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Introduction

The role of positive end-expiratory pressure (PEEP) guided by lower inflection point (LIP) in the pressure-volume (PV) curve after recruitment maneuver (RM) in severe acute respiratory distress syndrome (ARDS) to maintain expiratory end alveolar recruitment is controversial. LIP may reflect the open pressure of most alveoli at the inhalation phase, rather than alveolar closure pressure at exhalation (1).

It was previously reported that alveolar recruitment occurs above the inspiratory inflection point and PEEP = LIP+2–3 cm H2O did not maintain alveolar recruitment (1–3). Point of maximum curvature (PMC) pressure in the PV curve indicated the initiation of alveolar closure in exhalation. Previous studies suggested that PEEP guided by PMC was reasonable and significantly higher than that guided by LIP, leading to significant unfavorable impact on ventilation and blood flow as well as a higher risk of ventilator-induced lung injury (VILI) (4–6). Airway pressure release ventilation (APRV) involved the modification of continuous positive airway pressure (CPAP), and had been proven to decrease mean arterial pressure (MAP), as well as improve hemodynamics and alveolar collapse and prevent barotrauma (7–9).

Therefore, in the present study, we established a canine model of severe ARDS, and set high APRV pressure guided by PMC after RM, in order to maintain stable hemodynamics and alveolar recruitment, and improve oxygen delivery (DO2).

Materials and methods

Animal model

In total, 18 healthy dogs (8 male and 10 female) were provided by the Laboratory Animal Center of Xuzhou Medical College (Jiangsu, China; non-SPF). Tracheotomy was performed after anesthesia, and intubation of trachea cannula (diameter 7.5 mm). Volume control ventilation was performed, as well as tidal volume (VT) 6 ml/kg, breath rate 30 times/min, inspiration duration of 0.8 sec, inspiratory pause of 0.1 sec, fraction of inspired oxygen (FiO2) 80%, and PEEP 5 cm H2O (1 cm H2O=0.098 kPa).

Deep venous catheter was intubated in the right internal jugular vein and connected with a pulse contour cardiac output (PiCCO) instrument (Pulsion Medical Systems SE, Munich, Germany) through a temperature detector. PiCCO arterial canal (Pulsion Medical Systems SE) was intubated in the right femoral artery. For the ARDS model, 0.2 ml/kg oleic acid was mixed with an equal volume of autologous blood and pumped into vein. Arterial blood was collected for blood gas analysis every 30 min. The dogs with oxygenation index [partial pressure of oxygen in arterial blood (PaO2)/FiO2] ≤100 mmHg for 30 min constituted a successful animal model and was included in the study (10).

The dogs received continuous intravenous injection of 1–2 mg × kg−1 × h−1 pentobarbital sodium for sedation. During the experiment, infusion was performed to maintain MAP 80 mmHg (1 mmHg=0.133 kPa) and central venous pressure (CVP) >5 cm H2O before RM.

The present study was approved by the ethics committee of Xuzhou Medical College.

PV curve and lung RM

After the animal model became stable, a static PV curve was plotted using a super-syringe technique, with LIP=18±1.4 cm H2O, and PMC=11±1.3 cm H2O (5). RM was performed after hemodynamics became stable. Respiratory mode was biphasic-positive airway pressure (BiPAP), Phigh=40 cm H2O, Phigh=25 cm H2O, with an inspiration to expiration ratio of 1:2, while Phigh was altered to 30 cm H2O after 90 sec (11).

Experimental groups

The dogs were randomized into 3 groups after RM: Blip group, Plow = LIP+2 cm H2O; Bpmc group, Plow = PMC; Apmc group, Plow = PMC. In the APRV group, Phigh was set as PMC, with an inspiratory duration of 4 sec, expiratory durationof 0.4 sec, and Plow 10 cm H2O.

Measurements

Thirty seconds after RM became stable, it was set as 0 h. The changes of hemodynamics, oxygenation and DO2 were observed at 0, 1, 2 and 4 h after RM in ARDS dogs. Hemodynamics measurements included heart rate (HR), MAP, cardiac index (CI) and CVP. Additionally, blood gas analysis was PaO2 for calculation of the oxygenation index. DO2 involved DO2=10 × CI × arterial oxygen content (CaO2), and CaO2=1.34 × blood oxygen saturation (SaO2) × Hb+0.003 × PaO2.

