key: cord-011363-o1f398vn
authors: Pitoni, Sara; D’Arrigo, Sonia; Grieco, Domenico Luca; Idone, Francesco Antonio; Santantonio, Maria Teresa; Di Giannatale, Pierluigi; Ferrieri, Alessandro; Natalini, Daniele; Eleuteri, Davide; Jonson, Bjorn; Antonelli, Massimo; Maggiore, Salvatore Maurizio
title: Tidal Volume Lowering by Instrumental Dead Space Reduction in Brain-Injured ARDS Patients: Effects on Respiratory Mechanics, Gas Exchange, and Cerebral Hemodynamics
date: 2020-04-22
journal: Neurocrit Care
DOI: 10.1007/s12028-020-00969-5
sha: 
doc_id: 11363
cord_uid: o1f398vn

BACKGROUND: Limiting tidal volume (V(T)), plateau pressure, and driving pressure is essential during the acute respiratory distress syndrome (ARDS), but may be challenging when brain injury coexists due to the risk of hypercapnia. Because lowering dead space enhances CO(2) clearance, we conducted a study to determine whether and to what extent replacing heat and moisture exchangers (HME) with heated humidifiers (HH) facilitate safe V(T) lowering in brain-injured patients with ARDS. METHODS: Brain-injured patients (head trauma or spontaneous cerebral hemorrhage with Glasgow Coma Scale at admission < 9) with mild and moderate ARDS received three ventilatory strategies in a sequential order during continuous paralysis: (1) HME with V(T) to obtain a PaCO(2) within 30–35 mmHg (HME1); (2) HH with V(T) titrated to obtain the same PaCO(2) (HH); and (3) HME1 settings resumed (HME2). Arterial blood gases, static and quasi-static respiratory mechanics, alveolar recruitment by multiple pressure–volume curves, intracranial pressure, cerebral perfusion pressure, mean arterial pressure, and mean flow velocity in the middle cerebral artery by transcranial Doppler were recorded. Dead space was measured and partitioned by volumetric capnography. RESULTS: Eighteen brain-injured patients were studied: 7 (39%) had mild and 11 (61%) had moderate ARDS. At inclusion, median [interquartile range] PaO(2)/FiO(2) was 173 [146–213] and median PEEP was 8 cmH(2)O [5–9]. HH allowed to reduce V(T) by 120 ml [95% CI: 98–144], V(T)/kg predicted body weight by 1.8 ml/kg [95% CI: 1.5–2.1], plateau pressure and driving pressure by 3.7 cmH(2)O [2.9–4.3], without affecting PaCO(2), alveolar recruitment, and oxygenation. This was permitted by lower airway (− 84 ml [95% CI: − 79 to − 89]) and total dead space (− 86 ml [95% CI: − 73 to − 98]). Sixteen patients (89%) showed driving pressure equal or lower than 14 cmH(2)O while on HH, as compared to 7 (39%) and 8 (44%) during HME1 and HME2 (p < 0.001). No changes in mean arterial pressure, cerebral perfusion pressure, intracranial pressure, and middle cerebral artery mean flow velocity were documented during HH. CONCLUSION: The dead space reduction provided by HH allows to safely reduce V(T) without modifying PaCO(2) nor cerebral perfusion. This permits to provide a wider proportion of brain-injured ARDS patients with less injurious ventilation.

Acute respiratory distress syndrome (ARDS) affects up to 30% of critically ill patients with acute brain injury [1] [2] [3] [4] [5] , representing an independent predictor of worse clinical outcome [6] .

The use of low tidal volume (V T ) to limit plateau pressure and driving pressure (i.e., plateau pressurepositive end-expiratory pressure, ∆P) reduces ventilator-induced lung injury (VILI) and improves survival in ARDS patients [7] [8] [9] . Nonetheless, lower V T yield increased risk of hypercapnia, which is deleterious [10] , especially in patients with brain injury: In this particular subset of patients, tight control of arterial partial pressure of carbon dioxide (PaCO 2 ) is needed to prevent any secondary brain injury due to increases in cerebral blood flow and intracranial pressure [11] .

Consequently, in brain-injured patients with ARDS, two competing priorities arise: use of low V T for lung protection and tight PaCO 2 control to maintain proper cerebral blood flow and prevent undue intracranial pressure increases. The optimal balance between brain and lung protection during mechanical ventilation is not well established, and no recommendation exists on ventilatory management of these patients. In clinical practice, patients with acute brain injury and ARDS often receive V T exceeding 6 ml/kg of predicted body weight (PBW) [12] [13] [14] [15] [16] .

