Intrapulmonary shunt and alveolar dead space in a cohort of patients with acute COVID-19 pneumonitis and early recovery.

BACKGROUND: Pathological evidence suggests that coronavirus disease 2019 (COVID-19) pulmonary infection involves both alveolar damage (causing shunt) and diffuse microvascular thrombus formation (causing alveolar dead space). We propose that measuring respiratory gas exchange enables detection and quantification of these abnormalities. We aimed to measure shunt and alveolar dead space in moderate COVID-19 during acute illness and recovery. METHODS: We studied 30 patients (22 males; mean±sd age 49.9±13.5 years) 3-15 days from symptom onset and again during recovery, 55±10 days later (n=17). Arterial blood (breathing ambient air) was collected while exhaled oxygen and carbon dioxide concentrations were measured, yielding alveolar-arterial differences for each gas (P A-aO2 and P a-ACO2 , respectively) from which shunt and alveolar dead space were computed. RESULTS: For acute COVID-19 patients, group mean (range) for P A-aO2 was 41.4 (-3.5-69.3) mmHg and for P a-ACO2 was 6.0 (-2.3-13.4) mmHg. Both shunt (% cardiac output) at 10.4% (0-22.0%) and alveolar dead space (% tidal volume) at 14.9% (0-32.3%) were elevated (normal: <5% and <10%, respectively), but not correlated (p=0.27). At recovery, shunt was 2.4% (0-6.1%) and alveolar dead space was 8.5% (0-22.4%) (both p<0.05 versus acute). Shunt was marginally elevated for two patients; however, five patients (30%) had elevated alveolar dead space. CONCLUSIONS: We speculate impaired pulmonary gas exchange in early COVID-19 pneumonitis arises from two concurrent, independent and variable processes (alveolar filling and pulmonary vascular obstruction). For most patients these resolve within weeks; however, high alveolar dead space in ∼30% of recovered patients suggests persistent pulmonary vascular pathology.

Nasal CPAP and surfactant for treatment of respiratory distress syndrome and prevention of bronchopulmonary dysplasia.

UNLABELLED: The Scandinavian approach is an effective combined treatment for respiratory distress syndrome (RDS) and prevention of bronchopulmonary dysplasia (BPD). It is composed of many individual parts. Of significant importance is the early treatment with nasal continuous positive airway pressure (nCPAP) and surfactant treatment. The approach may be supplemented with caffeine citrate and non-invasive positive pressure ventilation for apnoea. The low incidence of BPD seen as a consequence of the treatment strategy is mainly due to a reduced need for mechanical ventilation (MV). CONCLUSION: Early-postnatal treatment with nCPAP and surfactant decreases the severity and mortality of RDS and BPD. This is mainly due to a diminished use of MV in the first days of life.

Prolonged exposure to inhaled nitric oxide does not affect haemostasis in piglets.

OBJECTIVE: To examine possible adverse effects on haemostasis from prolonged exposure to inhaled nitric oxide (iNO). DESIGN AND SETTING: Blinded, randomised, experimental animal study in a university animal laboratory. INTERVENTIONS: Anaesthetised and intubated piglets received central venous, arterial, and transabdominal urinary catheters. Twelve piglets were studied with triggered pressure support ventilation breathing with an air-oxygen mixture for 30 h with nitric oxide (NO), 40 parts per million (ppm) (n = 6) or without NO gas (n = 6) added. The tests of platelet function were assessed in a separate 1-h experiment in which 12 additional animals were blindly randomised to receive intravenous acetylsalicylic acid (ASA) (n = 7) or placebo (n = 5). MEASUREMENTS AND RESULTS: All 12 animals were clinically stable during the study period of 30 h. Haemostasis was assessed in terms of bleeding time and platelet function by Adeplat-S, reflecting platelet adhesion. Prothrombin fragment 1 + 2, fibrin D-dimer, tissue plasminogen activator and prothrombin complex were measured to investigate whether inhaled NO (iNO) had any effects on thrombin formation, fibrin formation, fibrinolysis or coagulation. All parameters including bleeding time and Adeplat-S were unaffected by iNO. ASA significantly increased bleeding time, but did not affect Adeplat-S. Nitrate in plasma and NOx (nitrate and nitrite) in urine increased significantly in pigs receiving iNO compared with controls. CONCLUSIONS: Prolonged exposure to iNO at 40[Symbol: see text]ppm did not affect bleeding time or coagulation parameters in healthy piglets. The findings do not support the hypothesis that iNO increases the risk of bleeding in humans.

