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Keywords:

  • delirium;
  • lung recruitment;
  • mechanical ventilation;
  • surfactant.

Abstract

  1. Top of page
  2. Abstract
  3. PHYSIOLOGICAL EFFECTS OF MECHANICAL VENTILATION
  4. VENTILATION-INDUCED CYTOKINE RELEASE
  5. VENTILATOR-ASSOCIATED PNEUMONIA
  6. PROPER MECHANICAL VENTILATION
  7. SEDATION IN MECHANICAL VENTILATION AND INTENSIVE CARE UNIT CARE
  8. CONCLUSION
  9. DISCLOSURES
  10. REFERENCES

There has been a marked increase in the volume of critical care services throughout the world in the last few years with the wide addition of intensive care units in developing nations. Despite extensive efforts in research and some progress in treatment, mortality and morbidity have not significantly decreased. Recent research has demonstrated that modifying standard practices of mechanical ventilation and sedation may contribute to improved patient outcomes. This article discusses how new aspects of physiologically based mechanical ventilation with minimal intravenous sedation may help decrease the incidence of nosocomial pneumonia, modulate systemic inflammatory response, and reduce the incidence of delirium. These interlinked modalities may someday contribute to decreased length of stay and a reduction in treatment-related complications. These concepts may also open new avenues to improve patient care and stimulate ongoing investigation in other areas related to physiologically based critical care practices. Mt Sinai J Med 79:116–122, 2012.© 2012 Mount Sinai School of Medicine

Recent years have seen a sharp increase in the care of critically ill patients throughout the world. The medical community has treated and supported patients through complex world pandemics such as the H1N11 using protocols developed for the care of mechanically ventilated patients with physiologically based standards. The medical response to such pandemics has resulted in high visibility of critical care medicine in the media. Advances in critical care medicine have led to a deeper understanding of the physiology of critical illness, but so far have not resulted in a corresponding improvement in mortality rates.2

In the 1960s, deaths in the intensive care unit (ICU) were usually attributed to blood loss, renal failure, or respiratory insufficiency.2 Today, patient deaths in the ICU are more likely due to cellular mechanisms associated with the activation of the systemic inflammatory response, which can lead to septicemia and multiorgan failure.

Today, patient deaths in the intensive care unit are more likely due to cellular mechanisms associated with the activation of the systemic inflammatory response, which can lead to septicemia and multiorgan failure.

Recent practice has attempted to modulate these cellular responses in patients by focusing on 2 of the most commonly used therapies in the ICU: mechanical ventilation and sedation. Many practitioners and researchers are aware of the epidemiology of nosocomial pneumonia3 and how mechanical ventilation is used to benchmark academic medical centers. Sedation of critical care patients has been a common practice, but only in the last 5 years has research started to link sedation with delirium and then back to cytokine modulation and mortality.4 Recent critical care practice attempts to minimize sedation and mobilize mechanically ventilated patients to prevent both ventilator- and sedation-induced complications. Linking these 2 basic treatment modalities may hold great promise.

This review will discuss some of the contributions, such as controlling tidal volumes, lung recruitment, and stabilization, that may have a great impact on cytokine modulation. The key to this will be to understand the pathogenic mechanisms of ventilator-associated lung injury and how these mechanisms are affected by sedation. There is a growing awareness of the interaction between these 2 care treatments of critical illness. It is possible that basic practices may hold more promise for patient care than new, more powerful drugs and expensive technology.

PHYSIOLOGICAL EFFECTS OF MECHANICAL VENTILATION

  1. Top of page
  2. Abstract
  3. PHYSIOLOGICAL EFFECTS OF MECHANICAL VENTILATION
  4. VENTILATION-INDUCED CYTOKINE RELEASE
  5. VENTILATOR-ASSOCIATED PNEUMONIA
  6. PROPER MECHANICAL VENTILATION
  7. SEDATION IN MECHANICAL VENTILATION AND INTENSIVE CARE UNIT CARE
  8. CONCLUSION
  9. DISCLOSURES
  10. REFERENCES

A pioneering study by Mead in 1959 showed that mechanically ventilated dogs experienced a progressive fall in pulmonary compliance.5 Since then, research has linked these changes in compliance to lung surfactant6 and identified 2 primary mechanisms of surfactant dysfunction triggered by mechanical ventilation.

