Variables Affecting Outcome in Critically Ill Patients*
Bart Chernow, MD, FCCP
* From the Johns Hopkins University School of Medicine, Baltimore, MD.
Correspondence to: Bart Chernow, MD, FCCP, Johns Hopkins University School of Medicine, 720 Rutland Ave, Suite 124, Baltimore, MD 21205-2196; e-mail: bchernow{at}jhmi.edu
 |
Abstract
|
|---|
Critical care medicine has evolved as a field of science and
clinical care. Despite important contributions to our understanding of
the molecular basis of critical illness, we still remain troubled by
our lack of insight into why some patients have favorable outcomes from
critical illness and others do not. This article explores the
hypothesis that at least five important variables may alter the outcome
of patients suffering from a variety of critical illnesses. These
variables include the premorbid immune or genetic status of the
patient, the patient’s gender, the circulating cholesterol
concentration, the patient’s age, and various iatrogenic and
nosocomial events. Insights into the importance of these five variables
may provide opportunities for physicians and scientists to improve
outcome in patients suffering from critical illness. Clearly, altering
iatrogenic and nosocomial events is already within the realm of
opportunity.
|
Introduction
|
|---|
Recently,
the Editor-in-Chief of CHEST created a new category for
articles published in this journal.1 That category
includes articles describing opinions and hypotheses. The present
article represents opinions and hypotheses that I have generated as a
physician-scientist in the area of critical care medicine. Many
critical care practitioners face the issue of trying to understand why
some patients die with a given condition, while other patients with the
same condition and equal severity of illness survive. The purpose of
this article is to describe five major categories that I believe may
help explain the still baffling circumstance of why certain patients
survive a critical medical insult, while others do not.
|
Background/History
|
|---|
Modern critical care may date its origins to the landmark article
published by Drinker and McKhann,2 describing the iron
lung for the treatment of the neuromuscular weakness-induced
respiratory failure of poliomyelitis. Others might date the modern era
of critical care to the early 1960s, with the description of
closed-chest cardiac massage3 and the use of a
synchronized capacitor discharge for defibrillation in the treatment of
cardiac arrhythmias.4 Regardless of when the modern advent
of critical care began, it has been quite clear that the scientific
database of this new discipline has increased exponentially over the
last 2 decades. Perhaps the scientific underpinnings of our specialty
have been most notable in the basic science and clinical research
contributions regarding sepsis and septic shock. Despite several
generations of new antimicrobial agents, the mortality rate of this
syndrome due to infectious diseases remains unacceptably high. The
mechanisms for the physiologic, pathologic, and characteristic
hemodynamic changes continue to be elucidated. In the late 1980s, we
learned that cytokines such as tumor necrosis factor (TNF) are released
in response to endotoxin, and the hemodynamic responses to endotoxin
were clearly delineated.56 It became
evident7 that the circulating TNF concentration in
patients could correlate with the level of infection and even the
mortality rate. As a consequence of recognizing the central role of
cytokines, a series of large studies were performed but were
unsuccessful in their attempt to demonstrate the efficacy of
anticytokine therapy in the treatment of septic
shock.891011 These failed therapies and other similarly
unsuccessful therapies have left the clinical community frustrated with
an apparent disconnection between what is found at the research bench
and what seems to work in humans with serious infection. To add further
concern to this issue, it has become clear that sepsis provides
patients with a marked disadvantage in terms of long-term
survival,12 even if the patient survives an acute episode.
Quartin et al12 studied a large population of patients
with sepsis. They followed the survivors of sepsis for 5 years and
compared their outcomes with a control group of similarly ill,
nonseptic subjects. They found that sepsis increases the risk of death
for up to 5 years after the initial septic event.
Clearly, the approach to dealing with this major clinical problem needs
to be modulated. Researchers from the American College of Chest
Physicians, in collaboration with the National Institutes of Health,
have helped to define a strategy for bridging the gap between the
research bench and the bedside.13 Anticytokine therapy has
worked in at least two other conditions,1415 and thus,
there is something unique about the septic episode that may preclude
the traditional anticytokine approach to therapy. In the meantime, new
experimental therapies continue to be described.1617 The
pivotal roles of nuclear factor kappa B181920 and the
various families of chemokines2122 have been discovered.
Perhaps modulating these variables may be helpful. With this
background, let me now turn to what I consider the five major variables
that may create discrepancies in predicted outcome in critically ill
patients by either clinical assessment or scoring systems: (1)
preinfectious or preoperative immune or genetic status; (2) gender; (3)
circulating cholesterol concentration; (4) age; and (5)
iatrogenic/nosocomial events.
|
Preinfectious/Preoperative Immune or Genetic Status
|
|---|
It is impossible in this short essay to define the enormous
variability that clearly exists within the genetic and immune makeup of
people. Several recent discoveries underscore the importance of these
genetic and immune differences between human beings. An example of the
genetic basis for a particular disease ailment is seen in a recent
article by Chen et al23 These investigators recently
discovered the genetic basis and molecular mechanism for what is known
as idiopathic ventricular fibrillation. Between 5% and 10% of
patients who suffer a cardiac arrest due to ventricular fibrillation
have no definable cardiac cause for the ventricular fibrillation event.