Heat and moisture exchangers (HME) and heated humidifiers (HH) are used for gas conditioning during invasive mechanical ventilation. Although they are simpler to use, HMEs carry relevant instrumental dead space and decrease the proportion of V T contributing to alveolar ventilation. Previous authors highlighted that replacing HME with HH decreases dead space, promotes CO 2 clearance and allows V T and plateau pressure reduction during ARDS [17] [18] [19] [20] : however, no data clarify to what extent ∆P is reduced by this approach and whether this is safe in patients with concomitant brain injury, for whom tight control of PaCO 2 is mandatory and any intervention has to be evaluated also from the perspective of cerebral hemodynamics.

We conducted a physiological study to elucidate to what extent V T reduction with HH allows to limit ∆P and whether this is safe in terms of cerebral hemodynamics.

The study was conducted in the general intensive care unit (ICU) of a university hospital in Rome, Italy, according to the principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the local institutional ethics committee. Written informed consent was obtained according to committee recommendation.

Acute brain-injured patients with ARDS were screened for enrollment. Acute brain injury was defined as a traumatic brain injury or a non-traumatic cerebral hemorrhage with a Glasgow Coma Scale at admission < 9. Diagnosis of ARDS was based on the criteria established by Berlin definition [21] . Patients were eligible for inclusion if they had acute brain injury, developed ARDS, and were monitored with invasive intracranial pressure for clinical purposes, with stable pressure values < 20 mmHg.

For safety reasons, because lowering V T may cause alveolar derecruitment and hypoxemia, patients with severe ARDS (PaO 2 /FiO 2 < 100 mmHg) were not considered for inclusion in the study. Other non-inclusion criteria were: age < 18, pregnancy, severe hemodynamic instability, contraindication to muscular paralysis, leaking chest tube, and decompressive craniotomy.

All patients were lying in the semi-seated position, intubated, sedated, paralyzed (cisatracurium 0.1 mg/kg), and mechanically ventilated in volume-controlled mode with an I-to-E ratio set at 1:2. A standard bitube circuit with Y-piece and HME filter (Hygrobac; DAR: dead space 84 ml, resistance 1.0 cmH 2 O/L/s) was used in the stabilization phase. Ventilatory parameters were set by the attending physician, who was not involved in the study, but was specifically asked to optimize the ventilator settings to obtain a PaCO 2 between 30 and 35 mmHg and PaO 2 > 70 mmHg or a SpO 2 ≥ 98%, as per standard of care in brain-injured patients.

Two humidification devices were used: HME (Hygrobac; DAR: dead space 84 ml, resistance 1.0 cmH2)/L/s) and HH (MR850, Fisher & Paykel, Auckland, New Zealand).

This crossover study was organized into three phases. In phase I (HME1), a HME placed distally to the Y-piece of the circuit, as in the stabilization phase. Mechanical ventilation, as prescribed by the attending physician, was maintained for 30 min without any changes in the settings: Afterward, all relevant data were collected. In phase II (HH), the HME was removed and a HH was placed in the inspiratory limb of the circuit and V T was titrated (20-30 ml decrease every 10 min) to obtain PaCO 2 equal to the one detected at the end of HME1; study data were collected 30 min after reaching the target PaCO 2 level. In phase III (HME2), an HME was placed again distally to the Y-piece of the circuit and all baseline settings were resumed.

All patients received cisatracurium continuous infusion, at a standard dose of 35 mg/h [22] . Patients' sedation, vasopressor dose, set PEEP, respiratory rate, FiO 2 , and I-to-E ratio were kept unchanged over the entire course of the experiment.

Endotracheal suctioning was performed at study entry and was not repeated over the course of the study period, unless specifically required.

The following parameters were continuously monitored (SC7000 Monitor, Siemens, Erlangen, Germany) during the study: heart rate, arterial blood pressure, intracranial pressure, cerebral perfusion pressure, and SpO 2 .

Blood flow velocity in the middle cerebral artery was measured at the end of each study step with a 2 MHz pulsed Doppler ultrasound device (transcranial Doppler [TCD] H21-Hitachi Medical System Europe, Zug Switzerland).

The ventilator (ServoVentilator 900C, Siemens-Elema, Sweden) and a mainstream capnograph (CO 2 analyzer 930, Siemens-Elema, Sweden) were connected to a personal computer. The ventilator system transducers produced signals representing pressure in the expiratory line, ventilator flow rate, and CO 2 at airway opening. These signals were filtered to avoid aliasing and were converted from analog to digital at 50 Hz. The flow signal was calibrated under BTPS (body temperature and pressure, saturated) conditions with a 1-L syringe. Pressure was calibrated using a water manometer and CO 2 using a gas mixture with a known composition.

