Ventilatory load reduction by combined mild hypothermia and ultra-protective mechanical ventilation strategy in very severe COVID-19-related ARDS: a feasibility study.

doi:10.21203/rs.3.rs-1987249/v1

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Ventilatory load reduction by combined mild hypothermia and ultra-protective mechanical ventilation strategy in very severe COVID-19-related ARDS: a feasibility study.

https://doi.org/10.21203/rs.3.rs-1987249/v1

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Background: Low tidal volume (Vt) strategy is currently the standard of care for ARDS. However, this approach may result in harmful airway pressures in severe ARDS. We report the feasibility of a combined approach of very low-VT and mild therapeutic hypothermia (MTH) to decrease the ventilatory load in a very severe COVID-19-related ARDS cohort.

Methods: Seven patients were reported. Inclusion criteria were patients ≥ 18years-old, very severe COVID-19-related ARDS, driving pressure (DP) > 15 cmH₂O despite low-VT strategy, and extracorporeal therapies were not available. Patients with uncontrolled superinfection, active bleeding, severe brain injury, or end-of-life care were excluded. MTH was induced with a surface cooling device aiming at 34ºC. MTH was maintained for 72h, followed by rewarming of 1ºC per day. VT was adjusted as tolerated, aiming at 4 ml/kg PBW. Data are shown in mean±SEM. Mixed effects analysis and Dunnett's test were used for comparisons. Significance was set at p<0.05

Results: Target temperature was achieved during the first hour. Ventilatory load decreased during the first 24h, minute ventilation 180±4.7 to 154±7.5 ml/kg/min (p=0.007) and mechanical power 36±1.9 to 29±2.1 J/min (p= 0.03). At 48h VT decreased from 5.4±0.2 to 4.2±0.3 ml/kg. Surviving patients did not worsen after rewarming. Five patients survived ICU and were discharged home.

Conclusions: A combined strategy of MTH and ultra-protective mechanical ventilation decreased minute ventilation and mechanical power in very severe COVID-19-related ARDS. The decreasing of ventilatory load may allow maintaining MV within safety thresholds.

Lung protective ventilation

Mild Hypothermia

COVID-19

Acute respiratory distress syndrome

Hypoxemia.

Mechanical Ventilation (MV) is a lifesaving therapy. Still, it is well known that it can cause and amplify damage to the lung, a phenomenon known as ventilator-induced lung injury (VILI). Therefore, safety thresholds are recommended to attenuate VILI, summarized in Protective MV, and low-VT strategy at the patient's bedside. This approach reduces mortality in acute respiratory distress syndrome (ARDS) by decreasing lung stress, strain, and tidal recruitment (1). However, in patients with very low respiratory system compliance (C_RS), the low-VT strategy can generate driving pressure (DP) and plateau pressures (Pplat) higher than the harmful limits (2). In these cases, the use of very low-VT (VT ≤ 4 ml/kg of predicted body weight [PBW]) is recommended. Still, it may lead to unfavorable consequences such as severe respiratory acidosis. Thus, extracorporeal CO₂ removal (ECCO₂-R) is usually an adjuvant therapy (3, 4). However, when ICU capacity is overwhelmed, for example, during the SARS-CoV-2 pandemic, the availability of extracorporeal respiratory support is scarce, especially in limited resource settings (5).

Therapeutic hypothermia is the controlled decrease of body temperature for clinical use. Hypothermia induces a hypometabolic state, which is helpful in many situations like cardiopulmonary bypass, after cardiac arrest, among others. Therapeutic hypothermia decreases global oxygen consumption and CO₂ production, which might benefit patients with severe ARDS, reducing the ventilatory load. In these conditions, a very low-VT could be used, allowing the maintenance of MV within the safety thresholds (6).

We report the use of very low-VT combined with mild therapeutic hypothermia (MTH) as rescue therapy in seven severe COVID-19-related ARDS who developed catastrophic ARDS refractory to MV, prone position, and neuromuscular blockade, facing the unavailability of extracorporeal support therapies.