Therefore, this entity is known as idiopathic ventricular fibrillation.
Since there are > 300,000 sudden deaths due to ventricular
fibrillation in the United States each year, this genetically based
entity is not trivial, but may clearly explain why some patients have
an unexpected cardiac arrest due to ventricular fibrillation.
There is a strong genetic influence on how patients will respond to
critical illness or injury. As an example, in patients who suffer a
fatal meningococcal infection, the genetic influence on cytokine
production may be extremely important.24 If TNF production
(an example of proinflammatory cytokine release) is low, and
interleukin-10 production (anti-inflammatory cytokine release) is high,
the risk for death is markedly increased. Van Dissel et
al25 recently confirmed this work in febrile patients and
demonstrated that if patients have an increased ratio of interleukin-10
to TNF-
concentrations, a fatal outcome is more likely. Stüber
et al26 demonstrated that there is a genomic polymorphism
within the TNF locus that influences the amount of TNF released into
the circulation. Patients with an exaggerated TNF response were found
to have a higher mortality rate due to this polymorphism. Similarly,
there is a polymorphism at the β2-adrenergic receptor
that may make some patients more prone to desensitization to
bronchodilators.27 Another example of the genetic basis
for disease is the finding that plasma homocysteine levels may be
important predictors of mortality in patients with coronary artery
disease.28
Preoperative antiendotoxin antibody concentrations are inversely
related to outcome following open heart surgery. If the preoperative
antiendotoxin antibody concentrations are increased, the postoperative
complication rate is decreased. Low levels are associated with a high
morbidity rate.29 The finding that some patients have high
endotoxin core antibody concentrations and also circulating levels of
cytokine antagonists may explain why some of the anticytokine and
antiendotoxin therapies have failed.30 A growing body of
evidence regarding what Dr. Roger Bone31 called
"immunologic dissonance" supports the concept of an association
between ratios of inflammatory and anti-inflammatory cytokine
concentrations and outcome.3233
|
Gender
|
|---|
Women seem to do better than men in terms of outcome from serious
infections. Immune function is clearly augmented in female subjects due
to increased circulating concentrations of immunoglobulins and higher
plasma concentrations of prolactin.34 Prolactin has
important effects on the immune system,35 and in fact, it
is my bias that the increased plasma concentrations of prolactin in
women may be particularly important in the survival advantage that they
exhibit with serious infection. Women respond to injury and trauma with
increased serum insulin-like growth factor-1 concentrations in
comparison to men, in whom insulin-like growth factor-1 concentrations
decrease.36 Men seem to demonstrate immunosuppression
perhaps as a consequence of higher testosterone
concentrations.37 Testosterone blocking agents or
estradiol administration may be useful in augmenting immune status in
male trauma patients.37 Women may have different stress
hormone responses than men.38 The survival advantage in
sepsis that women have over men is not seen in other conditions. For
example, coronary artery disease and its consequences affect women with
equal severity to men, and in some cases, women have worse
outcomes.3940
|
Cholesterol Concentrations
|
|---|
We have been trained to think of hypercholesterolemia as being
bad, and hypocholesterolemia as being good. However, a growing body of
evidence supports the concept that marked hypocholesterolemia may
actually increase the risk of death in critically ill patients. Indeed,
it has been demonstrated that circulating cholesterol concentrations
< 120 mg/dL are associated with an increased risk of death in
critically ill patients.41 Furthermore, it has been shown
that in the extreme elderly (> 85 years of age), increased
circulating cholesterol concentrations are associated with long life
due to diminished death rates from serious infection and
cancer.42 Some of the reasons for this discrepancy between
traditional teaching and observations that we have made at the clinical
bedside have now been made clear. We now understand that lipoproteins
(high-density lipoprotein, [HDL], low-density lipoprotein [LDL],
etc) may serve as "mops" within the circulation to sop up endotoxin
and other foreign substances. In fact, a series of experiments
demonstrated that low lipid concentrations exist in various forms of
critical illness,43 and administration of high-density
lipoprotein may offer a protective effect for the prevention and
treatment of endotoxemia.4344 High circulating LDL
concentrations due to LDL receptor deficiency protect subjects against
lethal doses of endotoxin and Gram-negative bacteria.45
Clinicians should always consider that a patient who has a total
cholesterol concentration < 120 mg/dL in the ICU may have a serious
microbial infection. In addition, it does not appear that lowering a
patient’s cholesterol concentration from high levels into the normal
range adversely affects immune function. This latter theory has been
tested and found to be correct.46
|
Age
|
|---|
Age is clearly a relevant factor in outcome from serious illness.
