanical ventilation such as a high-flow nasal cannula or noninvasive positive-pressure
ventilation (NIPPV) may be beneficial in patients with ARDS.
High-flow nasal cannula uses a system of heated humidification and large-bore nasal prongs to deliver
oxygen at flows of up to 50-60 L/min.

35. Mechanical Ventilation goals in ARDS
• maintain oxygenation
• avoiding oxygen toxicity and complications of mechanical ventilation.
maintaining oxygen saturation in the range of 85-90%, with the aim of reducing the fraction of inspired oxygen
(FiO2) to less than 65% within the first 24-48 hours.
necessitates the use of moderate-to-high levels of positive end-expiratory pressure (PEEP).
mechanical ventilation may promote a type of acute lung injury termed ventilator-associated lung injury.
Lung protective ventilation strategy?
low tidal volumes and limited plateau pressures improves survival when compared with conventional tidal
volumes and pressures.
ARDS Network study, patients with ALI and ARDS were randomized to mechanical ventilation either at a tidal
volume of 12 mL/kg of predicted body weight and an inspiratory pressure of 50 cm water or less or at a tidal
volume of 6 mL/kg and an inspiratory pressure of 30 cm water or less;
study was stopped early after interim analysis of 861 patients demonstrated that subjects in the low-tidal-
volume group had a significantly lower mortality rate (31% versus 39.8%).
previous studies with low tidal volumes allowed patients to be hypercapnic (permissive hypercapnia) and
acidotic to achieve the protective ventilation goals of low tidal volume and low inspiratory airway pressure,
ARDS Network study allowed increases in respiratory rate and use of bicarbonate to correct acidosis.
This may account for the positive outcome in this study as compared with earlier studies that had failed to
demonstrate a benefit.

36. Mechanical Ventilation
tidal volume of 6 mL/kg predicted body weight is recommended, with adjustment of the tidal volume to as low as 4
mL/kg if needed to limit the inspiratory plateau pressure to 30 cm water or less.
Increase the ventilator rate and administer bicarbonate as needed to maintain the pH at a near normal level (7.3).
ARDS Network study, patients ventilated with lower tidal volumes required higher levels of PEEP (9.4 vs 8.6 cm water)
maintain oxygen saturation at >85%
Measuring esophageal pressures with an esophageal balloon catheter allows estimation of transpulmonary pressure.
Basing ventilator strategy on these pressures as PEEP is titrated might allow determination of “best PEEP” levels for
improving oxygenation and minimizing volutrauma and atelectasis.
Using the protective ventilation strategy of lower tidal volumes, limited plateau pressure, and higher PEEP improves
survival in ARDS.
Amato et al, through a retrospective review of more than 3500 patients with ARDS reported in nine prior studies, found
that the most important ventilation variable in determining survival is delta P (plateau pressure minus PEEP).
Delta P is a reflection of lung compliance and is reliable for predicting survival in patients with ARDS who are not
spontaneously breathing.
In these patients, lower levels of delta P improved survival.
Higher levels of PEEP and lower tidal volumes did not improve survival, unless they were associated with lower levels
of delta P.

37. use of paralytics remains controversial.
Patients with severe ARDS may also benefit from the early use of neuromuscular
blocking agents.
In a group of patient with severe ARDS (PaO2/FiO2< 120) diagnosed within 48 hours,
paralysis with cisatracurium for the next 48 hours was shown to improve 90-day
mortality, when compared with placebo (31.6% for cisatracurium vs 40.7% for placebo);
increase ventilator-free days; and reduced barotrauma.
There was no increased incidence of prolonged muscle weakness in the group that was
paralyzed.
However, a more recent study in 2019 of patients with a PaO2/FiO2 ratio of less than
150 mm Hg for less than 48 hours did not demonstrate any improvement in mortality,
ventilator-free days, or rates of barotrauma.
Neuromuscular blocking agents should be used selectively.
These agents may be beneficial in patients with very severe ARDS, those who have
problems synchronizing breathing with the ventilator, and patients with poor lung
compliance.

