Mesenchymal stromal cells - One novel therapy of interest

These cells, at a nascent stage, is attractive in targeting multiple therapeutic pathways in ARDS and are known to respond to their biological microenvironment while being a part of the heterogeneous treatment effects in different patient phenotypes.

Vasoactive Intestinal Peptide (VIP) formulations :

The underlying hypothesis of VIP is that underlying hypothesis is that VIP defends AT-II cells, prevents cytokine storm, and increases the lung’s oxygen concentration and gas exchange.

In April 2022, the drug was approved by DCG(I) in India for the management of ARDS in severe COVID-19 patients.

The below figure assesses the various therapeutic targets that could be aligned depending on the pathophysiology of ARDS.

Aviptadil, a synthetic form of VIP, has been granted a marketing approval in India for the treatment of Acute respiratory distress syndrome (ARDS) in patients with severe COVID-19.

• Vasoactive Intestinal Peptide (VIP) is produced in the body and is highly localized in the lungs. Approximately 70% of it is present in the lungs and some is also present in the nasal mucosa.
• VIP affects the respiratory and immune systems by –
• Relaxing the airway pulmonary vasculature and smooth muscles.
• Inhibits its proliferation.
• Induces bronchodilation and increases pulmonary surfactant production.
• It has an anti-inflammatory effect and defense mechanism against septic shock.

Aviptadil is a synthetic Vasoactive Intestinal Peptide (VIP) that has been studied in respiratory disease conditions like asthma, acute lung injury, pulmonary arterial hypertension, sarcoidosis and idiopathic pulmonary fibrosis and is designated as an ‘Orphan Drug’ by USFDA and EMA. Trials conducted in USA and India shows encouraging results in ARDS associated with COVID-19 patients in terms of reduction in mortality rate and hospital stay.

Evidence showed that the group with ARDS patients treated with Aviptadil survived longer than those who were given the placebo treatment along with the standard of care treatment as recommended by the Government of India. The trial also went on to assess that the patients may experience hospital-free survival rather than ICU survival.

• Oxygenation targets/major treatment guidelines.
• Ventilatory management.
• Adjunctive therapies.

Using respiratory mechanics in ARDS: Calculations and Outcomes.

Respiratory Mechanics during Passive Ventilation

There is a dearth of description for larger groups to understand and interpreting the measured variables of respiratory mechanics – their physiological meanings and reference ranges.

Following charts provide a basis of clinical reference ranges to calculate the Respiratory Mechanics:

Definition of abbreviations : ARDS = acute respiratory distress syndrome; Ccw=chest wall compliance; CL = lung compliance; Crs = respiratory system compliance; Ecw=chest wall elastance; EL-lung elastance; EL/Ers = the ratio of lung elastance to respiratory system elastance; Ers = respiratory system elastance; Rrs = respiratory system resistance at inspiration; VC = vital capacity.
*Mean values reported in or derived from Chiumello and colleagues (83), in which 6 ml/kg Vr and 5 cm H2O of positive end-expiratory pressure were used in 24 patients with moderate or severe ARDS.
*Mean values reported in or derived from D'Angelo and colleagues (65) on 18 anesthetized paralyzed patients for minor surgery in the supine position. Predicted VC for men (L) = 5.76 x height (m)-0.026 X age (yr)-4.34; for women (L)=4.43 × height (m)-0.026 X age (yr)-2.89.

Specific studies and formulas concluded the following findings –

• The use of small Vt, low ΔP, and low Pplat in ARDS is supported by physiological data and controlled trials.
• The use of PEEP to minimize cyclic derecruitment, atelectrauma, inhomogeneity, and stress raisers has a strong biologic rationale.
• Despite the improvements in mortality with the use of these concepts, controversy remains with respect to titration of Vt and PEEP.
• Measurement of ΔP, Pl, or strain allows individualized Vt prescriptions to minimize the risks of VILI.
• Similarly, bedside assessment of recruitment may allow clinicians to determine patients most likely to benefit from the application of a high PEEP.

The following table summarizes and compares four guidelines and their treatment options:

ARDS = Acute Respiratory Distress Syndrome. PaO2 = Partial Pressure of Arterial Oxygen. FiO2 = Fraction of inspired Oxygen.

