Journal of Intensive Medicine 22022) 92-102 Contents lists available at ScienceDirect Journal of Intensive Medicine ELSEVIER Journal homepage: wivw.elseviercomvocatajointm Original Article Assessment of respiratory support decision and the outcome of invasive mechanical ventilation in severe COVID-19 with ARDS* Shuhan Cai", Fangfang Zhu", Hongtao Hu'", Hui Xiang", Dawei Wang", Jing Wang", Lu Lil, Xiao Yang", Aihua Qin', Xin Rao™, Yun Luo, Jianguo Lil”, Kianoush B. Kashani, Bo Hu", Zhiyong Peng!” “gree of Cita Cae Melk, Pogo onto Wok Univ, Wika. Hb 4071, Cina 2 Cn Res Cor of bral care Mee, Waa bt 49071, cna Sosa of Reiland Hrpeensin, Don of Paar and rea Cae Mie, epee, May Cli; Rocher, BO S905, USA *owsan of Panay ant Cea Gare Mein Depron a i Na Cline, Racer MN S55, USA ARTICLE INFO ABSTRACT Keni ockgound The coronavrss disease 2019 (COVID-19) van ongoing pandemic Invasive mechanical ventilation {irene forthe management of COVID- with ete espa dates yc ARDS). We ned to,se he impact of compliance wih resiaory deco apport sytem on the oteames Opens with ep mn in” OVD. ttad ARES who eed IM Sever se ey conv 2 Maho tn ths reopectv,singlecentr, cae sere sty, patent with COVIDSassocated ARDS who eon ‘ured IV at Zong Het of Wh Unset, Chi rom ory th, 202, to March 2h, 2020, ‘eth a lp to pi 2%, 2020, er ice: Demosapie, incl, bray, aig, nd ‘management inomaton were colle ar anaee, Compliance mth the opty pp deen tm wes doce pds elatanhip with 2-day morally was evaluated. eas: The study included 46 COVID-19ssocied ARDS patents who reed IMV. The median ge of he 46 patents was 68.5 yeaa 3 were en The pal restr of ater orygen(P0,)/racton np gen (FO) ro aint cae (ICD smi ses TOA mm, The medi length oY tras 120 (terquarde range (ORT: 60-273) day, andthe mean respaary suppor decison coe Was 110 (ig 78-160), To 28 day er ID amisin, 18 (39.190) ptet ed Survives had» ignicay ger retry sipot dais cre than nosis (13. (103-170) v.85 (60-103, P= ODD, Ug ervraprating strstr (ROC) cre to ns the ration fap spor decison ‘corn 2-day morality the are under she curve AUC) wt 0.796 condense ital fl0.657-0934 P0001) and thecutoff as 15 Gery 0.579, specifiy ~0.859), Patents wth ager sere (>12.5), sere ore ely to survive a 28 day aller CU amis logan est, P< 0.001. Cincom or severe COVID Saad ARDS wth MV, following the spat suport ec and _ssesingeompledon would prone the pores of ventlaon With a decision ser of >113 the mrt at Beaver ICU admison showed am ovo eres este repatory dares syndrome (ARDS) Introduction pandemic. Although most of the cases were mild, about 20% deteriorated and developed severe pneumonia and acute respi- ‘The coronavirus disease 2019 (COVID-19) caused by severe ratory distress syndrome (ARDS), which has led to millions of acute respiratory coronavirus 2 (SARS-CoV-2) in an ongoing deaths. Patients with COVID-19 pneumonia present with dysp- © ‘Given his ole as Eitoril Board Member, Prof. Kkanush B. Kashani had_n involvement inthe peer-review ofthis article and has no acces to information regarding its per review: Prof, Dechang Chen whois the co editor-in-chief took the responsibilty for peer-review progres and made the final decision Coresponing author Bo tiv and Zhiyong Pen, Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Clinical Research Center of ube! Criteal Care Medien, Waban, Hubei 430071, China, ‘Emall dss: hobbier1979@163.com (B Hu, pengzyS@hounalcom (2 Peng) © Shuhan Cai Fangfang Zhu and Hongo Hu eoneibuted equally to this study ps /dos.ong/ 10.1016 jot 2021.12.00 Received 21 September 2021 Receives in revised form 12 November 2021; Accepted 10 December 2021. Managing Fair: ingling Bao Available online 3 Febrvary 2022 Copyright © 2022 The Asthors. Published by Elsevier LV. on behalf of Chinese Metical Associaton. This isan open access article under the CC BY-NCND license (ute /eeaivecommons.rg/henses/by n0-4/4.0/)5 Cah F 2h vera nea, high respiratory drive, and severe hypoxemia, eventually complicated with multiorgan dysfunction and death. Invasive mechanical ventilation (IMV) is considered an es- sential supportive tool for patients with COVID-19-associated, ARDS, Overall, 71-88% of patients with COVID-19-associated, ARDS admitted to the intensive care unit (ICU) received IMV.{*1 While IMV is used to provide respiratory support," it may result in lung damage due to barotrauma, volu- trauma, and atelectrauma'"! lead to ventilator-associated, pneumonia."