38. Positive end-expiratory pressure and continuous positive airway
With PEEP, positive pressure is maintained throughout expiration, but when the patient inhales
spontaneously, airway pressure decreases to below zero to trigger airflow.
With CPAP, a low-resistance demand valve is used to allow positive pressure to be maintained
continuously. Positive-pressure ventilation increases intrathoracic pressure and thus may decrease
cardiac output and blood pressure.
Because mean airway pressure is greater with CPAP than PEEP, CPAP may have a more profound
effect on blood pressure.
patients tolerate CPAP well.
appropriate levels of CPAP is thought to improve the outcome in ARDS. By maintaining the alveoli in
an expanded state throughout the respiratory cycle, CPAP may decrease shear forces that promote
ventilator-associated lung injury.
The best method for finding the optimal level of CPAP in patients with ARDS is controversial.
just enough CPAP to allow reduction of the FiO2 below 65%.
Another approach, favored by Amato et al, is the so-called open lung approach, in which the
appropriate level is determined by the construction of a static pressure volume curve. This is an S-
shaped curve, and the optimal level of PEEP is just above the lower inflection point. Using this
approach, the average PEEP level required is 15 cm water.

39. A 2010 review by Briel et al found that treatment with
higher of PEEP demonstrated no advantage over
treatment with lower levels in patients with ALI or ARDS;
however, among patients with ARDS, higher levels were
associated with improved survival.
A study by Bellani et al found that in patients with ALI
managed with relatively high PEEP, metabolic activity of
aerated regions was associated with plateau pressure and
regional tidal volume that was normalized by end-
expiratory lung gas volume; no association was found
between cyclic recruitment /derecruitment and increased
metabolic activity.

40. Pressure-controlled ventilation (PCV)
If high inspiratory airway pressures are required to deliver even low tidal volumes,
pressure-controlled ventilation may be initiated.
Clinician sets the level of pressure above CPAP (delta P) and the inspiratory time (I-time)
or inspiratory/expiratory (I:E) ratio.
resultant tidal volume depends on lung compliance and increases as ARDS improves.
PCV may also result in improved oxygenation in some patients not doing well on volume-
controlled ventilation (VCV).
If oxygenation is a problem, longer I-times, such that inspiration is longer than expiration
(inverse I:E ratio ventilation) may be beneficial; ratios as high as 7:1
PCV, using lower peak pressures, may also be beneficial in patients with bronchopleural
fistula, facilitating closure of the fistula.
beneficial in ARDS,
In a multicenter controlled trial comparing VCV with PCV in ARDS patients, Esteban found
that PCV resulted in fewer organ system failures and lower mortality rates than VCV,
despite use of the same tidal volumes and peak inspiratory pressures.

41. High-frequency ventilation -jet or oscillatory uses low tidal volumes
(approx 1-2 mL/kg) and high respiratory rates (3-15 breaths per second).
Given that distention of alveoli is known to one of the mechanisms promoting
ventilator-associated lung injury, high-frequency ventilation would be expected
to be beneficial in ARDS.
**early improvement in oxygenation but no improvement in survival.
randomized controlled trial included 548 adults with moderate-to-severe ARDS
who were randomized to conventional ventilation or high-frequency oscillatory
ventilation (HFOV). terminated early for harm due to an in-hospital mortality rate
of 47% in patients receiving HFOV and 35% in the conventional arm.
HFOV is not recommended as a treatment strategy for ARDS.
Partial liquid ventilation has also been tried in ARDS. A randomized controlled
trial that compared it with conventional mechanical ventilation determined that
partial liquid ventilation resulted in increased morbidity (pneumothoraces,
hypotension, and hypoxemia), and a trend toward higher mortality.

42. Airway pressure release ventilation
Airway pressure release ventilation (APRV) is another ventilatory mode that uses
a long duration (T high) of a high positive airway pressure (P high) followed by a
short duration (T low) at a low pressure (P low).
The time spent at a P high as compared with P low is an inverse ratio to normal
breathing patterns.
patient may spend 5.2 seconds at P high and 0.8 seconds at P low.
The theory is that time at P high significantly increases and maintains alveolar
recruitment, thereby improving oxygenation.
APRV may improve oxygenation, but there have been no randomized controlled
trials demonstrating improved survival with ARDS.
Physicians should exercise caution with APRV in patients with obstructive lung
disease, owing to the relatively short exhalation time and possible hyperinflation
and barotrauma.