Tidal volume was measured as digital integration of expiratory flow signal. Tidal volume/kg of predicted body weight (PBW) was computed, with PBW calculated as described elsewhere [7] .

Total PEEP (PEEP TOT ) was measured during end-expiratory occlusions, while airway plateau pressure (P PLAT ) was measured during a 2-second end-inspiratory occlusion. Driving pressure (∆P) was computed as the difference between P PLAT and PEEP TOT . Static respiratory system compliance (C RS ) was calculated as V T /∆P. Total, airway, and alveolar dead space was computed using volumetric capnography, according to a method validated elsewhere [23, 24] . Respiratory system mechanics, gas exchange, physiological dead space, and hemodynamics were measured in each phase of the protocol.

Elastic pressure-volume curves at set and zero PEEP were recorded in each phase of the study during low sinusoidal flow inflation, according to a method previously described in detail [25] [26] [27] [28] [29] . The linear C RS was calculated as the steeper segment between the lower inflection point and upper inflection point of the curve at zero PEEP. The derecruited volume from set PEEP to zero PEEP was measured (Rec) and consisted in the volume difference between the pressure-volume curves recorded at set PEEP and zero PEEP that were graphically superimposed and compared at an elastic pressure of 20 cmH 2 O [30, 31] . Rec was also normalized to the applied level of set PEEP: Rec/PEEP TOT was computed as the ratio between Rec and PEEP TOT , and patients were classified as having a highly recruitable profile when Rec/ PEEP TOT > 14.5 ml/cmH 2 O [32] .

Primary endpoint of this physiological study was to assess during isocapnic conditions the gain provided by HH in terms of V T , P PLAT , and, ∆P reduction, as compared to HME.

Safety endpoints were the effects of a low V T strategy on cerebral perfusion, as defined by cerebral perfusion pressure and blood flow velocity in the middle cerebral artery, and on respiratory mechanics and lung recruitment, as defined by lower and upper inflection points, linear and static C RS , Rec, and Rec/PEEP TOT .

Given the physiological design of the study, we did not perform a formal sample size calculation. Based on other investigations on the topic [17, 18, 20] , we planned to enroll 15-18 patients that appear an adequate sample to draw conclusions on the specific endpoints addressed in the present investigation.

Categorical data are showed as number of events (% 

Eighteen patients met inclusion criteria and were enrolled in the study. Demographics and clinical characteristics are shown in Table 1 .

Consistently with the design of the protocol, no changes in PaCO 2 , respiratory rate, set, and total PEEP were found among the three study steps (all p > 0.05; Table 2 , Fig. 1 ).

Tidal volume, plateau pressure, driving pressure, total dead space, airway dead space, and alveolar tidal volume were significantly lower during HH as compared to HME1 (all p < 0.05; Heart rate, arterial pressure, intracranial and cerebral perfusion pressure, and flow velocity in the middle cerebral artery were similar in the three study steps ( Fig. 3) .

The application of HH allowed an average V T reduction of 120 [95% CI: 98-144] ml (p < 0.001) along with a decrease in V T /kg PBW of 1.8 [95% CI: 1.5-2.1] ml/ kg (p < 0.001) (Fig. 2) . The use of lower tidal volume was associated with an increase in 2.3 ml/cmH 2 

Our results show that, in brain-injured patients with ARDS, the use of HHs permits to reduce tidal volume and ∆P without affecting cerebral hemodynamics and arterial CO 2 tension.

Consistently with previous investigations [17, 18, 20, 33] HHs, as compared to HMEs, significantly reduced total and airway dead space. The measured dead space reduction provided by HHs was 86 [95% CI: 73-98] ml and is consistent with the 90-ml instrumental dead space declared by HME manufacturer. In our study, this Several strategies have been proposed to mitigate VILI and improve clinical outcome during ARDS: Among these, the most convincing are lower V T , prone positioning and, possibly, mid-to-high PEEP with/without muscle paralysis in most severe patients [7, 22, [34] [35] [36] [37] . Prone positioning may yield increases in intracranial pressure [38] ; the use of high PEEP may not be safe in all braininjured patients due to its possible detrimental effects on central venous pressure, venous return, cardiac output, and intracranial pressure [39] ; thus, lowering V T appears as the only available intervention to enhance lung protection in this context [40] . This appears of crucial importance when brain injury coexists, as these patients are burdened by high risk of respiratory complications, high tracheostomy rates, prolonged mechanical ventilation, and worse clinical outcome [2, 13, 41, 42] .