The local institutional review board approved the analysis of a concurrent descriptive and analytical study of deidentified data prospectively collected for administrative purposes. We included patients equal to or older than 18 admitted due to SARS-CoV-2 respiratory failure to a dedicated COVID-19 ICU between July 1st, 2020, and July 31st, 2021. We included patients with very severe COVID-19-related ARDS according to EOLIA trial criteria (7). We routinely use low VT in ARDS patients targeting DP < 15 cmH₂O and active circuit humidification in severe ARDS. We excluded patients with uncontrolled superinfection, active bleeding, signs of severe brain injury, or end-of-life care.

In our institution, MTH is proposed as a compassionate treatment, and consent of patients' families is mandatory. Hypothermia was induced by Blanketrol® III (Cincinnati Sub-Zero) automated surface cooling device, aiming for 34ºC servo-controlled core body temperature within 1 hour of initiation. Core body temperature was measured by an esophageal probe. MTH is maintained for 72h, followed by a rewarming phase of 1ºC per day until normothermia (36ºC).

VT was progressively decreased, aiming at 4 ml/kg PBW. Target PaO2 was ≥ 60 mmHg, and arterial pH ≥ 7.2. Gas exchange measurements are corrected to the patient's core body temperature at the time of blood sampling.

Demographic and clinical data were recorded, including daily arterial blood gases, ventilator parameters (VT, DP, Pplat, PEEP, C_RS, and RR), core body temperature, and global dysoxia markers (arterial lactate, central venous oxygen saturation, and venous-to-arterial CO2 gradient). The ventilatory load was measured with minute ventilation (Vmin) and the previously reported comprehensive formula for Mechanical power (MP) (8). Lymphocyte count, C-reactive protein, ferritin, and D-dimer were registered before and after MTH. We actively monitored the development of new bacterial and fungal superinfections and bleeding.

Normality distribution was assessed by Anderson darling test, and data are shown in mean ± SEM or median (IQR). Mixed effects analysis and Dunnett's test were used for comparisons. Significance was set at p < 0.05

From July 2020 to July 2021, 170 COVID-19 patients were screened, and 7 (5 males, two females) were enrolled. Their median age was 54 years-old (44‒58), PBW was 68 kg (60‒72 kg), 85,7% had comorbidities, four patients had morbid obesity, and two had arterial hypertension. All subjects were in prone position, with deep sedation and neuromuscular blockade, and 6 received recruitment maneuvers. Median PaO₂/FIO₂ ratio was 98 mmHg (72‒113), PaCO₂ was 69 (68–73), VT was 5.4 ml/kg PBW (5–5.9), DP was 16 cmH₂O (15–18), Pplat 31 cmH₂O (30–33), PEEP was 14 cmH₂O (13–15), C_RS was 19.4 ml/cmH2O (17.9–25.4), and RR was 34/min (32–34) at baseline. In addition, five patients had Septic Shock, 5 Acute Kidney Injury (3 required renal replacement therapy), and one received therapeutic plasma exchange for thrombotic microangiopathy.

The baseline temperature was 37.4ºC (37–37.6), reaching the target temperature within 1 hour. After 48h of MTH, VT decreased a 29.6% (95%CI 13.1–38.7%, p < 0.01), DP decreased 31% (95%CI 9.8–52.7%, p < 0.01), and PaCO₂ decreased 13.6% (95%CI 1.2–26.1%, p = 0.034), without changes in C_RS. Ventilatory load had a significant decrease during the first 24h, as shown by reduction of Vmin in 12% (95%CI 1–32%, p = 0.007) and MP in 14% (95%CI 6.8–21%, p = 0.002). At the end of the MTH period, the VT, DP, and Pplat remained consistently close to 3.9 ml/kg PBW, 12 and 26 cmH₂O, respectively, maintaining a lower ventilatory load. Survivors maintained their clinical improvement during and after rewarming, highlighting only a slight (no significant) increase in VT (close to 4.4 ml/kg PBW, p = 0.6), and a slow improvement in oxygenation (Fig. 1).