Table : Guideline recommendations for ARDS management

In ARDS, nutrition support is necessary to prevent cumulative caloric deficits, malnutrition, loss of lean body mass, and deterioration of respiratory muscle strength.

It was also seen that early delivery of enteral nutrition was associated with the modulation of stress and the systemic immune response as well as the attenuation of disease severity.

The American-European Consensus Conference on ARDS recommends :

“Nutritional supplementation should be attempted after a few days of critical illness because of its associations with a more favorable outcome.”

• The administration of nutrition depends on the patient’s underlying illness, with the primary focus falling on the level of gastrointestinal function.
• Conditions such as severe acute pancreatitis, intestinal failure, and sepsis-induced ileus require the use of parenteral nutrition.
• In most cases, Enteral nutrition is the preferred nutritional support method due to its reduced septic risk, lower cost, and role in maintaining the gastrointestinal barrier function.
• Evidence have proven that enteral nutrition may, in fact, be superior to parenteral nutrition in affecting clinical outcomes of ARDS patients.
• Choice of enteral access is decided by the patients aspiration risk. Patients with a known potential for delayed gastric emptying (sepsis, diabetic gastroparesis, head trauma, or narcotic use) are most likely to benefit from post pyloric enteral tube placement since this method would minimize GERD and may result in greater success.
• Energy requirements in ARDS: Energy requirements are different in different cases of ARDS patients. Indirect calorimetry (IC) is the most accurate method for measuring energy expenditure in hospitalized patients. Initial measurements are used at the time of nutritional support’s initiation and may be varied as the energy expenditure changes depending on patients condition.
• High ventilator settings might make using IC unfeasible. An alternative method, reverse Fick equation is used to when oxygen consumption (and, therefore, energy requirements) need to be determined. This happens If an ARDS patient requires hemodynamic monitoring via pulmonary artery catheter.
• Using general calculations, an additional method for determining energy requirements using body weight is promoted by researchers. In this, providing the critically ill patient with 25 to 30 kcal/kg per day has been recommended. These are standard energy requirements.
• Increased protein energy requirements are seen due to rapid protein turnover known to occur in hypermetabolic states with protein requirements ranging from 1.2 to 2 g/kg per day in sepsis and trauma.
• Excessive carbohydrate (exceeding 5 mg/kg per minute) may significantly increase work of breathing in severely stressed patients.
• Nutritional-support regimens that provide a balance of carbohydrate and fat as nonprotein energy should be adequate for optimal substrate utilization. If significant hypercapnia limits successful ventilator management and/or weaning, total energy intake should be evaluated to ensure that adequate (but not excessive) calories are provided. A reduction in carbohydrate intake may be useful if significant hypercapnia persists.

Immunonutrition was an emerging concept applied to ARDS which involves the modulation of the immune system by some dietary nutrients and these supplementary immunonutrients may alter the course of critical illness following sepsis, trauma, or surgery. Special formulas of immunonutrients are available, consisting of a combination of antioxidant vitamins (vitamin C, vitamin E, beta‐carotene), trace elements (selenium, zinc), essential amino acids (glutamine, arginine) or essential fatty acids, such as omega‐3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid), and gamma‐linolenic acid (GLA). In patients with ARDS, significant imbalance in the antioxidant system with a relative increase in oxidative stress leads to increased alveolar injury. And in general, antioxidants supplementation shows a favorable outcome. While recognition of the potentially beneficial role of antioxidants in treating the inflammatory response exists, there are no specific recommendations for supplementation.

What are the other enteral formula options ?

1. A reduced-carbohydrate formula supplemented with eicosapentaenoic acid and g-linolenic acid
   Eicosapentaenoic acid and g-linolenic acid are precursors of prostaglandins of the 1 and 3 series and leukotrienes of the 5 series and they have anti-inflammatory properties that include vasodilation, inhibition of platelet aggregation, and reduced release of free oxygen radicals while also reducing the arachidonic acid metabolites thromboxane A2 and prostaglandin E2 responsible for the inflammatory cascade and the resulting lung injury of ARDS.
   Studies prove that patients receiving a formula supplemented with eicosapentaenoic acid and g-linolenic acid showed significant improvements in oxygenation by the fourth day of the study and reductions in both ventilator time (11 days versus 16.3 days in control group, P=.011) and length of stay in the intensive care unit (12 days versus 17.5 days control group, P=.016). Also, patients receiving the formula had lower number of neutrophils in recovered BAL fluid on the fourth study day and throughout the study period.