43. Prone positioning
60-75% of patients with ARDS have significantly improved
oxygenation when turned from the supine to the prone position.
improvement in oxygenation is rapid and substantial enough to allow
reductions in FiO2 or level of CPAP.
The prone position is safe, with appropriate precautions to secure all
tubes and lines, and does not require special equipment.
improvement in oxygenation may persist after the patient is returned
to the supine position
may occur on repeat trials in patients who did not respond initially.
Possible mechanisms
• recruitment of dependent lung zones,
• increased functional residual capacity (FRC),
• improved diaphragmatic excursion,
• increased cardiac output
• improved ventilation-perfusion matching.

44. Despite improved oxygenation with the prone position, early randomized controlled trials of
the prone position in ARDS did not demonstrate improved survival.
Italian study- survival rate to discharge from the ICU and the survival rate at 6 months were
unchanged compared with patients who underwent care in the supine position, despite a
significant improvement in oxygenation.
French study- prone position for at least 8 hours per day, did not document a benefit from the
prone position in terms of 28- or 90-day mortality, duration of mechanical ventilation, or
development of ventilator-associated pneumonia (VAP).
However, a subsequent randomized controlled trial in which patients with severe ARDS were
placed in the prone position early and for at least 16 hours a day
significant mortality benefit. patients with severe ARDS (PaO2/FiO2 of < 150) were
randomized to prone position after 12-24 hours of stabilization. The 28-day mortality rate was
16% in the prone group and 32.8% in the supine group.
Patients were turned manually. A specialized bed was not required.

45. Extracorporeal Membrane Oxygenation
A large multicenter trial in the 1970s demonstrated that extracorporeal membrane
oxygenation (ECMO) did not improve the mortality rate in ARDS patients.
A later trial using extracorporeal carbon dioxide removal along with inverse-ratio
ventilation also did not improve survival in ARDS.
However, during the H1N1 flu epidemic in 2009, ECMO appeared to improve survival in
patients with H1N1-associated ARDS who could not be oxygenated with conventional
mechanical ventilation.
2018 study of venovenous ECMO for ARDS. In this study, patients with very severe
ARDS (PaO2/FiO2 of < 50) were randomized to venovenous ECMO or conventional
management with ECMO rescue for refractory hypoxemia.
a trend toward lower mortality (35% ECMO vs 46% control), there was no statistically
significant difference in 60-day mortality.
Extracorporeal carbon dioxide removal may also be an option for ARDS. Extracorporeal
carbon dioxide removal uses a less invasive system than venovenous ECMO, similar to
hemodialysis.
Carbon dioxide removal would allow lower-intensity mechanical ventilation and possibly
less ventilator-associated lung injury. This is currently under study.

46. Nutritional Support
nutritional support by 48-72 hours of mechanical ventilation usually is recommended. Enteral
nutrition via a feeding tube is preferable to IV hyperalimentation unless it is contraindicated
because of an acute abdomen, ileus, GI bleeding, or other conditions.
different combinations of nutritional components have been investigated with mixed results.
low-carbohydrate high-fat enteral formula including anti-inflammatory and vasodilating
components (eicosapentaenoic acid and linoleic acid) along with antioxidants has been
demonstrated in some studies to improve outcome in ARDS.
prospective, randomized study of ARDS patients in Brazil given an enteral formula containing
antioxidants, eicosapentaenoic acid, and gamma-linoleic acid compared with a standard isocaloric
formula, Pontes-Arruda et al demonstrated improved survival and oxygenation with the specialized
diet.
2011, a randomized controlled trial compared enteral supplementation with omega-3 fatty acids,
gamma-linolenic acid, and antioxidants to an isocaloric control in 272 patients diagnosed with
acute lung injury.
study was stopped early for futility since the n-3 group had a 60-day mortality rate of 26.6% and
the control group had a 16.3% 60-day mortality rate.

47. open-label, multicenter trial (the EDEN study) randomized 1000 adult
patients who required mechanical ventilation within 48 hours of developing
acute lung injury to receive either trophic or full enteral feeding for the first 6
days. Initial lower-volume trophic enteral feeding did not improve ventilator-
free days, 60-day mortality, or infectious complications compared with initial
full enteral feeding, but it was associated with less gastrointestinal
intolerance.
Frequent position changes should be started immediately, as should
passive—and, if possible, active—range-of-motion activities of all muscle
groups.
Elevation of the head of the bed to a 45° angle is recommended to diminish
the development of VAP.
minimizing sedation and earlier ambulation ---
associated with less posttraumatic stress disorder in survivors and was the
preferred approach by patients’ families. If at all possible, use of minimal
sedation, sedation holidays, and more ambulation appear to be the goals of
management once severe cardiovascular insufficiency, if present, has
resolved.