*! Even with similar IMV management strategies, the incidence of mortality among patients requiring IMV is, variable. While high mortality rates were reported from China (81%)!"1 and New York City (88.199), relatively lower mor- tality was noted in the Lombardy region of Italy (26-35%)! To further clarify these controversial reports, we aimed to assess the impact of a standardized respiratory support decision system with its associated scoring tool on the mortality of pa- tients with COVID-19-associated ARDS requiring IMV."! Methods, Design, setting, and patients ‘This retrospective study was conducted atthe Zhongnan Hos- pital of Wahan University, Hubei, China, which was a des- ignated COVID.19 hospital by the Chinese government. The Zhongnan Hospital of Wuhan University ethics committee ap- proved the study (No. 2020011). Given the observational ret- rospective nature of the study, the need for weitten informed consent from each patient was waived. We retrospectively analyzed all consecutive adult patients (218 years) with COVID-19-associated ARDS who required IMV from January 8th, 2020, to March 24th, 2020. During the treat- rent period, COVID-19 was diagnosed by both chest CT sean and real-time reverse transcription polymerase chain reaction. Patients with COVID-19-associated ARDS were managed ac- cording to the previous ARDS and sepsis guidelines, as well as references for ARDS and IMV.""= Patients who stayed in the ICU for <24 h were excluded. Data collection We reviewed the clinical electronic medical records and nursing notes for all enrolled patients. The recorded data in- cluded demographics, medical history, underlying comorbidi- ties, complications, radiological examinations, vital signs, lab- ‘oratory test results, medications, need for the high-flow nasal cannula (HENC) or non-invasive ventilation (NIV), mechanical ventilator settings, use of neuromuscular blockers (NMBAs) or prone positioning, need for extracorporeal membrane oxygena- tion (ECMO), and the mortality of 28-day after ICU admission (28 dICU). The Acute Physiology and Chronic Health Evalu- ation II (APACHE 11) score was calculated on the day of ICU admission, and the Sequential Organ Failure Assessment score (SOFA) was assessed both on the day of ICU admission and at intubation. Lung injury score (LIS) was recorded according to the scoring system proposed by Murray et al!) on the day ‘of ICU admission, The date of disease onset was defined as the day when the symptoms of COVID-19 started. ARDS was Judged based on the Berlin definition.'"%" The total length of Ire of ree Meine 2 (2022) 82-102 non-invasive devices (Le., HFNC or NIV) before the initiation of IMV was defined as the total duration of HENC and NIV from the day of use to the time of intubation. The total length of me- chanical ventilation was counted from the day of intubation to the day of weaning from the ventilator or death, Respiratory support decision protocol and compliance scoring “The respiratory support decision protocol was an evidence- based protocol that relied on the Surviving Sepsis Campaign: Guidelines on the Management of Critically II Adults with Coro- navirus Disease 2019!" and other current references for ARDS, and IMV. Physicians SC, LL, XY, and BH sereened the guidelines, and references and designed the protocol. Then, the entire team, discussed and revised the protocol in three rounds until consen- sus was achieved. The final protocol is described in Figure 1. In the absence of life-threatening hypoxemia and severe res- piratory distress, respiratory support vias initiated with HENC (or NIV. The use of non-invasive respiratory support continued if hypoxemia and respiratory distress symptoms improved within 2h (SPO, > 92%, Vt < 9 mL/kg, respiratory rate [RR] < 30 times/min)!*'"! with fraction of inspired oxygen (Fi0,) <70%. Otherwise, endotracheal intubation and IMV were required. In the presence of life-threatening hypoxemia or severe respiratory distress, emergency endotracheal intubation and, IMV were recommended. The IMV setting was based on the lung-protective strategy,"2!" including low tidal volume (IV) (4-8 mL/kg ideal body weight) and inspiratory pressures, (plateau pressure <30 emHl,0), driving pressure <15 cmHi,0,, as well as positive end-expiratory pressure (PEEP) set based fon the lung compliance. The use of NMBAs, prone position- ing, recruitment maneuvers (RMs), as well as titrated PEEP ac- cording to the best respiratory-system compliance were con- sidered when: (1) partial pressure of arterial oxygen (Pa0,) to the fraction of