Workplace NO and NO2 during combined treatment of infants with nasal CPAP and NO.

OBJECTIVE: To determine the workplace concentrations of NO and NO(2) in and around a paediatric incubator during inhaled NO (iNO) treatment and during an accidental emptying of NO cylinders into room air. DESIGN: We simulated iNO-nasal CPAP treatment in order to assess the impact on the occupational environment. Furthermore, two full NO cylinders for therapy, 1,000 ppm, 20 litres, 150 bar and 400 ppm, 10 litres, 150 bar, were emptied as rapidly as possible into an intensive care unit (ICU) room. SETTING: University hospital ICU. MEASUREMENTS AND RESULTS: To correctly gauge the contribution from iNO-CPAP we constructed a system measuring breathing zone and room ventilation inlet-outlet values during a 10-ppm iNO treatment of a simulated infant. Maximal breathing zone values were 17.9 +/- 7.0 (mean +/- 95% CI) ppb for NO and 25.2 +/- 4.8 ppb for NO(2). If room inlet values were subtracted, the contributions to breathing zone values emanating from iNO-CPAP were 14.8 +/- 4.6 ppb for NO and 14.6 +/- 4.6 ppb for NO(2). At the ventilation outlet the maximal contributions were 4.2 +/- 2.9 ppb NO and 9.6 +/- 4.3 ppb NO(2). During rapid total release of a gas cylinder in the ICU room, simulating an accident, we found transient NO levels comparable to the high therapeutic dosing range, but only low NO(2) levels. CONCLUSIONS: Neither 8-h time-weighted average (TWA) nor 15 min short-term exposure limits (STEL) were exceeded during normal operation or during a simulated accident. The contribution of nitrogen oxides from treatment to workplace air were minor compared to those from ambient air.

A pilot study of inhaled nitric oxide in preterm infants treated with nasal continuous positive airway pressure for respiratory distress syndrome.

OBJECTIVE: To explore the acute effects of inhaled nitric oxide (iNO) on oxygenation, respiratory rate, and CO2 levels in spontaneously breathing preterm infants treated with nasal continuous positive airway pressure (nCPAP) for moderate respiratory distress syndrome (RDS). DESIGN AND SETTING: Randomized, prospective, double-blind, cross-over study in the neonatal intensive care units of a university hospital. PATIENTS: 15 infants treated for RDS, with a median gestational age of 32 weeks (27-36), birth weight 1940 g (1100-4125), and postnatal age at the beginning of study 23 h (3-91). nCPAP pressure was kept constant at 4.3 cmH2O (3.4-5.1). INTERVENTIONS: We examined effects on gas exchange and vital signs during a 30-min exposure to 10 ppm iNO or placebo gas (nitrogen). RESULTS: Before administering test gases the baseline arterial to alveolar oxygen tension ratio (aAPO2) was 0.19+/-0.06. aAPO2 remained unchanged during placebo but increased to 0.22+/-0.05 (+20%) during iNO exposure. Respiratory rate and arterial carbon dioxide tension remained unchanged, as did heart rate, blood pressure, and methemoglobin. Follow-up at 30 days of age showed no deaths, delayed morbidity, or need for supplemental oxygen. CONCLUSIONS: Adding 10 ppm nitric oxide to nasal CPAP treatment in preterm infants suffering from RDS results in a moderate but statistically significant improvement in oxygenation, with no effect on respiratory drive or systemic circulatory parameters.

Lung physiology and histopathology during cumulated exposure to nitric oxide in combination with assisted ventilation in healthy piglets.

