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Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: A prospective study
Abstract
To evaluate the outcome in patients with severe adult respiratory distress syndrome (ARDS) managed with limitation of peak inspiratory pressure to 30 to 40 cm H2O, low tidal volumes (4 to 7 mL/kg), spontaneous breathing using synchronized intermittent mandatory ventilation from the start of ventilation, and permissive hypercapnia without the use of bicarbonate to buffer acidosis. Also, to compare hospital mortality rate with that predicted by the Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system and the "ventilator score."
A ten-bed general intensive care unit in a university hospital.
Prospective, descriptive study.
Fifty-three patients with severe ARDS having a lung injury score of > or = 2.5.
Data recording.
The hospital mortality rate was significantly lower than that predicted by the APACHE II scores (26.4% vs. 53.3%, p = .004), even after correcting the latter for the effect of hypercapnic acidosis (26.4% vs. 51.1%, p = .008). The mortality rate increased with increasing number of organ failures, but was only 43% in patients with > or = 4 organ failures, 20.5% with < or = 3 organ failures, and 6.6% with only respiratory failure. The mean maximum PaCO2 was 66.5 torr (range 38 to 158 torr [8.87 kPa, range 5.07 to 21.07]), and the mean arterial pH at the same time was 7.23 (range 6.79 to 7.45). There was no correlation between the maximum PaCO2 or the corresponding pH and the total respiratory rate at the same time. No pneumothoraces developed during mechanical ventilation.
These results lend further support to the hypothesis that limitation of peak inspiratory pressure and reduction of regional lung overdistention by the use of low tidal volumes with permissive hypercapnia may reduce ventilator-induced lung injury and improve outcome in severe ARDS. This hypothesis is supported by a large body of experimental evidence, which also suggests that ventilator-induced lung injury may result in the release of inflammatory mediators, and thus may have the potential to augment the development of multiple organ dysfunction. However, the hypothesis requires testing in a randomized trial as acute hypercapnia could potentially have some adverse as well as beneficial effects.
... Gaseous molecules such as oxygen (O 2 ) and CO 2 are sensed by lung cells eliciting specific responses via intracellular signaling pathways [6][7][8][9][10][11][12][13][14]. Hypercapnia, an elevation in the arterial CO 2 tension, is generally well tolerated in mechanically ventilated patients with acute respiratory distress syndrome (ARDS), but recent studies suggest that a high concentration of CO 2 , independently of hypoxia, can act a gaso-signaling molecule resulting in adverse consequences via the alteration of transcription factor activity and microRNA (miR) expression in the lung [6][7][8][9]13,[15][16][17][18][19]. Specifically, our recent study showed that high CO 2 levels increased airway smooth muscle contractility via activation of the caspase-7-mediated miR-133a-RhoA signaling [9]. ...
... This study showed that the relation between PCO2 level and FOT values in healthy volunteers was not evident (Figure 3), suggesting that changes in CO2 levels at normal PCO2 range may not affect pulmonary functions. The term 'permissive hypercapnia' has been proposed for a while and the strategy is currently accepted in treating patients [18,19,49]. It has been increasingly evident that elevated CO2 acts as a signaling molecule with unwanted effects on the local lung and whole body [15,47,[49][50][51][52][53][54]. ...
... Since one of the targets to treat subjects with COPD is to evaluate the narrowed small airways, the current study supports targeting to correct PCO2 level as the new strategy [48] to treat subjects with COPD and hypercapnia. The term 'permissive hypercapnia' has been proposed for a while and the strategy is currently accepted in treating patients [18,19,49]. It has been increasingly evident that elevated CO 2 acts as a signaling molecule with unwanted effects on the local lung and whole body [15,47,[49][50][51][52][53][54]. ...
Chronic obstructive pulmonary disease (COPD) is a respiratory illness characterized by airflow limitation and chronic respiratory symptoms with a global prevalence estimated to be more than 10% in 2010 and still on the rise. Furthermore, hypercapnic subject COPD leads to an increased risk of mortality, morbidity, and poor QoL (quality of life) than normocapnic subjects. Series of studies showed the usefulness of the forced oscillation technique (FOT) to measure small airway closure. Traditional findings suggested that hypercapnia may not be the main treating targets, but recent findings suggested that blood stream CO2 may lead to a worse outcome. This study aimed to seek the relationship between CO2 and small airway closure by using FOT. Subjects with COPD (n = 124; hypercapnia 22 and normocapnia 102) were analyzed for all pulmonary function values, FOT values, and arterial blood gas analysis. Student’s t-test, Spearman rank correlation, and multi linear regression analysis were used to analyze the data. COPD subjects with hypercapnia showed a significant increase in R5, R20, Fres, and ALX values, and a greater decrease in X5 value than normocapnic patients. Also, multiple linear regression analysis showed R5 was associated with hypercapnia. Hypercapnia may account for airway closure among subjects with COPD and this result suggests treating hypercapnia may lead to better outcomes for such a subject group.
... One of the consequences of limiting driving pressure, tidal volume ventilation and respiratory rate is the rise in arterial PaCO 2 , a concept known as permissive hypercapnia (Hickling et al., 1994;Contreras et al., 2015;Costa et al., 2021). Although the differential mechanisms of biological vs mechanical effects of permissive hypercapnia have not been systematically investigated, several clinical studies have investigated lung protective ventilation with permissive hypercapnia as a tolerated side effect (Bidani et al., 1994;Hickling et al., 1994;Acute Respiratory Distress Syndrome et al., 2000). ...
... One of the consequences of limiting driving pressure, tidal volume ventilation and respiratory rate is the rise in arterial PaCO 2 , a concept known as permissive hypercapnia (Hickling et al., 1994;Contreras et al., 2015;Costa et al., 2021). Although the differential mechanisms of biological vs mechanical effects of permissive hypercapnia have not been systematically investigated, several clinical studies have investigated lung protective ventilation with permissive hypercapnia as a tolerated side effect (Bidani et al., 1994;Hickling et al., 1994;Acute Respiratory Distress Syndrome et al., 2000). Hypercapnia has been associated with a reduction in the effects of excessive lung stretch by an intracellular mechanism that remains elusive (Ismaiel and Henzler, 2011). ...
Background and Objective: Lung-protective mechanical ventilation is known to attenuate ventilator-associated lung injury (VALI), but often at the expense of hypoventilation and hypercapnia. It remains unclear whether the main mechanism by which VALI is attenuated is a product of limiting mechanical forces to the lung during ventilation, or a direct biological effect of hypercapnia.
Methods: Acute lung injury (ALI) was induced in 60 anesthetized rats by the instillation of 1.25 M HCl into the lungs via tracheostomy. Ten rats each were randomly assigned to one of six experimental groups and ventilated for 4 h with: 1) Conventional HighV E Normocapnia (high V T , high minute ventilation, normocapnia), 2) Conventional Normocapnia (high V T , normocapnia), 3) Protective Normocapnia (V T 8 ml/kg, high RR), 4) Conventional iCO 2 Hypercapnia (high V T , low RR, inhaled CO 2 ), 5) Protective iCO 2 Hypercapnia (V T 8 ml/kg, high RR, added CO 2 ), 6) Protective endogenous Hypercapnia (V T 8 ml/kg, low RR). Blood gasses, broncho-alveolar lavage fluid (BALF), and tissue specimens were collected and analyzed for histologic and biologic lung injury assessment.
Results: Mild ALI was achieved in all groups characterized by a decreased mean PaO 2 /FiO 2 ratio from 428 to 242 mmHg ( p < 0.05), and an increased mean elastance from 2.46 to 4.32 cmH 2 O/L ( p < 0.0001). There were no differences in gas exchange among groups. Wet-to-dry ratios and formation of hyaline membranes were significantly lower in low V T groups compared to conventional tidal volumes. Hypercapnia reduced diffuse alveolar damage and IL-6 levels in the BALF, which was also true when CO 2 was added to conventional V T . In low V T groups, hypercapnia did not induce any further protective effect except increasing pulmonary IL-10 in the BALF. No differences in lung injury were observed when hypercapnia was induced by adding CO 2 or decreasing minute ventilation, although permissive hypercapnia decreased the pH significantly and decreased liver histologic injury.
Conclusion: Our findings suggest that low tidal volume ventilation likely attenuates VALI by limiting mechanical damage to the lung, while hypercapnia attenuates VALI by limiting pro-inflammatory and biochemical mechanisms of injury. When combined, both lung-protective ventilation and hypercapnia have the potential to exert an synergistic effect for the prevention of VALI.
... In multiple studies of ALI and low tidal volume ventilation with permissive hypercapnia, arterial pH less than 7.2 is well tolerated and associated with improved outcome in ARDS by limiting further ventilator-induced lung injury (VILI) by mechanical ventilation. Considerable experimental data suggest that VILI results in release of inflammatory mediators, which may have the potential to augment development of multiorgan dysfunction [20,23,[28][29][30]. Similarly, in patients with diabetic ketoacidosis [31]. ...
