Limiting positive end-expiratory pressure to protect renal function in SARS-CoV-2 critically ill patients.

Dear Editor,

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) related pneumonia is a risk factor for acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI) [1,2]. While the mechanisms of AKI in this context are not yet elucidated, it is likely that providing a lung protective mechanical ventilation with high levels of positive end-expiratory pressure (PEEP) may worsen renal function [[2], [3], [4], [5]]. Accordingly, strategies of PEEP titration [6] and hemodynamic management in SARS-CoV-2 related ARDS are still open to discussion. Herein, we report our experience in SARS-CoV-2 critically ill patients before and after having modified our practices in the view of the high occurrence of AKI that needed renal replacement therapy (RRT) in the first cases we managed. Our hypothesis was that limiting the level of PEEP (<12 cmH2O) while targeting upward mean arterial pressure (>75 mm Hg) during the first 48 h after the intubation would decrease the need for RRT.

Methods

During “period 1” (between 04 and 15 March 2020), all mechanically ventilated patients with confirmed SARS-CoV-2 admitted to our intensive care unit received volume-controlled ventilation with a tidal volume of 6 mL.kg-1 of ideal body weight and PEEP stepwise increased to reach a plateau pressure below 28 cmH2O. A conservative fluid strategy (i.e. fluid expansion based on bedside evaluation of the cardiac preload dependence) was applied and norepinephrine infusion targeted a mean arterial pressure >65 mm Hg. During “period 2” (from 16 March to 06 April 2020), the following changes were applied: 1) PEEP was limited to 10–12 cmH2O; 2) liberal fluid strategy was applied (no systematic preload dependence evaluation) and 3) norepinephrine was administrated to achieve a mean arterial pressure >75 mm Hg. We collected baseline patient's characteristics, ventilatory and hemodynamic management, daily clinical and biological data and the need for RRT until day 14. The Lung Injury Score (so called Murray score), which is a four-category scale including: 1, chest roentgenogram score; 2, hypoxemia score; 3, PEEP score; 4, respiratory system compliance score was also collected at admission [7]. During the two periods, the management of RRT was similar and followed our local guidelines based on the delayed RRT strategy group of the AKIKI study [8]. The primary endpoint was the proportion of patients requiring RRT at day 14. The statistical analysis compared patient's baseline characteristics, therapeutic management and the proportion of patients with AKI. Our local ethics committee approved the study (CER Sorbonne University, N°2020 – CER-2020-32). Patients or their family gave their oral consent.

Results

Seventy-three patients were included, 20 during “period 1” and 53 during “period 2”. Baseline characteristics were not different between periods (Table 1 ). All patients had AKI at day 14 according to the Kidney Disease: Improving Global Outcomes (KDIGO) definition (Table 1) [9]: 11 patients were classified AKI KDIGO 1 (four patients with creatinine criteria and seven patients with low urine output criteria), 26 patients were classified AKI KDIGO 2 (four patients with creatinine criteria and 22 with low urine output criteria) and 36 patients were classified AKI KDIGO 3 (27 patients with creatinine criteria and nine with urine output criteria).

Table 1

Characteristics of patients on admission, therapeutic management and study endpoints.

	Period 1	Period 2	p value
	n = 20	n = 53
Patient's characteristics
Age, year	58 (48–67)	57 (53–67)	0.742
Male gender, n (%)	15 (75)	45 (85)	0.327
Body mass index, kg.m-2	30 (28–33)	28 (26–32)	0.862
Simplified Acute Physiology Score 2	35 (29–50)	33 (27–41)	0.256
Sequential Organ Failure Assessment	9 (6–10)	7 (5–9)	0.399
Chronic hypertension, n (%)	10 (50)	20 (32)	0.426
Diabetes, n (%)	7 (35)	14 (17)	0.565
Chronic renal failure, n (%)	1 (5)	8 (17)	0.429
Hemodynamic, ventilatory and renal function at admission
Mean arterial pressure, mm Hg	64 (59–73)	65 (57–77)	0.958
PaO2/FiO2	165 (111–218)	116 (88–156)	0.007
Lung Injury score (Murray)	11 (9–12)	11 (10−12)	0.087
Creatinine, μmol.L−1	78 (67–107)	87 (66–130)	0.457
Hemodynamic management within first 48 h
Norepinephrine administration, n (%)	16 (80)	49 (92)	0.203
Maximal dose of norepinephrine, μg.kg−1.min−1	0.20 (0.1–1.0)	0.30 (0.2–0.6)	0.555
Fluid expansion, mL	1000 (125–2100)	2000 (1500–2750)	0.021
Averaged mean arterial pressure, mm Hg	87 (82–92)	91 (86–99)	0.095
Mean arterial pressure ≥ 75 mm Hg, n (%)	6 (30%)	35 (66%)	0.008
Ventilatory management within first 48 h
Tidal volume, mL.kg−1	4.8 (4.4–5.1)	4.8 (4.2–5.3)	0.343
Averaged Positive end expiratory pressure, mm Hg	14 (14–15)	12 (10–12)	0.001
Peak airway pressure, mm Hg	64 (48–70)	52 (42–60)	0.100
Study endpoints at day 14
KDIGO 1, n (%)	1 (5)	10 (19)	0.139
KDIGO 2, n (%)	4 (20)	22 (41)	0.087
KDIGO 3, n (%)	15 (75)	21 (40)	0.007
Renal replacement therapy, n (%)	9 (45)	11 (21)	0.038
Extracorporeal membrane oxygenation, n (%)	4 (20)	11 (21)	0.999
Extubation, n (%)	5 (25)	12 (23)	0.999
Intensive care unit mortality, n (%)	7 (35)	14 (26)	0.469

