Ventilatory Ratio in Hypercapnic Mechanically Ventilated Patients with COVID-19-associated Acute Respiratory Distress Syndrome.

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) × PaCO (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 (4–6). 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): PaO/FiO 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

Characteristic	Patients (N = 8)
Exposure history	8/8
Age, yr	63.2 ± 11.0
Sex, M	7/8
Body mass index, kg/m2	22.7 ± 2.3
Predicted body weight, kg	64.7 ± 6.0
Chronic medical illness
Hypertension	4/8
Diabetes	3/8
Coronary heart disease	1/8
Chronic obstructive pulmonary disease	1/8
Obstructive sleep apnea syndrome	1/8
Hepatitis B	1/8
Smoker	3/8
Presenting symptoms onset
Fever	8/8
Cough	7/8
Generalized weakness	4/8
Shortness of breath	3/8
Real-time RT-PCR of throat swab	8/8
Radiologic characteristics
Bilateral pneumonia	8/8
Multiple mottling and ground-glass opacity	8/8
Noninvasive ventilation before intubation	1/8
Duration of noninvasive ventilation, d	1
HFNC before intubation	7/8
Duration of HFNC, d	2.6 ± 2.2
PaO2/FiO2 ratio, mm Hg	102.0 ± 29.7
APACHE II score	21.6 ± 5.3
SOFA score	9.1 ± 2.7
Weaning before day 28 at ICU	5/8
Discharge before day 28 at ICU	5/8
28-d mortality at ICU	0/8

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 (PaCO, 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 (4–6).

Table 2.

Ventilator Settings

Variables	Low Vt (Initial 4 Patients)	Intermediate Vt (Initial 4 Patients)	P Value	Intermediate Vt (8 Patients)
Vt, ml/kg PBW	7.0 ± 0.6	7.7 ± 0.8	0.022	7.5 ± 0.6
PaCO2, mm Hg	57.7 ± 5.2	44.1 ± 3.6	0.003	41.8 ± 3.7
PaO2/FiO2 ratio	207 ± 61	241 ± 38	0.402	230 ± 49
RR, beats/min	21.5 ± 2.0	21.0 ± 1.4	0.182	20.1 ± 1.5
Ve, L/min	9.1 ± 1.0	9.8 ± 1.0	0.020	9.3 ± 1.0
Ventilation ratio	2.1 ± 0.3	1.7 ± 0.2	0.018	1.6 ± 0.2
Pplat, cm H2O	23.3 ± 2.2	23.3 ± 3.1	>0.999	23.6 ± 2.7
PEEP, cm H2O	11.0 ± 1.2	10.0 ± 1.4	0.250	9.6 ± 1.2
ΔP, cm H2O	12.3 ± 1.7	13.5 ± 2.7	0.080	14.1 ± 2.5
Cst, ml/cm H2O	35.7 ± 5.8	36.1 ± 7.9	0.595	33.9 ± 7.6
EELV, ml	—	2,559 ± 61	—	2,285 ± 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). PaCO 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 PaO/FiO 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 PaCO 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 PaO/FiO 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 PaCO, which would be captured by VR (6). VR, a novel method to monitor ventilatory adequacy at the bedside (4–6), 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. PaCO 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.