inspired oxygen (FiO;) ratio (PaO,/Fi0,) ‘was <150 mmHg, (2) plateau pressure was >30 emHO, and (3) lung compliance was <30 mL/emH,0. ECMO initiation was considered if despite optimized mechanical ventilation, (1) PaO,/Fi0, was <50 mmblg for >3 h; (2) PaO,/Fi0, was <80 mmilg for >6 h; (3) arterial blood gas pH<7.25, partial pressure of carbon dioxide (PaCO,)>60 mmHg for >6 h, or RR >35 breaths/min, respectively; (4) arterial blood gas pl¥<7.2,, or plateau pressure>30 cmHl,0, or RR >35 breaths/min, re spectively; and (5) respiratory failure was complicated with car- diogenic shock or cardiac arrest! Furthermore, ECMO was considered if two of the following criteria were reached 48 h of optimized mechanical ventiation: (1) PaO,/Fi0, in- crease by <20%, (2) PaCO, 248 mmilg, and (3) lung compli ance <30 mL/emH,0. ‘To evaluate the quality and completion of the provided respiratory support, we designed a scoring system accord- ing to the critical parts of the respiratory support protocol, [Table 11.05.2228 Nine items used in this tool provided a range of scores from =6 to 18 points. For each respiratory decision, a certain period of observation and management was, permitted before the score was calculated by two groups (FZ. and HX vs. HH and JW). Ifthe ealculated scores were different between the two groups, SC and BH assigned the final score for ceach patient.5 Cok F 2h I Meta = > Lung conte or a wax Ire of ree Meine 2 (2022) 82-102 — —— Figure 1. The resplzatory support weatment proces of adult severe COVID-19 patents (COVID-1: Coronavirus disease 2019, ECMO- Extracorporeal membvane oxygenation 0,:Fractlon of ispred exygen; HENC: High ow nasl cannulas NIV: Now Jnasive ventilation; PxCOy: Artery paral pressure of carbon dione; PaO: Partial pressure of arterial oxygen; PEEP: Positive end-expiratory pressure; Plat: Platform pressure: RR: Resprtory at; SO, Oxygen saturation. ‘Statistical analysis Categorical variables were summarized as counts and per- ‘centages. Proportions for categorical variables were compared using the chi-squared and Fisher's exact tests, as appropriate. Continuous variables were summarized as mean + standard de- viation when the data were normally distributed, and the groups ‘were compared by Student's test; otherwise, median and in- terquartile range (IQR) were used, and the Mann-Whitney U test ‘was used to examine differences between the groups, Univariate logistic regression analysis was performed forall known factors that could be associated with 28 d-ICU in COVID-19 patients, in- cluding demographics, underlying diseases, and decision seore. We used a univariate Cox regression analysis forall factors that could be associated with the 28 d-ICU, including demographics, SOFA and APACHE I scores, and the respiratory decision score. A receiver operating characteristic (ROC) curve was generated, to detect the best discriminative variable of 28 d-ICU in COVID- 19 patients. The area under the curve (AUC) and the Youden index were calculated for the 28 d-ICU. A two-sided a of <0.05, ‘was considered statistically significant. All statistical analyses ‘were performed using the Statistical Package for the Social Set- ences (version 26.0, IBM Corporation, Armonk, NY, USA). Results Baseline characteristics ‘The study included 46 COVID-19-associated ARDS patients who required IMV and were admitted to the ICU of Zhong: nan Hospital of Wuhan University from January 8th, 2020, to March 24th, 2020. The median age was 68.5 years (IQR: 60.3-79.3), and 31 (67.4%) were men, The mean duration from first symptoms to development of dyspnea, hospital admission, ARDS, and ICU admission were 9.9 + 6.7 days, 10.7 = 6.2 days, 14.8 + 10.2 days, and 14.9 + 8.9 days, respectively. OF the 46 pa- tients, 38 (82.6%) had coexisting medical conditions. Hyperten- sion (23 [50.0%), diabetes (8 {17.4%%]), cardiovascular disease5 Cok F 2h I Meta ‘Table 1 Evaluation of the quality of respiratory suppor decision implementation Ire of ree Meine 2 (2022) 82-102 inition ‘oi ta poo hypercapnia SO, <7ON Or RAB ac, > 50 mit) nts IBV ine (30> when lyon a hypercapnia) ‘Avo fata reapirsey dite CR > 40 imes/min or es esx Hod (te acd > mmol) Inte an Vin ine no» whe fl espa srs happens) manaesiet and ination ni on HO, 2 70h tomattain the ae Sy Inte and 1M in <12 een the Fi, > 70% ‘Iv managment and ination ime fu 0, 70% tomaitan he ge SPO: ang poten vein statesy «4 Vee Bg Gea dy eight) Ppt «30am Ppa owe 3 0 within 2 when Flat > 30 em. Dring pressure 15 cao DAs iia io ‘voi 90,770, <150 ml ‘sng NMBAS for te IY with 90,0, < 150 meen Bhat ination foe wn Avo 04/710, < 100 mt Prone poston »12 day for IV nants with 0/0, < 100mm Venn feta 48 ater inbatin by Soe dimen ener Mo ination and I management ‘een 04/0, increases 2% ‘eeved PaCO, «48 ml ‘eve flags >30 mL/emt,0 ‘ood HOMO. 504/F0, <0 mals over? har P204/FO,< 0 sully over 6 ‘Aerial ood yn pl < 725 and PC, > 6D malig ver 8 ae well 4 AR oer 35 R35 imei ater! Moe ga pl < 72 and pate pres 230 cl 0 Compictad with earhgenic bok er asst Make ie suet protective vena sey lnchling dive premure espatory drive manieent ring MV Deletion $5, <0 ats > daring hopin Inefctve RM wer pefoael fo more han te, “drain of high PEEP ta esl in cone ng comp enced 12 ECMO npemenatn ater 7 aye of IM ‘Caat Static compliance; ECMO: Extracorporeal membrane oxygenation; FO,: Faction of nspred oxygen; HENC: High low nasal cannula; MV Invasive mechanical ‘enulation; NIV! Non-nvasive venation; NMBAS: Neuromuscular locking agen P2CO,: Paral pressure of exrbon dlaxie; Ps, Pata pressure of arterial, ‘oxygen; PEEP: Posive endexpeatorypresure; Ppl (11 (23.9%), and cerebrovascular disease (9 [19.6%]) were the most common coexisting comorbidities. Inthe 28 days after ICU admission, 28 (60.99) patients survived, and 18 (39.1%) died. Demographics and comorbidities were similar among non- survivors and survivors [Table 2] Vital signs and laboratory parameters At ICU admission, the heart rate (HR) (99.0[1QR: 84.8- 109.8] beats/min) and RR (24.S{IQR: 20,0-30.8] beats/min) peste; IM Reerliment maneuver, RR: Respirator) rate SO, Oxygen saturation. were higher than the normal range. The PaO,/FiO; ratio was low (104 [1QR: 72-154] mmtlg), while PaCO, was within the normal range (39.0 (IQR: 31.8-42.5] mmHg). Although the total white blood cell count was normal (9.7 [1QR: 5.3- 147] x_ 10°), the lymphocyte count was low (0.64 (IOR: 0.37-0.89] x 10°/1), b-dimer (1855 [IQR: 496-8418] mg/L), and lactate dehydrogenase (476.5 IQR: 370.3-598.5] U/L) lev- els were elevated. Interleukin-6 (IL-6) level (82.7(1QR: 20.6- 203.3] pg/ml.) was higher than the normal range (0-7 pg/ml. [APACHE Il and SOFA scores were 19.0 (IQR: 14.8-25.0) and5 Cah F 2h vera Ire of ree Meine 2 (2022) 82-102 Table _Demagraphics and baseline characteris of pints with severe COVID.T9 and ARDS. Contain Tesla #6) Nessun r= 18) ‘Sevialin= 28) ra Paalae Am Gan) eas 3-793) rao wos813) 08576 0957 om Malesex S174) nea 18061) ons oss yperteson 25,600) nie. 12425) 1.460 oz Dies sara) sas7) 578) oo oor Creve ease nes) siz) ana) 028 re Cerebro dese 906) sas7) ears) oss O81 coro 243) 156) 166) S108 ove hn ver dase tan iso ow 1390 oar Malignancy a7 188) 307 oe ose ‘nse ins) “To espa admission 107 +62 uz ers tors 09s ose ‘ain presented as medion (inverquarle range), (8), an mean = tandand deviation. ARDS: Acute respratorydlsues syndrome; CKD: Chronic Kdney disease: COPD: Chronic obstructive pulmonary disease; COVID-19: Goronavius disease 2019; 1 tensive cae unit 7.0 (IQR: 5.0-9.0), respectively. The Murray LIS was 3.25 (IQR: 3.00-3.50), and all patients showed bilateral infiltrations in the chest radiograph. At the time of intubation, in comparison with ICU admission, there were no significant changes in most of the parameters, except PaCO, (47.4 [IQR: 39.7-58,6] mmHg) and. D-dimer (2541 [IQR: 1179-7672] mg/L) elevation [Table 3] Compare to non-surviving patients at 28 days after ICU ad- mission, the survivors had similar vital signs (including HR, RR, and mean arterial pressure{MAP]) and APACHE II and SOFA scores, both at the time of ICU admission and intubation. In lab- ‘oratory findings, the differences between the survival and non: survival groups were minimal, except alanine aminotransferase (25.0 [16.3-57.5] U/L vs. 43.0 [265-965] U/l, P = 0.039) and total bilirubin (12.5 [7.8-17.9] mol/L vs. 18.4 [10.5-25.3] mol/L, P = 0,043) that at the timing of intubation were lower in survivors (Table 3} ‘Main interventions and organ dysfunctions ‘Thirty (65.2%) patients received HFNC, and 26 (56.5%) ind- viduals were on NIV before intubation, The length of HENG and NIV before intubation was 53 (IQR: 0-180) h, and the time from hospital admission to intubation was 4.0 (IQR: 1.5-9.5) days ‘After intubation, the initial IMV settings were FiO, 75% (IQR: 50-100%), tidal volume (VO) 6.0 (OR: 5.8-6.0) mL/kg of ideal body weight, and PEEP 10 (IQR: 8-10) emH,O. The me- dian Pa0,/Fi0. ratio after intubation was 113.0 (IQR: 83.9- 177-7) mmlig, and the static compliance (Cstat after intubation ‘was 28 (IQR: 17-26) mL/eml,0. The total length of IMV was 12.0 (IQR: 6.0-27.8) days. During the IMV period, 35 (76.196) patients received NMBAs, 28.0 (60.9%) received prone position- ing, and 11 (23.9%) received ECMO [Table 4] ‘Only a small proportion of patients received antiviral therapy for SARS-CoV-2 (umifenovir, 11 [23.9%I; lopinavie/rtonavir, 4 18.7%) following ICU admission, and nearly all patients re- ceived antibacterial therapy (coverage against Gram-negative bacteria, 44 [95.7%]; Gram pestive bacteria, 43 [93.5%]; and fungal infection, 18 (39.19). Glucocorticoid therapy was used in 37 (80.4% patients (Table 4). ‘The most common complications during the illness period included shock (42 [91.3%]), arrhythmia (25 [54.3%]), acute cardiac injury (23 (50%), and acute kidney injury (AKI) (7 (37.0%) [Table 4), ‘Compare to non-survivors at 28-day after ICU admission, sur- vivors had the following non-significant trends: (1) a shorter time on HENC and NIV (48 [0-200] h vs. 72h (0-180] hy P = 0,831); (2) a shorter time interval between hospital ad- and IMV initiation (4,0(1.0-7.0] days vs. 8 [2.5-12.0] 131}; and (3) a higher static lung compliance after days, P intubation (29[17-40] mL/emHl,0 vs. 22{17-34] mL/emli,0 , 162) [Table 4]. Respiratory support decision score ‘Among all included patients, the median respiratory support decision score was 11.0 (IQR, 7.8-16.0). At 28 daysafter ICU admission, the decision score was significantly higher in sur- vival group than non-survival group (15.0 [10.3-17.0] vs. 8.5, (6.0-10.3), P = 0.001) [Table 4). Based on univariate logis- tic regression analysis, a higher respiratory support decision score was associated with lower 28 d-ICU (odds ratio [OR]: 0.763; 95% confidence interval [CI]: 0.640-0.909, P = 0.002) [Table 5} Code N_ (achieving static lungs compliance of, >30 mL/emH,0 after 48 h of IMV by fine adjustment) was noted only in 16 (34.8%) patients, Code I (driving. pressure <15 emHi,0 within 24 h of IMV) was seen in 23 (50.0%) pa. tients, and Code 0 (decision process for ECMO initiation) was observed in 27 (58.7%) patients. Code R (SO, <80% lasts for >6 h during hospitalization) was present in 13 (28.3%) patients and associated with deduction in total score [Supplementary Table 1] At 28 days after ICU admission, survival group had a sf nificantly higher proportion of Code C (HFNC oxygen concen- tration and intubation timing, 75.0% vs. 38.9%, P = 0.014); Code H (Plat pressure (Pplat} < 30 cmH,O within 24 h of IMY, 78.6% ¥s. 33.3%, P = 0.002); Code I (driving pressure <15 emlH,O within 24 h of IMV, 64.3% vs. 27.8%, P = 0.016);Joel of ree Meine 2 (2022) 82-102 5 Cok F 2h I Meta weg juonbas 2408 8x0 posse yo aus spo snot ao ponds yo wong “6102 2 ones wevdos eh se (@r=u we car psp ABE en "qUY pu G-aIAOD aaH95 yn suaNe yo stpuresed Gomsoge PUR IB IA earge,5 Cah F 2h vera Ire of ree Meine 2 (2022) 82-102 ‘Table a Main interventions and organ dysfunctions in patients with severe COVID-19 and ARDS. em Task) Newsunial@=i8)Sunkalie=28) WZ Pale TENG bere soves) Baan Ten os at NIV before 251555) 1058) tear.) oon os16 Iter btween hops adion and mechanic vetton ny) 40CL. 5-95) 8025120 sour Ts O1at Toa length of HENC + NIV belre (8) 5510-180) 7200-18) 4800-200 0213 ost “oa length mech ventaon (8) Rowows 95 (65123) Wes@os8) 1740087 ‘Water ian (mL) e00(5860) 6069-60) 6006360) oom 1.00 Osa intatation 0). 70500-1000) S50G751000) ——-7HOHEI-1000) OK OBS 40/0, ao afl intubation a) M30638:1777) 10159-1538) 86 TLSI828) 09H 0305 PEEP baton co) 1016-10) 10¢-10) 106-10) ba on (Getafe ntti mem, 38117-36) mur 2007-40) rama Restor spat dein ore Toei — 85 (60102) Ts0dos17) 3386 80 Lapse ona (Kale) san 2a 200 o27 asa Union Aeit nes) 3uen Sas6) oss 056 Chaco tery arm) 6439) 206) Oise O61 Ant Gram neat acters dr 60057) ‘sa000) 26925) rae a6 ‘at Gram ponte cea rg sas) 1sa000) 59) 20 ast ‘ing og soe) 422) Heo) 35 0060 ‘Sek 2019 18.000) en 2s aos ‘ewe contac ory 23500) 10686) 136.) 0355 064 aan 25640 1088) 15338) 007 a5 a oro) 71389) 10657) bor ome Data expressed as modlan(nterquarle rage) and n Go AKL Acite kidney injury; ARDS: Acute espiatory dsiresssyndcome; COVID-19: Coronavirus disease 2019; stat State compliance; ECMO: Fatracorporeal mem brane oxygenation: FiO: ration of inspired oxygen; HENC: High-low nasal eanula; MV: Invasive mechanical vetiltion; NIV: Non-invasive ventilation; NMBAS: Neuromuscular locking agents; PaOO,: Partial pressure of eatbon doxie; PO, Partial pressure of arterial oxygen; PEEP: Positive end-expiratory pressure; Ve Tidal volume. 