... Respiratory acidosis has direct suppressive effects on the myocardium and vasculature that result in decreases in cardiac output and peripheral vascular resistance; however, an opposing strong neuroendocrine response results in release of catecholamines and glucocorticoids, raising cardiac output and blood pressure over a very wide range of PaCO 2 [20,56], There is convincing evidence in the critical care literature emphasizing the safety of hypercapnic acidosis. In many studies of patients undergoing permissive hypercapnia, a pH of well below 7.2 appeared to be well tolerated [20,[28][29][30]56,57]. The safety of hypercapnic acidosis is further supported by reports that individuals, both adults and children, have survived exposure to extreme levels. ...
Purpose of review:
Respiratory acidosis is commonly present in patients with respiratory failure. The usual treatment of hypercapnia is to increase ventilation. During the recent surge of COVID-19, respiratory acidosis unresponsive to increased mechanical ventilatory support was common. Increasing mechanical ventilation comes at the expense of barotrauma and hemodynamic compromise from increasing positive end-expiratory pressures or minute ventilation. Treating acute respiratory acidemia with sodium bicarbonate remains controversial.
Recent findings:
There are no randomized controlled trials of administration of sodium bicarbonate for respiratory acidemia. A recent review concluded that alkali therapy for mixed respiratory and metabolic acidosis might be useful but was based on the conflicting and not conclusive literature regarding metabolic acidosis. This strategy should not be extrapolated to treatment of respiratory acidemia. Low tidal volume ventilation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) has beneficial effects associated with permissive hypercapnia. Whether the putative benefits will be negated by administration of alkali is not known. Hypercapnic acidosis is well tolerated, with few adverse effects as long as tissue perfusion and oxygenation are maintained.
Summary:
There is a lack of clinical evidence that administration of sodium bicarbonate for respiratory acidosis has a net benefit; in fact, there are potential risks associated with it.
... Hypercapnia, an elevation in the arterial carbon dioxide (CO 2 ) tension, is a complication of inadequate alveolar gas exchange in patients with severe acute and chronic lung diseases [7] including asthma [5,6,[8][9][10][11][12][13][14][15][16][17]. It has been initially reported that hypercapnia was innocuous or even protective in mechanically ventilated patients with severe asthma [9,10], acute lung injury and acute respiratory distress syndrome (ARDS) [18][19][20][21], where the concepts of "permissive" and even "therapeutic" hypercapnia have been proposed for the mechanically ventilated patients. The lower tidal volumes during protective ventilation can lead to hypercapnia and an associated drop in pH resulting in hypercapnic respiratory acidosis that has been reported as a protective effect via the inhibition of the nuclear factor-κB (NF-κB) pathway, a pivotal transcription activator in inflammation and ...
... Mechanical ventilation with "permissive hypercapnia" for severe asthma is currently an accepted therapeutic strategy [22,70]. The "permissive hypercapnia" approach is based on observational reports from the 1980s to 1990s [9,10,18,21] and is generally well tolerated for short periods of time if oxygenation is preserved and severe respiratory acidosis is avoided [70]. However, more recent studies challenge the "permissive hypercapnia" approach in view of new evidence suggesting that hypercapnia is harmful [23,26,27,136,137]. ...
Asthma is a common chronic respiratory disorder with relatively good outcomes in the majority of patients with appropriate maintenance therapy. However, in a small minority, patients can experience severe asthma with respiratory failure and hypercapnia, necessitating intensive care unit admission. Hypercapnia occurs due to alveolar hypoventilation and insufficient removal of carbon dioxide (CO2) from the blood. Although mild hypercapnia is generally well tolerated in patients with asthma, there is accumulating evidence that elevated levels of CO2 can act as a gaso-signaling molecule, triggering deleterious effects in various organs such as the lung, skeletal muscles and the innate immune system. Here, we review recent advances on pathophysiological response to hypercapnia and discuss potential detrimental effects of hypercapnia in patients with asthma.
... RR reduction (one of the equational determinants of Power RS ) is known to be associated with lesser lung injuries in ARDS animal models under protective ventilation, but also with mortality in ARDS patients when associated with V T reduction (34). Experimental studies demonstrated the importance of RR in VILI development in ARDS models receiving conventional ventilation strategies (35)(36)(37). ...
Background
Experimentally, ultra-protective ventilation (UPV, tidal volumes [VT] < 4 mL.kg⁻¹) strategies in conjunction with veno-venous extracorporeal membrane oxygenation (VV-ECMO) are associated with lesser ventilator-induced lung injuries (VILI) during acute respiratory distress syndrome (ARDS). However, whether these strategies reduce lung inflammation more effectively than protective ventilation (PV) remains unclear. We aimed to demonstrate that a UPV strategy decreases acute lung inflammation in comparison with PV in an experimental swine model of ARDS.
Methods
ARDS was induced by tracheal instillation of chlorhydric acid in sedated and paralyzed animals under mechanical ventilation. Animals were randomized to receive either UPV (VT 1 mL.kg⁻¹, positive end-expiration pressure [PEEP] set to obtain plateau pressure between 20 and 25 cmH2O and respiratory rate [RR] at 5 min⁻¹ under VV-ECMO) or PV (VT 6 mL.kg⁻¹, PEEP set to obtain plateau pressure between 28 and 30 cmH2O and RR at 25 min⁻¹) during 4 h. After 4 h, a positron emission tomography with [¹¹C](R)-PK11195 (ligand to TSPO-bearing macrophages) injection was realized, coupled with quantitative computerized tomography (CT). Pharmacokinetic multicompartment models were used to quantify regional [¹¹C](R)-PK11195 lung uptake. [¹¹C](R)-PK11195 lung uptake and CT-derived respiratory variables were studied regionally across eight lung regions distributed along the antero-posterior axis.
Results
Five pigs were randomized to each study group. Arterial O2 partial pressure to inspired O2 fraction were not significantly different between study groups after experimental ARDS induction (75 [68–80] mmHg in a PV group vs. 87 [69–133] mmHg in a UPV group, p = 0.20). Compared to PV animals, UPV animals exhibited a significant decrease in the regional non-aerated compartment in the posterior lung levels, in mechanical power, and in regional dynamic strain and no statistical difference in tidal hyperinflation after 4 h. UPV animals had a significantly lower [¹¹C](R)-PK11195 uptake, compared to PV animals (non-displaceable binding potential 0.35 [IQR, 0.20–0.59] in UPV animals and 1.01 [IQR, 0.75–1.59] in PV animals, p = 0.01). Regional [¹¹C](R)-PK11195 uptake was independently associated with the interaction of regional tidal hyperinflation and regional lung compliance.
Conclusion
In an experimental model of ARDS, 4 h of UPV strategy significantly decreased lung inflammation, in relation to the control of VT-derived determinants of VILI.
... Many of these patients require the assistance of invasive mechanical ventilation (IMV) in the management of respiratory failure. A strategy of preventing ventilator induced lung injury (VILI) by reducing inspiratory pressures and the driving pressure on IMV has been shown to reduce mortality [1,2]. The current standard of care in treating patients with acute hypoxic respiratory failure is to use low tidal volume (< 6 ml/kg predicted body weight) ventilation [3]. ...
Background
Several extracorporeal carbon dioxide removal (ECCO2R) devices are currently in use with variable efficacy and safety profiles. PrismaLung+ is an ECCO2R device that was recently introduced into clinical practice. It is a minimally invasive, low flow device that provides partial respiratory support with or without renal replacement therapy. Our aim was to describe the clinical characteristics, efficacy, and safety of PrismaLung+ in patients with acute hypercapnic respiratory failure.
Methods
All adult patients who required ECCO2R with PrismaLung+ for hypercapnic respiratory failure in our intensive care unit (ICU) during a 6-month period between March and September 2022 were included.
Results
Ten patients were included. The median age was 55.5 (IQR 41–68) years, with 8 (80%) male patients. Six patients had acute respiratory distress syndrome (ARDS), and two patients each had exacerbations of asthma and chronic obstructive pulmonary disease (COPD). All patients were receiving invasive mechanical ventilation at the time of initiation of ECCO2R. The median duration of ECCO2R was 71 h (IQR 57–219). A significant improvement in pH and PaCO2 was noted within 30 min of initiation of ECCO2R. Nine patients (90%) survived to weaning of ECCO2R, eight (80%) survived to ICU discharge and seven (70%) survived to hospital discharge. The median duration of ICU and hospital stays were 14.5 (IQR 8–30) and 17 (IQR 11–38) days, respectively. There were no patient-related complications with the use of ECCO2R. A total of 18 circuits were used in ten patients (median 2 per patient; IQR 1–2). Circuit thrombosis was noted in five circuits (28%) prior to reaching the expected circuit life with no adverse clinical consequences.
Conclusion(s)
PrismaLung+ rapidly improved PaCO2 and pH with a good clinical safety profile. Circuit thrombosis was the only complication. This data provides insight into the safety and efficacy of PrismaLung+ that could be useful for centres aspiring to introduce ECCO2R into their clinical practice.
