Task Force on Research in Cardiopulmonary Dysfunction in Critical Care Medicine

Pathogenesis of Acute Tissue Injury and Repair

Various insults (trauma, sepsis, ischemia, or toxic exposure) can cause acute tissue injury in a variety of organ systems. A complex web of interactions among circulating inflammatory cells, resident cells, and cytokines is initiated. The common result of this cascade of events is inflammation, characterized by an increase in microvascular permeability to cells, protein, and water. Cytokines, soluble substances synthesized by cells, mediate the processes of chemotaxis, inflammatory and endothelial cell adhesion, and other forms of intercellular communication. Subsequently, leukocytes migrate into the tissues and release substances that cause tissue injury. In the process, resident macrophages are activated and contribute further to the inflammatory response.

Two mechanisms, oxygen metabolite production and hypoxia/reperfusion injury, have been reported to be causal agents of acute tissue injury. High inspiratory levels of oxygen, various chemicals, and phagocytic cells can generate the oxygen radicals that disrupt cellular homeostasis and promote cell death. In experimental models, scavenging of oxygen radicals by superoxide dismutase, catalase, glutathione peroxidase, and other endogenous protective substances has been shown to prevent organ injury. Hypoxemia and ischemia decrease the mitochondrial production of ATP, which subsequently results in formation of detrimental oxygen radicals. When ischemia is reversed and reperfusion occurs, tissue damage is also potentiated by increased formation of oxygen radicals.

During the inflammatory cascade, resident cells respond in an organized manner. In addition to expressing adhesion molecules, endothelial cells and macrophages produce substances that modulate thrombosis and coagulation, enzymes that remodel the extracellular matrix, and agents that change vascular tone. One important molecule that is released is nitric oxide, a potent vasodilator.

It is now known that the lung epithelial cell functions as more than a simple structural barrier, influencing airway function, secretions, and inflammatory responses. Research in asthma has demonstrated that epithelial cells can potentially control the acute inflammatory cascade.

The activity of resident cells can also be adversely affected during critical illness. In sepsis, mediators that impair myocardial contractility have been identified and may be responsible for clinically relevant cardiovascular depression in 20% of sepsis patients.

During acute lung injury (ALI), cells migrate from the interstitium into the alveoli, where they proliferate and deposit connective tissue products. The degree of fibroproliferation may influence acute inflammatory changes and the ability of the architecture of the alveolar-epithelial interface to be restored to its preinjured state. The fate of these inflammatory cells has recently been described.

Studies have demonstrated that intercellular and intracellular signals not only are important for cellular proliferation but also play a major role in programmed cell death (apoptosis). Additional investigations have revealed that the viability of a cell also is determined by an appropriate interaction between a cell and its neighboring cells and extracellular matrix. These discoveries have expanded the potential of therapeutic options in acute tissue injury. Interventions that enhance or modulate this intrinsic repair machinery could potentially reverse the pulmonary dysfunction observed during acute tissue injury.

Intrinsic Tissue Defense Mechanisms

Critically ill patients frequently develop secondary infections that further complicate their clinical course. Animal models suggest that disruption of the gut mucosal barrier and induction of pathological activity of microbes in the gut facilitate their penetration through the mucosal lining into regional lymph nodes and eventually into the systemic circulation. Changes in mucosal cells and the carbohydrate-rich glycocalyx layer in the upper respiratory tract enhance adherence of bacteria and subsequent colonization of the lower respiratory tract. Alveolar macrophages do not function normally or destroy these organisms because the environment of the lower respiratory tract is altered. In addition, the response of the immune system (macrophages and lymphocytes) to bacteria and other infectious agents is altered, further increasing risk of infection and failure of wound healing. The presence of various cytokines and inflammatory mediators and influx of plasma components may contribute to ineffective clearance of bacteria and increased risk of nosocomial pneumonias.

Determinants of Tissue Oxygenation

The level of systemic oxygen transport and delivery (DO₂) is determined indirectly by metabolic demand and directly by degree of arterial oxygenation, cardiac output, and amount of hemoglobin. Critical illness may decrease DO₂ because of cardiopulmonary dysfunction or acute blood loss. Use of pulmonary artery catheterization has increased understanding of the relation between systemic oxygen transport and oxygen consumption, although clinical interpretation of this relation is controversial. In animal experiments, oxygen consumption remains constant until oxygen transport falls below a critical level. Further decreases in oxygen transport produce corresponding decreases in oxygen consumption. Conversely, in many critically ill patients, oxygen consumption appears to rise with each increase in oxygen transport. This phenomenon has been called oxygen supply dependency.