48. Medications
No drug has proved beneficial in the prevention or management of acute respiratory distress
syndrome (ARDS).
Early administration of corticosteroids to septic patients does not prevent the development of ARDS.
inhaled or instilled synthetic surfactant,
intravenous (IV) antibody to endotoxin,
ketoconazole, ibuprofen,
Statins
tried , not effective.
Small sepsis trials suggest a potential role for antibody to tumor necrosis factor (TNF) and
recombinant interleukin (IL)–1 receptor antagonist.
Inhaled nitric oxide (NO), a potent pulmonary vasodilator, seemed promising in early trials, but in
larger controlled trials, it did not change mortality rates in adults with ARDS.
systematic review, meta-analysis, and trial sequential analysis of 14 randomized controlled trials,
including 1303 patients,
--inhaled nitric oxide did not reduce mortality and results in only a transient improvement in
oxygenation.
Inhaled prostacyclin not been shown to improve survival.

49. Methylprednisolone (Solu-Medrol)
Development of the late phase of ARDS may represent
continued uncontrolled inflammation, and corticosteroids
may be considered a form of rescue therapy that may
improve oxygenation and hemodynamics but does not
change mortality (except that corticosteroids increase
mortality in patients who have had ARDS for >14 d).
High-dose methylprednisolone has been used in trials of
patients with ARDS who have persistent pulmonary
infiltrates, fever, and high oxygen requirement despite
resolution of pulmonary or extrapulmonary infection.
Pulmonary infection is assessed with bronchoscopy and
bilateral bronchoalveolar lavage (BAL) and quantitative
culture.

50. there might be a role for high-dose corticosteroid therapy in patients with
late (fibroproliferative phase) ARDS.
However, an ARDS Study Network trial of methylprednisolone for patients
with ARDS persisting for at least 7 days demonstrated no benefit in terms
of 60-day mortality. ] Patients treated later in the course of ARDS, 14 days
after onset, had worsened mortality with corticosteroid therapy.
Although no survival advantage was shown in patients treated with
methylprednisolone, short-term clinical benefits included improved
oxygenation and increased ventilator-free and shock-free days.
Patients treated with corticosteroids were more likely to experience
neuromuscular weakness, but the rate of infectious complications was not
increased.

51. Diff. Diagnoses
Cardiogenic pulmonary edema and fluid overload:
The differentiation between hydrostatic pulmonary edema and ARDS can be
difficult, since the hypoxemia and radiological appearance are similar in the two
conditions.
Although the Berlin criteria require left heart failure to be ruled out to diagnose
ARDS, the two conditions often coexist.
Pure hydrostatic pulmonary edema usually responds quickly to diuretics and other
cardiac-specific therapies.
Atelectasis: Bilateral infiltrates and hypoxemia due to alveolar collapse can be
confused with ARDS but usually respond dramatically to alveolar recruitment
strategies.
should be treated in an identical fashion with lung-protective ventilation.
Interstitial lung diseases -idiopathic pulmonary fibrosis can present with acute
clinical deterioration together with radiological (new-onset diffuse infiltrates) and
physiological (hypoxemia, low lung compliance) similar to ARDS. The history of
chronic illness and previous radiographs/pulmonary function tests may help in the
diagnosis.
.

52. Presentation Title 9/3/20XX 52
Acute interstitial pneumonia (Hamman Rich) can present with subacute
evolution of respiratory functional impairment and diffuse radiological infiltrates
with no known predisposing factors to ARDS.
When the differential diagnosis is uncertain, open lung biopsy should be
considered prior to initiation of immunosuppressant therapy.
Acute eosinophilic pneumonia presents with bilateral infiltrates.
abundance of eosinophils in the bronchoalveolar lavage. 6) Occasionally, a
radiological infiltrative pattern can be caused by malignancy. (bronchoalveolar
carcinoma)
Diffuse Alveolar hemorrhage due to vasculitis processes such as
Goodpasture’s syndrome and Wegener’s granulomatosis presents with
hypoxemia, diffuse radiological infiltrates and hemoptysis (although this
symptom can be absent).
The presence of acute anemia and hemorrhagic sputum by fiberoptic
bronchoscopy and bronchoalveolar lavage usually confirm the diagnosis of
alveolar hemorrhage. Serologic testing and lung and kidney biopsies are used
to narrow the differential diagnosis

