American Journal of Respiratory and Critical Care Medicine

To the Editor:

Lung-protective ventilation with low Vt has become a cornerstone of management in patients with acute respiratory distress syndrome (ARDS) (1, 2). However, a consequence of low-Vt ventilation is hypercapnia, which has significant physiological effects and may be associated with higher hospital mortality (2, 3).

Ventilatory ratio (VR), defined as [minute ventilation (ml/min) × PaCO2 (mm Hg)]/[predicted body weight × 100 (ml/min) × 37.5 (mm Hg)] (4), is a simple bedside index of impaired efficiency of ventilation and correlates well with physiological Vd fraction (Vd-to-Vt ratio, Vd/Vt) in patients with ARDS (46). However, the VR and appropriate lung ventilation strategy for coronavirus disease (COVID-19)-associated ARDS remain largely unknown.

Here, we report a case series highlighting ventilatory ratio in hypercapnic mechanically ventilated patients with COVID-19–associated ARDS in our ICU and their individualized ventilation strategies.

Case Series

The study was approved by the ethics committee of the First Affiliated Hospital of Guangzhou Medical University. The requirement for informed consent was waived because the study was observational and the family members were in quarantine.

The First Affiliated Hospital of Guangzhou Medical University is the designated center for patients with COVID-19 in Guangdong, China. We included eight consecutive patients (seven male; mean age, 63.2 ± 11.0 yr) who were intubated in another hospital before being transferred to our ICU. All patients had a history of exposure in Wuhan City or direct contact with patients with confirmed COVID-19. All patients reported fever, cough, shortness of breath, and generalized weakness before hospitalization and tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the basis of real-time PCR of throat swab specimens. All patients were diagnosed with ARDS according to the Berlin definition (7): PaO2/FiO2 ratio, 102.0 ± 29.7 mm Hg (mean ± SD), with Acute Physiology and Chronic Health Evaluation II score 21.6 ± 5.3 and Sequential Organ Failure Assessment score 9.1 ± 2.7 (Table 1).

Table 1. Baseline Characteristics of Eight Patients with Acute Respiratory Distress Syndrome Infected with SARS-CoV-2

CharacteristicPatients (N = 8)
Exposure history8/8
Age, yr63.2 ± 11.0
Sex, M7/8
Body mass index, kg/m222.7 ± 2.3
Predicted body weight, kg64.7 ± 6.0
Chronic medical illness 
 Hypertension4/8
 Diabetes3/8
 Coronary heart disease1/8
 Chronic obstructive pulmonary disease1/8
 Obstructive sleep apnea syndrome1/8
 Hepatitis B1/8
 Smoker3/8
Presenting symptoms onset 
 Fever8/8
 Cough7/8
 Generalized weakness4/8
 Shortness of breath3/8
Real-time RT-PCR of throat swab8/8
Radiologic characteristics 
 Bilateral pneumonia8/8
 Multiple mottling and ground-glass opacity8/8
Noninvasive ventilation before intubation1/8
 Duration of noninvasive ventilation, d1
HFNC before intubation7/8
 Duration of HFNC, d2.6 ± 2.2
PaO2/FiO2 ratio, mm Hg102.0 ± 29.7
APACHE II score21.6 ± 5.3
SOFA score9.1 ± 2.7
Weaning before day 28 at ICU5/8
Discharge before day 28 at ICU5/8
28-d mortality at ICU0/8

Definition of abbreviations: APACHE = Acute Physiology and Chronic Health Evaluation; HFNC = high-flow nasal cannula oxygen therapy; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SOFA = Sequential Organ Failure Assessment.

Data are presented as mean ± SD or n/N unless otherwise noted.

A ventilation strategy using a low Vt of 6.0 ml/kg predicted body weight (PBW) was used in the first four consecutive patients. However, they had respiratory distress with low oxygen saturation as measured by pulse oximetry, so we immediately increased Vt to 7.0 ± 0.6 ml/kg PBW (Table 2). This resulted in an acceptable plateau pressure (23.3 ± 2.2 cm H2O) and driving pressure (12.3 ± 1.7 cm H2O). However, all four patients developed hypercapnia (PaCO2, 57.7 ± 5.2 mm Hg). Respiratory system compliance was only moderately reduced (static respiratory system compliance, 35.7 ± 5.8 ml/cm H2O). To examine this issue, we measured VR; the mean value was 2.1 ± 0.3 in the initial four patients, suggesting high Vd/Vt (46).

Table 2. Ventilator Settings

VariablesLow Vt (Initial 4 Patients)Intermediate Vt (Initial 4 Patients)P ValueIntermediate Vt (8 Patients)
Vt, ml/kg PBW7.0 ± 0.67.7 ± 0.80.0227.5 ± 0.6
PaCO2, mm Hg57.7 ± 5.244.1 ± 3.60.00341.8 ± 3.7
PaO2/FiO2 ratio207 ± 61241 ± 380.402230 ± 49
RR, beats/min21.5 ± 2.021.0 ± 1.40.18220.1 ± 1.5
Ve, L/min9.1 ± 1.09.8 ± 1.00.0209.3 ± 1.0
Ventilation ratio2.1 ± 0.31.7 ± 0.20.0181.6 ± 0.2
Pplat, cm H2O23.3 ± 2.223.3 ± 3.1>0.99923.6 ± 2.7
PEEP, cm H2O11.0 ± 1.210.0 ± 1.40.2509.6 ± 1.2
ΔP, cm H2O12.3 ± 1.713.5 ± 2.70.08014.1 ± 2.5
Cst, ml/cm H2O35.7 ± 5.836.1 ± 7.90.59533.9 ± 7.6
EELV, ml2,559 ± 612,285 ± 355

Definition of abbreviations: Cst = static respiratory system compliance; ΔP = driving pressure; EELV = end-expiratory lung volume; PBW = predicted body weight; PEEP = positive end-expiratory pressure; Pplat = plateau pressure; RR = respiratory rate.

