Inhaled Nitric Oxide Vs Epoprostenol in Peer Reviewed Articles
Crit Care Explor. 2020 Oct; 2(10): e0259.
Evaluation of the Efficacy and Safe of Inhaled Epoprostenol and Inhaled Nitric Oxide for Refractory Hypoxemia in Patients With Coronavirus Disease 2019
Jeremy R. DeGrado, PharmD, BCCCP, BCPS, 
i Paul G. Szumita, PharmD, FCCM, FASHP, BCCCP, BCPS,ane Brian R. Schuler, PharmD,1 Kevin Thousand. Dube, PharmD, BCCCP, BCPS,1 Jesslyn Lenox, MHA, RRT-NPS, AE-C,2 Edy Y. Kim, MD, PhD,3,, 4 Gerald L. Weinhouse, MD,2, 3, 4 and Anthony F. Massaro, Medico3,, iv
Jeremy R. DeGrado
oneDepartment of Pharmacy, Brigham and Women's Hospital, Boston, MA.
Paul M. Szumita
1Section of Pharmacy, Brigham and Women's Infirmary, Boston, MA.
Brian R. Schuler
iSection of Chemist's, Brigham and Women'southward Hospital, Boston, MA.
Kevin M. Dube
oneDepartment of Chemist's, Brigham and Women'southward Hospital, Boston, MA.
Jesslyn Lenox
2Department of Respiratory Therapy, Brigham and Women's Infirmary, Boston, MA.
Edy Y. Kim
3Division of Pulmonary and Critical Intendance Medicine, Brigham and Women's Hospital, Boston, MA.
ivHarvard Medical School, Boston, MA.
Gerald L. Weinhouse
2Department of Respiratory Therapy, Brigham and Women's Hospital, Boston, MA.
3Partition of Pulmonary and Critical Intendance Medicine, Brigham and Women's Hospital, Boston, MA.
4Harvard Medical School, Boston, MA.
Anthony F. Massaro
3Division of Pulmonary and Disquisitional Care Medicine, Brigham and Women'due south Hospital, Boston, MA.
ivHarvard Medical Schoolhouse, Boston, MA.
Abstract
Objectives:
The objectives of this study were to evaluate the efficacy and safe of inhaled epoprostenol and inhaled nitric oxide in patients with refractory hypoxemia secondary to coronavirus disease 2019.
Blueprint:
Retrospective single-heart study.
Setting:
ICUs at a large academic medical middle in the United states of america.
Patients:
Thirty-eight developed critically ill patients with coronavirus affliction 2019 and refractory hypoxemia treated with either inhaled epoprostenol or inhaled nitric oxide for at least 1 60 minutes betwixt March 1, 2020, and June 30, 2020.
Interventions:
Electronic chart review.
Measurements and Main Results:
Of 93 patients screened, 38 were included in the analysis, with balmy (4, 10.5%), moderate (24, 63.two%), or severe (x, 26.3%), with acute respiratory distress syndrome. All patients were initiated on inhaled epoprostenol every bit the initial pulmonary vasodilator and the median time from intubation to initiation was 137 hours (68–228 h). The median alter in Pao 2/Fio ii was 0 (–12.8 to 31.half-dozen) immediately post-obit assistants of inhaled epoprostenol. Sixteen patients were classified every bit responders (increment Pao 2/Fio 2 > 10%) to inhaled epoprostenol, with a median increase in Pao ii/Fio two of 34.ane (24.3–53.9). The mean alter in Pao 2 and Spo 2 was –0.55 ± 41.eight and –0.6 ± 4.7, respectively. Xi patients transitioned to inhaled nitric oxide with a median change of xi (3.half dozen–24.viii) in Pao 2/Fio 2. A logistic regression assay did non identify any differences in outcomes or characteristics between the responders and the nonresponders. Minimal adverse events were seen in patients who received either inhaled epoprostenol or inhaled nitric oxide.
Conclusions:
We establish that the initiation of inhaled epoprostenol and inhaled nitric oxide in patients with refractory hypoxemia secondary to coronavirus disease 2019, on average, did not produce pregnant increases in oxygenation metrics. Even so, a grouping of patients had significant improvement with inhaled epoprostenol and inhaled nitric oxide. Administration of inhaled epoprostenol or inhaled nitric oxide may be considered in patients with severe respiratory failure secondary to coronavirus affliction 2019.
