Prevention of ventilator-associated pneumonia (VAP) is essential in patients admitted to the intensive care unit (ICU) on invasive mechanical ventilation (MV), because VAP prolongs length of stay, increases antibiotic use and ultimately hospital costs (1, 2).
Body position has a pivotal role in the pathogenesis of VAP. Indeed, it is well acknowledged that ICU patients, lying on the bed in supine fully horizontal position, are at higher risk of VAP (3). In contrast, the semirecumbent position (SRP) prevents the gastro-pulmonary route of colonization and pulmonary infections, and has been endorsed by several healthcare agencies as an effective VAP preventive strategy (2, 4). However, in recent years, a considerable body of evidence from laboratory experiments reappraised preventive efficacy of the SRP, because in such position gravity-driven pulmonary aspiration of colonized oropharyngeal secretion is promoted (5). In light of these challenging arguments, the Trendelenburg position (TP) has been advocated as a potential alternative to prevent pulmonary aspiration, enhance mucus clearance (6), and ultimately avoid VAP (5). Such position could favor clearance of pathogens from the respiratory system and theoretically reduces risks of pulmonary infections. Additionally, laboratory studies demonstrated that the TP also limits dissemination of pathogens from within the endotracheal tube biofilm (7). Notably, a recently completed multicenter clinical trial has tested in critically ill patients the efficacy, safety, and feasibility of the lateral-TP in the prevention of VAP (8). The study was prematurely discontinued due to an unexpected low incidence of VAP and lack of benefits associated with the lateral-TP in secondary outcomes. In addition, post-hoc analysis highlighted potential harm in patients who presented pulmonary infiltrates upon enrolment into the study.
Of note, the TP is commonly used in clinical settings, mostly for brief periods, i.e., in the operative room (9) or during central venous catheterization. Yet, potential risks associated with prolonged use of the TP are still elusive. To date, there is evidence that steep TP could induce significant changes in the body homeostasis. Theoretically, in specific patient populations, i.e., with cardiac diseases, respiratory failure, or brain illnesses, even slight TP orientation could lead to serious complications (9, 10). Cardiovascular and respiratory changes, induced by this position, not only depend on the degree and duration of the intervention, but also by the patient's comorbidities and concomitant treatments (11). In critically ill, mechanically ventilated patients, the potential short and long-term effects of the TP on the brain are of particular concern. Indeed, these patients are already at higher risk of brain damage, particularly when injurious ventilatory settings are applied (12–15). In this context, the TP could further enhance or even promote cerebral injury and worsen patient's outcomes.
Consequently, we addressed aforementioned hypothesis and conducted a secondary analysis of a previous study (5) aimed at investigating in pigs on MV for 72 h, the VAP preventive effects of TP and a ventilatory strategy aimed at improving mucus clearance and reduce pulmonary aspiration of oropharyngeal pathogens. This secondary analysis was primarily aimed at investigating the potential injurious effects of the TP on the brain, in comparison with animals in the SRP.
We conducted a secondary analysis, specifically focused on the cerebral effects of TP, in some of the animals enrolled in our previous prospective, randomized laboratory study (5). Animals were managed according to Spanish law (DECRET 214/1997, July 30, 1997) and University of Barcelona regulations on welfare and management of animals used in scientific testing and research. The protocol was approved by the animal experimentation institutional review board. Throughout this manuscript, we followed ARRIVE guidelines (16) on reporting in-vivo animal experiments. Additional details on animal handling and methods are reported in previous publications (5, 17).
We studied 17 healthy Large White–Landrace pigs (30.6 ± 2.6 kg), enrolled into a study to assess the efficacy of a ventilatory strategy and the TP in the prevention of VAP (5). Animals were anesthetized, oro-tracheally intubated (Hi-Lo Evac, Covidien, Boulder, Colo), and connected to a mechanical ventilator (SERVO-I, Maquet, NJ). Pigs were initially ventilated in volume-control with square-wave inspiratory flow, duty cycle (TI/TTOT) 0.33, tidal volume 10 mL/kg, positive end-expiratory pressure (PEEP) 2 cmH2O, and respiratory rate adjusted to maintain PaCO2 within the physiological range. Ceftriaxone (50 mg/kg) was administered to prevent endogenous pneumonia. The right or left internal jugular vein was surgically dissected and an 8-Fr mm catheter (Introflex percutaneous sheath introducer, Edwards Lifesciences, Irvine, Calif) was inserted. Then, a 7-Fr Swan-Ganz catheter (Swan-Ganz PAC, Edwards Lifesciences) was advanced through the introducer. The cannulated jugular vein was ultimately ligated. Also, we surgically cannulated the femoral artery with a 3F polyethylene catheter (Plastimed, Prodimed, St Leu-la-Forêt, France) for systemic arterial pressure monitoring and collection of blood samples. Animals did not receive deep venous thrombosis prophylaxis with heparin.