Inhaled nitric oxide (iNO) is routinely used for hypoxic respiratory failure and persistent pulmonary hypertension of the newborn, and investigation of its new indications requiring various levels of iNO is underway. Cumulated exposure of high level of iNO may exert adverse effects on lung function and morphology, which may be confounded with ventilator-associated lung injury. Sixteen healthy piglets (5.5-11 kg) were anaesthetised, intubated and mechanically ventilated at low FiO(2) on continuous positive airway pressure and pressure support mode. The animals were randomly allocated to receive 40 ppm iNO (NO group, n=8) or no iNO (Control group, n=8). In both groups at 24 and 48 h, mild to moderate lung injury was observed, with mean values of PaO(2)/FiO(2)<300 mmHg. Compared to the Control, iNO at 40 ppm for 24-48 h did not adversely affect dynamic compliance or resistance of respiratory system, oxygenation, pulmonary and systemic hemodynamics. Neither did it affect composition and surface activity of surfactant phospholipids and white cell counts in bronchoalveolar lavage fluid. Inhaled NO resulted in elevated total serum nitrite/nitrate to 352+/-90 micromol/l and methemoglobin (MetHb) to 5.0+/-3.4%, in contrast to 88+/-38 micromol/l and 0.88+/-0.52% in the Control; 50% of the iNO animals having MetHb>3%. The lung injury scores as well as alveolar expansion were similar between the two groups at 24 h. At 48 h, low wet/dry lung weight ratio and lung injury score were found in the NO group. We conclude that no significant adverse effects on lung physiology and structure were found in the piglets receiving 40 ppm iNO for 24 or 48 h, on the contrary lung injury was moderately alleviated. The significantly impaired gas exchange over time associated with discrete morphological changes suggests adverse effects of prolonged positive pressure breathing and not necessarily exposure to oxides of nitrogen.

Pharmacodynamics and pharmacokinetics of inhaled nitric oxide in dogs with septic acute respiratory distress syndrome.

AIM: To evaluate pharmacodynamics and pharmacokinetics of inhaled nitric oxide (iNO) in dogs with acute respiratory distress syndrome (ARDS). METHODS: ARDS, induced after iv injection of endotoxin, was evidenced by reduction of paO2/FiO2 from (62.5 +/- 2.8) to (26 +/- 4) kPa and dynamic lung compliance (Cdyn) from (14.8 +/- 0.7) to (8.6 +/- 0.6) mL.kPa-1 . kg-1, increase of dead space (VD/VT) from (0.14 +/- 0.06) to (0.58 +/- 0.05), intrapulmonary shunting (Qs/Qt) from 4.7 % +/- 1.7 % to 39 % +/- 7 %, and pulmonary vascular resistance index (PVRI) from (16 +/- 4) to (51 +/- 8) kPa.s.L-1 . m-2 (all P < 0.05), along with severe intrapulmonary neutrophil recruitment and peripheral neutropenia. The animals were then treated as either a control or an NO group (n = 6 each, iNO 0.4 - 3.2 micromol/L) for another 10 h. RESULTS: More survival was found in NO group (4/6 vs 0/6, P < 0.05). iNO at 0.8, 1.6, and 3.2 micromol/L (20, 40, and 80 ppm) resulted in > 40 % increase of paO2/FiO2 and Cdyn, a reduction of VD/VT to 0.32, Qs/Qt to < 25 %, and PVRI by > 50 % (30.8 kPa . s . L-1 . m-2) compared to the control. Optimal iNO dose was around 0.8 micromol/L as higher methemoglobin (MetHb, > 3 %) was found at higher NO. iNO had no adverse effects on surfactant phospholipids and lung fluid balance, but attenuated expression of tumor necrosis factor alpha,beta2 integrin CD11b, and interleukin-8 mRNA in the lungs by 22 %, 44 %, and 25 %, respectively (P < 0.05). CONCLUSION: Pharmacodynamics of iNO in this model was related to improvement in gas exchange, Cdyn, PVRI, and suppression of proinflammatory cytokine expression in the lungs, and its adverse effect was mainly confined to MetHb at higher NO dose.