... Mechanical ventilation, a cornerstone of modern intensive care, is a lifesaving intervention for critically ill patients, and its appropriate use significantly improves survival. However, positive pressure ventilation (PPV) results in direct harm to the lungs, thereby impacting mortality especially in patients with acute respiratory distress syndrome (ARDS) (Hickling et al., 1990;Hickling et al., 1994;Brower et al., 2000;Amato et al., 2015). Such harm has been termed ventilator-induced lung injury (VILI) and is classically thought to result from alveolar overdistension (volu-trauma) and/or atelectasis (atelect-trauma) along with the resultant biological injury (biotrauma) (Slutsky and Ranieri, 2013). ...
Ventilator-induced lung injury (VILI) impacts outcomes in ARDS and optimization of ventilatory strategies improves survival. Decades of research has identified various mechanisms of VILI, largely focusing on airspace forces of plateau pressure, tidal volume and driving pressure. Experimental evidence indicates the role of adverse cardiopulmonary interaction during mechanical ventilation, contributing to VILI genesis mostly by modulating pulmonary vascular dynamics. Under passive mechanical ventilation, high transpulmonary pressure increases afterload on right heart while high pleural pressure reduces the RV preload. Together, they can result in swings of pulmonary vascular flow and pressure. Altered vascular flow and pressure result in increased vascular shearing and wall tension, in turn causing direct microvascular injury accompanied with permeability to water, proteins and cells. Moreover, abrupt decreases in airway pressure, may result in sudden overperfusion of the lung and result in similar microvascular injury, especially when the endothelium is stretched or primed at high positive end-expiratory pressure. Microvascular injury is universal in VILI models and presumed in the diagnosis of ARDS; preventing such microvascular injury can reduce VILI and impact outcomes in ARDS. Consequently, developing cardiovascular targets to reduce macro and microvascular stressors in the pulmonary circulation can potentially reduce VILI. This paper reviews the role of cardiopulmonary interaction in VILI genesis.
... Studies with bicarbonate infusions have shown no benefit in improving pH and suggest many treatment-related adverse effects, including hypervolemia, hyperosmolarity, and increased lactate levels [79]. e ARDS network clinical trial and the ARMA study allowed bicarbonate infusions when the pH fell below 7.15 [60,[80][81][82]. ...
Acute hypercapnic ventilatory failure is becoming more frequent in critically ill patients. Hypercapnia is the elevation in the partial pressure of carbon dioxide (PaCO2) above 45 mmHg in the bloodstream. The pathophysiological mechanisms of hypercapnia include the decrease in minute volume, an increase in dead space, or an increase in carbon dioxide (CO2) production per sec. They generate a compromise at the cardiovascular, cerebral, metabolic, and respiratory levels with a high burden of morbidity and mortality. It is essential to know the triggers to provide therapy directed at the primary cause and avoid possible complications.
... Enfermedades como el síndrome de distrés respiratorio agudo (SDRA) se pueden beneficiar de una ventilación protectora guiada por la EMSR (3)(4)(5)(6). Contrario a la restricción pulmonar que se presenta en el SDRA, las enfermedades obstructivas del SR requieren estrategias de ventilación distintas cuya base puede ser entendida de mejor manera aplicando la EMSR (7,8). ...
Introducción: la ventilación mecánica es una práctica común en las unidades de cuidados intensivos y anestesiología. Tiene implicaciones terapéuticas, pero también es potencialmente nociva para el sistema respiratorio y los órganos distantes, por lo cual es imprescindible monitorizar los parámetros ventilatorios de manera continua. Objetivo: describir la ecuación del movimiento del sistema respiratorio y sus aplicaciones clínicas en el paciente bajo ventilación mecánica. Desarrollo: la ecuación del movimiento del sistema respiratorio integra las fuerzas dinámicas generadas por el ventilador y las propiedades intrínsecas del pulmón y la caja torácica. Expresa la presión en el sistema respiratorio en relación con el volumen, la elastancia, la resistencia, el flujo de aire y las presiones generadas por el ventilador y el paciente. Las presiones elevadas en el sistema respiratorio se asocian a una mayor mortalidad en pacientes con ventilación mecánica, por lo que la identificación de los componentes que condicionan la elevación de las presiones mediante la ecuación del movimiento del sistema respiratorio permite realizar modificaciones a los parámetros programados del ventilador para mantener una ventilación protectora. Conclusión: la toma de decisiones basada en la ecuación del movimiento del sistema respiratorio permite realizar ajustes en los parámetros ventilatorios según las características y enfermedades del paciente bajo ventilación mecánica.
... Differences in outcomes exist between metabolic acidosis and respiratory acidosis with similar pH ranges. This observation suggests that the underlying disorder may be more important than the absolute degree of acidaemia [15]. However, some causes of metabolic acidosis seem to have worse outcomes than others. ...
Introduction: acid-base disorders are very common in critically ill patients and contribute significantly to morbidity and mortality. The aim of this study was to identify the types of acid-base disorders at the time of admission to the intensive care unit (ICU) and its associated ICU and in-hospital mortality.
Methods: we conducted a retrospective cohort study of all adult patients that were admitted to the ICU and had an arterial blood gas sample at the time of admission from 1 January 2019 to 31 December 2019. Using the traditional approach, acid-base disorders were categorised into six disorders. Variables predicting in-hospital death were identified using logistic regression.
Results: a total of 375 patients were included. The median age for the entire cohort was 39 (IQR 30–52) years and 48.3% (n=181) were female. Mixed acid-base disorders were the most common at 48.8% (n=183), followed by no disorder at 24.8% (n=93), metabolic acidosis at 9.3% (n=35), metabolic alkalosis at 6.7% (n=25), respiratory acidosis at 6.1% (n=23) and respiratory alkalosis at 4.3% (n=16). A total of 94 (25.0%) patients died. There were no differences in ICU (p = 0.35) or in-hospital death (p = 0.32) by acid-base disorder. Male sex (aOR: 5.8, 95% CI 1.55-21.42; p < 0.01), APACHE II score (aOR: 1.17, 95% CI 1.06-1.30; p < 0.01) and the corrected anion gap (aOR: 1.14, 95% CI 1.02-1.27; p = 0.02) were identified as predictors of in-hospital death using multivariable logistic regression.
Conclusion: there was no association between acid-base disorders at the time of ICU admission and ICU or in-hospital death. Therefore, in our setting, acid-base disorders at the time of ICU admission should not be used to predict the outcome of patients requiring intensive care.
... Chronic pulmonary restriction could be a problem for these subjects when they are exposed to conditions that force them to increase ventilatory capacity. From intensive care medicine, due to the possible impact of mechanical ventilation, the effect of ventilating restrictive lungs with high flow volumes has been extensively studied, since they generate an inflammatory response, either by damage through alveolar opening and closing (atelectrauma), or by overdistension (volutrauma) [40][41][42]. This injury is caused by the activation of alveolar macrophages due to the expression of damage associated molecular patterns (DAMPs), released by the destroyed cells of the alveolar epithelium, and such activation of the macrophages can induce further injury. ...
One of the etiopathogenic factors frequently associated with generalized organ damage after spinal cord injury corresponds to the imbalance of the redox state and inflammation, particularly of the respiratory, autonomic and musculoskeletal systems. Our goal in this review was to gain a better understanding of this phenomenon by reviewing both animal and human studies. At the respiratory level, the presence of tissue damage is notable in situations that require increased ventilation due to lower thoracic distensibility and alveolar inflammation caused by higher levels of leptin as a result of increased fatty tissue. Increased airway reactivity, due to loss of sympathetic innervation, and levels of nitric oxide in exhaled air that are similar to those seen in asthmatic patients have also been reported. In addition, the loss of autonomic control efficiency leads to an uncontrolled release of catecholamines and glucocorticoids that induce immunosuppression, as well as a predisposition to autoimmune reactions. Simultaneously, blood pressure regulation is altered with vascular damage and atherogenesis associated with oxidative damage. At the muscular level, chronically elevated levels of prooxidants and lipoperoxidation associated with myofibrillar atrophy are described, with no reduction or reversibility of this process through antioxidant supplementation.
... A clear threshold for hypercapnia was reported in 11/29 of the included studies, that was defined as PaCO 2 ≥ 38 mmHg [19], PaCO 2 ≥ 45 mmHg [11,25,41], ≥ 48 mmHg [23], ≥ 50 mmHg [5,28,33,35,44] or ≥ 55 mmHg [34]. Information regarding V T were reported in all but three studies [5,26,27]. Permissive hypercapnia, imposed hypercapnia under PV, and [19,20,22,24,25,29,31,32], 21 studies (9514 patients) [5, 11, 21-23, 26-28, 30, 33-44] and one (369 patients) [11] study, respectively. The latter study [11] was unique for imposed hyperca pnia in NPV and reported < 1% (3/369) patients with sustained PaCO 2 > 45 mmHg, precluding any further analysis of imposed hypercapnia under NPV. ...
Purpose:
Hypercapnia is frequent during mechanical ventilation for acute respiratory distress syndrome (ARDS), but its effects on morbidity and mortality are still controversial. We conducted a systematic review and meta-analysis to explore clinical consequences of acute hypercapnia in adult patients ventilated for ARDS.