The ∆P, which is V T normalized to C RS and is a surrogate of the dynamic strain [43] , represents the final [47] , the use of HH was not associated with improved clinical outcome in wide unselected cohorts of mechanically ventilated patients [48] . In previous studies, however, the use of HH was not systematically accompanied by V T reduction as it is in our protocol, so that any possible benefit could have been underestimated. In our study, the use of low V T leads to a significant increase in static C RS without affecting the linear compliance measured between lower and upper inflection point. Lung volume, as defined by Rec, did not change nor patients' position varied among the study steps, and chest wall elastance was likely constant over the entire course of the study, thus suggesting that any observed change in respiratory mechanics reflects variations in lung mechanics: In particular, the results inhering static and quasi-static compliance indicate some degree of lung overdistention when higher V T were used, as already suggested by other authors [20, 49, 50] .

Although previous data indicate that lower V T can favor alveolar derecruitment [7, 51, 52] , we do not report significant derecruitment or oxygenation worsening during V T reduction. Lung volume change as a response to PEEP may significantly vary among patients according to different degrees of lung recruitability [53, 54] . Accordingly, only 17-22% of our patients showed a high recruitability profile (i.e., > 14.5 ml/cmH 2 O of PEEP), as compared to 50% of patients in previous ARDS cohorts Fig. 1 PaCO 2 , middle cerebral artery mean blood flow velocity, intracranial pressure, and cerebral perfusion pressure in the three study steps. Individual data and medians with interquartile ranges are displayed [32] , so that the scarce derecruitment effect of lower tidal volume observed in our study may be explained by this particular characteristic of the studied population. In this sense, because of the risk of further impairment in oxygenation that can be fatal in brain-injured subjects, we did not enroll patients with severe ARDS who, indeed, show the highest lung recruitability profile [54, 55] . Moreover, higher PEEP (up to 20 cmH 2 O or further) may be required to achieve optimal lung recruitment [56] and such values may be difficult to apply in brain-injured patients.

Finally, and most importantly, our approach is simple, easily bedside available and showed a broad safety spectrum: No hemodynamic instability, abrupt increases in end tidal CO2 (EtCO 2 ) and intracranial pressure, decreases in SpO 2 and cerebral perfusion pressure, or any other adverse events were detected over the course of the entire study. Similarly, the use of low V T was not associated with changes in cerebral perfusion pressure or blood flow velocity in the middle cerebral artery.

The main limitation of the present study is its sequential crossover design, since the predetermined order of interventions may have affected the outcome. However, we tried to mitigate this aspect introducing a HME2 step, when all the baseline conditions were resumed. The substantial equivalence between most of the parameters in step HME1 and HME2 suggests that the patients were not subject to changes in respiratory, hemodynamic, and cerebral conditions during any of the study period, thus contributing to the strength and reproducibility of our findings. The small differences between HME1 and HME2 can be ascribed to the limited sample and the statistical rank-based test used for the analysis. Finally, initial tidal volumes and respiratory rates reflect individual Fig. 2 Tidal volume, plateau pressure, and driving pressure, in the three study steps. Individual data are displayed. Horizontal line indicating driving pressure = 14 cmH 2 O is showed: Note that 16/18 (89%) of patients have a driving pressure ≤ 14 cmH 2 O in the HH step, as compared to 7/18 (39%) and 8/18 (44%) during HME1 and HME2 (p < 0.001). * indicates p < 0.05 for comparison HME1 versus HH; ° indicates p < 0.05 for comparison HME2 versus HH clinician's attitude in the treatment of patients with brain injury, and a strictly low-tidal ventilation strategy was not applied at baseline. This is consistent with previous reports, indicating that patients with brain injury are often exposed non-protective ventilation settings [12] [13] [14] [15] [16] . Indeed, the aim of this study was limited to the assessment of the physiological effects of changing from an HME device to HH.

The use of HH in patients with brain injury and ARDS reduces instrumental dead space and allows to reduce tidal volume and driving pressure in isocapnic conditions, with no alveolar derecruitment, hypoxemia, changes in cerebral perfusion pressure nor blood flow. This increases the proportion of patients receiving mechanical ventilation within safety limits. Given its safeness and strong pathophysiological plausibility, we deem this intervention can be recommended among the first-line ventilatory management in brain-injured ARDS patients. Fig. 3 Partitioning of dead space in the three study steps. Median and interquartile ranges are displayed. Total dead space was lower during HH, as compared to HME1 and HME2 (p < 0.001). The reduction in dead space was due to a lower airway dead space in the HH step. * indicates p < 0.05 for comparison HME1 versus HH; ° indicates p < 0.05 for comparison HME2 versus HH

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