At the end of MTH, there was there was a significant decrease in C-reactive protein (232 [171–243] to 11 [10–30] mg/L, p = 0.04), and a trend to decrease Procalcitonin (0.56 [0.24–0.93] to 0.24 [0.18–0.26] ng/mL, p = 0.08), Ferritin (1540 [848–1782] to 829 [658–889] ng/mL, p = 0.14), and D-dimer (445 [388–1025] to 330 [220–735] mg/mL, p = 0.23).

None of the global dysoxia markers worsened over time (Fig. 2). On the fifth day, only one patient required vasopressor support. Three patients presented bacterial superinfections (Pseudomona aeruginosa and Klebsiella pneumoniae identified in tracheal cultures) and one hemoptysis. No other complications attributable to hypothermia were identified.

Five patients survived till hospital discharge. Unfortunately, two patients died due to progression of multiple organ failure at 48 and 72h of MTH. All survivors required a tracheostomy due to prolonged MV, weaning, and rehabilitation. MV was discontinued on day 60 (46–64) after admission. The artificial airway was removed on day 71 (57–75), supplementary oxygen was discontinued on day 95 (88–107), and discharged home on day 100 (92–108) after admission.

We report a case series of compassionate use of MTH for very severe COVID-19-related ARDS that allowed a very low-VT strategy to reduce DP, Pplat, and ventilatory load over the lungs (Vmin and MP), without affecting markers of global dysoxia. Rescue therapies for these patients, including extracorporeal therapies, were unavailable because of the overwhelmed health system during the first wave of the SARS-CoV-2 pandemic.

Protective MV is the standard of care for ARDS. VILI significantly contributes to the morbidity and mortality of ARDS patients, and it has been demonstrated that low-VT and low-pressure MV are associated with improved survival (1). However, in severe ARDS patients, it is challenging to preserve appropriate gas exchange while maintaining protective MV. In these cases, very low-VT combined with MTH allows minimizing the mechanical load on lungs with profoundly reduced C_RS, allowing lung rest, a slow recovery of lung function, and reasonable survival. C_RS lower than 30 ml/cmH₂O is a known independent predictor of mortality in COVID-19 ARDS (9). The protective pathophysiological effects of MTH on the lungs have been reported in preclinical and small clinical studies and case reports (6, 10–13). Interestingly, MTH allowed a marked reduction in ventilatory load, allowing the use of very low-VT and DP within safe limits, allowing a slow and sustained improvement in gas exchange, such as those described in other ultraprotective MV cohorts (3, 4). Thus, MP steadily decreased, a parameter directly associated with higher mortality in severe COVID-19 (14).

The main risks related to MTH are nosocomial infections, which occurred in almost half of the patients. Bleeding was infrequent. Both risks are present in other rescue therapies that allow very low VT combined with ECCO₂-R, such as ECMO and Novalung® (15–17). Both complications must be closely monitored during MTH (18, 19). Regarding hemodynamics, dysoxia markers and vasopressor requirements did not worsen during MTH.

In summary, we report the use of very low-VT ventilation (≈ 4 ml/kg PBW) combined with MTH, allowing decreasing ventilatory load and maintaining ventilatory parameters within safety limits. This approach might be helpful in the rescue of patients with severe ARDS due to COVID-19 and severely decreased C_RS. However, future studies are required to determine whether very low-VT ventilation combined with MTH will improve survival in severe ARDS patients due to any causes.

Ethics approval and informed consent

The local institutional review board approved this study. (Servicio de Salud Metropolitano Central, Santiago, Chile, Acta 423/2021).

Informed consent was obtained according to committee recommendation.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request

Analyzed data

Competing interests

The authors declare that they have no competing interests.

Funding

No funding was secured for this research

Authors' contributions

PC and FD conceived the study, designed the study, analyzed data, wrote the preliminary draft, had full access to all the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. DM, SR, and YR collected and curated data, analyzed data, and edited and reviewed the final manuscript. All authors read and approved the final manuscript

Acknowledgements

We are deeply grateful to healthcare workers and pediatric teams worldwide, especially the Unidad de Paciente Crítico Pediátrico at Hospital el Carmen de Maipú, Chile, for their courage, professionalism, and dedication to patient care during the COVID-19 pandemic.