Methods:
We searched Medline, Embase, and the Cochrane Library via the OVID platform for studies published from 1946 to 2021. "Permissive hypercapnia" defined hypercapnia in studies where the group with hypercapnia was ventilated with a protective ventilation (PV) strategy (lower VT targeting 6 ml/kg predicted body weight) while the group without hypercapnia was managed with a non-protective ventilation (NPV); "imposed hypercapnia" defined hypercapnia in studies where hypercapnic and non-hypercapnic patients were managed with a similar ventilation strategy.
Results:
Twenty-nine studies (10,101 patients) were included. Permissive hypercapnia, imposed hypercapnia under PV, and imposed hypercapnia under NPV were reported in 8, 21 and 1 study, respectively. Studies testing permissive hypercapnia reported lower mortality in hypercapnic patients receiving PV as compared to non-hypercapnic patients receiving NPV: OR = 0.26, 95% CI [0.07-0.89]. By contrast, studies reporting imposed hypercapnia under PV reported increased mortality in hypercapnic patients receiving PV as compared to non-hypercapnic patients also receiving PV: OR = 1.54, 95% CI [1.15-2.07]. There was a significant interaction between the mechanism of hypercapnia and the effect on mortality.
Conclusions:
Clinical effects of hypercapnia are conflicting depending on its mechanism. Permissive hypercapnia was associated with improved mortality contrary to imposed hypercapnia under PV, suggesting a major role of PV strategy on the outcome.
... PALICC also recommended permissive hypercapnia as a management strategy to minimize ventilator-induced lung injury for patients with moderate-tosevere PARDS.13,63,87 Low-VT tidal volume, pressure-limited ventilation with permissive hypercapnia may improve ARDS outcome.63,89,90 A pH range of 7.15-7.30 ...
Background: Acute respiratory distress syndrome (ARDS) is a significant cause of mortality and morbidity amongst critically ill children. The purpose of this narrative review is to provide an up-to-date review on the evaluation and management of paediatric ARDS (PARDS).
Methods: A PubMed search was performed with Clinical Queries using the key term “acute respiratory distress syndrome”. The search strategy included clinical trials, meta-analyses, randomized controlled trials, observational studies and reviews. Google, Wikipedia and UpToDate were also searched to enrich the review. The search was restricted to the English literature and children.
Discussion: Non-invasive positive pressure ventilation, lung-protective ventilation strategies, conservative fluid management and adequate nutritional support all have proven efficacy in the management of PARDS. The Pediatric Acute Lung Injury Consensus Conference recommends the use of corticosteroids, high-frequency oscillation ventilation and inhaled nitric oxide in selected scenarios. Partial liquid ventilation and surfactant are not considered efficacious based on evidence from clinical trials.
Conclusion: PARDS is a serious but relatively rare cause of admission into the paediatric intensive care unit and is associated with high mortality. Non-invasive positive pressure ventilation, lung-protective ventilation strategies, conservative fluid management and adequate nutrition are advocated. As there has been a lack of progress in the management of PARDS in recent years, further well-designed, large-scale, randomized controlled trials in this field are urgently needed.
... However, current clinical practice rarely considers the fact of dynamic transitions [40]. While most clinical practice guidelines recommended to ventilate ARDS by limiting tidal volume < 6 ml/kg and plateau pressure < 30 cmH 2 O [41][42][43]. it is largely unknown how to adjust ventilator parameters when the patient's condition changed during disease course. We further proved that a ventilation strategy with MP deviated away from the optimal MP (ΔMP) was associated with higher mortality risk, supporting the use of DTR to improve mortality outcome for ARF patients. ...
Background
Mechanical ventilation (MV) is the key to the successful treatment of acute respiratory failure (ARF) in the intensive care unit (ICU). The study aims to formalize the concept of individualized MV strategy with finite mixture modeling (FMM) and dynamic treatment regime (DTR).
Methods
ARF patients requiring MV for over 48 h from 2008 to 2019 were included. FMM was conducted to identify classes of ARF. Static and dynamic mechanical power (MP_static and MP_dynamic) and relevant clinical variables were calculated/collected from hours 0 to 48 at an interval of 8 h. ΔMP was calculated as the difference between actual and optimal MP.
Findings
A total of 8768 patients were included for analysis with a mortality rate of 27%. FFM identified three classes of ARF, namely, the class 1 (baseline), class 2 (critical) and class 3 (refractory respiratory failure). The effect size of MP_static on mortality is the smallest in class 1 (HR for every 5 Joules/min increase: 1.29; 95% CI: 1.15 to 1.45; p < 0.001) and the largest in class 3 (HR for every 5 Joules/min increase: 1.83; 95% CI: 1.52 to 2.20; p < 0.001).
Interpretation
MP has differing therapeutic effects for subtypes of ARF. Optimal MP estimated by DTR model may help to improve survival outcome.
Funding
The study was funded by Health Science and Technology Plan of Zhejiang Province (2021KY745), Key Research & Development project of Zhejiang Province (2021C03071) and Yilu "Gexin" - Fluid Therapy Research Fund Project (YLGX-ZZ-2,020,005).
... Lung protective ventilation entered mainstream clinical practice with the publication of the first ARDS Network study in 2000; this landmark study demonstrated that limiting plateau pressure and reducing tidal volume (V T ) to 6 mL/kg predicted body weight (PBW), compared with V T of 12 mL/kg, improved survival, shortened duration of mechanical ventilation, attenuated systemic inflammation and reduced the incidence and amount of extra-pulmonary organ failure [9]. Of course these findings were built on more than two decades of laboratory work from Webb and Tierney to Saumon and Dreyfuss, followed by early observational studies in patients by Hickling and colleagues [10][11][12]. An expert panel convened in the early 1990s called for randomized clinical trials of lung-protective ventilation [13], and this led to several smaller studies [14][15][16][17], that ultimately informed this practice-changing trial [9]. ...
Care for patients with acute respiratory distress syndrome (ARDS) has changed considerably over the 50 years since its original description. Indeed, standards of care continue to evolve as does how this clinical entity is defined and how patients are grouped and treated in clinical practice. In this narrative review we discuss current standards – treatments that have a solid evidence base and are well established as targets for usual care – and also evolving standards – treatments that have promise and may become widely adopted in the future. We focus on three broad domains of ventilatory management, ventilation adjuncts, and pharmacotherapy. Current standards for ventilatory management include limitation of tidal volume and airway pressure and standard approaches to setting PEEP, while evolving standards might focus on limitation of driving pressure or mechanical power, individual titration of PEEP, and monitoring efforts during spontaneous breathing. Current standards in ventilation adjuncts include prone positioning in moderate-severe ARDS and veno-venous extracorporeal life support after prone positioning in patients with severe hypoxemia or who are difficult to ventilate. Pharmacotherapy current standards include corticosteroids for patients with ARDS due to COVID-19 and employing a conservative fluid strategy for patients not in shock; evolving standards may include steroids for ARDS not related to COVID-19, or specific biological agents being tested in appropriate sub-phenotypes of ARDS. While much progress has been made, certainly significant work remains to be done and we look forward to these future developments.
... Alveolar epithelial repair is critical for patients to recover from lung injury (Berthiaume et al., 1999). Hypercapnia, particularly hypercapnia-associated acidosis, has been proposed to improve outcomes of patients with acute lung injury, acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI), which triggered the emergence of "permissive" and even "therapeutic" hypercapnia concepts (Hickling et al., 1994;ARDS Network, 2000;Contreras et al., 2015). The protective ventilation strategy was initially linked with the effects of hypercapnic acidosis on the host immune system, with the attenuation of NF-κB activity, a transcription factor that regulates inflammation, injury and repair (Contreras et al., 2015;Shigemura et al., 2017;Cummins et al., 2020). ...
Carbon dioxide (CO2) is produced in eukaryotic cells primarily during aerobic respiration, resulting in higher CO2 levels in mammalian tissues than those in the atmosphere. CO2 like other gaseous molecules such as oxygen and nitric oxide, is sensed by cells and contributes to cellular and organismal physiology. In humans, elevation of CO2 levels in tissues and the bloodstream (hypercapnia) occurs during impaired alveolar gas exchange in patients with severe acute and chronic lung diseases. Advances in understanding of the biology of high CO2 effects reveal that the changes in CO2 levels are sensed in cells resulting in specific tissue responses. There is accumulating evidence on the transcriptional response to elevated CO2 levels that alters gene expression and activates signaling pathways with consequences for cellular and tissue functions. The nature of hypercapnia-responsive transcriptional regulation is an emerging area of research, as the responses to hypercapnia in different cell types, tissues, and species are not fully understood. Here, we review the current understanding of hypercapnia effects on gene transcription and consequent cellular and tissue functions.