10 Percent % ABCDEFGHI Figure 2. The completed proportion of each respiratory support decision itm i {Aras per the Gade A-Tin Table 1. J (Non survival I Survival KLMNOPQRST IMU pation with severe COVID-19 and ARDS. ARDS: Acute respiratory distress syndrome; COVID19: Coronavirus disease 2019; IMV: Invasive mechanical ventilation, (Compared with non survival, P < 005, P < 001. Code J (using of NMBAS, 75.0% vs. 38.9%, P = 0.014); Code NN (achieved Cstat of lungs >30 mL/emH,0 after 48h IMV by fine adjustment, 50.0% vs. 11.1%, P = 0.007); Code 0 (avoid ECMO or decision of initiating ECMO in time, 71.4% vs, 38.9%, P = 0.029); and Code P (avoid ECMO or make right super protective ventilation strategy during ECMO, 82.1% vs, 44.4%, P = 0.008) achievement than the non-survivorsal group [Figure 2; Supplementary Table 1]. Based on the uni- variate logistic regression analysis, the 28 ¢-ICU was lower when the following codes were met (Cole C: OR = 0.212, 95% CI: 0.059-0.760, P=0.017; Code H: OR =0.136, 95% CI: 0.036— OR = 0.214, 95% CI: 0.059-0.775, 212, 95% CI: 0.059-0.760, P= 0.017; Code N: OR = 0.125, 95% Cl: 0.024-0.648, P = 0.013; Code 0: OR: 0.255, 95% Cl = 0.073-0.891, P = 0.032; code P: OR = 0.174, 95% GI: 0.045-0.665, P = 0.011) [Table 5). Using the ROC curve to assess the performance of respira tory support decision score in prediction of 28 é-ICU, the AUC was 0.796 (95% CI: 0.657-0.934, P = 0.001) and the cutoff was 679, specificity = 0.889) [Figure 3A]. We cohort into two groups based on the respi- ratory support decision score cutoff of 11.5 (11.5 group in- cluded 21 patients, and <11.5 group included 25 patients). The >1LS group had lower 28 ¢-ICU than the <11.5 group (9.5% vs. 64.0%, P < 0.001), but had non-significant differences in clinical characteristics (age, APACHE Tl, SOFA, and LIS) and in- tervention (total length of HENG + NIV, total length of IMV, interval between hospital admission, and IMV) [Supplementary5 Cah F 2h vera Ire of ree Meine 2 (2022) 82-102 ‘ables isk factors asciated with lease 254-1CU mortality in patents with severe COVID-19 and ARDS according to univariate legit regression analysis as and ro 0970-1057 ona Wt ol cll een 10°71) 1.085, osirtast owe zhocyte count 1097) oss exsi-a7ia os08 Pele coue (x 1070) oor Prominin) srs emer gt) 1.000 {reine bina U/L) 1016 Lette desydragease (U/L) 0 ‘Anne amintanstree (U1) 1.03 996-1010 ome ‘Aspartate aminuts (U/L) 1.02 997-1097 os tiie va) 1050) Gom-u8 08 Wit od cll ecu (<10"1) 10 kote count 10) oa Pelt cout 1070) ry) Prati ine) 124s Hypenenstive rpanin pt) 909 ibis mo 1060 Ineval betes itl ison sd cial entation 9) ost ‘Tot oh of HENC + NIV Eefore IV (ys) 0959 Respir support dco sere ele Bim ro Gulet bats bois ales oa oor tex ors ors ale? arr bon Gale See bs? Gates S000 rs 28 ICU: 28 day morality fer ICV admission; AKL Acute Kidney injury; ARDS: Acute espiatory distress syndrome Cl Confidence ineval COVID-19: Coronavirus ‘sease 2019; HENC: High low nasl cannula; ICU: Intensive care unit IM: Invasive mechanical ventilation; LIS Lung injury score, NIV: Now invasive ventlton, (OR Od aio, Table 2]. Patients with a higher score (>11.5) were more likely to survive 28 days after ICU admission (log-rank test, P< 0.001) than those with a lower score (<11.5) [Figure 3B]. Discussion In this retrospective study, we assessed the quality of im- plementation of a respiratory support decision system and pro- vided an assessment score for evaluating such quality in patients, with COVID-19-associated ARDS who required IMV. For these patients, compliance with the respiratory support decision and {implementation of the assessment score was associated with im- provement in the ventilation process. IMV is usually considered as a supportive management strat- egy and is often life-saving for patients with respiratory failure. However, the risk associated with IMV, especially ventilator- induced lung injury (VID 2" and right heart strain resulting from acute cor pulmonale secondary to ARDS‘! should be considered. In this study, we reported the implementation of a respira tory support decision system based on the current level of evi dence and best practices for the management of respiratory fail- ure in COVID-19-assoeiated ARDS.'"'