After surgical preparation, pigs were randomized in the following groups:
- Control group: to be ventilated as reported above, but without PEEP, placed prone and with the bed oriented 30° in anti-TP to model the SRP;
- Inverse-ratio ventilation and PEEP (IRV-PEEP) group: positioned as in the control group, but the TI/TTOT was adjusted daily to achieve a mean expiratory-inspiratory flow bias of 10 L/min, and PEEP was set at 5 cm H2O;
- Trendelenburg group: Positioned in 5° TP and ventilated as in the control group (TP group).
Shortly after randomization, and 4 h thereafter, the endotracheal tube cuff was inflated to 40 cm H2O and PEEP was set to 10 cm H2O. The surgical bed was oriented 15° above horizontal. Then, 5 mL of 108 ceftriaxone-resistant Pseudomonas aeruginosa suspension was instilled into the oropharynx. After 15 min, the animals were placed in the randomized position; the internal cuff pressure was deflated to 28 cm H2O, and PEEP was readjusted according to randomization. We previously reported all methodological details of this model of VAP (17).
Respiratory mechanics were assessed daily as previously reported (5). Airway pressures and respiratory system compliance were measured and computed using standard formulas. Every 12 h, the following gas exchange and hemodynamic parameters were measured: mean arterial pressure (MAP), central venous pressures (CVP) as previously reported (5). Cerebral perfusion pressure (CPP) was computed as the difference between the MAP and the CVP, assuming that the intracranial pressure was lower than the CVP.
In order to evaluate the potential effects of inflammation on the brain, we measured interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor (TNF-α) levels in plasma with a porcine multiplex immunoassay kit (PCYTMG-23K-13PX Porcine Cyto/Chemo Premixed, Millipore Corp, Billerica, Mass) using high-throughput multiplex Luminex technology (Luminex 200 System, Luminex, Austin, Tex). All samples were tested twice and the values averaged.
Autopsy and definition of ventilator-associated pneumonia
Animals were euthanized 72 h after tracheal intubation and autopsied as previously reported (5). Two lung-tissue samples were biopsied from the most-affected region of each of the five lobes for histological and microbiological assessments. We diagnosed VAP based on microbiological and histological criteria. Lung histology was evaluated according to previously published methods using a 6-point injury score (17, 18). We biopsied each lobe and an experienced pathologist evaluated the lung tissue by using a validated pneumonia severity score (from 0 to 5 points): 0 point = no pneumonia; 1 point = purulent mucous plugging; 2 points = bronchiolitis; 3 points = pneumonia; 4 points = confluent pneumonia; and 5 points = abscessed pneumonia. Classification of each specimen was based upon the worst category observed. Furthermore, quantitative cultures were performed using standard methods. We assessed Pseudomonas aeruginosa growth by mass spectrometry (Microflex-LT, BrukerDaltonics) and automated bacterial identification (MALDI-BioTyper, BrukerDaltonics). A histological pneumonia score ≥ 3, associated with a quantitative P aeruginosa culture ≥ 3 log cfu/gr defined microbiological/histological VAP (19).
Pig's head was severed through the atlanto-axial joint. The scalp was separated from the skull and the cranium was opened with frontal and temporal incisions. The dura was cut along the lateral margins and reflected up to the midline. Finally, the whole brain was removed by severing the cranial nerve roots and the spinal cord above the first cervical vertebrae. The brain was fixed in 10% formaldehyde for posterior histological and immunochemistry analyses. First, we scored presence of cerebral petechial hemorrhages upon gross examination using the following scale: 1 = low, 2 = medium, 3 = high. Secondly, to assess histological patterns, we prepared 4 μm sections of the dentate gyrus, which were embedded in paraffin and stained with hematoxylin and eosin (H&E). Per each section, we assessed apoptosis of five areas through light microscopy (DM250, Leica, Wetzlar, Germany): cleaved caspase-3 assay (Asp175, Cell Signaling, Asp 175, Cell Signaling Technology, Inc. Danvers, MA), and TUNEL assay (In Situ Cell Death Detection Kit, Roche Diagnostics, Indianapolis, Ind). ImageJ software (National Institutes of Health; Bethesda, Mass) was used to quantify eosinophilic neuronal necrosis in H&E sections and immune-positive cells in caspase-3 and TUNEL assays (20).