Keywords: astute respiratory distress syndrome, coronavirus disease 2019, epoprostenol, nitric oxide, pulmonary vasodilator, refractory hypoxemia
The acute respiratory distress syndrome (ARDS) is an inflammatory process that is associated with decreased lung compliance, severe hypoxemia, and increased pulmonary shunt (1). ARDS typically develops within vii days of initial symptom onset or clinical insult and is associated with mortality rates of 40–45% (1–iii). The pathophysiology of ARDS includes diffuse alveolar damage occurring early in the exudative phase, leaky alveolar capillaries, and pulmonary edema (ane). ARDS can atomic number 82 to a reduction in lung compliance and severe hypoxemia, along with insults to other organs. The Berlin criteria further ascertain ARDS into three stages based on a patient's Pao 2/Fio 2 on positive cease-expiratory force per unit area (PEEP) greater than or equal to 5 cm H2O: balmy (200 mm Hg < Pao 2/Fio 2 ≤ 300 mm Hg), moderate (100 mm Hg < Pao 2/Fio two ≤ 200 mm Hg), or astringent (Pao 2/Fio 2 ≤ 100 mm Hg) (iii).
Optimal management of ARDS is complex and centers around strategies that improve the efficacy and safety of mechanical ventilation, such utilization of lower tidal volumes and higher PEEP, prone-positioning, and use of neuromuscular blocking agents (1, iv–vii). Inhaled pulmonary vasodilators, such every bit inhaled epoprostenol (iEPO) and inhaled nitric oxide (iNO), take been shown to amend hypoxemia past increasing blood menses to well-ventilated portions of the lung, leading to improvements in ventilation and perfusion matching (8–10). In add-on to refractory hypoxemia secondary to ARDS, iEPO and iNO may provide benefits in patients with pulmonary arterial hypertension or right heart dysfunction (11). Despite a lack of information demonstrating improvements in terminate points such as mortality with pulmonary vasodilator use, iNO and iEPO are considered as adjunctive therapies in patients with ARDS or right ventricular dysfunction (12–15).
Patients who are diagnosed with coronavirus disease 2019 (COVID-19) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may develop respiratory distress that requires mechanical ventilation (16–22). A recent assay found 29% of patients COVID-19 had respiratory failure that progressed to ARDS (23). The differences, if any, between ARDS related to COVID-19 versus another etiology are still unknown, simply inhaled vasodilators have been recommended as potential options for refractory hypoxemia (ii, xvi). The purpose of this analysis was to evaluate the efficacy and safety of pulmonary vasodilators (iEPO or iNO) in patients with COVID-xix and refractory hypoxemia.
MATERIALS AND METHODS
This was a retrospective, observational written report at Brigham and Women's Hospital that received Partners institutional review board approving. We identified consecutive adult patients with COVID-19 and ARDS that were admitted to any ICU and received either iEPO or iNO while mechanically ventilated. Patients had to receive at to the lowest degree 1 60 minutes of either iEPO or iNO and have results from an arterial blood gas (ABG) within the offset 6 hours of therapy. Patients were excluded if they received extracorporeal membrane oxygenation back up prior to initiation of the pulmonary vasodilator, concomitant iEPO and iNO, or parenteral prostacyclin. Patients were also excluded if they did non have a baseline ABG, if their baseline ABG was greater than vi hours prior to initiation, if were transferred from an outside institution on iNO or iEPO, or if neuromuscular blockade or prone-positioning was initiated betwixt ABGs checked at baseline and subsequently initiation of inhaled vasodilator therapy.