Regional distribution of DO₂ is altered during critical illness, causing cellular hypoxia and generalized dysfunction in certain organ systems. Organ-specific hypoperfusion has been postulated to be due to regional differences in endothelial cell production of nitric oxide and endothelin. On a cellular level, critical illness adversely alters chemical reactions within the cell. Even when adequate oxygen transport is achieved, adequate availability of cellular energy and normal cell function are not guaranteed.

Organ-Organ Interaction and Multiple Organ Dysfunction

Recent research efforts have revealed that dysfunction in a single organ may negatively influence the function of distant organs because of mechanical, physiological, or biochemical interactions, and the sequence of organ dysfunction varies. Specifically, acute dysfunction of any major organ system, including cardiac, pulmonary, renal, hepatic, gastrointestinal, and central nervous system, may adversely affect organ-organ interactions.

Definitions and Diagnoses

Consensus groups of experts in critical care medicine have attempted to develop uniformly acceptable definitions for ALI, acute respiratory distress syndrome (ARDS), and systemic inflammatory response syndrome (referred to as sepsis in the presence of infection). A significant amount of research in this area has also focused on identifying clinical markers to predict critically ill patients who will develop ARDS. Numerous circulating mediators are present in patients who have or are at risk for ARDS, yet no single predictive marker that is highly sensitive and specific has been identified.

Mechanisms of Disease and Therapeutic Interventions

Therapeutic advances include pharmacological therapy, mechanical ventilation, nutritional support, fluid management, and cardiovascular support. Advances have also been made in understanding the physiology and pathophysiology of critical illness.

Pharmacological therapy. Most pharmacological approaches that prevent or at least diminish acute tissue inflammation have been tested in animal models or in small, uncontrolled clinical trials. Several large trials of agents, such as high-dose corticosteroids given acutely for sepsis and ARDS, prostaglandin E₁ infusion for ARDS, and administration of anti-endotoxin antibodies for sepsis have failed to show significant improvements in survival. Corticosteroids, given during the fibroproliferative phase of ARDS, have been associated with clinical improvement in small, uncontrolled studies. Other agents, including inhaled nitric oxide, various forms of anticytokine therapy, and surfactant replacement, have shown promise. However, few of these agents have been rigorously tested in well-designed, controlled clinical trials.

Mechanical ventilation. The primary goal of mechanical ventilation is to achieve adequate ventilation and oxygenation to support organ function without causing excessive morbidity. Most research in this area has addressed mechanisms of ventilator-induced injury caused by pressure (barotrauma), other complications of mechanical ventilation, proper modes of ventilation for patients with ALI, and techniques for withdrawing mechanical ventilation.

Increased morbidity due to barotrauma, oxygen toxicity, cardiovascular compromise, and complications of neuromuscular blockade has been reported in patients requiring mechanical ventilation, and various types of barotrauma have been described in the literature. In different animal models, ventilation with high peak pressures has been shown to induce ALI in otherwise normal lungs. Pathological studies of these damaged lungs reveal hyaline membranes, increased vascular permeability, and eventual fibroblast proliferation.

Lung damage can also result from high levels of inspired oxygen. The extent of oxygen toxicity is related to oxygen concentration and duration of exposure. Agents are often required to induce sedation and paralysis to facilitate mechanical ventilation, and these agents can induce hypotension, retention of secretions, incomplete lung expansion (atelectasis), and muscle wasting. Use of neuromuscular blocking agents has also been associated with prolonged paralysis and primary muscle disease (myopathy).

Awareness of these complications has led to development of specific goals of mechanical ventilation for ALI. Based on animal studies, the aim of mechanical support is to maintain a certain minimum lung volume with positive end-expiratory pressure (PEEP) to prevent collapse of potentially recruitable alveoli and use low tidal volumes to decrease the potential for barotrauma. Increased mean airway pressures may improve oxygenation, and minimization of patient-ventilator asynchrony may facilitate mechanical ventilation. To achieve these goals, various modes of ventilation have been advocated, including high-frequency ventilation, high-frequency oscillation, proportional-assist ventilation, extracorporeal membrane oxygenation, extracorporeal carbon dioxide removal, intravenous gas exchange, pressure-controlled ventilation, tracheal gas insufflation, and airway pressure release ventilation. However, none of these techniques have been demonstrated unequivocally to result in improved outcome.