... [25][26][27] For patients with ARDS, the use of lower tidal volumes during ventilation was also an effective treatment that could reduce the release of inflammatory cytokines and detrimental lung stretch. [28][29][30] An early clinical trial reported the lower tidal volume was approximately World J Emerg Med, Vol 11, No 4, 2020 8.1 mL/kg compared with traditional tidal volume, which was approximately 12.2 mL/kg. [31] We didn't find significant differences in tidal volumes between survivors and non-survivors because we employed low tidal volumes as a routine treatment for all ARDS patients. ...
Background:
Fluid management is crucial to acute respiratory distress syndrome (ARDS) secondary to sepsis. However, choices of fluid resuscitation strategies and fluid input volumes remain a thorny problem. Our study aimed to elucidate the relationship between fluid balance and prognosis of ARDS patients secondary to sepsis.
Methods:
Our study included 322 sepsis patients from Ruijin Hospital between 2014 and 2018, and 84 patients were diagnosed as ARDS within 72 hours after onset of sepsis according to Berlin ARDS Definition.
Results:
Among the 322 sepsis patients, 84 (26.1%) were complicated with ARDS within 72 hours. ARDS patients had a lower oxygenation index (PaO2/FiO2 166.4±71.0 vs. 255.0±91.2, P<0.05), longer duration of mechanical ventilation (11 [6-24] days vs. 0 [0-0] days, P<0.05) than those without ARDS. Sepsis patients with ARDS showed daily positive net fluid balance during seven days compared with those without ARDS who showed daily negative net fluid balance since the second day with significant statistical differences. Among the 84 sepsis patients with ARDS, 58 (69.0%) died. Mean daily fluid input volumes were much lower in survivors than in non-survivors (43.2±16.7 mL/kg vs. 51.0±25.2 mL/kg, P<0.05) while output volumes were much higher in survivors (45.2±19.8 mL/kg vs. 40.2±22.7 mL/kg, P<0.05). Using binary logistic regression analysis, we found that the mean daily fluid balance was independently associated with mortality of sepsis patients complicating with ARDS (P<0.05).
Conclusions:
Early negative fluid balance is independently associated with a better prognosis of sepsis patients complicated with ARDS.
... These are consistent with the change of hypoxemia and permissive hypercapnia in ARDS. [27][28][29][30] We reported in our previous study that hypercapnia could induce IL-1β overproduction in hypoxia-activated microglia. However, the underlying mechanism has remained unclear. ...
Background
Hypoxemia is a typical symptom of acute respiratory distress syndrome. To avoid pulmonary morbidity, low tidal volume ventilation is often applied. The ventilation strategy will certainly cause hypercapnia. This study aimed to explore whether hypercapnia would promote microglial pyroptosis via inhibiting mitophagy in adult rats with hypoxemia.
Methods
The cerebral oxygen extraction ratio (CERO2) and partial pressure of brain tissue oxygen (PbtO2) in a rat model of hypercapnia/hypoxemia were assessed. The reactive oxygen species (ROS) production and the expression of LC3‐II/I, p62, caspase‐1, gasdermin D‐N domains (GSDMD‐N), IL‐1β, and IL‐18 in microglial cells were detected.
Results
Hypercapnia decreased the PbtO2 levels of the hypoxic rats, which was further evidenced by the increased levels of CERO2. Expression levels of LC3‐II were reduced, while p62 expression was increased by hypercapnia in hypoxic microglia. Hypercapnia increased the production of ROS and the expression of caspase‐1, GSDMD‐N, IL‐1β, and IL‐18 in hypoxia‐activated microglia. Scavenging ROS inhibited microglial pyroptosis and expression of IL‐1β and IL‐18.
Conclusions
These results suggest that hypercapnia‐induced mitophagy inhibition may promote pyroptosis and enhance IL‐1β and IL‐18 release in hypoxia‐activated microglia.
... The use of lower tidal and minute volumes with LPV strategies is limited by the resultant respiratory acidosis [13][14][15]. The rationale to integrate ECCO 2 R into the management of severe ARDS is to allow more protective ventilation, i.e., providing very low tidal volumes (V T ) (less than 6 mL/kg PBW) with conventional MV, while avoiding extreme levels of respiratory acidosis. ...
Background:
Invasive mechanical ventilation is lifesaving in the setting of severe acute respiratory failure but can cause ventilation-induced lung injury. Advances in extracorporeal CO2 removal (ECCO2R) technologies may facilitate more protective lung ventilation in acute respiratory distress syndrome, and enable earlier weaning and/or avoid invasive mechanical ventilation entirely in chronic obstructive pulmonary disease exacerbations. We evaluated the in vitro CO2 removal capacity of the novel PrismaLung+ ECCO2R device compared with two existing gas exchangers.
Methods:
The in vitro CO2 removal capacity of the PrismaLung+ (surface area 0.8 m2, Baxter) was compared with the PrismaLung (surface area 0.35 m2, Baxter) and A.L.ONE (surface area 1.35 m2, Eurosets) devices, using a closed-loop bovine blood-perfused extracorporeal circuit. The efficacy of each device was measured at varying pCO2 inlet (pinCO2) levels (45, 60, and 80 mmHg) and blood flow rates (QB) of 200-450 mL/min; the PrismaLung+ and A.L.ONE devices were also tested at a QB of 600 mL/min. The amount of CO2 removed by each device was assessed by measurement of the CO2 infused to maintain circuit equilibrium (CO2 infusion method) and compared with measured CO2 concentrations in the inlet and outlet of the CO2 removal device (blood gas analysis method).
Results:
The PrismaLung+ device performed similarly to the A.L.ONE device, with both devices demonstrating CO2 removal rates ~ 50% greater than the PrismaLung device. CO2 removal rates were 73 ± 4.0, 44 ± 2.5, and 72 ± 1.9 mL/min, for PrismaLung+, PrismaLung, and A.L.ONE, respectively, at QB 300 mL/min and pinCO2 45 mmHg. A Bland-Altman plot demonstrated that the CO2 infusion method was comparable to the blood gas analysis method for calculating CO2 removal. The resistance to blood flow across the test device, as measured by pressure drop, varied as a function of blood flow rate, and was greatest for PrismaLung and lowest for the A.L.ONE device.
Conclusions:
The newly developed PrismaLung+ performed more effectively than PrismaLung, with performance of CO2 removal comparable to A.L.ONE at the flow rates tested, despite the smaller membrane surface area of PrismaLung+ versus A.L.ONE. Clinical testing of PrismaLung+ is warranted to further characterize its performance.
... These findings are consistent with the hypoxemia and permissive hypercapnia changes observed in patients with ARDS. [27][28][29][30] Hypercapnia has been reported to attenuate endotoxin-induced inflammation by inhibiting activation of nuclear factor-jB. 14,15 In contrast, we found that treatment with 7% and 10% CO 2 enhanced the expression levels of IL-1b, TNF-a, and IL-6 in hypoxic whole blood cultures. ...
Objective
This study investigated whether hypercapnia influenced the inflammatory response of hypoxic blood.
Methods
Human whole blood was cultured with 0.2% oxygen (O2) and treated with 5%, 7%, or 10% carbon dioxide (CO2). Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 were evaluated in whole blood cultures. Reactive oxygen species (ROS) production and expression levels of caspase-1 and IL-1β were evaluated in THP-1 monocytic cells.
Results
IL-1β, TNF-α, and IL-6 levels were higher in the hypoxia + 7% CO2 group than in the hypoxia + 5% CO2 group. The hypoxia + 10% CO2 group had the highest IL-1β, TNF-α, and IL-6 levels, compared with the hypoxia + 7% CO2 and hypoxia + 5% CO2 groups. Expression levels of IL-1β, TNF-α, and IL-6 were significantly negatively correlated with pH levels in the cell culture medium. Treatment with 7% and 10% CO2 increased the production of ROS and the expression of caspase-1 and IL-1β in hypoxia-activated THP-1 cells.
Conclusions
High levels of CO2 treatment increased expression levels of IL-1β, TNF-α, and IL-6 in hypoxic whole blood cultures. High levels of CO2-induced ROS overproduction and NLRP3 inflammasome activation in monocytes may comprise a target to mitigate the inflammatory response of hypoxic blood.
Target values for arterial carbon dioxide tension (PaCO 2 ) in extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) are unknown. We hypothesized that lower PaCO 2 values on ECMO would be associated with lighter sedation. We used data from two independent patient cohorts with ARDS spending 1,177 days (discovery cohort, 69 patients) and 516 days (validation cohort, 70 patients) on ECMO and evaluated the associations between daily PaCO 2 , pH, and bicarbonate (HCO 3 ) with sedation. Median PaCO 2 was 41 (interquartile range [IQR] = 37–46) mm Hg and 41 (IQR = 37–45) mm Hg in the discovery and the validation cohort, respectively. Lower PaCO 2 and higher pH but not bicarbonate (HCO 3 ) served as significant predictors for reaching a Richmond Agitation Sedation Scale (RASS) target range of −2 to +1 (lightly sedated to restless). After multivariable adjustment for mortality, tracheostomy, prone positioning, vasoactive inotropic score, Simplified Acute Physiology Score (SAPS) II or Sequential Organ Failure Assessment (SOFA) Score and day on ECMO, only PaCO 2 remained significantly associated with the RASS target range (adjusted odds ratio 1.1 [95% confidence interval (CI) = 1.01–1.21], p = 0.032 and 1.29 [95% CI = 1.1–1.51], p = 0.001 per mm Hg decrease in PaCO 2 for the discovery and the validation cohort, respectively). A PaCO 2 ≤40 mm Hg, as determined by the concordance probability method, was associated with a significantly increased probability of a sedation level within the RASS target range in both patient cohorts (adjusted odds ratio = 2.92 [95% CI = 1.17–7.24], p = 0.021 and 6.82 [95% CI = 1.50–31.0], p = 0.013 for the discovery and the validation cohort, respectively).