Brigham and Women'due south Infirmary'due south full guideline related to caring for patients with COVID-nineteen can exist constitute at covidprotocols.org (24). The definition of ARDS is consistent with Berlin criteria (acute onset, bilateral opacities, and Pao ii/Fio 2 < 300 mm Hg with a minimum PEEP of v cm H2O, not explained by cardiac failure or fluid overload). Our guideline recommends consideration of pulmonary vasodilator therapy in mechanically ventilated patients with ARDS afterward or in conjunction with other strategies, such equally use of low tidal-volume ventilation, best PEEP protocol, decumbent-positioning, and neuromuscular blockade (24). Patients with alveolar hemorrhage or left ventricular dysfunction are excluded from receiving pulmonary vasodilators. Our recommended dose range for iNO and iEPO is one–80 ppm and 0.01–0.05 mcg/kg/min, respectively. iEPO is our starting time-line pulmonary vasodilator and is initiated at 0.05 mcg/kg/min based on ideal body weight and recommended to continue if the Pao ii increases greater than 10% from baseline. If patients do not respond to iEPO (less than x% comeback in Pao 2 or Pao 2/Fio 2 ratio), iNO is considered after iEPO discontinuation and is initiated at 20 ppm, with a recommendation to titrate up to 80 ppm if the Pao 2 does not increase greater than 10%. ABGs are recommended at baseline and 2 hours afterwards pulmonary vasodilator therapies are initiated. Weaning of both agents is done slowly over several hours with recommendation to restart or uptitrate if Pao two decreases.
Pertinent patient data were collected, such as Astute Physiology and Chronic Health Evaluation (APACHE) II score on ICU admission, Sequential Organ Failure Cess score prior to iEPO initiation, baseline demographics, and relevant past medical history. The main end indicate was the change in Pao ii/Fio ii ratio afterward initiation of pulmonary vasodilator therapy. Other oxygenation metrics, such every bit the modify in Pao ii, pulse oxygenation saturation (Spo 2), and the percentage of patients with an increase of at least 10% in Pao 2 and Pao 2/Fio two ratio, were collected. Patients were classified as "responders" to iEPO or iNO if they had an increase in Pao 2/Fio ii ratio greater than 10% on the next ABG. Characteristics of responders and nonresponders were compared. Ventilator settings and oxygenation metrics were collected at baseline and during the first 24 hours of therapy. The average dose and duration for iEPO and iNO were assessed in all patients. Adverse drug events were collected using the post-obit criteria: bleeding (International Society on Thrombosis and Haemostasis/Scientific and Standardization Committee bleeding cess tool), methemoglobinemia (> 2%), tachycardia (new onset center rate > 100 beats/min or 20% increment inside ii 60 minutes), hypotension (new onset hateful arterial pressure < 65 mm Hg or 20% increase in vasopressors in 2 hr), and thrombocytopenia (platelet count decreased to < l,000/µL during therapy) were nerveless. Hemodynamic effects were assessed within 2 hours of initiation, whereas other adverse drug events were assessed throughout entire course of inhaled pulmonary vasodilator.
We summarized categorical data using frequencies and percentages. Continuous data were summarized using mean and sds or medians and interquartile ranges where appropriate. Chi-square test or Fisher verbal exam was used when appropriate for categorical data. Continuous data were analyzed using paired t test or unpaired t test, where advisable. An blastoff of less than or equal to 0.05 was deemed statistically significant for all tests. We used a multivariable logistic regression model to investigate possible predictors of responsiveness to iEPO therapy. Nosotros included variables with p value of less than 0.ii from the univariate analysis as well as ideal trunk weight and APACHE II score based on previous literature. Statistical tests were performed using Stata Statistical Software, Version fifteen.1 (StataCorp, College Station, TX).
RESULTS
Overall, 93 patients who received inhaled pulmonary vasodilators were screened for written report inclusion, of which 47 were excluded for the following reasons: negative for SARS-CoV-two (n = 41), ABG not drawn within half-dozen hours prior or after initiating iEPO (n = 3), no baseline ABG (due north = 2), baseline Pao 2/Fio 2 greater than 300 (n = 1), and received iEPO prior to access (north = 1). Of the 46 patients that met inclusion criteria, eight were after excluded due to initiation of neuromuscular blockade and/or prone-positioning between the baseline and postinhaled vasodilator therapy ABGs. Baseline characteristics of the 38 remaining patients that were included are summarized in Table 1 . Overall, most patients had moderate or severe ARDS at the time of inhaled pulmonary vasodilator initiation. Prone-positioning and neuromuscular blockade were initiated at some point during the ICU class in almost all patients. The median time from intubation to initiation of iEPO was 158 hours. Other therapies related to COVID-xix or critical illness, which were trialed prior to the showtime of inhaled pulmonary vasodilators, are listed in Table one. Adjunctive therapies administered are displayed according to the date patients tested positive for SARS-CoV-ii in the Supplementary Table (http://links.lww.com/CCX/A385).