-®! IMV should be imple- ‘mented as a rapid and efficient respiratory support method for life-threatening respiratory failure. Protective ventilation strat- egy including low Vt (4-8 mL/kg),'*! restricted plateau pres- sure (<30 emH,0),""! a driving pressure (<15 emH,0), and ap- propriate PEEP for the static lung compliance was applied in the IMV management to minimize VILI among patients enrolled in our study.!* Alveolar salvage therapies, the use of NMBAs,'*! and prone positioning!°*~"" should be considered for the pa- tients with Pa0,/Fi0, < 150 mmtlg and in the early stages of ARDS, Because RM may directly over distend aerated lung and could, paradoxically, lead to increased VILI or alter hemo- dynamic status, the use of RM should be only limited to appro- priate cases among ARDS patients“! In a randomized cl cal trial, the authors showed that in patients with moderate-to- severe ARDS, the 28-day all-cause mortality was higher in lung, recruitment and titrated PEEP group in comparison with the low PEEP group.) Assessment of lung reeruitablity should be per- formed before RM, so RM and titrated PEEP can only be used, among those with recruitment potential. Extracorporeal lung, support therapies are also viable options to protect the lungs, while the key question is how to balance the trade-offs between, patient self-inflicted lung injury (P-SILD, the complications of extracorporeal circuits, and the side effects of IMV.'°! When the5 Cah F 2h vera Ire of ree Meine 2 (2022) 82-102 Ne a 8. sy paren oc Log Rank ate 01 —— Figure 3. ROCeurve of respiratory support decision sore to 2ay mortality and surviving analy with diferent decision sore range (115 and >11 5). A: ROC curve. The AUC was 0.796 (95% Cl 0557-0934, P= 0.001) andthe et off was 115 (sem vity = 0679, specificity = 0.889). B: Surviving analysis. Using the Jogarank test patents with higher score (11.5) had higher proportion of survival than those with a store of <11.5 (P= 0.01). AUG: Area under the curve; C: Confidence interval ROC: Receiver operating characteris optimal lung-protective strategy and alveolar salvage therapy are found ineffective, ECMO should be considered.) ‘The prolonged use of HENG or NIV in the presence of strong respiratory drive may lead to P-SILI among COVID-19- associated ARDS patients.(*"" Frat et al!” found that under standard oxygen therapy, patients with a RR 230 breaths/min ‘were more likely to need intubation than patients with a RR. +<30 breaths/min. For NIV, a Pa,/FiO, ratio <200 mmiig and, a TV of >9 ml/kg of predicted body weight were independent predictors of intubation."! ‘To assess compliance with the respiratory support decision system, an evaluation score tool was designed based on respi- ratory support and cardiopulmonary protection principles. The items in the tool were chosen to assess the effect of different oxy- gen supplement therapies, controlling respiratory drive, intuba- tion timing, and initiation of ECMO. Limitations in resources, may delay the implementation of the respiratory support deci- sion system and its assessment, as observed in our study (6-12,h delay in the implementation of the support system). A\ large number of patients achieved Codes A (87.0%), B (76.196), D (67.46), (68.696), F (69.69%), G (100%), K (78.3%), L (89.196), and Q (82.6%), and there were no differences be- tween the survivors and non-survivors [Figure 2; Supplemen- tary Table 1]. This may indicate that clinical providers con- lered these codes as clinically critical. While nearly 40% of patients were at risk of acute cor-pulmonale due to hyperear- bia (Code M),"* it was not an independent risk factor for death in this cohort. The proportion of patients who achieved, Codes € (60.996), H (60.9%), 1 (50.0%), J (60.9%), N (34.89%), © (58.7%), and P (67.4%) were relatively low in all the pa- tients, and yet there were statistical differences between the survivors and non-survivors [Figure 2; Supplementary Table 1; ‘Table 5], Maintaining SpO, by using high oxygen concentration (FiO, > 0.7) may lead to hyperoxic acute lung injury" (Code ©). Ina recent study, in patients with ARDS, early exposure to a conservative-oxygenation strategy with an SPO, between 88% and 92% did not inerease the 28 ¢-1CU, when compared with ‘maintaining the SPO, > 969%." In the lung-protective mechan- {cal ventilation strategy, although low TV ventilation was imple- ‘mented for all the patients, the plateau pressure was >30 cmH,O (Code H) in 50% of patients, and >60% of the patients had dri ing pressure >15 emll,0 (Code. In other studies, similar rela- tionships have been reported.'