Carboxytherapy (based on the administration of carbon dioxide (CO2)) is gaining more and more recognition nowadays both among doctors and patients, and its effects have been studied for many years. The direct administration of CO2 induces vasodilation, leading to improved blood circulation and metabolic processes as well as the body inherent regenerative mechanisms. The impact of carboxytherapy on various medical conditions includes the generation of new capillaries, alleviation of hypoxia, and the release of oxygen and growth factors into tissues. CO2 therapy stimulates fibroblasts to synthesize collagen and promote the formation of new blood vessels, a phenomenon known as neovascularization. Diverse methods of CO2 administration have shown significant improvements in various pathological conditions by enhancing oxygenation, regulating tissue perfusion, and facilitating the reduction of fat cells. This literature review compiles studies that explore the potential benefits of carboxytherapy in the context of various medical conditions. Methods. The search for scientific information was conducted in the electronic databases PubMed and Google Scholar. Results: The literature provides a comprehensive understanding of the mechanisms underlying the action of CO2 and the diverse medical applications in which it is employed. The analysis covers a wide spectrum of conditions and states where carboxytherapy demonstrates its utility. Conclusions. Carboxytherapy serves as a valuable tool for increasing blood flow, alleviating hypoxia, mitigating inflammation, and reducing oxidative stress. These attributes make carboxytherapy a promising addition to the treatment of various pathological processes. In the realm of medical therapy, carboxytherapy presents an effective and safe alternative to traditional pharmacotherapy, or it can complement existing treatment approaches, contributing to comprehensive patient care.
Objective:
This study aims to assess the impact of different subtypes of extreme acidosis on the mortality of critically ill patients.
Methods:
This retrospective cohort study included critically ill patients who were admitted to the intensive care unit (ICU) with a pH level <7. Clinical data and blood gas analyses were collected from electronic medical records. The primary outcome was in-hospital mortality. The use of vasopressors, mechanical ventilation (MV), and renal replacement therapy (RRT), the duration of MV and RRT, and the length of ICU and hospital stay were secondary outcomes. The simplified Stewart approach to acid-base disorders was used to analyze the causes of acidosis.
Results:
A total of 231 patients with 371 arterial blood gas analyses with pH < 7 were admitted from January 2012 to December 2021 and 222 were included in the study. Out of the 222 patients analyzed, respiratory acidosis was the primary disorder in 11.3% of patients (n = 25), metabolic acidosis in 33.8% (n = 75), and mixed acidosis in 55% (n = 122). Overall mortality was 42.8% (n = 95). No significant difference was observed in mortality among patients with respiratory, metabolic, or mixed acidosis (28%, 42.7%, and 45.9%, respectively; p = 0.26). The primary disorder affected the use of vasopressors and MV, the duration of MV, and the length of ICU and hospital stay. Patients with extreme acidosis due to unmeasured anions with lactate levels of 4 mmol/L or higher had higher mortality compared with patients with lactate levels <4 mmol/L (55.6% and 27.7%, respectively; p = 0.007).
Conclusion:
Among critically ill patients with extreme acidosis, the primary disorder is not associated with mortality, but it is associated with the use of vasopressors and MV, the duration of MV, and the length of ICU and hospital stay. Additionally, hyperlactatemia is a predictor of poor prognosis in patients with extreme acidosis.
Lung-protective ventilation (LPV) strategies refer to the ventilator settings that allow a protection of the lungs from injuries related to high volumes and consequently high alveolar and transpulmonary pressures during invasive mechanical ventilation. Lung-protective ventilation proved benefits on mortality in ARDS patients and in patients without ARDS. The first component of LPV is the reduction of the tidal volumes, but other ventilator settings such as increased respiratory rate, protective oxygenation and optimized PEEP are also part of LPV. In addition to the ventilator settings, the total dead space involved in CO2 elimination is frequently overlooked. In this regard, the humidification strategy should prioritize heated humidification to minimize instrumental dead space. Indeed, dead space is part of the formula of the alveolar ventilation: Valv = (tidal volume − total dead space) × respiratory rate. This formula reflects the effective ventilation for CO2 clearance. The different components of the total dead space (alveolar dead space, anatomic dead space and instrumental dead space) must be known to optimize mechanical ventilation during lung-protective ventilation. This is particularly true in most severe patients when tidal volumes are low or very low (below 6 ml/kgPBW) and respiratory rate is high (above 25 breaths/min). In this situation, if dead space is not minimized, there is a risk of CO2 accumulation leading to hypercapnic acidosis. While “permissive hypercapnia” has been the first name of lung-protective ventilation, severe hypercapnia has been initialy accepted and encouraged, and associated severe respiratory or mixed acidosis in ICU patients was tolerated. Progressively, this tolerance for high PaCO2 and severe acidosis has been questioned. Recent data highlight the deleterious effects of excessively high PaCO2 leading to increased arterial pulmonary hypertension, right ventricle failure and possibly increased mortality. Other unfavourable effects of hypercapnia have been described, and the current trend is to be more cautious with excessively high PaCO2. The current management in most ICU patients with or without ARDS includes lung-protective ventilation and should also incorporate heart-protective ventilation with optimization of CO2 removal to target normal PaCO2 or mild hypercapnia. In this regard, the humidification strategy is critical through the limitation of instrumental dead space that is mainly related to heat and moisture exchangers and other connectors.KeywordsARDSLung-protective ventilationPermissive hypercapniaRight heart failureHumidificationDead spaceHeat and moisture exchangersHeated humidifiersCarbon dioxide
Background:
Lung-protective ventilation (reduced tidal volume and limited plateau pressure) may lead to CO2 retention. Data about the impact of hypercapnia in patients with ARDS are scarce and conflicting.
Methods:
We performed a non-interventional cohort study with subjects with ARDS admitted from 2006 to 2021 and with PaO2 /FIO2 ≤ 150 mm Hg. We examined the association between severe hypercapnia (PaCO2 ≥ 50 mm Hg) on the first 5 days after the diagnosis of ARDS and death in ICU for 930 subjects. All the subjects received lung-protective ventilation.
Results:
Severe hypercapnia was noted in 552 subjects (59%) on the first day of ARDS (day 1); 323/930 (34.7%) died in the ICU. Severe hypercapnia on day 1 was associated with mortality in the unadjusted (odds ratio 1.54, 95% CI 1.16-1.63; P = .003) and adjusted (odds ratio 1.47, 95% CI 1.08-2.43; P = .004) models. In the Bayesian analysis, the posterior probability that severe hypercapnia was associated with ICU death was > 90% in 4 different priors, including a septic prior for this association. Sustained severe hypercapnia on day 5, defined as severe hypercapnia present from day 1 to day 5, was noted in 93 subjects (12%). After propensity score matching, severe hypercapnia on day 5 remained associated with ICU mortality (odds ratio 1.73, 95% CI 1.02-2.97; P = .047).
Conclusions:
Severe hypercapnia was associated with mortality in subjects with ARDS who received lung-protective ventilation. Our results deserve further evaluation of the strategies and treatments that aim to control CO2 retention.
The effects of lower tidal volume ventilation (LTV) were controversial for patients with acute respiratory distress syndrome (ARDS). This systematic review and meta-analysis aimed to evaluate the use of LTV strategy in patients with ARDS. We performed a literature search on MEDLINE, CENTRAL, EMBASE, CINAHL, “Igaku-Chuo-Zasshi”, clinical trial registration sites, and the reference of recent guidelines. We included randomized controlled trials (RCTs) to compare the LTV strategy with the higher tidal volume ventilation (HTV) strategy in patients with ARDS. Two authors independently evaluated the eligibility of studies and extracted the data. The primary outcomes were 28-day mortality. We used the GRADE methodology to assess the certainty of evidence. Among the 19,864 records screened, 13 RCTs that recruited 1874 patients were included in our meta-analysis. When comparing LTV (4–8 ml/kg) versus HTV (> 8 ml/kg), the pooled risk ratio for 28-day mortality was 0.79 (11 studies, 95% confidence interval [CI] 0.66–0.94, I ² = 43%, n = 1795, moderate certainty of evidence). Subgroup-analysis by combined high positive end-expiratory pressure with LTV showed interaction (P = 0.01). Our study indicated that ventilation with LTV was associated with reduced risk of mortality in patients with ARDS when compared with HTV.
Trial registration: UMIN-CTR (UMIN000041071).