First, mechanical ventilation has been shown to enhance the release of surfactant from type II pneumocytes in to the alveolus.7–10 This material is subsequently lost into the small airways as a result of compression of the surfactant film when the surface of the alveolus becomes smaller than the surface occupied by the surfactant molecules.11

The second mechanism that affects surfactant in mechanically ventilated patients is based on the conversion of surface-active large surfactant aggregates into non–surface-active small surfactant aggregates.12,13 Surfactant changes associated with mechanical ventilation are reversible as a result of metabolically active processes that involve de novo production of surfactant.8 This is the interplay between secretion and production of large aggregates, and the uptake, clearance, and reconversion of small aggregates in the type II pneumocyte14; changes in delivery and titration of mechanical ventilation should correct this imbalance between large and small aggregates. A large number of clinical trials using multiple formulations of both animal and artificial surfactant have shown that the loss of natural surfactant cannot be successfully replaced in adult patients13; therefore, preserving patient surfactant levels and function is crucial.

The second mechanism that affects surfactant in mechanically ventilated patients is based on the conversion of surface-active large surfactant aggregates into non–surface-active small surfactant aggregates.

An alveolus with surfactant impairment is predisposed to end-expiratory collapse, which is affected by shear forces. This collapse triggers atelectasis, which places a great deal of stress on the alveolus and the surfactant system. The early work of Mead5 discussed ventilation-induced lung injury and the effects of shear forces on epithelial stretching. Mead demonstrated that due to pulmonary interdependence of alveoli, the forces acting on fragile lung tissue in nonuniformly expanded lungs are both applied transpulmonary pressures and the shear forces that are present in the interstitium between opened and closed alveoli15; this balance between opened and closed alveoli is the basis of the concept of lung recruitment.

VENTILATION-INDUCED CYTOKINE RELEASE

  1. Top of page
  2. Abstract
  3. PHYSIOLOGICAL EFFECTS OF MECHANICAL VENTILATION
  4. VENTILATION-INDUCED CYTOKINE RELEASE
  5. VENTILATOR-ASSOCIATED PNEUMONIA
  6. PROPER MECHANICAL VENTILATION
  7. SEDATION IN MECHANICAL VENTILATION AND INTENSIVE CARE UNIT CARE
  8. CONCLUSION
  9. DISCLOSURES
  10. REFERENCES

A key study by Tremblay and colleagues in an isolated lung model demonstrated that different ventilation strategies can affect the production of cytokines and inflammatory mediator expression.16 This study measured several common mediators, such as tumor necrosis factor-α, interferon 1-β, interleukin-6,IL-10, macrophage inflammatory protein 2, and interferon γ, in the presence or absence of a preexisting inflammatory stimulus. The authors showed that the use of high peak inspiratory lung volumes and no positive end-expiratory pressure (PEEP) during mechanical ventilation may have a synergistic effect on the release of proinflammatory mediators from the lung tissue. The absence of PEEP showed how cyclic opening and collapse of alveoli can affect pathophysiology. The addition of 10 cmH2O of PEEP at comparable peak inspiratory lung volumes, or lowering peak inspiratory lung volume when ventilating with zero PEEP, resulted in reduced cytokine levels.

A key study by Tremblay and colleagues in an isolated lung model demonstrated that different ventilation strategies can affect the production of cytokines and inflammatory mediator expression. This study measured several common mediators, such as tumor necrosis factor-α, interferon 1-β, interleukin-6, JL-10, macrophage inflammatory protein 2, and interferon γ, in the presence or absence of a preexisting inflammatory stimulus.

This and other recent studies have shown that mechanical ventilation creates shear stresses at the interstitial interface between open and closed atelectatic regions of the lung.17,18

Proinflammatory factors and the release of cytokines can have a significant impact on patient mortality and morbidity. Mechanical ventilation can thus either trigger or amplify the systemic inflammatory response and lead to the cascade of organ failure.19–21 In critically ill patients, the lung may play a central role in cytokine response that may be attenuated by a strategy to minimize overdistention and recruitment/derecruitment of the lung and therefore act on multiple organs.21 Several current studies are investigating this immunomodulation and how it may affect critical care. A meta-analysis of previous research may have a positive impact on patient outcomes, length of stay, and healthcare costs.