*) Only 34.8% of patients had, ung compliance of >30 ml/emH,O after 48 h of IMV (Code 1N). As the median PaO,/FiO, ratio of these patients was only 113 (1QR: $3.9-177.7) mmg, all patients with a Pa0,/F10, ra- tio <150 mmHg received NMBAS, yet 39.1% of the cases did not achieve Code J due to late initiation of NMBAs. In patients, ‘with poor lung compliance, conventional alveolar salvage ther- apy did not protect the lungs; thus, initiating ECMO (Code 0) and resting lung during ECMO (Code P) were found to be inde- pendently associated with a lower tisk of death. In this research, we used three eodes (Le. R, §, and T) that ‘were deducted from the total score. Thirteen patients (five sur- vivors and eight non-survivors) had a history of SO, < 80% for >6 h during hospitalization, and seven patients (two survivors and five non- survivors) had non-effective RM or improper PEEP level during IMV. A randomized clinical trial showed that in patients with moderate-to-severe ARDS, a strategy with lung re- cruitment and titrated PEEP compared with low PEEP increased the 28-day all-cause mortalty.("! The absence of statistical dif. ferences in our study might be because of the small sample size. ‘As shown in Tables 2-5, there were no differences in most pa- rameters between survivors and non-survivors except for some. respiratory decision support system scores. The patients in- cluded in this study, regardless of survival status, were gen-5 Cok F 2h I Meta erally older and critically ill when admitted to ICU. As shown, in Table 3, all patients had a Murray LIS of >3, with median APACHE II and SOFA scores of 20 and 7, respectively, for sur- vivors, and median APACHE Il and SOFA scored of 19 and 7 for non-survivors, respectively. In the early period of the pan- demic, uncertainty and non-standard treatment were common; therefore, the completion of some critical details in the respira- tory decision support system was crucially important and might be able to influence patient's clinical outeomes. According to the ROC curve and respiratory support deci- sion score with a cutoff of 11.5 as an independent risk factor of the 25 d-ICU, complying with the protocolized respiratory support decision system process to improve the quality of respi- ratory support could potentially reduce the risk of death among, patients with COVID-19-associated ARDS who requize IMV, par- ticularly in resource-limited settings. ‘Our study has some limitations. This was a single-center ret- rospective study with a small sample size, which may limit its generalizability and conclusions. For the same reason, we are not able to imply any causal relationship as our findings are solely associations. Hence, prospective studies with large sample sizes are required to verily our results. Because SARS-CoV-2 is a relatively new virus, some items of our standard seoring system ‘were mostly based on experts’ opinions and lacked evidence: based medical support. Conclusions For patients with COVID-19-associated ARDS who required IMV, complying with and implementing the respiratory support decision system can likely improve the ventilation process. The ‘mortality at 28 days after ICU admission was lower with a deci- sion score of >11.5 than with a decision score <11.5. Funding ‘This work was supported by the Chinese Medical Informa- tion and Big Data Association (Bo Hu, No. 2-2019-1.003) and by the Translational Medicine and Interdiseiplinary Research Joint Fund of Zhongnan Hospital of Wuhan University (Bo Hu, No. ‘2NJC202011), and the key project of the Ministry of Science and ‘Technology of China (Zhiyong Peng, No. 2020¥FC0841300). Conflicts of Interest ‘The authors declare that they have no known competing f- ‘nancial interests or personal relationships that could have ap- peared to influence the work reported in this paper. Acknowledgments None. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/),jointm. 2021.12.003. Ire of ree Meine 2 (2022) 82-102 References (1 Wang D, Ha 8G Zh FL Zhang J eta. Cline erates of 138 (Gana JAMA 702032311) 4061-9, do. jm 20001585 ‘Guay Mo, NU ZY, HY, Lang WH, OW CO, He J, eta. Cnc character tes eons eae 2019 Ty Chia Wg Mee 22,3218) 1708-20. ‘dots0 nents SGrasell G, Zango A. Zell A, Aatell M, Cabra 1, Cae A et a ‘Domi ICUs ofthe Lamu Regier, Uy. JAMA 2020:290151574- 8, ot10.1001/ama.a205358. Yang Yu Yu J, Shu H Xia J, Uw Hota. lineal cous and outesmes ‘of ertally pata wid SARS-CoV2powurona in Vuban Chia sgl ‘etre, eeepc, ober ty Lane Resp Med 2005)075 8 eeto ole/sanis.asbooan79 5. 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