TABLE 1.
Baseline Demographics of Patients Receiving Inhaled Pulmonary Vasodilators
| Variable | n = 38 |
|---|---|
| Age, twelvemonth (hateful ± sd) | 61 ± 12 |
| Female person (northward [%]) | xiv (36.8) |
| Height, in. (mean ± sd) | 66.9 ± 4 |
| Weight (bodily), kg (hateful ± sd) | 89.five ± 19 |
| Weight (platonic), kg (hateful ± sd) | 64.9 ± xi.5 |
| Trunk mass index, kg/m2 | 30.8 ± 5.5 |
| Acute Physiology and Chronic Health Evaluation II on ICU access (mean ± sd) | 26.9 ± 8.5 |
| Sequential Organ Failure Assessment on iEPO initiation (mean ± sd) | 12.one ± 2.8 |
| By medical history (north [%]) | |
| Systolic heart failure | 2 (five.iii) |
| Chronic obstructive pulmonary disease | 2 (5.3) |
| Asthma | 5 (13.2) |
| Hypertension | 23 (sixty.5) |
| Diabetes mellitus | fifteen (39.five) |
| Coronary avenue disease | iv (10.five) |
| Pulmonary arterial hypertension | 0 |
| Malignancy | 4 (10.5) |
| Transplant | 1 (2.6) |
| Chronic kidney affliction | 4 (10.5) |
| Liver disease | 1 (two.6) |
| Echo during ICU admission (north [%]) | 21 (55.3) |
| RV mild dilatation | 1 (2.half-dozen) |
| RV strain | two (v.3) |
| RV reduced function | 4 (x.5) |
| Initial inhaled pulmonary vasodilator (n [%]) | |
| iEPO | 38 (100) |
| Inhaled nitric oxide | 0 (0) |
| Time from intubation to iEPO, hr (mean ± sd) | 157.viii ± 114.8 |
| Transfer from another establishment (north [%]) | 27 (71.1) |
| Intubated at another institution (north [%]) | 25 (65.eight) |
| Acute respiratory distress syndrome severity at inhaled pulmonary vasodilator initiation (n [%]) | |
| Balmy | 4 (10.five) |
| Moderate | 24 (63.two) |
| Severe | 10 (26.three) |
| Invasive mechanical ventilation (north [%]) | 38 (100) |
| Therapeutic anticoagulation (due north [%]) | 12 (31.6) |
| Vasopressors (n [%]) | 25 (65.8) |
| Other therapies trialed prior to iEPO (north [%]) | |
| Neuromuscular occludent | 34 (89.5) |
| Prone-positioning | 33 (86.8) |
| Hydroxychloroquine | 22 (57.9) |
| Tocilizumab | ten (26.three) |
| Steroids | iv (10.5) |
| Dornase | 3 (seven.9) |
All 38 patients received iEPO equally the initial inhaled pulmonary vasodilator and 11 transitioned to iNO during their access. A complete list of ventilator settings, mechanics, and oxygenation metrics can exist found in Table two . The median starting dose of iEPO was 0.05 mcg/kg/min. The median change in the Pao 2/Fio 2 ratio and Pao 2/Fio 2 pct was 0 (–12.viii–31.6) and 0% (–nine.5 to thirty.4%), respectively (Fig. ane ). Sixteen of 38 patients (42.1%) were classified as responders and 11 patients (28.9%) had an increment of at to the lowest degree x% in Pao 2. In the 16 responders to iEPO, the median change in Pao 2/Fio 2 and Pao 2/Fio two percentage was 34.i (24.3–53.9) and 31.7% (25.7–twoscore.5%), respectively (Fig. 2 ). The median change in Pao ii and Pao 2 pct was 22.five mm Hg (7.5–38.3 mm Hg) and 29.4% (10.1–44.4%), respectively, among responders.
Change in Pao 2/Fio 2 following initiation of inhaled epoprostenol.
Pao 2/Fio 2 before and after inhaled epoprostenol in responders (n = 16) and nonresponders (n = 22).
TABLE 2.