KDIGO: Kidney Disease Improving Global Outcomes.

Lung Injury score (Murray score) is a four-category scale consisted of the following categories: 1, chest roentgenogram score; 2, hypoxemia score; 3, positive end-expiratory score; 4, respiratory system compliance score.

The proportion of patients requiring RRT and those with AKI KDIGO 3 at day 14 was significantly lower during “period 2”, 11 (21%) vs. 9 (45%) p = .038 and 21 (40%) vs. 15 (75%) p = .007 respectively (Table 1, Fig. 1 ). The proportion of patients with AKI KDIGO 3 was significantly lower on day 2 and on day 7 during “period 2”, 11 patients (21%) vs. 10 (50%) p = .015 and 17 patients (38%) vs. 13 (76%) p = .007 respectively. The timeline of AKI onset was one day (1–2) after intubation, without significant difference between the two periods (p = .192).

Fig. 1

Proportion of patients with acute kidney injury, need for renal replacement therapy and mortality in the ICU according to the period of the study. Period 1 was characterized by high level of positive end expiratory pressure and conservative fluid strategy. Period 2 was characterized by limited positive end expiratory pressure, liberal fluid strategy and higher mean arterial pressure.

KDIGO: Kidney Disease Improving Global Outcomes; RRT: renal replacement therapy; MAP: mean arterial pressure; PEEP: positive and expiratory pressure.

As compared to their counterparts, patients admitted during “period 2” received more fluids (2000 mL [IQR 1500–2750] vs. 1000 mL [IQR 125–2100] p = .021), had a lower PEEP level (12 [IQR 10–12] vs. 14 [IQR 14–15] p < .001) and a majority of patients had higher mean arterial pressure during the first 48 h (35 patients (66%) vs. 6 (30%) p = .008) (Table 1, Fig. 1). The peak airway pressure was similar in the two groups (Table 1). Despite a lower PEEP level during “period 2”, the Lung Injury Score was similar between the two groups, as well as the mortality (Table 1).

Discussion

Our findings suggest that changing our practices was associated with a decreased need for RRT and a lower proportion of patients with AKI KDIGO 3. This might not be a causal relationship and further confirmation is warranted. Several factors may contribute to AKI onset, as comorbidities such as hypertension or diabetes mellitus. These factors are well-known factors of renal vulnerability and have been recently identified as risk factors for AKI in patients with ARDS [2,10]. In patients with SARS-CoV-2 related ARDS, impairment of gas exchange and severe hypoxemia has been recognized as others risk factors [2]. The association between PEEP and AKI has been suggested in physiological studies [2,4,5] but recently, Panitchone et al. have suggested an association between peak airway pressure and AKI [10]. This association was not found in our patients. However, in the early phase of SARS-CoV-2 related ARDS, pulmonary mechanics may be different from traditional ARDS, with different phenotypes characterized by low lung recruitability, normal compliance and without need for very high PEEP or even deleterious effects of the latter [6]. The timeline of AKI onset is another issue. In our patients, we have found that AKI occurred most commonly within 24 h of intubation, as Hirsch et al. have already suggested [11].

The main limitation of our study is the retrospective design that limits the causal relationship of our findings. In addition, the significant proportion (20%) of patients with extra-corporeal membrane oxygenation could have influence our findings but this case mix was inherent to our activity as expert-center. Nevertheless, our experience suggests the existence of a critical cross-talk between lungs and kidney function [2,12] in SARS-CoV-2 critically ill patients. Careful monitoring of lung and kidney interaction is required in these patients. High levels of PEEP may not be required in the early phase of SARS-CoV-2 related ARDS.

Declaration of Competing Interest

Martin Dres received fees from Lungpacer (expertise, lectures). Other authors had no conflict of interest to declare.