Statistical analysis

SPSS 13.0 software (Chicago, IL, USA)was used for statistical analysis. Data were presented as mean ± SD. Analysis of variance was used for inter-group comparison. P<0.05 indicated statistically significant results.

Results

General

Hemothorax and pulmonary edema were identified in specimens of ARDS dogs. Furthermore, hemorrhage in the region of proximal spine was evident although there was no pneumothorax.

There was no significant difference in the MAP, CI and Hb between ARDS dogs when compared to before model establishment (P>0.05) (Table I). For PaO2/FiO2 and static lung compliance there was a significant decrease observed following establishment of the ARDS model when compared to values prior to model (P<0.05). However, the differences between the 3 groups were not statistically significant (P>0.05).

Table I. Measurements at baseline and in the ARDS models.

Table I.

Measurements at baseline and in the ARDS models.

Item/group	Baseline	ARDS	t	P-value
MAP (mmHg)
Blip	144.2±8.9	104.8±8.2	7.317	0.000
Bpmc	136.8±5.6	103.6±6.6	8.620	0.000
Apmc	137.8±6.5	105.8±10.3	5.905	0.000
F	0.311	0.551	–	–
P-value	0.739	0.652	–	–
CI (l/min/cm2)
Blip	4.3±0.7	2.6±0.4	4.739	0.000
Bpmc	3.4±0.3	2.5±0.4	4.047	0.001
Apmc	4.7±0.6	2.5±0.4	6.856	0.000
F	2.409	0.181	–	–
P-value	0.132	0.834	–	–
Hb (g/l)
Blip	142±12	140±14	0.244	0.847
Bpmc	148±12	136±15	1.404	0.155
Apmc	144±14	138±15	0.632	0.557
F	1.067	1.313	–	–
P-value	0.444	0.305	–	–
Static lung compliance (ml/cm H2O)
Blip	31.3±1.6	13.9±0.8a	4.888	0.000
Bpmc	34.3±1.1	14.9±0.8a	24.37	0.000
Apmc	32.7±2.1	14.7±0.8a	18.01	0.000
F	0.946	1.410	–	–
P-value	0.418	0.29	–	–
PaO2/FiO2 (mmHg)
Blip	398±10	90±12a	44.31	0.000
Bpmc	424±13	92±9a	47.184	0.000
Apmc	414±15	92±10a	40.14	0.000
F	1.044	1.073	–	–
P-value	0.382	0.326	–	–

{ label (or @symbol) needed for fn[@id='tfn1-etm-0-0-3456'] } In comparison to baseline

a P<0.05. ARDS, acute respiratory distress syndrome; MAP, mean arterial pressure; CI, cardiac index; PaO₂, partial pressure of oxygen in arterial blood; FiO₂, fraction of inspired oxygen.

Hemodynamics

CI in the Bpmc group at 0, 1, 2 and 4 h was significantly lower than that before RM (P<0.05), and in the Blip and Apmc groups (P<0.05). CI in Blip group at 0, 1, 2 and 4 h was not significantly different from that before RM. CI in the Apmc group at 0 h was decreased, although the difference was not significant, and CI gradually increased (Fig. 1).

Figure 1. Effect of APRV on CI (1 × min−1 × m−2) after RM. In comparison to before RM, *P<0.05; inter-group comparison, △P<0.05; in comparison to 0 h, ▲P<0.05. APRV, airway pressure release ventilation; CI, cardiac index; RM, recruitment maneuver.

HR in the Bpmc group was significantly increased compared to that before RM and also when compared to the Blip and Apmc groups (P<0.05), whereas HR in the Blip and Apmc groups was not significantly altered (P>0.05). MAP in the Bpmc group was significantly lower compared to that before RM and also when compared to the Blip and Apmc groups (P<0.05), whereas MAP in the Blip and Apmc groups was not significantly altered (P>0.05) (Tables II and III).

Table II. Effect of APRV on MAP (mmHg) after RM.

Table II.