Effectiveness of Inhaled Pulmonary Vasodilators
| Result | Earlier iEPO (n = 38) | After iEPO (n = 38) | Before iNO (n = xi) | After iNO (due north = 11) | p |
|---|---|---|---|---|---|
| Time of baseline ABG, hr (mean ± sd) | 2.6 ± 2.2 | 1.vi ± 1.4 | |||
| Time of get-go mail service-iPVD ABG, hr (hateful ± sd) | 2.seven ± 2.3 | two ± 0.9 | |||
| Proned at time of iPVD kickoff (due north [%]) | nineteen (fifty) | 19 (50) | vi (54.five) | half dozen (54.5) | |
| Paralyzed at time of iPVD start (n [%]) | 26 (68.4) | 26 (68.four) | 11 (100) | xi (100) | |
| Baseline ABG while on iPVD (n [%]) | 0 (0) | 5 (45.5) | |||
| Pao two (hateful ± sd) | xc ± 36 | 89 ± 38 | 84 ± 26 | 98 ± 27 | |
| Fio 2 (mean ± sd) | 0.7 ± 0.2 | 0.7 ± 0.ii | 0.8 ± 0.2 | 0.8 ± 0.ii | |
| Spo two (hateful ± sd) | 94 ± 4.1 | 93 ± 6 | 93 ± 5 | 96 ± 2 | |
| Pao 2:Fio 2 (mean ± sd) | 130 ± 49 | 138 ± 56 | 119 ± 51 | 133 ± 48 | |
| PEEP (mean ± sd) | fifteen ± 3 | 15 ± 3 | 16 ± 3 | 16 ± 3 | |
| Tidal volume (hateful ± sd) | 389 ± ninety | 392 ± 90 | 372 ± 74 | 384 ± 74 | |
| Respiratory rate | 25 ± 6 | 26 ± 5 | |||
| Compliance | 32 ± x (due north = 26) | 35 ± xv (northward = 21) | |||
| Resistance | 13 ± five (north = 26) | 12 ± 3 (n = 22) | |||
| Plateau pressure level | 27 ± 4 (n = xxx) | 28 ± 4 (north = 24) | |||
| Change Pao ii:Fio 2 (mean ± sd) | 7.viii ± 40.8 | 13.6 ± 15.eight | 0.56 | ||
| Percent change Pao 2:Fio 2 (mean ± sd) | 9.6 ± 30.ii | 15.2 ± sixteen.4 | 0.58 | ||
| Increment > x% Pao 2:Fio two α | 16 (42.i) | 7 (63.six) | 0.21 | ||
| Change Pao ii (mean ± sd) | –0.55 ± 41.eight | 14 ± fourteen.iii | 0.23 | ||
| Pao ii increase > 10 mm Hg (hateful ± sd) | 11 (28.ix) | 6 (54.five) | 0.12 | ||
| Pao two increment > 10%α | 12 (31.6) | 7 (63.6) | 0.06 | ||
| Change Spo 2 (mean ± sd) | –0.6 ± 4.7 | ii.9 ± 4.three | 0.14 | ||
| Increased PEEP (n [%]) | 2 (5.3) | 0 (0) | one | ||
| Change in PEEP (mean ± sd) | –0.14 ± one.1 | 0 ± 0 | due north/a | ||
| Increased Fio 2 (northward [%]) | 3 (seven.ix) | 2 (xviii.ii) | 0.1 | ||
| Change in Fio 2 (mean ± sd) | –0.05 ± 0.13 | 0.1 ± 0 | 0.37 |
The median starting dose of iNO in the 11 patients transitioned was twenty ppm (20–30 ppm). The iNO dose was somewhen increased to eighty ppm in seven patients (64%). The median alter in the Pao 2/Fio 2 ratio and Pao two/Fio 2 percentage was 11 (iii.6–24.8) and xvi.7% (i.6–25.8%), respectively. There was an increment by at to the lowest degree 10% in vii of the 11 patients (63.4%) in both Pao 2/Fio 2 and Pao 2. In the seven patients who were classified equally responders to iNO, the median increase in Pao 2/Fio 2 and Pao 2/Fio 2 percentage was 23.ii (16.5–28.2) and 25.2% (eighteen.3–30.vii%), respectively. The median increase in Pao 2 and Pao 2 percentage was 26 mm Hg (xvi.v–29.v mm Hg) and 34.9% (21–41.3%), respectively. There was a trend toward more than significant improvements in Pao 2 and Spo ii while receiving iNO compared with iEPO, just it was not statistically significant (Table 2).