53. Take Home Points:
formal guidelines for the management of ARDS
published in the Annals of Intensive Care in June 2019,
recommended:
∙ Prone positioning should be used to reduce mortality in patients with
ARDS who have a PaO2/FiO2 ratio < 150 mm Hg.
∙ A tidal volume of around 6 mL/kg of ideal body weight should be
used as a first approach in patients with ARDS, in the absence of
severe metabolic acidosis, including patients with mild ARDS.
∙ Once tidal volume is set to around 6 mL/kg ideal body weight ,
plateau pressure should be continuously monitored and should not
exceed 30 cm H2O.
∙ High-frequency oscillation ventilation should not be used in patients
with ARDS.
∙ Although high PEEP is recommended in patients with moderate or
severe ARDS, it is not recommended in patients with mild ARDS.

54. OOOOOOOOOOO—what is this?

55. Chest radiograph in a patient with acute
respiratory distress syndrome (ARDS).
The patient was treated with perfluorocarbon
►Partial Liquid Ventilation in Adult Patients
with Acute Respiratory Distress Syndrome
• American Journal of Respiratory and Critical Care
Medicine >
• Volume 173, Issue 8
►American Journal of Respiratory and Critical Care Medicine
►Robert M. Kacmarek , Herbert P.
Wiedemann , Philip T. Lavin , Mark K.
Wedel , Ahmet S. Tütüncü , and Arthur S.
Slutsky
PLV at both high and low doses did not improve
outcome in ARDS compared with CMV and
cannot be recommended for patients with ARDS.
∙ More pneumothoraces, hypoxic episodes,
and hypotensive episodes in the PLV
patients.
PFC: clear inert liquid,
mechanical ventilation is provided with a
standard ventilator
rationale -PFCs improve gas exchange by
recruiting dependent lung regions
by clearing retained secretions
redistributing blood flow to ventilated regions
use of PLV abrogates lung injury due to the low
surface tension
and anti-inflammatory properties

56. Voxelotor as a Treatment of Persistent Hypoxia in the ICU (chestnet.org)
Volume 164, Issue 1, July 2023, CHEST JOURNALs a Treatment of Persistent Hypoxia in the ICU
Omar Al-Qudsi MD John M. Reynolds MD John C. Haney MD Ian J. Welsby MBBS
Department of Anesthesiology, Duke University Medical Center, Durham, NC
Division of Transplant Pulmonology, Department of Medicine, Duke University School of Medicine, Durham, NC
Division of Thoracic Transplant Surgery, Department of Surgery, Duke University School of Medicine, Durham, NC
Hypoxia is encountered frequently in the ICU
The oxygen-hemoglobin dissociation curve describes hemoglobin’s affinity for a given PO2 and factors affecting
uptake and offload.
Research in manipulating this relationship between hemoglobin and oxygen is sparing.
Voxelotor is a hemoglobin oxygen-affinity modulator that is approved by the US Food and Drug Association for use
in the management of sickle cell disease.
2 patients without sickle cell disease who underwent treatment with this novel agent to assist with chronic hypoxia
and weaning of mechanical support.
Voxelotor as a Treatment of Persistent Hypoxia in the ICU

57. Hypoxia is the most frequently encountered pathologic feature in the ICU,
Methods to ameliorate hypoxia are wide-ranging,
oxygen delivery and uptake.
Increased Fio2 via supplemental oxygen delivery,
optimization of positive end expiratory pressure to improve V˙/Q˙ mismatch,
RBC transfusion to manipulate blood oxygen content, and measures to decrease demand
focus on different parts of the oxygen delivery and consumption cycle.
,
One area that has few therapeutic options available is the oxygen-hemoglobin dissociation curve,
which determines the amount of oxygen-bound hemoglobin for a given Po2.
Voxelotor is a hemoglobin-oxygen affinity modulator that stabilizes the oxygenated hemoglobin state
success as a treatment for patients with sickle cell disease.
Case reports- two patients without sickle cell disease with refractory hypoxemia who underwent treatment with voxelotor.