One new strategy, permissive hypercapnia (excess carbon dioxide), assigns a higher priority to avoiding elevated pulmonary pressures than to maintaining adequate ventilation, so that partial pressure of arterial carbon dioxide is allowed to rise above normal values. Improved understanding of patient-ventilator interactions helps limit the work of breathing, reduces adverse cardiovascular consequences, and improves coordination between the breathing rhythms of patient and machine. Certain innovative and revitalized approaches to mechanical ventilation, such as noninvasive ventilation, have been shown to be effective in acute, reversible pulmonary dysfunction and chronic cardiopulmonary dysfunction in selected patients.

Prolonged ventilatory support is associated with increased morbidity, disability, and cost. However, premature withdrawal of mechanical ventilation is also fraught with complications. Standard parameters for predicting successful extubation include minute ventilation, tidal volume, respiratory rate, and negative inspiratory force. Recently, improved predictors, such as the ratio of frequency to tidal volume, have been developed and hold promise for predicting successful extubation. Many methods of weaning patients from mechanical ventilation are being used, but no technique has been shown to be clearly superior.

Nutritional support. The obligatory rise in energy expenditure and protein catabolism associated with critical illness necessitates administration of nutritional support. New approaches have been developed that avoid excessive calorie, glucose, and fat loading while ensuring provision of specific essential nutrients (eg, glutamine, arginine, nucleic acids), growth factors (eg, epidermal growth factor), adequate protein, balanced vitamins, and appropriate trace elements. Although parenteral (by injection through a route other than the alimentary canal) and enteral (by way of the small intestine) administration supply equivalent nutritional support, enterally fed patients have a lower incidence of infections and other complications.

Fluid management. Proper fluid management in critically ill patients has become more complex as understanding and use of systemic oxygen transport have increased. Several studies have reported survival advantages in surgical patients in whom DO₂ can be raised to supranormal values. Consequently, measurement of oxygen transport parameters has become almost routine in the ICU environment, even though it is unclear whether implications from available literature can be universally generalized. Recently, improved techniques (eg, gastric tonometry—measurement of tension or pressure) have been developed for assessing regional tissue hypoxemia. It has been reported that these techniques are more sensitive in identifying regional tissue hypoxia than other available clinical tools.

Cardiovascular support. Cardiogenic shock is caused by severe reduction in cardiac performance due to myocardial infarction, sepsis, myocarditis (inflammation of the heart muscle), cardiomyopathy (noninflammatory disease of the heart muscle), or valvular heart disease. In recent years, a number of mechanisms of transient myocardial dysfunction have been identified: stunned myocardium, hibernating myocardium, and sepsis-associated myocardial depression. These mechanisms are potentially reversible and, with proper management, patients may recover cardiac performance.

In cardiogenic shock induced by myocardial infarction, retrospective studies suggest that restoration of coronary blood flow using balloon angioplasty or coronary artery surgery (but not thrombolytic therapy) is associated with improved survival. In sepsis-associated myocardial dysfunction, retrospective trials suggest that pharmacological enhancement of cardiac performance with inotropic agents and vasopressors may improve survival.

Profound abnormalities of the peripheral vasculature occur in septic shock, respiratory failure, and a number of other critical illnesses. A decrease in systemic vascular resistance is accompanied by vasodilatation of some vascular beds, vasoconstriction of other vascular beds, leukocyte aggregation in the microvasculature, and widespread endothelial cell dysfunction. These abnormalities lead to maldistribution of peripheral vascular blood flow, which may contribute to organ dysfunction in critical illness. Because this peripheral vascular defect contributes to the hypotension occurring with sepsis and other critical illnesses, vasopressor agents are frequently used as treatment. A better understanding of the pathogenesis of peripheral vascular dysfunction and its relation to multiple organ dysfunction is needed.

Malignant ventricular and supraventricular arrhythmias frequently complicate management of critically ill patients. Serious arrhythmias can be monitored, diagnosed, and suppressed by use of electrical cardioversion, antiarrhythmic agents, or pacing technology. Warning arrhythmias, rhythms that frequently precede development of more serious heart rhythm abnormalities, also can be monitored. However, accurate diagnosis, prognostic implications, and management of these warning arrhythmias have not been determined.

Patient Monitoring

Monitoring devices are used to guide therapeutic decisions, identify early functional deterioration, and facilitate rapid intervention. Today, highly sophisticated monitoring technology is often considered necessary in the ICU.