VENTILATOR-ASSOCIATED PNEUMONIA

  1. Top of page
  2. Abstract
  3. PHYSIOLOGICAL EFFECTS OF MECHANICAL VENTILATION
  4. VENTILATION-INDUCED CYTOKINE RELEASE
  5. VENTILATOR-ASSOCIATED PNEUMONIA
  6. PROPER MECHANICAL VENTILATION
  7. SEDATION IN MECHANICAL VENTILATION AND INTENSIVE CARE UNIT CARE
  8. CONCLUSION
  9. DISCLOSURES
  10. REFERENCES

Lung infection acquired from mechanical ventilation, so-called nosocomial pneumonia or ventilator-associated pneumonia (VAP), is the second most frequent cause of hospital-acquired infection in the United States. Its incidence ranges from 120 to 220 cases per 1000 ICU admissions. It is becoming one of the most commonly measured and discussed markers collected and studied by government healthcare agencies and a leading cause of death from hospital-acquired infections, with a crude associated mortality rate of approximately 30%.22 Its true mechanism is not completely understood, but it is the subject of many ongoing active investigations that fill journals each year.

Lung infection acquired from mechanical ventilation, so-called nosocomial pneumonia or ventilator-associated pneumonia, is the second most frequent cause of hospital-acquired infection in the United States. Its incidence ranges from 120 to 220 cases per 1000 intensive care unit admissions.

Several strategies aimed at its prevention have been recommended. Some, such as hand-washing, which is key in preventing the spread of any infection, are not specific to the lung. Some widely used strategies in pulmonary management, such as positioning to prevent aspiration of upper-airway secretions, avoidance of large gastric volumes, maintenance of ventilator circuits, stress-ulcer prophylaxis, antibiotic therapy, and use of mouth care, have gained wide support.23 Selective decontamination of the digestive tract, one of the most discussed therapies, has been practiced by several large centers but as of yet has not been associated with reduced mortality.24 Not much research has been done into modulating mechanical ventilation to affect the translocation of organisms both into and out of the lung, which may be one of the major reasons ICU patients develop these nosocomial infections.

Based on the common observation that mechanically ventilated patients often develop pneumonia25 and bacteremia, the question may be raised whether mechanical ventilation can induce damage and promote bacteremia and/or sepsis. It is conceivable that bacteria can more readily gain access to the circulation from damaged lung parenchyma than from previously normal lung tissues.26,27 This effect may be due to surfactant dysfunction and the shear forces between open and atelectatic areas. It has been established that preserving end-expiratory lung volume with PEEP may have a beneficial effect on the course of infection by decreasing bacterial counts from the lung tissue. This effect has been demonstrated in studies of mechanically ventilated lungs inoculated with bacteria.28 This loss of a protective compartment29 in patients with VAP may be an important aspect that has not been widely studied. These data may suggest that ventilation-induced changes in the barrier function of the lung epithelium and/or endothelium to bacteria may contribute to the development of bacteremia and endotoxemia as a major contributor to organ dysfunction and morbidity. This bacterial translocation may be due to both an increased translocation of bacteria from the alveolar space directly into the bloodstream and a loss of surfactant and its immunologic effect.

It is conceivable that bacteria can more readily gain access to the circulation from damaged lung parenchyma than from previously normal lung tissues.

Pulmonary surfactant was initially identified as a lipoprotein complex that reduces surface tension at the air-liquid interface of the lung. This definition has been reassessed in light of studies that show that surfactant also functions in pulmonary host defense and that surfactant proteins are expressed in nonpulmonary sites.30,31 The host defense functions of surfactant are primarily mediated by collectin proteins SP-A and SP-D. Both in vitro and in vivo studies show that SP-A and SP-D enhance the uptake of particles and pathogens by at least 3 different mechanisms: by opsonizing pathogens, functioning as activation ligands, and regulating cell-surface-receptor expression. Reidy and colleagues demonstrated that alveolar macrophages in the presence of SP-A show enhanced apoptotic cell uptake, probably corresponding with those of blood monocytes.32 Thus proper mechanical ventilation with lung recruitment and the ability to stabilize alveolar beds open to prevent surfactant loss may be the key to the reduction of pneumonia and modulation of nosocomial pneumonia.