Effect of APRV on MAP (mmHg) after RM.

Group	Before RM	0 h	1 h	2 h	4 h	F	P-value
Blip	116±14	107±12	109±13	109±15	114±12	0.806	0.453
Bpmc	114±15	90±12a,b	91±13a,b	92±14a,b	92±11a,b	11.942	0.001
Apmc	114±14	104±12	102±13	103±11	106±14	1.395	0.243
F	0.045	8.803	8.823	8.369	8.419	–	–
P-value	0.956	0.021	0.021	0.026	0.023	–	–

{ label (or @symbol) needed for fn[@id='tfn3-etm-0-0-3456'] } In comparison to before RM

a P<0.05; inter-group comparison

b P<0.05. APRV, airway pressure release ventilation; MAP, mean arterial pressure; RM, recruitment maneuver.

Table III. Effect of APRV on HR (beat/min) after RM.

Table III.

Effect of APRV on HR (beat/min) after RM.

Group	Before RM	0 h	1 h	2 h	4 h	F	P-value
Blip	106±14	102±8	103±12	102±15	104±12	0.803	0.452
Bpmc	104±15	125±9a,b	124±12a,b	122±14a,b	122±13a,b	10.256	0.017
Apmc	104±14	114±14	100±14	98±13	96±14	1.369	0.234
F	0.045	6.803	6.823	6.369	6.419	–	–
P-value	0.956	0.034	0.032	0.038	0.036	–	–

{ label (or @symbol) needed for fn[@id='tfn6-etm-0-0-3456'] } In comparison to before RM

a P<0.05; inter-group comparison

b P<0.05. APRV, airway pressure release ventilation; HR, heart rate; RM, recruitment maneuver.

Blood gas analysis

Oxygenation in the 3 groups after RM was improved compared to before RM (Fig. 2). Comparisons between the groups showed that the oxygenation index in the 3 groups at 1 and 2 h was not significantly different than at 0 h (P>0.05). The oxygenation index at 0 h in the Blip group was significantly lower than that in the Apmc and Bpmc groups (P<0.05). The oxygenation index at 0 h in Apmc group was higher than that in Blip and Bpmc groups (P<0.05). As shown in Table IV, PaO2 after RM in Bpmc group was gradually increased (P<0.05), while PaO2 after RM in Blip and Apmc groups was not significantly increased (P>0.05).

Figure 2. Effect of APRV on PO2/FiO2 (mmHg) after RM. In comparison to before RM, *P<0.05; inter-group comparison, △P<0.05; in comparison to 0 h, ▲P<0.05. APRV, airway pressure release ventilation; FiO2, fraction of inspired oxygen RM, recruitment maneuver.

Table IV. Effect of APRV on PaCO2 (mmHg) after RM.

Table IV.

Effect of APRV on PaCO2 (mmHg) after RM.

Group	Before RM	0 h	1 h	2 h	4 h	F	P-value
Blip	35±9	37±7	43±8	42±7	35±7	0.923	0.876
Bpmc	32±7	37±9	47±9a	51±8a,b	53±13a,b	16.103	0.000
Apmc	33±9	36±8	39±8	43±7	42±7	2.494	0.342
F	0.666	0.708	1.554	3.421	6.788	–	–
P-value	0.519	0.471	0.316	0.218	0.036	–	–

{ label (or @symbol) needed for fn[@id='tfn9-etm-0-0-3456'] } In comparison to before RM

a P<0.05; inter-group comparison

b P<0.05. APRV, airway pressure release ventilation; PaCO₂, partial pressure of oxygen in arterial blood; RM, recruitment maneuver.

DO2

Alteration of the DO2 ratio (DO2 after RM/DO2 before RM) reflected DO2 in different groups. DO2 in the Bpmc group at 0, 1, and 4 h was significantly lower than that in the Blip and Apmc groups, and not significantly improved compared to before RM (Fig. 3). DO2 in the Blip and Apmc groups after RM was improved compared to that before RM and in the Bpmc group. However, DO2 at 4 h in the Blip group was significantly lower than that at 0 h and in the Apmc group (P<0.05). DO2 at 4 h in the Apmc group was higher than that at 0 h, in the Blip and Bpmc groups (P<0.05).