Use of cardiac monitoring has improved our ability to recognize and subsequently treat serious arrhythmias. Similarly, it has been suggested that information derived from pulmonary artery catheterization (ie, estimation of intracardiac filling pressures, cardiac output, and systemic oxygen transport and consumption) is more accurate than routine clinical assessment. However, the patient groups that can benefit from this technique and the optimal use of hemodynamic monitoring have not been determined. Studies that examine the question of benefit have demonstrated lower, equal, and higher mortality rates in patients with pulmonary artery catheters; these reports also suffer from selection bias and are not randomized trials. A lower mortality has been reported when clinical decisions were based on measurements obtained with newer devices that detect regional tissue hypoxia more accurately (eg, gastric tonometry).

Respiratory monitoring devices provide guidance in assessing gas exchange, respiratory mechanics, and properties related to mechanical ventilation. Pulse oximetry (determination of arterial oxygen saturation) has become standard equipment in the ICU, and new catheters have been developed that continuously monitor intra-arterial blood gas measurements. Most mechanical ventilators allow simple determination of compliance of the respiratory system, end-expiratory alveolar pressure, mean airway pressure, minute ventilation, and indicators of patient-ventilator synchrony. Newer equipment also displays airway pressure and airflow. The measurements allow early detection of potentially deleterious consequences of mechanical ventilation and decrease risk of pulmonary and hemodynamic complications.

Current monitoring techniques for assessing neurological status of critically ill patients may be inadequate. Sophisticated monitoring initially developed for neurosurgery has been used with increasing frequency in the ICU environment. Machines that automatically process electroencephalography signals and generate “user-friendly” data have been developed and could be useful in assessing level of sedation, response to anticonvulsant therapy, and degree of sleep deprivation. For patients with acute hepatic failure, intracranial pressure monitors have been reported to be helpful in detecting acute changes in cerebral perfusion pressure. More recently, transcranial Doppler ultrasonography has been recommended as a noninvasive measurement of increased intracranial pressure by measuring changes in cerebral blood flow.

Definitions

Although several consensus conferences have developed uniform clinical, pathological, and physiological definitions of ALI, ARDS, and sepsis, these definitions have not been scientifically validated. Furthermore, a standard definition of multiple organ dysfunction syndrome should be formulated and subsequently validated. The task force also recommends clinical trials to compare the correlation of these new “standard” definitions with various outcome measures.

Mechanisms of Disease

The initial expression, magnitude of response, and duration of action of inflammatory mediators should be further investigated in critically ill patients and high-risk individuals. Studies are recommended to clarify the mechanisms by which factors (eg, alterations in systemic oxygen transport and consumption, immunomodulatory agents, physical stresses, and nutrients and nutritional supplementation) are beneficial or deleterious to critically ill patients with cardiopulmonary dysfunction. Multiple outcome measures, including markers of molecular function, physiological status, overall patient morbidity and mortality, resource utilization, and economic impact, will need to be collected.

Pharmacological Intervention

Clinical trials are needed to assess the utility of several preexisting therapeutic modalities in the ICU and to evaluate newly developed pharmacological interventions. Individual trials should examine agents that enhance the repair process after acute tissue injury, modulate altered systemic and pulmonary vascular dysfunction, enhance surfactant function, and improve management of severe airflow limitation in a critical care setting. In addition, clinical researchers need to evaluate the appropriate use of vasopressors, inotropic agents, fluids, and nutritional support in patients with cardiopulmonary dysfunction.

Mechanical Ventilation

Many standard modes of mechanical ventilation have not been critically evaluated. Clinical trials should address the impact of various ventilatory strategies on duration of ventilation, subsequent changes in ventilatory and gas exchange parameters, and mortality. The utility of muscle training, biofeedback, various modes of partial ventilatory support to optimize patient-ventilator interactions, and adjuvant modes of ventilatory support should also be examined.

Equally important is assessment of the efficacy and limitations of noninvasive ventilation strategies. Studies should probe the incidence, distribution, and physiological effects of dynamic hyperinflation and determine the precise factors that increase risk of barotrauma. Improved and more effective noninvasive techniques should be developed and assessed for monitoring patient-ventilator interaction, patient reserve, aerated lung volume, respiratory mechanics, and auto-PEEP during spontaneous breathing.