PROPER MECHANICAL VENTILATION

  1. Top of page
  2. Abstract
  3. PHYSIOLOGICAL EFFECTS OF MECHANICAL VENTILATION
  4. VENTILATION-INDUCED CYTOKINE RELEASE
  5. VENTILATOR-ASSOCIATED PNEUMONIA
  6. PROPER MECHANICAL VENTILATION
  7. SEDATION IN MECHANICAL VENTILATION AND INTENSIVE CARE UNIT CARE
  8. CONCLUSION
  9. DISCLOSURES
  10. REFERENCES

With this base in physiology, it is possible to modulate morbidity and mortality outcomes in the ICU. Because mechanical ventilation is the core therapy in the care of patients in the ICU and the operating room, modifying the practice would have the highest yield. One of the most basic concepts that has greatly affected patient care is using normal physiological tidal volumes of 5–7 cc/kg lean weight instead of the supernormal levels that were common in the last 40 years. Although all mammals breathe at this lower tidal volume,33 the popularity of higher tidal volumes of 10–12 cc/kg lean body weight was a standard in the ICU that was developed in the 1960s. Studies in the late 1990s that went back to these physiological roots have now moved practice away from these supernormal levels. These observations were first made by Amato and colleagues34 and in the widely referenced trial performed by the ARDS Network, a group funded by the National Heart, Lung, and Blood Institute to conduct clinical trials in patients with acute respiratory distress syndrome (ARDS).35 The data from these studies reinforced the link between stress, stretch, and overdistention, and physical damage to alveolar beds. Even though these data have been widely presented, the majority35 of centers have not embraced these normal tidal volumes as standard therapy. Another area of new active investigation is diaphragmatic dysfunction and various new modes of neural-controlled ventilators, but this is still an area of active study. With the expansion of electronic order writing and protocols in respiratory therapy, we are hopeful that this most basic concept of safe tidal volumes will be utilized by all ICUs.

Atelectasis is common in mechanically ventilated patients and affects surfactant, cytokine modulation, bacterial translocation, and VAP. The practice of lung recruitment, or the open lung concept, was first described by Lachmann in 1992.36 Lung volume is optimized early on by a recruitment maneuver, which subsequently reduces mean airway pressure to a level above the airway pressure where lung collapse occurs with the titration of PEEP.37,38 It is widely accepted that atelectasis36 may have negative effects on lung physiology and that we should address ways to recruit the lung in the treatment of patients undergoing mechanical ventilation. The exact way to perform this recruitment maneuver and the ideal PEEP level are under active investigation39–41 and await large randomized clinical trials in specific patient populations.

Lung volume is optimized early on by a recruitment maneuver, which subsequently reduces mean airway pressure to a level above the airway pressure where lung collapse occurs with the titration of positive end-expiratory pressure.

SEDATION IN MECHANICAL VENTILATION AND INTENSIVE CARE UNIT CARE

  1. Top of page
  2. Abstract
  3. PHYSIOLOGICAL EFFECTS OF MECHANICAL VENTILATION
  4. VENTILATION-INDUCED CYTOKINE RELEASE
  5. VENTILATOR-ASSOCIATED PNEUMONIA
  6. PROPER MECHANICAL VENTILATION
  7. SEDATION IN MECHANICAL VENTILATION AND INTENSIVE CARE UNIT CARE
  8. CONCLUSION
  9. DISCLOSURES
  10. REFERENCES

Sedation and neuromuscular blockade are 2 emergent areas that are coupled with the optimal delivery of mechanical ventilation. There has been growing interest in sedation practices in the ICU. Recognition of delirium and confusion that arise in critically ill patients has shifted the analysis from the short-term to the longer-term effects of these “innocuous” practices.4 Sedation of the critically ill mechanically ventilated patient is not a single-faceted issue. The focus is no longer on simply creating deeply unconscious and compliant patients, but on using titratable agents to find the level of sedation that creates the best long-term outcomes. Sedation practices that focus on short-term practical effectiveness may be associated with the potential for both mortality4 and longer-term psychoaffective and cognitive issues when patient delirium prolongs the need for mechanical ventilation.42

Sedation should minimize the use of sedative agents, enable the utilization of physiologically based mechanical ventilation, support spontaneous breathing, and lead to early weaning from mechanical ventilation. We should monitor and treat delirium in the ICU, separate patients from mechanical ventilation, and reduce length of stay and mortality rates. Early mobilization, even on mechanically ventilated patients, can also affect pulmonary parameters, such as functional residual capacity, and improve patient mental well-being. In many centers, it is a routine part of care to walk mechanically ventilated patients. Patients who are more interactive can be more actively weaned from mechanical ventilation and the use of noninvasive mechanical ventilation.