The mean durations of infusion of iEPO and iNO are shown in Table three . iEPO was continued for 77.7 hours in responders and 26.2 hours in nonresponders, whereas iNO was administered for 58.3 and 35.9 hours, respectively. Overall outcomes, such as adverse events, elapsing of mechanical ventilation, and length of stay, are found in Tabular array 3. Few side effects, such as new onset hypotension or tachycardia, bleeding, or thrombocytopenia, occurred. 6 patients (50%) that received iNO developed methemoglobin levels greater than ii%.
Tabular array 3.
Outcomes of Patients on Inhaled Vasodilator Therapy
| Variable | iEPO (due north = 38) | iNO (northward = 11) | Overall (northward = 38) |
|---|---|---|---|
| iEPO duration, hr (hateful ± sd) | 47.9 ± 58.6 | ||
| iNO duration, hr (mean ± sd) | 50.2 ± 31.iii | ||
| Initial dose (mean ± sd) | 0.05 ± 0 mcg/kg/min | 29.1 ± xviii.vii ppm | |
| New hypotension (n [%]) | ane (two.half dozen) | 0 (0) | |
| New tachycardia (due north [%]) | i (ii.six) | 0 (0) | |
| Bleeding (n [%]) | iv (10.5) | two (18.2) | |
| Patients administered packed red blood cells (n [%]) | two (5.3) | 2 (18.2) | |
| Thrombocytopenia (n [%]) | 1 (ii.6) | 0 (0) | |
| Methemoglobinemia (n [%]) | 0 (0) | 6 (55) | |
| Duration mechanical ventilation, 60 minutes (mean ± sd) | 443.nine ± 239.ane | ||
| ICU length of stay, hr (hateful ± sd) | 524.5 ± 318.i | ||
| ICU mortality (n [%]) | 19 (50) | ||
| Reintubations (north [%]) | 6 (15.eight) | ||
| Tracheostomy (n [%]) | 6 (15.eight) |
Responders to iEPO were compared with nonresponders in their baseline characteristics, concomitant therapeutic interventions, and time from intubation to initiation of iEPO (Table iv ). No differences were observed to be statistically pregnant between the two groups. At that place was a tendency toward college tidal volumes and higher lung compliance in the responders when compared with nonresponders. We estimated the associations of APACHE 2, ideal body weight, baseline tidal volume, baseline lung compliance, and nomenclature of severe ARDS at the time of iEPO initiation regarding iEPO responsiveness using a multivariable logistic regression model. None of the variables tested were significantly different between the responders and nonresponders (Table 4).
TABLE 4.
Comparing of Responders to Nonresponders to Inhaled Epoprostenol
| Variable | Univariate | Multivariate | |||
|---|---|---|---|---|---|
| Responders (northward = 16) | Nonresponders (north = 22) | p | OR (95% CI) | P | |
| Age, twelvemonth (hateful ± sd) | 63 ± 10 | 59 ± 15 | 0.36 | — | — |
| Superlative, in. (mean ± sd) | 67 ± 4.2 | 66.one ± 3.5 | 0.48 | — | — |
| Platonic body weight, kg (hateful ± sd) | 64.7 ± 10.9 | 63.4 ± xi.3 | 0.72 | 0.87 (0.63-1.22) | 0.42 |
| Acute Physiology and Chronic Health Evaluation Ii (mean ± sd) | 28.8 ± 10 | 25 ± seven | 0.18 | 1.23 (0.96-1.59) | 0.09 |
| Time from intubation to iEPO, hr (mean ± sd) | 178.7 ± 129 | 142.7 ± 103.8 | 0.35 | -- | -- |
| Tidal book at iEPO initiation, mL (hateful ± sd) | 420 ± 80 | 365 ± 93 | 0.06 | 1.02 (0.97-one.07) | 0.42 |
| (n=20)a | |||||
| Compliance at iEPO initiation | 35.7 ± 12.3 | 29.v ± 7.4 | 0.12 | ane.09 (0.95-i.25) | 0.22 |
| (n=11) | (due north=15) | ||||
| Mild ARDS (n [%]) | i (6.3) | 3 (thirteen.vi) | 0.45 | -- | -- |
| Moderate ARDS (due north [%]) | ix (56.3) | xv (68.2) | 0.45 | -- | -- |
| Severe ARDS (n [%]) | 6 (37.5) | 4 (xviii.2) | 0.xviii | 10.6 (0.22-516.4) | 0.23 |
| Correct ventricle strain or dysfunction (n [%]) | 2 (12.5) | four (18.2) | 0.63 | -- | -- |
| Baseline therapeutic anticoagulation (n [%]) | v (31.3) | 7 (31.8) | 0.86 | -- | -- |
| Duration mechanical ventilation, hr (hateful ± sd) | 422.5 ± 244.ane | 459.5 ± 239.9 | 0.64 | -- | -- |
| ICU LOS, hr (mean ± sd) | 515.two ± 352.1 | 527.6 ± 300.seven | 0.91 | -- | -- |
| ICU mortality (northward [%]) | 9 (56.iii) | 10 (45.five) | 0.52 | -- | -- |
Discussion
