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(Circulation. 1995;91:1-7.)
© 1995 American Heart Association, Inc.
Articles |
Task Force on Research in Cardiopulmonary Dysfunction in Critical Care Medicine
From the National Heart, Lung, and Blood Institute, Bethesda, Md.
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Introduction |
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 Top Introduction Report of the Task...Research Accomplishments and...Recommendations Summary |
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Critical care medicine is a multidisciplinary treatment approach that involves such specialties as anesthesiology, internal medicine, pediatrics, and surgery and is usually practiced in the hospital intensive care unit (ICU). The concept of delivering specialized, technologically sophisticated care within a dedicated setting originated with the postoperative recovery room of the post–World War II era and rapidly gained acceptance with the appearance of the first coronary care units in the early 1960s. Over the past several decades, ICUs have become standard features in hospitals across the United States.
The US House of Representatives Committee on Appropriations highlighted critical care medicine as a special area of interest and concern in its report on the fiscal year 1993 budget for the Department of Health and Human Services. Noting that critical care costs account for about 28% of total acute care hospital costs, the Committee encouraged the National Heart, Lung, and Blood Institute (NHLBI) ". . . to consider the potential benefits to society of enhanced research on effective practices and treatments in this technology-dependent field."
To identify new opportunities and chart a course for future research efforts, the NHLBI in 1993 convened a Task Force on Research in Cardiopulmonary Dysfunction in Critical Care Medicine. Composed of national experts in basic, clinical, and population-based research, the task force was charged to review the state of knowledge of cardiopulmonary dysfunction and care in critical care medicine over the past 5 years and develop a comprehensive plan, including scientific priorities, for NHLBI support of critical care research in cardiopulmonary dysfunction over the next several years.
During a series of four meetings held over the course of 13 months, the task force members worked to develop a detailed report of their findings and conclusions. The full report is available on the NHLBI Gopher (accessible through the Internet Gopher client–Server: gopher.nhlbi.nih.gov, Port: 70). A printed copy can be obtained from Charlene French, NHLBI, Bldg 31, Room 5A03, National Institutes of Health, 31 Center Dr, MSC 2482, Bethesda, MD 20892-2482.
The summary that follows was prepared by the task force to highlight its overall findings. It presents a broad view of the progress that has been made and the challenges and opportunities that remain.
The Institute is very pleased to have this report to guide its future activities with respect to cardiopulmonary dysfunction in critical care medicine. We are indebted to the task force chair, Dr Reuben M. Cherniack; the subgroup chairs, Drs Sharon Rounds, Gordon Bernard, John J. Marini, and Scott T. Weiss; and the members for their thoughtful and valuable contribution to this important endeavor.
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Report of the Task Force |
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TopIntroductionReport of the Task...Research Accomplishments and...Recommendations Summary |
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The past few decades have seen the development of ICUs in most hospitals in the United States. In these units, technologically sophisticated care is provided for critically ill patients. In 1983, a consensus conference of expert investigators, physicians, and other healthcare professionals held by the National Institutes of Health defined critical care medicine as "a multidisciplinary and multiprofessional medical-nursing field concerned with patients who have sustained or are at risk of sustaining acute life-threatening single or multiple organ system failure because of disease or injury."
Patients in the ICU constitute an extremely heterogeneous population with regard to admission diagnosis, comorbid conditions, age, race, sex, and socioeconomic status. Despite this extreme variability, a feature common to many if not most of these patients is cardiopulmonary dysfunction. Significant progress has been achieved in understanding cardiopulmonary dysfunction in critically ill patients over the past decade. Advances have occurred in all areas of scientific investigation, from gene translation to population-oriented studies. These developments provide an excellent and stable foundation for new research initiatives and continued growth of research projects already in progress.
ICUs are clearly beneficial in treating acute reversible disorders, and studies have demonstrated improved survival, especially in ICUs with highly integrated and coordinated care. However, because of innovative medical technology and patients who require minute-to-minute therapy and observation, the cost of intensive care is extremely high. While using approximately 7% of hospital beds in the United States, intensive care accounts for 20% to 30% of total hospital costs and represents 1% of the gross national product.
The Task Force on Research in Cardiopulmonary Dysfunction in Critical Care Medicine was asked to assess the current state of knowledge in cardiopulmonary dysfunction in adults in the critical care environment and recommend future research approaches that would lead to improved understanding of the pathophysiology of critical illness, better management of critically ill patients, and improved health care. Research accomplishments, opportunities, and recommendations for the future are summarized below.
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Research Accomplishments and Opportunities |
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TopIntroductionReport of the Task...Research Accomplishments and...Recommendations Summary |
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Many research accomplishments and opportunities exist in basic research, clinical research, and epidemiological research related to cardiopulmonary dysfunction in critical care medicine.