58. 58
Case Report 1
61-year-old White woman -past medical history of idiopathic noncirrhotic portal hypertension and idiopathic pulmonary fibrosis
s/p liver txplnt. oxygen dependent at rest and with ambulation believed to be driven mainly by hepatopulmonary syndrome from
liver failure. s/p successful liver transplantation
significantly hypoxic after surgery, requiring veno-venous extracorporeal membrane oxygenation (ECMO) support.
postoperative course - numerous operative visits related to bleeding and vascular complications, but most notable for continued
hypoxemia despite extracorporeal support.
d/t inability to wean quickly from venovenous ECMO underwent tracheostomy placement and transitioned to an Avalon dual-lumen
cannula (Getinge).
Despite physical therapy, diuresis, and trials of inhaled pulmonary vasodilators patient was unable to tolerate prolonged ECMO sweep
trials, limited by acute desaturation with activity.
postoperative day 82, the decision to proceed with a trial of voxelator after emergency investigational new drug approval and patient
consent.
started on 500 mg voxelator tid administered enterally.
This initial treatment only lasted 4 days because of a repeat operating room visit resulting from abdominal bleeding and a lack of
enteral access.
Voxelator was reinstituted 4 days later at the same dosage.
Response to therapy was difficult to track given the confounding influences of the ventilator and venovenous ECMO, although her
ability to tolerate longer sweep trials with a lower FIO2 was apparent clinically.
Furthermore, tracking of hemoglobin modification by the voxelator molecule (send-out lab; Global Blood Therapeutics) showed
46% to 48% modification that coincided with tolerating a prolonged sweep trial; Removal of ECMO achieved successfully on
postoperative day 97.
Voxelotor ultimately discontinued 10 days later after venovenous ECMO was discontinued and the patient tolerated humidified
oxygen via a tracheostomy collar while performing physical therapy. Discharged home 1 to 21 L/min of oxygen. No deleterious
effects attributed to voxelator were observed during her care.

59. Graph demonstrating increasing duration of sweep trials with decreasing FIO2 concentration after institution of
voxelotor.
x = start of voxelotor treatment; y = pause in treatment because of operating room visit and lack of enteral access.
59

60. Case Report 2
61-year-old woman -history of tobacco abuse, COPD, OSA, mitral valve stenosis after bioprosthetic mitral-valve
replacement, pulmonary hypertension, and severe tricuspid regurgitation with 4 L of home oxygen ,symptoms of
decompensated heart failure and hypoxic respiratory failure.
Cardiac catheterization -severe stenosis of the bioprosthetic valve, severe pulmonary hypertension, and severe tricuspid
regurgitation.
Despite aggressive diuretic therapy, condition continued to deteriorate, requiring multiple inotropic agents as well as heated
high-flow nasal cannula (100% FIO2, 55 L) for oxygenation.
Transferred for evaluation of possible cardiac surgical interventions or transplantation.
After multidisciplinary evaluation by pulmonary hypertension and cardiac surgical specialists, decompensation postulated as
a result of severe mitral stenosis along with untreated severe pulmonary hypertension. Decision to proceed with mitral
valve replacement and tricuspid valve repair followed by management of the pulmonary hypertension. She underwent redo-
sternotomy, mechanical mitral valve replacement (27-mm St. Jude; Abbott), and placement of a tricuspid ring
(32-mm Carpentier-Edwards Physio II; Edwards) with cleft and commissure closure.
Post op> cardiac ICU with an open chest to assist with right ventricular function, and the chest was closed on postoperative
day 1.
Pulmonary hypertension was managed with inhaled pulmonary vasodilators (nitric oxide and epoprostenol) before institution
of oral therapy (sildenafil).
Postoperative course was remarkably stable from a hemodynamic standpoint, but notable for severe hypoxic respiratory
failure culminating in tracheostomy.

61. cause of this lung failure was believed to be infectious, severe pulmonary hypertension and parenchymal changes
from chronic lung disease.
continued to require high amounts of oxygen support via ventilator (60%-80%) despite diuretics, inhaled
bronchodilators, and management of postoperative pneumonias.
Various attempts to wean from oxygen support failed, despite aggressive physical therapy. high FIO2 requirement
prevented discharge to a long-term weaning facility.
Four months into the ICU stay, it was decided to attempt treatment with voxelotor as rescue to help wean the patient
from oxygen requirement. Emergency investigational new drug authorization was obtained and the patient provided
consent for treatment.
Voxelotor 300 mg bid was started initially with a slow increase in dosage.
Response to voxelotor was monitored through twice daily attempts to wean her from the ventilator while monitoring
changes in oxygen saturation.
Oxygen saturation to FIO2 ratios were recorded with a slow improvement in oxygenation over the 2 weeks after
institution of voxelotor.