This study evaluated the use of iEPO and iNO in patients with refractory hypoxemia secondary to COVID-19. Overall, 41% of the patients were classified equally responders to iEPO. However, we observed no change on average in the Pao 2 or Spo 2, and less than a 10% increase in median Pao 2/Fio 2. Although there were only 11 patients that transitioned to iNO, in that location was a similar observed alter in Pao ii/Fio ii. These results are different from what previous studies take shown when inhaled vasodilators take been used for refractory hypoxemia in ARDS unrelated to COVID-19 (8, 9).
This study differs from previous data examining the use of iEPO and iNO in ARDS in that we exclusively evaluated patients with respiratory failure secondary to COVID-19. Both iEPO and iNO have had mixed results in patients with ARDS, demonstrating comeback in oxygenation but failing to ameliorate mortality (12–14). Several analyses comparison both agents have shown iEPO to be noninferior to iNO in patients with ARDS regarding safety, changes in oxygenation, and improvement in clinical outcomes, such as ventilator-free days (8, x, 25). Information technology is unclear if and how ARDS in patients with COVID-19 differs, simply we saw less of an comeback in oxygenation metrics compared with previous studies (8, ix, 26). Our patients had significant differences at baseline, specifically decreased utilise of corticosteroids and increased employ of neuromuscular blockade and decumbent-positioning, compared with previous studies evaluating ARDS unrelated to COVID-nineteen (9, 26). Early data described risk factors of developing ARDS in patients with COVID-19 that included elevated inflammation-related indices such as C-reactive protein and ferritin (27). Additionally, SARS-CoV-2 may be linked with the induction of cytokine tempest, leading to the worsening of illness severity and patient outcomes (28). However, although inflammatory markers may be elevated in patients with COVID-19-related ARDS, they may not be significantly unlike from patients who develop ARDS unrelated to COVID-19 (29). Overall, information technology is unclear if we observed less of an comeback with iEPO or iNO in our study due to the population being comprised completely of patients with COVID-nineteen or for some other reason, such as smaller sample size.
We did non notice a articulate indicate to help predict which patients with refractory hypoxemia secondary to COVID-19 may benefit from iEPO or iNO therapy. We hypothesized that earlier initiation of inhaled pulmonary vasodilators in relation to development of ARDS may be beneficial, simply that was non observed. We did observe a trend toward higher tidal volumes in patients classified as responders when compared with nonresponders, perchance indicating that nonresponders may have had inadequate distribution of the medication to produce vasodilation and clinical upshot. Although the baseline lung compliance in our cohort overall was low, we observed a trend toward college compliance in responders to iEPO therapy when compared with nonresponders. Gattinoni et al (30) have described the different phenotypes of COVID-19-related ARDS: type L, characterized by normal or high compliance, low ventilation-to-perfusion ratio, small increase in lung weight, and low recruitability, and blazon H, characterized past low compliance, right-to-left shunt, pregnant increases in lung weight, and loftier recruitability. Although ARDS may be classified every bit type L early, Camporota et al (31) describe the potential to shift to type H effectually 5–seven days, which may necessitate a modify in ventilatory strategies. Roesthuis et al (32) evaluated 14 patients with COVID-19-related ARDS and demonstrated decreased PEEP was associated with an increase in lung compliance and a subtract in expressionless space ventilation. Our cohort received iEPO approximately 6.5 days after intubation on boilerplate. Since iEPO is more probable to be efficacious in patients with functional alveoli, it is possible that earlier assistants of iEPO or iNO may have produced greater clinical effects. Larger studies should be done to see if trends that were seen in our data, such as increased tidal volumes, APACHE II scores, and percent of severe ARDS in responders, are confirmed. Additionally, the efficacy and safety of iEPO should be looked at farther in patients with unlike ARDS phenotypes.