Basic Research
The past decade has seen the application of
exciting new
techniques that have improved understanding of the pathogenesis of
acute tissue injury and repair mechanisms, intrinsic tissue defense
mechanisms, determinants of tissue oxygenation, and organ-organ
interaction and multiple organ dysfunction during the acute
inflammatory process.
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.
Clinical Research
Over the past 5 years, several large
clinical trials have
made significant contributions to the practice of critical care
medicine. In addition, many important clinical studies have advanced
understanding of the mechanics and pathophysiology of cardiopulmonary
dysfunction and confirmed hypotheses generated from basic science
research. These advances are briefly described below in three areas:
definitions and diagnoses, mechanisms of disease and therapeutic
interventions, and patient monitoring.
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.
Epidemiological Research
Epidemiological research in critical
illness is directed at
investigation of the distribution and determinants of disease in
patients admitted to ICUs and the ensuing morbidity, mortality, and
costs. The outcome of each patient is determined by multiple
epidemiological factors, including premorbid conditions, severity of
illness on presentation, response to therapy, and incidence of
complications. Over the past 5 years, investigators have focused on
effects of various premorbid conditions and diseases on mortality and
development and examination of prognostic scoring models.
Age is one premorbid condition that affects ICU outcomes. Older patients (>75 years old) are more likely to require life-support measures but are significantly less likely to survive or regain their previous level of activity. Although not adequately examined in critically ill patients, effects of race, sex, and socioeconomic status have been shown to alter outcome measures in other disease states (eg, asthma and cardiac disease). Extrapolating from these results, it is possible that similar variables also affect the outcome of critically ill patients.
Comorbid diseases (eg, chronic obstructive pulmonary disease, cancer, AIDS, transplantation, and neurological diseases) also influence outcome. Specific acute events, including ARDS, sepsis, multiple organ dysfunction syndrome, trauma, burns, and asthma, precipitate most admissions to the ICU. Each event, independent of the individual premorbid condition, influences patient outcome. Combination of a specific condition with an individual premorbid state may increase mortality. For example, ARDS mortality increases substantially in ARDS patients >70 years old.
To aid in risk stratification, several prognostic scoring systems have been developed and are being used increasingly. Their goal is to predict various outcomes to facilitate future studies and assist in evaluation of quality assurance, therapeutic trials, and resource allocation. Unfortunately, an ideal system does not presently exist.
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Recommendations |
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TopIntroductionReport of the Task...Research Accomplishments and...Recommendations Summary |
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The task force identified 12 important research areas for the future, which are, in order of priority, (1) clinical research: definitions, mechanisms of disease, pharmacological intervention, mechanical ventilation, and patient monitoring; (2) epidemiological research: outcome studies and risk stratification systems; (3) basic research: in vitro techniques and animal models, and mechanisms of acute tissue injury; and (4) research environment and training: a network of clinical excellence, a national core animal facility, and training.
Over the past decade, progress in basic science has far surpassed clinical application of the advances made. Therefore, the task force believes that higher priority should be assigned to advancement of clinical research and epidemiological studies without, however, compromising basic research support for studies of the mechanisms of injury and repair and maintenance of homeostasis.
Clinical Research
The task force recommends that highest
priority be given to
initiating clinical studies to examine the validity of definitions used
in critical care medicine, including mechanisms of acute disease
processes, pharmacological modalities, mechanical ventilation, and
patient monitoring devices. In addition, emphasis should be placed on
establishing the proper infrastructure to perform these studies.
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.
Epidemiological Research
The primary goals of future
epidemiological studies of
cardiopulmonary dysfunction in critical care medicine are to improve
understanding of the demographics of ICU patients with cardiopulmonary
dysfunction and to optimize use of intensive care therapy.
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.
Basic Research
The task force recommends two high-priority
areas for future basic
research: (1) development of improved in vitro techniques and animal
models and (2) investigation of molecular and cellular mechanisms of
acute tissue injury.
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.
Research Environment and Training
The task force recommends
development of a network of clinical
excellence, a national core animal facility, and enhanced training
opportunities.
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.
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Summary |
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TopIntroductionReport of the Task...Research Accomplishments and...Recommendations Summary |
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Research accomplishments during the past decade have led to a much greater understanding of molecular, cellular, and pathophysiological derangements occurring in the lung and other organ systems during critical illness. Despite this progress, care of critically ill patients with cardiopulmonary dysfunction remains a major health challenge. Expansion of research efforts is imperative and particularly opportune at this time because of exciting developments in understanding various mediators involved in inflammation and repair. Future advances in treating critical illness depend on basic understanding of the pathogenesis and pathophysiology of acute injury and repair. Key observations gained through clinical and epidemiological studies must be tested in the basic science laboratory. Increased and coordinated efforts in epidemiological, clinical, and basic research are essential for future progress.
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