Because of the unbalanced number of animals among study groups and the small sample sizes (three to seven pigs per group), we analyzed the data by using nonparametric methods. Kruskal–Wallis was applied to test significant differences among groups. In case of significance, post-hoc comparisons through Wilcoxon–Mann Whitney test were carried out. Post-hoc comparisons between groups with the TP group were adjusted using Dunnet methods. Percentages were analyzed using Fisher exact test. Of note, this secondary analysis was conducted using data of our previous experimental study (5). Thus, a sample size of at least seven animals per group was calculated on the basis of the primary outcome of the original study. Indeed, the study was originally powered to detect a difference in P aeruginosa lung burden between control, treatment, and TP groups of 3 ± 1.5 log CFU/gr, 1 ± 1.5 log CFU/gr, and 0 ± 1.5 log CFU/gr, respectively, for an assumed effect size of 0.83, a fixed power of 0.85%, and an alpha error probability of 0.05. We used SPSS v.21 software (IBM Corp, Chicago, Ill) and SAS 9.4 (SAS, Cary, NC) for all statistical analyses.
Three animals were included in the control group; while six were included in the IRV-PEEP and seven into the TP groups. All animals completed the 72-hour study.
Petechial cerebral hemorrhage score differed among study groups (P = 0.013), specifically it was higher in the TP group, than in the other groups (P = 0.011 vs. control and P = 0.028 vs. IRV-PEEP group) (Fig. 1). Figure 2 shows cell apoptosis in the dentate gyrus, within the hippocampal formation. In TP animals, there were more hypereosinophilic cells and with shrunken dark blue nuclei, indicating deteriorating neurons compared with IRV-PEEP group (P = 0.006). Also, markers of induced apoptosis, i.e., cells with cleaved caspase and TUNEL immune-positive were higher in TP animals (Fig. 2). Finally, Figure 3 shows representative images of cell counts in the dentate gyrus of the hippocampal formation (damaged areas in the left panel).
Throughout the study time, we did not find any statistically significant differences in systemic pro- and anti-inflammatory cytokines among study groups (Fig. 4).
Figure 5 shows dynamics of gas exchange among study groups, and throughout study times. Most significant differences in gas exchange parameters occurred during the first 30 h of MV.
Mean arterial pressure differ among study groups (P < 0.001) and in the control, IRV-PEEP and TP group was 80.1 ± 10.6, 73.7 ± 11.1, and 89.8 ± 10.1 (P < 0.050 vs. control and IRV-PEEP groups), respectively. In contrast, central venous pressure in the control, IRV-PEEP, and TP group was not statistically different, 6.8 ± 5.6, 6.8 ± 2.9, and 6.1 ± 2.1, respectively (P = 0.226). Thus, as reported in Figure 6, the resulting cerebral perfusion pressure varied among study groups (P < 0.001).
Lung colonization and ventilator-associated pneumonia
As reported in Table 1, the TP strongly decreased P aeruginosa pulmonary burden up to 0.22 ± 0.21 cfu/gr as compared with control (2.27 ± 0.88 cfu/gr) and IRV-PEEP animals (2.31 ± 0.42 cfu/gr). As a result, microbiological/histological VAP did not develop in such position; whereas microbiological/histological VAP incidence was 67% and 86%, in the control and IRV-PEEP, respectively (P = 0.003).
In the present analysis in mechanically ventilated pigs, the TP had a significant effect on the brain. In particular, animals in TP were at higher risk of brain petechial hemorrhages, and degeneration/apoptosis of the neurons of the dentate gyrus. These findings could have been possibly caused by cardiovascular changes driven by the TP.
The TP shifts the blood from the lower part of the body to the central veins, decreasing blood pooling in the lower body and favoring the filling and the distension of the upper central veins (21). Also, the TP generally displaces upward abdominal contents, against the diaphragm, as a result lung volume decreases, particularly in morbidly obese patients. Based on these effects, in clinical settings, the TP is often applied to facilitate central venous catheterization (22) and laparoscopic surgical procedures (23). Interestingly, as shown in various reports (22, 24), even steep TP causes only transient cardiopulmonary changes and marginal complications, assuming that such position is maintained for short periods of time. Of note, we found that in animals in TP, MAP significantly increased, as early as after 18 h from the beginning of the study. This is in line with clinical findings showing improved hemodynamic figures in mechanically ventilated patients in TP undergoing cardiac surgery (25), and increased MAP in patients with coronary artery disease (26) or in elderly postoperative patients (23).