Although the overall average changes in Pao 2/Fio two, Pao two, and Spo 2 were not significant, 41% of patients met the definition of responders based on the modify in Pao 2/Fio 2 ratio. Withal, we observed that patients who did not initially respond were continued on both agents for over 24 hours, on average. Information technology is probable that improvement in oxygenation due to inhaled pulmonary vasodilators should exist realized quickly, if a response occurs at all. Therefore, these agents should be able to be trialed and assessed for an impact shortly, allowing for discontinuation if no initial benefit is seen since both are associated with high costs (33). Additionally, although we did not meet a large amount of adverse reactions with either agent, peradventure serious side effects such every bit hemodynamic instability and methemoglobinemia tin can occur.
While both iEPO and iNO were evaluated in this report, we cannot compare their efficacy, since the xi patients who received iNO had previously trialed iEPO. iNO may have theoretical benefits based on in vitro studies demonstrating activity against SARS-CoV (34). A case of outpatient iNO administration in a patient with pulmonary arterial hypertension and COVID-19 was recently published and described significant improvement in respiratory symptoms (35). Additionally, a recent case serial described oxygenation improvements with the use of iNO in pregnant patients admitted with astringent COVID-19 (36). We observed a trend toward a more significant improvement in Spo 2 after receiving iNO as well as a trend toward increasing the Pao two and Pao two percentage changes when compared with iEPO. However, information technology should be emphasized that only 11 patients were transitioned from iEPO to iNO.
This written report has several limitations. First, this is a retrospective study at a single academic medical eye. Although all patients in this study were admitted with respiratory failure secondary to COVID-xix, it is possible that other populations of patients with COVID-19 may see a do good with these agents. Some other limitation of this written report is that nosotros did not look at the effects of iEPO and iNO in different groups of patients, and therefore cannot draw much from the efficacy compared with each other. Additionally, due to the retrospective nature of the report, nosotros were unable to control for other management strategies and therapeutic changes that occurred in trying to optimize oxygenation. Nosotros attempted to minimize the effect of other interventions such equally neuromuscular blockade or prone-positioning by excluding patients who were paralyzed or proned during the initiation of inhaled pulmonary vasodilators. Minimal changes on patients' ventilator settings were made as iEPO or iNO was started; however, it is possible that other interventions interfered with the interpretation of drug effects. Additionally, we did not account for interventions and changes that occurred from the time of ordering iEPO or iNO and the fourth dimension of initiation, which may accept resulted in improvements in Pao 2/Fio 2, leading to the administration of these agents in some patients who transitioned from moderate to mild ARDS. Another limitation, despite having guidelines and recommendations related to initiation and weaning of inhaled pulmonary vasodilators, it is likely that providers used these agents differently. Finally, although this study is the largest analysis of inhaled pulmonary vasodilators in patients with COVID-19, it contains a relatively small number of patients.
CONCLUSIONS
We institute that the initiation of iEPO and iNO in patients with refractory hypoxemia secondary to COVID-19, on boilerplate, did non produce significant increases in oxygenation metrics such as Pao ii/Fio 2, Pao 2, or Spo 2 despite minimal other misreckoning interventions. Withal, a grouping of patients had significant improvement in measured clinical parameters with iEPO and iNO. Assistants of iEPO or iNO may be considered in patients with severe respiratory failure secondary to COVID-19.
ACKNOWLEDGMENT
We give thanks Leo F. Buckley, PharmD, and Gretchen Stern, PharmD, BCPS, for help with statistical analysis.
Supplementary Material
Footnotes
Supplemental digital content is available for this article. Straight URL citations appear in the printed text and are provided in the HTML and PDF versions of this commodity on the journal'south website (http://journals.lww.com/ccejournal).
This inquiry did not receive any specific grant from funding agencies in the public, commercial, or non-for-turn a profit sectors.
The authors have disclosed that they do not accept any potential conflicts of interest.
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