Sedation should minimize the use of sedative agents, enable the utilization of physiologically based mechanical ventilation, support spontaneous breathing, and lead to early weaning from mechanical ventilation.

Many new protocols and drugs are in development to aid in decreasing sedation and support more natural breathing. The use of new agents such as the α-2 agonist dexmedetomidine has become more common and may hold some promise. How this non–γ-aminobutyric acid agent affects delirium is under investigation. Several investigators have noted that their patients on dexmedetomidine were in a tranquil state but were able to understand and communicate their needs in response to verbal stimulation by the medical staff.43 The use of this drug compared with the standard therapy, lorazepam, showed a marked decrease in brain dysfunction and improved patient outcomes.44

Assessment tools for delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU) as described by Ely and colleagues, should be used in every ICU.45 There may also be a role for the use of antipsychotics in subsets of mechanically ventilated patients46 to modulate delirium once it is identified with one of these scales. Also, simple, cost-effective environmental measures, such as painting ceilings sky-blue as presented by the Society of Critical Care Medicine design award in 2011, may have some sedating effect and need to be studied.

Neuromuscular blockade has long been used as a rescue therapy in patients with ARDS who cannot be ventilated. Recent evidence suggests a survival benefit associated with the early selective use of competitive neuromuscular blocking agents.47 In a study in patients with severe ARDS, early administration of several types of the neuromuscular agents improved adjusted 90-day survival and increased time off the ventilator without muscle weakness. These results may be associated with the possibility of early alveolar recruitment and an enhanced ability to deliver physiological tidal volumes in these patients by removing the resistance of the chest wall. Further studies are needed to evaluate ideal patient populations for neuromuscular blockade, the ideal length of use for these compounds, and the best type of mechanical ventilation.

Recent evidence suggests a survival benefit associated with the early selective use of competitive neuromuscular blocking agents.

CONCLUSION

  1. Top of page
  2. Abstract
  3. PHYSIOLOGICAL EFFECTS OF MECHANICAL VENTILATION
  4. VENTILATION-INDUCED CYTOKINE RELEASE
  5. VENTILATOR-ASSOCIATED PNEUMONIA
  6. PROPER MECHANICAL VENTILATION
  7. SEDATION IN MECHANICAL VENTILATION AND INTENSIVE CARE UNIT CARE
  8. CONCLUSION
  9. DISCLOSURES
  10. REFERENCES

The lung may play a key role in the treatment of all critically ill patients. The use of mechanical ventilation has had a considerable impact on patient morbidity and mortality in the last decade. As basic knowledge of the science associated with mechanical ventilation grows, it becomes clear that natural normal physiological endpoints, such as regular tidal volumes, lung recruitment, and alveolar stabilization influence many factors outside of the lung. Organ function and the risk of nosocomial pneumonia are clearly modulated by this standard tool of critical care.

We should also begin to develop tools to control the other standard therapy of the ICU, sedation. Decreasing the levels of patient delirium and fostering early separation from mechanical ventilation to prevent delirium should be goals of treatment. As each piece of this puzzle falls into place, we can construct a more complete picture of how to best care for critically ill, mechanically ventilated patients. Revisiting these basic practices may also gain acceptance in the care of other treatment modalities, such as hemodynamic support, renal replacement therapy, and intracranial pressure monitoring management.

REFERENCES

  1. Top of page
  2. Abstract
  3. PHYSIOLOGICAL EFFECTS OF MECHANICAL VENTILATION
  4. VENTILATION-INDUCED CYTOKINE RELEASE
  5. VENTILATOR-ASSOCIATED PNEUMONIA
  6. PROPER MECHANICAL VENTILATION
  7. SEDATION IN MECHANICAL VENTILATION AND INTENSIVE CARE UNIT CARE
  8. CONCLUSION
  9. DISCLOSURES
  10. REFERENCES