62. 62
Line graph showing the oxygen saturation to FIO2 ratio after
voxelotor administration. S/F = SpO2/FIO2
Day Oxygen Saturation FIO2 Oxygen Saturation to FIO2 Ratio
1 91 0.8 114
2 87 0.75 116
3 91 0.7 130
4 87 0.7 124
5 85 0.6 142
6 85 0.6 142
7 85 0.5 170
8 87 0.7 124
9 86 0.6 143
10 87 0.4 218
11 86 0.45 191
12 92 0.5 184
13 83 0.45 184
14 90 0.55 164

63. Presentation Title 9/3/20XX 63
Unfortunately, sepsis developed in the patient related to ventilator-
associated pneumonia, and kidney function began to deteriorate.
She continued to worsen as a result of sepsis, culminating in severe
shock and right ventricular failure with bradycardia.
After family discussions, the ultimate decision was made to proceed
with a transition to comfort care.

64. Presentation Title 9/3/20XX 64
Discussion
Voxelotor is an oral agent that modifies the affinity
between hemoglobin and oxygen.
It acts through a covalent, reversible bond that results
in allosteric modification of hemoglobin, resulting in a
higher affinity for oxygen.
As a result, at the same given PO2, hemoglobin
molecules may retain a higher oxygen saturation.
Voxelotor has received US Food and Drug Association
approval for use in sickle cell disease.
By increasing the affinity of hemoglobin to oxygen,
voxelotor decreases sickling of hemoglobin S, which
occurs under hypoxic conditions.
This helps to correct the deformity of sickled RBCs
and extends their lifespan.

65. Chronic hypoxic respiratory failure is a multifactorial disease that may occur in patients
with longstanding pulmonary disease, including interstitial lung disease and COPD.
By modification of the affinity of hemoglobin to oxygen with voxelotor, patients may
have a higher percentage of oxygen-bound hemoglobin, preventing downstream effects of
hypoxia.
Given that offloading of oxygen at the tissue level is governed by local mediators (CO2,
hydrogen), voxelotor does not prevent the release of oxygen from hemoglobin.
In healthy volunteers undergoing normoxic and hypoxic exercise, a 14-day course of
voxelotor was shown to improve oxygen saturation without altering oxygen consumption.
5
This effect was more pronounced under hypoxic conditions. Similarly, voxelotor reduced
oxygen desaturation in stable patients with idiopathic pulmonary fibrosis undergoing
maximum exercise at day 29 of use compared with baseline.
Encouragingly, no reports of unexpected end-organ dysfunction occurred during extensive
use of voxelotor in the chronically ill sickle cell population, even in the setting of pre-
existing organ dysfunction.

66. Although lactate levels were not tracked during voxelotor treatment (in the absence of a metabolic acidosis),
future use of voxelotor in this setting should include careful monitoring of adequacy of oxygen delivery to tissues,
given the increased oxygen affinity of hemoglobin.
Lactate is a well-accepted surrogate for inadequate tissue oxygenation, even in the absence of metabolic acidosis,
and could be monitored serially during voxelotor use.
7
These case reports demonstrate the tolerability of voxelotor in two critically ill patients with chronic hypoxic
respiratory failure. The course of voxelotor treatment was short in both patients, although longer or more
permanent treatment could be implemented.
8
The small effect of voxelotor on oxygen saturation is not likely to be a disease-modifying process in patients with
acute lung injury, and its usefulness is more likely to lie in reducing FIO2 needs or in delivery method complexity.
Voxelotor also may be helpful in patients awaiting lung transplantation, acting as a bridge to avoid the effects of
mechanical ventilation while awaiting organ availability.
Further studies are required to test the plausibility of voxelotor in a critically ill population as well as identifying
patients who are most likely to benefit.

67. Reference:
Medscape
Critical Care Medicine
Acute Respiratory Distress Syndrome; Acute Hypoxemic
Respiratory Failure, Non-Cardiogenic Pulmonary Edema,
High-Permeability Pulmonary Edema
Alexander Fort
Maurizio Cereda
Uptodate

68. The way to get started is to quit talking and begin doing
Walt Disney
Never quit learning
68

69. 69

70. THANK YOU
Siva P Sivakumar, MD
drsivaicu@gmail.com