Data are presented as mean ± SD. P value indicates difference between low Vt and intermediate Vt of the initial four patients using a paired t test.

We then performed titration of Vt. An increased Vt (7.7 ± 0.8 ml/kg PBW) was applied to the initial four patients (Table 2). PaCO2 decreased significantly compared with Vt 7.0 ml/kg PBW (57.7 ± 5.2 vs. 44.1 ± 3.6 mm Hg; P = 0.003) with permitted plateau pressure (23.3 ± 3.1 cm H2O) and driving pressure (13.5 ± 2.7 cm H2O). Importantly, VR in the four patients was significantly decreased (1.7 ± 0.2 vs. 2.1 ± 0.3; P = 0.018) and PaO2/FiO2 was slightly improved (241 ± 38 mm Hg vs. 207 ± 61; P = 0.402) compared with Vt 7.0 ml/kg PBW. Therefore, an intermediate Vt of 7.5 ± 0.6 ml/kg PBW was applied to the subsequent four patients with COVID-19 ARDS. The PaCO2 was 41.8 ± 3.7 mm Hg, and VR was 1.6 ± 0.2.

Discussion

We found that hypercapnia was common in patients with COVID-19–related ARDS with low Vt ventilation. High VR was found in these patients, indicating inadequacy of ventilation in patients with ARDS with COVID-19. An intermediate Vt (7–8 ml/kg PBW) ventilation strategy was applied to the first four patients to increase pulmonary efficiency to eliminate CO2, and this was used in the next four patients.

Gas exchange consists of oxygenation and ventilation. Oxygenation is quantified by the PaO2/FiO2 ratio, and this method has gained wide acceptance, particularly since publication of the Berlin definition of ARDS (7). However, the Berlin definition does not include additional pathophysiological information about ARDS, such as alveolar ventilation, as measured by pulmonary dead space, which is an important predictor of outcome (8). Increased pulmonary dead space reflects the inefficiency of the lungs to eliminate CO2, which may lead to hypercapnia.

In our patients with ARDS with COVID-19, hypercapnia was common at ICU admission with low Vt ventilation. Assuming the anatomic portion of dead space is constant, increasing Vt with constant respiratory rate would effectively increase alveolar ventilation. Any such increase in Vt would decrease PaCO2, which would be captured by VR (6). VR, a novel method to monitor ventilatory adequacy at the bedside (46), was very high in our patients, reflecting increased pulmonary dead space and inadequacy of ventilation.

With an acceptable plateau pressure and driving pressure, titration of Vt was performed. PaCO2 and VR were significantly decreased when an intermediate Vt (7–8 ml/kg PBW) was applied. We suggest that intermediate Vt (7–8 ml/kg PBW) is recommended for such patients. Therefore, low Vt may not be the best approach for all patients with ARDS, particularly those with a less severe decrease in respiratory system compliance and inadequacy of ventilation.

In summary, we found that hypercapnia was common in patients with COVID-19–associated ARDS while using low Vt ventilation. VR was increased in these patients, which reflected increased pulmonary dead space and inadequacy of ventilation. An intermediate Vt was used to correct hypercapnia efficiently, while not excessively increasing driving pressure. Clinicians must have a high index of suspicion for increased pulmonary dead space when patients with COVID-19–related ARDS present with hypercapnia.

The authors thank Dr. Arthur S. Slutsky for the invaluable assistance with the manuscript.

1. Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A; Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:13011308.
2. Barnes T, Zochios V, Parhar K. Re-examining permissive hypercapnia in ARDS: a narrative review. Chest 2018;154:185195.
3. Tiruvoipati R, Pilcher D, Buscher H, Botha J, Bailey M. Effects of hypercapnia and hypercapnic acidosis on hospital mortality in mechanically ventilated patients. Crit Care Med 2017;45:e649e656.
4. Sinha P, Fauvel NJ, Singh S, Soni N. Ventilatory ratio: a simple bedside measure of ventilation. Br J Anaesth 2009;102:692697.
5. Sinha P, Fauvel NJ, Singh P, Soni N. Analysis of ventilatory ratio as a novel method to monitor ventilatory adequacy at the bedside. Crit Care 2013;17:R34.
6. Sinha P, Calfee CS, Beitler JR, Soni N, Ho K, Matthay MA, et al. Physiologic analysis and clinical performance of the ventilatory ratio in acute respiratory distress syndrome. Am J Respir Crit Care Med 2019;199:333341.
7. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al.; ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin definition. JAMA 2012;307:25262533.
8. Nuckton TJ, Alonso JA, Kallet RH, Daniel BM, Pittet JF, Eisner MD, et al. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 2002;346:12811286.

*These authors contributed equally to this work.

Corresponding author (e-mail: ).

Supported by National Science and Technology Major Project (No. 2017ZX10204401), National Natural Science Foundation of China (81970071), the Special Project for Emergency of the Ministry of Science and Technology (2020YFC0841300), and the Special Project of Guangdong Science and Technology Department (2020B111105001).

Author Contributions: Xiaoqing Liu, Xuesong Liu, Y.X., and Y.L. conceived and designed the study; Xiaoqing Liu, Xuesong Liu, Y.X., Z.X., Y.H., and Y.L. analyzed the data and wrote the manuscript; Xiaoqing Liu, Xuesong Liu, Y.X., Z.X., Y.H., S.C., S.L., D.L., Z.L., and Y.L. reviewed and revised the manuscript.

Originally Published in Press as DOI: 10.1164/rccm.202002-0373LE on March 23, 2020

Author disclosures are available with the text of this letter at www.atsjournals.org.

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