Permissive hypercapnia is commonly used in mechanically ventilated patients to avoid lung injury but its effect on pulmonary artery pressure (PAP) is still unclear, particularly in combination with tidal volume (Vt). Therefore, an in vivo study was performed on adult rabbits ventilated with low (9 ml/Kg, LVt group) or high (15 ml/Kg, HVt group) tidal volume (Vt) and alterations in PAP were estimated. Both groups of animals initially were ventilated with FiO2 0.3 (Normocapnia-1) followed by inhalation of enriched CO2 gas mixture (FiCO2 0.10) to develop hypercapnia (Hypercapnia-1). After 30 min of hypercapnia, animals were re-ventilated with FiO2 0.3 to develop normocapnia (Normocapnia-2) again and then with FiCO2 0.10 to develop hypercapnia (Hypercapnia-2). Systolic, diastolic and mean PAP were assessed with a catheter in the pulmonary artery. In HP-1 and HP-2, PaCO2 increased (p < 0.0001) in both LVt and HVt animals compared to baseline values. pH decreased to ≈7.2 in HP-1 and ≈7.1 in HP -2. In normocapnia, the rise in Vt from 9 to 15 ml/Kg induced an increase in static compliance (Cstat), plateau airway pressure (Pplat) and PAP. Hypercapnia increased PAP in either LVt or HVt animals without significant effect on Cstat or Pplat. A two-way ANOVA revealed that there was not a statistically significant interaction between the effects of hypercapnia and tidal volume on mPAP (p = 0.76). In conclusion, increased Vt per se induced an increase in Cstat, Pplat and PAP in normocapnia. Hypercapnia increased PAP in rabbits ventilated with low or high Vt but this effect was not long-lasting.
Background
Intravenous fluids are used commonly for almost all intensive care unit (ICU) patients, especially for patients in need of resuscitation. The selection and use of resuscitation fluids may affect the outcomes of patients; however, the optimal resuscitative fluid remains controversial.
Methods
We systematically searched PubMed, Embase, and CENTRAL. Studies comparing balanced crystalloids and normal saline in ICU patients were selected. We used the Cochrane Collaboration tool to assess the risk of bias in studies. The primary outcome was mortality at the longest follow-up. Secondary outcomes included the incidence of acute kidney injury (AKI) and new renal replacement therapy (RRT).
Results
A total of 35,456 patients from eight studies were included. There was no significant difference between balanced crystalloid solutions and saline in mortality (risk ratio [RR]: 0.96; 95% confidence interval [ CI ]:0.92–1.01). The subgroup analysis with traumatic brain injury (TBI) showed lower mortality in patients receiving normal saline (RR:1.25; 95% CI 1.02–1.54). However, in patients with non-TBI, balanced crystalloid solutions achieved lower mortality than normal saline (RR: 0.94; 95% CI 0.90–0.99). There was no significant difference in moderate to severe AKI (RR: 0.96; 95% CI 0.90–1.01) or new RRT (RR: 0.94; 95% CI 0.84–1.04).
Conclusions
Compared with normal saline, balanced crystalloids may not improve the outcomes of mortality, the incidence of AKI, and the use of RRT for critically ill patients. However, balanced crystalloids reduce the risk of death in patients with non-TBI but increase the risk of death in those with TBI. Large-scale rigorous randomized trials with better designs are needed, especially for specific patient populations.
Introduction: Post-injury respiratory failure is defined as inadequate gas exchange secondary to dysfunction of the chest wall, alveoli, pulmonary circulation, or central nervous system. Acute Respiratory Distress Syndrome (ARDS) develops in 12–25% of traumatically injured patients, and the lungs are the most common organ system affected in post-injury multiple organ failure (MOF). Pathophysiology: Acute respiratory failure is generally the result of two conditions: hypoxia and hypercapnia, which can precipitate failure independently or simultaneously. Hypoxia in defined as PaO2 < 50 mmHg, and hypercapnia is defined as PCO2 > 45 mmHg, with decreased minute ventilation. The pathophysiology of acute respiratory failure due to ARDS stems from both direct and indirect mechanisms of injury. Diagnosis: The diagnosis of acute post-injury respiratory failure/ARDS can be rapidly established and acted upon with bedside clinical exam and arterial blood gas analysis, precluding the need for advanced imaging or other technologically sophisticated diagnostics. Treatment: The main principles of respiratory failure treatment are: (1) support the patient while identifying and treating the underlying cause, and (2) prevent further pulmonary injury while supporting recovery. The ARDSnet mechanical ventilator protocol provides an evidence-based means to implement these principles in patients with PaO2/FiO2 ratios ≤300, bilateral infiltrates consistent with pulmonary edema, and no evidence of left atrial hypertension. Adjunctive rescue therapies when ARDSnet fails, such as prone positioning and ECMO, are possible but limited by resources in many practice environments. Outcomes/Long-term effects: The over-arching disease severity of post-injury respiratory failure/ARDS is underscored by outcomes in the adult population, with in-hospital mortality reaching 40% and 5-year mortality at 60%. Pulmonary fibrosis is a long-term sequela of ARDS for which an effective treatment remains obscure.
The main goal of ventilatory management for patients with ARDS is to prevent further injury of intact alveoli while maintaining adequate oxygenation and ventilation. This chapter will review established and evolving approaches in ventilatory management, as well as the underlying pathophysiology. Considerations in managing ARDS secondary to COVID-19 infection (CARDS) will also be discussed in this chapter.KeywordsVentilatory managementVentilator-induced lung injuryVILIPatient self-inflicted lung injuryP-SILICOVID-19
Rationale:
Hypercapnia may affect the outcome of sepsis. Very few clinical studies conducted in non-critically ill patients, have investigated the effects of hypercapnia and hypercapnic acidemia in the context of sepsis. The effect of hypercapnia in critically ill patients with sepsis remains inadequately studied.
Objective:
To investigate the association of hypercapnia with hospital mortality in septic critically ill patients.
Methods:
This is a retrospective study conducted in three tertiary public hospitals. Septic critically ill patients from three intensive care units between January 2011 and May 2019 were included. Five cohorts (exposure of at least 24, 48, 72, 120 and 168 hours) were created to account for immortal time bias and informative censoring. The association between hypercapnia exposure and hospital mortality was assessed with multivariable models. Subgroup analyses compared ventilated vs. non-ventilated and pulmonary vs. non-pulmonary sepsis patients.
Results:
We analyzed 84,819 PaCO2 measurements in 3,153 patients (57.6% male; median age was 62.5 years). After adjustment for key confounders, both in mechanically ventilated and non-ventilated patients and in patients with pulmonary sepsis, there was no independent association of hypercapnia with hospital mortality. In contrast, in ventilated patients, the presence of prolonged exposure to both hypercapnia and acidemia was associated with increased mortality (highest Odds Ratio of 16.5 for at least 120 hours of potential exposure; P = 0.007).
Conclusion:
After adjustment, isolated hypercapnia was not associated with increased mortality in septic patients. These hypothesis-generating observations suggest that as hypercapnia is not an independent risk factor for mortality, trials of permissive hypercapnia in sepsis may be safe.
The comprehension of the fluid flow in the upper airways is of paramount importance when treating patients under clinical conditions that demand mechanical ventilation. Barotrauma and overdistension are related to undesirable pressures and might be responsible for morbidity and mortality. In the current work we use computational fluid dynamics to investigate the pressure field in the upper respiratory airways. We performed a set of simulations varying the volumetric flow rate of mechanical ventilators and we have shown that the pressure profile can be calculated by means of the volumetric flow rate in accordance with a mathematical expression given by Pav=aV˙2, where Pav is the average pressure at selected sections of the upper airways and V˙ is the volumetric flow rate. Numerical findings provide evidence that the constant a varies with the location of the plane in the upper airways. We also show that some particular diameters of endotracheal tubes (ETT) must be used with care for a given range of volumetric flow rates. Overall, we document an important relationship among pressure, volumetric flow rate and selected internal diameters from ETT.
The paper summarizes data on modern approaches to the diagnosis, prevention and treatment of severe acute parenchymal respiratory failure of various origins, including ARDS due to bacterial viral pneumonia. The work is based on the data of modern well-organized studies, analysis of international clinical guidelines with a high degree of evidence, as well as the results of our own long-term experimental studies and clinical observations of the treatment of patients with ARDS of various origins, including viral pneumonia of 2009, 2016, 2020. Scientifically grounded algorithms for prevention, differential diagnosis and personalized therapy of severe acute respiratory failure using innovative medical technologies and a wide range of respiratory and adjuvant treatment methods have been formulated. The authors tried to adapt as much as possible the existing current recommendations for the daily clinical practice of anesthesiologists and resuscitators.