Yet, in TP animals, the main drawback of aforementioned increase in MAP was the consequential upsurge in the estimated CPP. In humans, in physiologic conditions, blood return from the brain is mediated by gravity, conversely, the TP hinders venous return from the upper body (21). These mechanisms are potentially linked to the evidence of petechial hemorrhages and dentate gyrus neural degeneration/apoptosis highlighted in our study. Indeed, it is important to emphasize that in our study there were no differences in systemic inflammation among groups, and there was no association between VAP and brain injury. In a recent study by Roberts et al. (27), in which healthy volunteers underwent magnetic resonance imaging of the brain before and after long-term (>6 weeks) bed rest in a 6° TP, structural brain changes were found, due to altered gravity gradients. In our study, brain alterations occurred in the TP group, but not in the two groups in which pigs were semirecumbent. Yet, our findings should be discussed critically, because pigs are quadruped. The cerebrovascular autoregulation mechanisms, which may have further compromised cerebral integrity, could be different in pigs and humans. Indeed, in pigs, neurological compensatory vascular mechanisms to maintain adequate cerebral blood flow are not as frequently demanded as in humans. Of note, in patients, neurologic complications have been marginally associated with the use of TP, and only when steep TP was applied during surgery, probably due to cerebral edema or ischemia (28). Sharp TP has also been associated with increased intracranial pressure in different robotic-assisted surgical procedures (29, 30). In neurosurgical patients, TP hindered cerebral venous drainage, thereby increasing cerebral blood volume and moderately intracranial pressure (9–13 mm Hg) (31). Finally, during laparoscopic gynaecological surgery, alterations in cerebral blood flow and intracranial pressure have been related to the use of TP (32).
A few clinical studies demonstrated moderate-to-severe cognitive impairment in patients who suffered by severe critical illnesses, such as acute respiratory distress syndrome, or septic shock (33). This evidence confirms that critically ill patients are at particular risk for neurological impairment. In our latest clinical trial evaluating VAP preventive efficacy of TP (8), we did find greater harm in patients who presented pulmonary infiltrates upon enrolment. These deleterious effects were not specifically related to neurological changes. Indeed, neurological examination upon ICU discharge reported similar findings between TP and SRP patients. Interestingly, in our latest animal study, we specifically found changes in the dentate gyrus, which plays a pivotal role in learning and memory (34). Nonetheless, the dentate gyrus is a structure with great plasticity and, under normal conditions, new cells are constantly generated. One experimental study found that the dentate gyrus presented a selective vulnerability to traumatic brain injury (35). The neurodegeneration and apoptosis found in our study could be related to alterations in the neurogenesis within this area. Yet, considering that we conducted a 72-h study without long-term follow-up, at this moment, the clinical implications of these findings are only speculative, but worthy further exploration.
A few strengths and limitations of our study should be thoroughly addressed. First, we were able to assess brain injury after 72 h of MV. This provides highly valuable data, considering that critically ill patients are commonly on MV for 3 to 4 days. Second, we performed extensive state-of-the-art neurologic assessment of the dentate gyrus and we were able to exclude the effects of concomitant confounding factors on the brain, such as VAP and inflammation. Nonetheless, extrapolation of our preliminary laboratory findings into the clinical scenario should be inferred cautiously for a few reasons. Indeed, this was a secondary analysis of a previous randomized laboratory study (5). This original study was carried out and powered to detect differences in incidences of VAP among groups positioned in Trendelenburg or anti-Trendelenburg position, and with various duty cycles and PEEP levels. In this subsequent analysis, we evaluated brain injury in only few animals of the control group and most of the animals of the IRV-PEEP and Trendelenburg groups. Thus, although this novel analysis generated new insights and relevant conclusions, it should be acknowledged the imbalance among groups, and potential limitations of this secondary analysis in fully characterizing the neurological effects of study interventions. Second, as for the analysis of inflammatory markers, it is important to emphasize that we only quantified systemic cytokines in blood, but analysis in brain tissue could have been more specific and yielded higher sensitivity in detecting differences among study groups. Third, as mentioned in previous paragraphs, some potential inter-species differences in cerebrovascular regulation could have affected our results. A few reports comparing human and porcine blood coagulation and fibrinolysis (36) acknowledged significant differences, and in our experiments, we did not administer heparin for deep venous thrombosis prophylaxis. Also, the animal's internal jugular vein was ligated during surgical preparation. These features could have altered brain homeostasis and ultimately convolute clinical extrapolation, still it is important to emphasize that although only one jugular vein was clamped, we found a uniform bilateral distribution of brain alterations.
In conclusion, we found in an animal model of MV at risk of VAP that the TP resulted in brain alterations, most likely triggered by hemodynamic effects. Thus, in the clinical settings, any positive effect of the TP must be weighed against potential negative effects. This report calls attention to the need of further assessments on the neurological safety of long-term TP in critically ill mechanically ventilated patients.
The authors acknowledge Mr John Giba for his invaluable support editing this manuscript.
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