Patient Monitoring

Although an ICU environment includes highly technical monitoring devices, how to optimize their use still is not clear. The efficacy of pulmonary artery catheterization in managing patients with septic or cardiogenic shock and in preoperative therapy of high-risk surgical candidates should be investigated. The utility of systemic oxygen transport measurements and the efficacy of maximizing oxygen delivery also need to be elucidated. Noninvasive techniques should be developed to accurately assess the adequacy of systemic oxygen transport to vital organ systems and to facilitate early recognition of organ dysfunction. Studies should be performed in patients with associated acute cardiac dysfunction to determine the diagnostic accuracy and prognostic implications of multiple-lead ECG monitoring, echocardiography, and cardiac imaging techniques. The ability to monitor the neurological status of critically ill patients also needs to be refined. Finally, researchers need to determine the relative efficacies of various modalities for delivering medications and develop reliable methods for monitoring the pharmacokinetics, pharmacodynamics, and interactions of medications in critically ill patients.

Outcome Studies

The task force recommends that high priority be given to outcome studies for ICU patients, measuring quality of life, functional status, cost-effectiveness, survival, and other important parameters in an extended posthospital course. Outcome should be examined in relation to the roles of race, ethnicity, sex, age, socioeconomic status, other patient characteristics, comorbid conditions, admission diagnoses, and complications of ICU care. Such studies should be aimed at developing reliable demographic data on ICU patients and identifying potential inequalities in ICU use.

Risk Stratification Systems

Risk stratification systems are essential for determining response to therapy and short- and long-term morbidity and mortality among diverse patient cohorts. These systems should be based on demographic information, premorbid and comorbid conditions, and ICU course. The focus of these predictive systems should be to identify specific patient populations for which intensive care is most efficacious.

In Vitro Techniques and Animal Models

The current revolution in molecular and cellular biology has heightened understanding of the mechanisms of acute tissue injury and repair. Specific advances have been made in understanding cell-cell interaction, acute tissue injury, cellular response to inflammation, and cellular repair mechanisms. These discoveries are partly a result of improved in vitro experimental techniques that now more accurately identify and characterize individual cells and their molecular constituents. To achieve further advances in these areas, appropriate animal models relevant to human pathophysiology are needed, as well as improved in vitro techniques for studying endothelial and epithelial cells and cell-cell interactions and communications.

Mechanisms of Acute Tissue Injury

The task force recommends specific cellular and molecular studies to advance understanding of the endogenous activity and regulation of cytokines, adhesion molecules, oxygen metabolites, and inherent antioxidant defense mechanisms during acute inflammation. Continued investigation to elucidate the pathophysiology of repair mechanisms is essential. Studies that address fundamental mechanisms of endogenous protection; cell population size and position; and generation, modulation, and repair are also needed.

Relevant animal models should be used to investigate the mechanisms of various stimuli in provoking an inflammatory response in different organ systems. Elucidating the role of altered airway function and impaired immunoprotective functions in the pathogenesis of nosocomial complications is important. Studies to ascertain mechanisms of the microvascular response to alterations in concentration of oxygen, adenosine, endothelin, nitric oxide, and other molecules are also encouraged. Changes in cellular energy metabolism during hypoxia and sepsis need to be examined, and better understanding is needed of the different susceptibilities of various organ systems to injury.

A Network of Clinical Excellence

To achieve and sustain excellence in clinical research, the task force recommends development of a network of clinical centers to facilitate collaboration among established investigators, multicenter research projects on cardiopulmonary dysfunction in critical illness, and coordination of large-scale multicenter clinical trials investigating the efficacy of potential therapeutic modalities for critically ill patients.

National Core Animal Facility

Long-term animal models are needed to improve understanding of the pathophysiology of cardiopulmonary dysfunction in humans. Because of the expense of such studies, the task force recommends development of one or more national core facilities for coordinating studies involving appropriate animal models of critical illness. This environment would enable and encourage groups of scientists to collaborate and study, in a controlled setting, new concepts in acute tissue injury, repair mechanisms, and other responses to injury. Emphasis should be placed on developing integrative models that combine molecular, cellular, and organ system function for assessing the effectiveness of pharmacological and biotechnological interventions in acute injury. Establishment of this basic science facility and the network of clinical excellence is expected to expedite the flow of ideas from basic science laboratories into clinical trials.

Training

Support for research trainees has been declining steadily, particularly for individuals involved in clinical and epidemiological investigations. The decreasing number of qualified role models, teachers, and knowledgeable investigators is affecting many areas of biomedical research and is extremely low in clinical research. Enhanced training opportunities are needed to foster interest and expertise in behavioral science, bioengineering, biostatistics, clinical trial management, epidemiology, physiology, ethics, and pharmacology. These opportunities should be enhanced without compromising continued support for basic research training, which is especially important to advance understanding of cardiopulmonary dysfunction in critically ill patients.