The paper summarizes data on modern approaches to the diagnosis, prevention and treatment of severe acute parenchymal respiratory failure of various origins, including ARDS due to bacterial viral pneumonia. The work is based on the data of modern well-organized studies, analysis of international clinical guidelines with a high degree of evidence, as well as the results of our own long-term experimental studies and clinical observations of the treatment of patients with ARDS of various origins, including viral pneumonia of 2009, 2016, 2020. Scientifically grounded algorithms for prevention, differential diagnosis and personalized therapy of severe acute respiratory failure using innovative medical technologies and a wide range of respiratory and adjuvant treatment methods have been formulated. The authors tried to adapt as much as possible the existing current recommendations for the daily clinical practice of anesthesiologists and resuscitators.
The coronavirus 2 (SARS-CoV-2) has resulted in an international pandemic. The SARS-CoV-2 affects cardiovascular, digestive and urogenital systems. In an attempt to develop a multimodal and targeted approach to the pathophysiology associated with viral lung injury, we reviewed lung histopathology, inflammation, surfactant biology and pathophysiology related to viral associated acute lung injury (ALI / ARDS). Histopathology of viral pneumonia/ARDS cases of the past 100 years has revealed that lung parenchymal and vascular pathologic changes described in the 1918 influenza pandemic, are no different from the histopathology observed in other viral pandemics. Given the inflammatory storm which can occur in COVID-19 infection, the patient is a candidate to develop the classic multi-organ dysfunction and / or failure (MOD/F) which may well include ALI and ARDS. Because there is a well described temporal change in the pathophysiology associated with ALI /ARDS, a "one size fit al" remedy will not suffice, hence our attempt at a targeted functional approach. For instance, variable results in adults treated with surfactant have relegated the use of surfactant in adult ARDS to an uncertainty. We speculate that early and repeated surfactant installation in adults is required in adults. Surfactant may also have beneficial effects on the inflammatory process in the ARDS lung. The increased clotting tendency associated with the inflammation (and ARDS), particularly the effect on the lung vasculature (acute pulmonary hypertension and increased dead space), causes mechanical pressure overload (and failure) of the right ventricle and mechanical respiratory failure. Active management of these should include inhibition of the accelerated coagulation and thrombolysis (via nebulization) and early inotropic support.
The paper summarizes data on modern approaches to the diagnosis, prevention and treatment of severe acute parenchymal respiratory failure of various origins, including ARDS due to bacterial viral pneumonia. The work is based on the data of modern well-organized studies, analysis of international clinical guidelines with a high degree of evidence, as well as the results of our own long-term experimental studies and clinical observations of the treatment of patients with ARDS of various origins, including viral pneumonia of 2009, 2016, 2020. Scientifically grounded algorithms for prevention, differential diagnosis and personalized therapy of severe acute respiratory failure using innovative medical technologies and a wide range of respiratory and adjuvant treatment methods have been formulated. The authors tried to adapt as much as possible the existing current recommendations for the daily clinical practice of anesthesiologists and resuscitators.
Adipose‐derived stromal cells (ADSCs) showed excellent capacity in regeneration and tissue protection. Low tidal volume ventilation (LVT) strategy demonstrates a therapeutic benefit on the treatment of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). This study, therefore, aimed to undertaken determine whether the combined LVT and ADSCs treatment exerts additional protection against lipopolysaccharide (LPS)‐induced ALI in rats. The animals were randomized into seven groups: Group I (control), Group II (instillation of LPS at 10 mg/kg intratracheally), Group III (LPS+LVT 6 ml/kg), Group IV (LPS+intravenous autologous 5 × 10⁶ ADSCs which were pretreated with a scrambled small interfering RNA [siRNA] of keratinocyte growth factor [KGF] negative control), Group V (LPS+ADSCs which were pretreated with a scrambled siRNA of KGF, Group VI (LPS+LVT and ADSCs as in the Group IV), and Group VII (LPS+LVT and ADSCs as in the Group V). We found that levels of tumor necrosis factor‐α, transforming growth factor‐β1, and interleukin (IL)‐1β and IL‐6, the proinflammatory cytokines, were remarkably increased in LPS rats. Moreover, the expressions of ENaC, activity of Na, K‐ATPase, and alveolar fluid clearance (AFC) were obviously reduced by LPS‐induced ALI. The rats treated by ADSCs showed improved effects in all these changes of ALI and further enhanced by ADSCs combined with LVT treatment. Importantly, the treatment of ADSCs with siRNA‐mediated knockdown of KGF partially eliminated the therapeutic effects. In conclusion, combined treatment with ADSCs and LVT not only is superior to either ADSCs or LVT therapy alone in the prevention of ALI. Evidence of the beneficial effect may be partly due to improving AFC by paracrine or systemic production of KGF and anti‐inflammatory properties.
Background
Considerable variability exists regarding CO2 management in early ARDS, with the impact of arterial CO2 tension on management and outcomes poorly understood.
Research Question
To determine the prevalence and impact of hypo- and hypercapnia on the management and outcomes of patients with early ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study, an international multicenter observational study.
Study Design and Methods
Our primary objective was to examine the prevalence of Day 1 and sustained (day 1 and 2) of hypocapnia (PaCO2 < 35mmHg), normocapnia (PaCO2 35-45mmHg) and hypercapnia (PaCO2 > 45mmHg) in patients with ARDS. Secondary objectives included elucidating the effect of CO2 tension on ventilatory management, and examining the relationship with ARDS outcome
Results
Of 2,813 patients analyzed, 551 (19.6%, 95%CI: 18.1-21.1) were hypocapnic, 1,018 (36.2%, 95%CI: 34.4-38.0) were normocapnic, while 1,214 (43.2%, 95%CI: 41.3-45.0) were hypercapnic, on day 1. Sustained hypocapnia was seen in 252 (9.3%, 95%CI: 8.2-10.4), sustained normocapnia in 544 (19.3%, 95%CI: 17.9-20.8) and sustained hypercapnia in 654 (24.1%, 95%CI: 22.5-25.7) patients. Hypocapnia was more frequent and severe in patients receiving non-invasive ventilation but was also observed in patients on controlled mechanical ventilation. Sustained hypocapnia was more frequent in middle income countries, while sustained hypercapnia was more frequent in Europe. ARDS severity profile was highest in sustained hypercapnia, and these patients received more protective ventilation. There was no independent association between arterial CO2 and outcome. In propensity matched analyses, hospital mortality was 36% in both sustained normocapnic and hypercapnic patients (P=1.0). ICU mortality was higher in patients with mild to moderate ARDS receiving sustained hypocapnia (38.1%) compared to normocapnia (27.1%).
Interpretation
There was no evidence for benefit or harm with hypercapnia. Of concern, ICU mortality was higher with sustained hypocapnia in mild-moderate ARDS.
Refractory hypoxemia is the main symptom of acute respiratory distress syndrome (ARDS). Low tidal volume ventilation is routinely applied in clinical practice to correct hypoxemia, which aims to prevent ventilator‑induced lung injury. However, this ventilation strategy inevitably leads to hypercapnia. Our previous study demonstrated that hypercapnia aggravated cognitive impairment in hypoxemic rats; however, the underlying mechanism remains unclear. The aim of the present study was to investigate whether hypercapnia exacerbates the blood‑brain barrier (BBB) disruption through inducing interleukin (IL)‑1β overproduction in the blood of hypoxemic rats. The BBB permeability in a rat model of hypercapnia/hypoxemia was evaluated. The levels of IL‑1β in the blood of rats and human whole‑blood cultures were assessed. The expression of IL‑1 receptor 1 (IL‑1R1), phosphorylated IL‑1R1‑associated kinase (p‑IRAK‑1) and tight junctional proteins in cerebral vascular endothelial cells was examined in vitro and in vivo. In addition, IL‑1Ra, an IL‑1 receptor antagonist, was used to determine whether hypercapnia affects tight junctional protein expression in hypoxic cerebral vascular endothelial cells through inducing IL‑1β overproduction. It was observed that hypercapnia alone did not disrupt the BBB, but aggravated the damage to the BBB integrity in hypoxemic rats. Hypercapnia increased IL‑1β expression in the blood of hypoxemic rats as well as in hypoxic human whole‑blood cultures. IL‑1R1 and p‑IRAK‑1 expression was increased, while that of tight junctional proteins was reduced by hypercapnia in hypoxemic cerebral vascular endothelial cells in vitro and in vivo. Additionally, the expression of tight junctional proteins was markedly increased following treatment with IL‑1Ra. These results suggest that hypercapnia‑induced IL‑1β overproduction in the hypoxemic blood may decrease tight junctional protein expression in cerebrovascular endothelial cells via the IL‑1R1/p‑IRAK‑1 pathway, further disrupting BBB integrity, and eventually resulting in increased BBB permeability.
Normal human physiology demands and maintains systemic pH in a very narrow range due to intracellular and extracellular mechanisms that correct for physiologic and pathologic perturbations. The most common mechanism for compensation of pH abnormalities is through the respiratory and renal systems, which control carbon dioxide (CO2) and bicarbonate (HCO3⁻) homeostasis. Carbon dioxide, a volatile acid, is a by-product of cellular aerobic respiration that combines with water to form carbonic acid (H2CO3) which can be catalyzed by carbonic anhydrase to produce protons (H⁺) and bicarbonate (HCO3⁻).
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