Prognosis or healthcare outcomes in ARDS :

Even with emerging therapies, ARDS remains a devastating clinical problem with high rates of morbidity and mortality. Understanding some prognostic factors associated with ARDS may assist in facilitating risk stratification and developing new therapeutic interventions to improve clinical outcomes.

• Clinical predictors for short-term and hospital mortality in ARDS consistent as follows :
  • older age, worse physiologic severity of illness (as measured by severity scores such as the Acute Physiology and Chronic Health Evaluation (APACHE) or Simplified Acute Physiology Score (SAPS)), shock on hospital admission, arterial pH less than 7.30, liver disease, early air leak, immunosuppression, triggering risk factor, and right ventricular dysfunction.
  • However, after treatment with lower tidal volume ventilation, these remain to be just –
  • severity of illness as measured by APACHE II or APACHE III
  • age, and
  • the presence of non-pulmonary organ failures.
  • Effects of race and ethnicity on mortality: A study predicted that African American and Hispanic patients have a higher mortality from ARDS than Caucasian patients and that maybe because of a mutation.
  • Diabetes :
  • A study showed that diabetes mellitus is not associated with development of ARDS in a large cohort of critically ill patients but might affect the outcomes as patients with diabetes had higher mortality regardless of ARDS status.
  • Short-term outcomes vs long-term outcomes :
  • Most studies focus on short-term mortality in ARDS but long-term mortality after ARDS and other critical illness is substantially higher than short-term mortality.
  • A study showed that patients hospitalized with ARDS (646 patients) showed substantially higher mortality at 1 year compared to in-hospital mortality (41 % vs. 24 %, p < 0.001). The independent predictors of death at 1 year were age, living somewhere other than home prior to admission, and serious comorbidities such as HIV and malignancy.
  • Physiological parameters and oxygenation :
  • Patients treated with lower tidal volumes with lower mortality as compared to higher tidal volumes with higher mortality had lower inspiratory plateau pressures.
  • Also, an elevated ratio of pulmonary dead space (calculated by the mean expired carbon dioxide fraction) to tidal volume (VD /VT) within 24 h of onset of ARDS was associated with higher mortality.
  • Oxygenation :
  • In short-term ARDS outcomes, the PaO2/FiO2 ratio measured using PEEP ≥ 10 cmH2O and FiO2 ≥ 0.5 at 24 h after ARDS onset showed substantial improvement in risk stratification for short term ARDS mortality.
  • Studies showed that, “PaO2/FiO2 with conventional therapy is a prognostic factor of better outcome in patients with ARDS.”
  • Genetic polymorphisms :
  • A number of genetic polymorphisms have been shown to be associated with mortality in ARDS, in genes including angiotensin-converting enzyme, extracellular superoxide dismutase, duffy antigen/receptor for chemokines, and vascular endothelial growth factor. A variety of biomarkers involved in the pathogenesis of endothelial and epithelial injury, inflammatory response and coagulation have been explored.

Primary Care for patients

• Post discharge from the ICU, patients with ARDS may have –
• A lower quality of life.
• Significant weakness from neuropathy or myopathy.
• Persistent cognitive impairment.
• Delayed return to work.
• Psychiatric illness is also common after ARDS :

17% to 43% of survivors report depression, 21% to 35% report posttraumatic stress disorder, and 23% to 48% report anxiety. These illnesses may have an increased risk of developing if there is :-

• a longer time to resolution of lung and multiorgan dysfunction, the use of systemic corticosteroids, acquisition of illness in the ICU.
• Many patients report social isolation and sexual dysfunction.
• Some harmful health effects of ARDS may be permanent. The caregiver should be made aware of this along with the patient.
• Although lung function approaches normal at five years, six-minute walking distance, physical function, and quality-of-life measures often remain decreased.

Hence, it is imperative that primary care physicians initiate, coordinate, and monitor continuing services for these patients.

Physicians should assess functional status at hospital follow-up and subsequent visits, ensuring that a multidimensional health care team (e.g., physical and occupational therapists, rehabilitation and home health care nurses, subspecialists) is used to promote optimal health and function.

Primary care physicians should screen for mental health disorders and treat or refer patients as needed.