Figure 3. Effect of APRV on DO2 after RM. In comparison to before RM, *P<0.05; inter-group comparison, △P<0.05; in comparison to 0 h, ▲P<0.05; in comparison to the Blip group, ◼P<0.05. APRV, airway pressure release ventilation; DO2, oxygen delivery RM, recruitment maneuver.

Discussion

PEEP guided by LIP in the open lung approach after RM in severe ARDS is a controversial intervention (1). Severe ARDS required RM to open collapsed alveoli, especially for extra pulmonary ARDS. RM increased lung volume, and improved oxygenation and lung compliance. However, PEEP was set to maintain open alveoli and prevent the re-collapse of alveoli after the open lung approach (1,12,13). Currently, most studies demonstrated that PEEP could be guided by LIP in PV curve, PEEP=LIP+2–3 cm H2O. LIP represented the transition component from low to high compliance in the inspiratory PV curve, i.e., the pressure on recruitment of most alveoli. It was reported that the point of maximum compliance in the inspiratory PV curve was able to reflect alveolar closure pressure indirectly. PEEP guided by LIP had the following limitations: i) maximum compliance represented by LIP in inhale branch indicated recruitment in most alveoli rather than end-exhale closure; ii) PV curve in ARDS did not necessarily have LIP; and iii) alveolar recruitment may occur above the high inflection point of inhale branch. PEEP=LIP+2–3 cm H2O did not maintain alveolar recruitment (14) and lung recruitment sufficiently (1–3). In the present study, oxygenation in the Blip group was significantly decreased 4 h after RM in comparison to 2 h, indicating that the collapse of some recruited alveoli at 4 h after RM, leading to decreased oxygenation and DO2.

PEEP guided by PMC was reasonable in theory. PMC in the PV curve indicated the initiation of alveolar closure in the exhale phase, i.e., with airway pressure decreasing, many alveoli collapsed rapidly. PEEP set at this point may prevent alveolar collapse in the exhale phase. However, PEEP guided by PMC was significantly higher than that guided by LIP, leading to a more unfavorable impact on ventilation and blood flow (15) as well as a higher risk of VILI. Therefore, it was not applied (16,17). Crotti et al rescued one ARDS patient with septicemia by RM, PEEP 25 cm H2O, LIP 16–18 cm H2O (18). Xu et al showed that PEEP guided by PMC may improve oxygenation and shunt significantly, however, CI and even DO2 were decreased (5). In the present study, hemodynamics in the Bpmc group was unstable, CI and MAP were decreased, and oxygenation at 4 h after RM was decreased, although these differences were not significant. Additionally, DO2 at 0, 1, 2 and 4 h was significantly decreased. Therefore, in the case of PEEP simply guided by PMC, unstable hemodynamics should be monitored to maintain DO2 and prevent increased PCO2 or barotrauma.

APRV may recruit collapsed lung tissue, maintain maximum and persistent alveolar recruitment as well as hemodynamics. APRV is a modification of CPAP (7). The addition of the pressure-relief valve in exhale branch allowed pressure control, time trigger, pressure limit and time switch, and spontaneous breath in the respiratory cycle (7). High pressure maintained alveolar recruitment while low pressure facilitated expelling CO2 and maintained open alveoli of diffusion constant. Although MAP was increased, peak airway pressure was decreased in order to expel CO2 and reduce barotrauma. Transient pressure relief may decrease intrathoracic pressure and promote right cardiac venous return. Spontaneous breath was not only able to reduce sedative dose, but also the pressure to intrathoracic heart and great vessels by increased airway pressure. This may promote venous return, increase CO2 and DO2, and improve organ perfusion (19).

In the present study, high APRV pressure in the Apmc group was guided by PMC to avoid alveolar collapse and maintain open lung, and further improve oxygenation; thus, oxygenation at 4 h after RM was improved. Additionally, the circulation became stable to improve DO2. It was also able to expel CO2 without increasing peak airway pressure.

In conclusion, high APRV pressure guided by PMC further opened lung, improved oxygenation significantly, maintained stable hemodynamics and improved DO2.

References