The Acute Respiratory Distress Syndrome Network Ventilation with lower tidal volume as compared with traditional tidal volume for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301–1308.
Boscolo, A., Sella, N., Lorenzoni, G. et al. Static compliance and driving pressure are associated with ICU mortality in intubated COVID-19 ARDS. Crit Care 2021;25:263.
Bein T, Weber-Carstens S, Goldmann A, et al. Lower tidal volume strategy (≈ 3 ml/kg) combined with extracorporeal CO2 removal versus 'conventional' protective ventilation (6 ml/kg) in severe ARDS: the prospective randomized Xtravent-study. Intensive Care Med. 2013;39(5):847–56.
Rozencwajg S, Guihot A, Franchineau G, et al. Ultra-protective ventilation reduces biotrauma in patients on venovenous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. Crit Care Med. 2019;47:1505–1512.
Díaz F, Kehr J, Cores C, et al. Clinical and organizational framework of repurposing pediatric intensive care unit to adult critical care in a resource-limited setting: Lessons from the response of an urban general hospital to the COVID-19 pandemic. J Crit Care. 2022;68:59–65.
Cruces P, Cores C, Casanova D, Pizarro F, Díaz F. Successful use of mild therapeutic hypothermia as compassionate treatment for severe refractory hypoxemia in COVID-19. J Crit Care. 2021;63:260–263.
Combes A, Hajage D, Capellier G, et al; EOLIA Trial Group, REVA, and ECMONet. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018;378(21):1965–1975.
Chiumello D, Gotti M, Guanziroli M, et al. Bedside calculation of mechanical power during volume- and pressure-controlled mechanical ventilation. Crit Care 2020;24: 417.
Choron RL, Iacono SA, Cong A, et al. The correlation of respiratory system compliance and mortality in COVID-19 acute respiratory distress syndrome: do phenotypes really exist? J Lung Pulm Respir Res. 2021;8(2):67–74
Cruces P, Ronco R, Erranz B, et al. Mild hypothermia attenuates mechanical ventilation-induced lung injury in a rat model. Exp Lung Res 2011;37:549–54.
Cruces P, Erranz B, Donoso A, et al. Mild hypothermia increases pulmonary anti- inflammatory response during protective mechanical ventilation in a piglet model of acute lung injury. Paediatr Anaesth 2013;23:1069–77.
Villar J, Slutsky AS. Effects of induced hypothermia in patients with septic adult respiratory distress syndrome. Resuscitation 1993;26:183–92.
Karnatovskaia LV, Festic E, Freeman WD, Lee AS. Effect of therapeutic hypothermia on gas exchange and respiratory mechanics: a retrospective cohort study. Ther Hypothermia Temp Manag 2014;4(2):88–95.
Schuijt, M.T.U., Schultz, M.J., Paulus, F. et al. Association of intensity of ventilation with 28-day mortality in COVID-19 patients with acute respiratory failure: insights from the PRoVENT-COVID study. Crit Care 2021;25:283.
Kim HS, Park S, Ko HH, Ha SO, Lee SH, Kim YK. Different characteristics of bloodstream infection during venoarterial and venovenous extracorporeal membrane oxygenation in adult patients. Sci Rep. 2021;11(1):9498.
Olson SR, Murphree CR, Zonies D, et al. Thrombosis and Bleeding in Extracorporeal Membrane Oxygenation (ECMO) Without Anticoagulation: A Systematic Review. ASAIO J. 2021;67(3):290–296.
Supady A, Combes A, Barbaro RP, et al. Respiratory indications for ECMO: focus on COVID-19. Intensive Care Med. 2022;9:1–12.
Varon J, Acosta P. Coagulopathy during therapeutic hypothermia: Where are the data? Resuscitation. 2009;80(7):726–7.
Rumbus Z, Matics R, Hegyi P, et al. Fever Is Associated with Reduced, Hypothermia with Increased Mortality in Septic Patients: A Meta-Analysis of Clinical Trials. PLoS One. 2017;12(1):e0170152.

No competing interests reported.

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Ventilatory load reduction by combined mild hypothermia and ultra-protective mechanical ventilation strategy in very severe COVID-19-related ARDS: a feasibility study.

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