Older men and women have an augmented inflammatory response. A
manifestation of this response is evidenced in age-related increases in
circulating adhesion molecule concentrations. We know that
concentrations of these adhesion molecules are increased in septic
shock, and the higher the concentration, the more likely it is that the
patient may die.47 Older men and women have higher
concentrations than similarly ill younger men and women,48
and as an example, older people have a higher probability of death from
severe burn injury than younger people.49 The effect of
age on survival from specific cardiac events has been reviewed
extensively in several recent articles.505152
|
Iatrogenic/Nosocomial Events
|
|---|
Adverse drug reactions in hospitalized patients account not only
for a great deal of morbidity, but also for a large number of
deaths.535455 Infection acquired in the ICU is common, and
time in the unit, especially with indwelling catheters, may contribute
to the frequency with which nosocomial infection occurs.56
Bloodstream infections due to central venous catheters are important. A
number of strategies have been developed to try to limit such
infections. Clinicians must be vigilant regarding this all-too-frequent
problem.575859
In addition to adverse drug reactions as a cause of adverse outcome,
the underuse of drugs may also alter outcome. Let us focus on
adrenergic receptor blockers as an example. A review on adrenergic
receptors has been written by Insel,60 and it is clear
that there is a specific adrenergic nervous system within the human
heart.61 One of the most important articles in recent
years, in my opinion, has been the work of Gauthier et
al.62 These investigators identified
β3-adrenergic receptors within the human heart. These
receptors mediate negative inotropic effects and may contribute to a
worsening of heart failure. The important observation herein leads to
an explanation for why β-adrenergic receptor blockade may be helpful
in patients with congestive heart failure. Our intuition as clinicians
should be to give β-adrenergic receptor agonists for hearts that
are not pumping effectively; however, β-blockers clearly improve
outcome, and β-agonists may worsen outcome!63
Prophylactic atenolol has been demonstrated to reduce myocardial
ischemia following surgery,64 and several other recent
publications support β-blocker-induced reduction of death as a
consequence of cardiac and noncardiac causes.6566
Underuse of β-adrenergic receptor antagonists in elderly patients who
survive acute myocardial infarction leads to worse
outcome.67 Recent articles continue to emphasize the
importance of β-blockade following myocardial
infarction68 and in congestive heart
failure.69
It is my opinion that we can work hard to prevent adverse drug effects
in our ICU patients, supporting the work of Cullen et
al,70 and that drug classes such as β-blockers are
important to use when indicated to try to limit worse outcome in
certain groups of patients, especially those patients with heart
failure.
|
Conclusions
|
|---|
Writing an article about variables that might contribute to
alterations in outcome in critically ill patients is difficult, and I
admit to the limitations inherent in such an essay. It is clear that
many other important variables may alter outcome, such as whether a
patient has used alcohol, is a cigarette smoker, has certain
comorbidities, and the state of the patient’s preexisting health prior
to a septic episode or other critical event. The aggressiveness with
which therapy is instituted and the length of time that the patient has
suffered critical illness may affect outcome. I do not wish to suggest
that the five groupings of variables I discussed should replace
severity of illness scoring systems or even have the same level of
importance. Rather, the purpose of this essay is to share information
stemming from my close following of the critical care literature, and
to perhaps provide insights to clinicians that may be helpful in
explaining to patients and their families why some patients do well and
others do not.
1. It is clear that there is interpatient variability based on genetic
makeup and premorbid immune status. As the human genomic project
advances, it is increasingly clear that single nucleotide polymorphisms
and other genetic differences help to define why we as individuals
respond differently to different types of critical events. We should
use this growing body of knowledge to explain to patients and their
families why we cannot account for a particular outcome by our other
methods of prediction.
2. Women seem to do better than men, and girls do better than boys
with infection. However, other forms of critical illness such as
cardiac injury do not provide the same level of survival advantage to
female subjects.
3. Lipoproteins may be important "mops" within the circulation for
dealing with endotoxemia. Clinicians should be aware that when severe
hypocholesterolemia is evident on the hospital admission
biochemical profile, serious microbial infection should be suspected.
4. Elderly men and women (> 75 years of age) may have an augmented
anti-inflammatory response that may lead to a higher mortality rate. As
we design cytokine-modulating therapies, age should be a consideration.
5. All of us should try to limit iatrogenic sources of infection, and
in particular, it is my opinion that an increased emphasis on reducing
adverse drug reactions and catheter-related infections is requisite.
Critical care medicine has come a long way in the last 20 years. I
believe that the quality of care provided in ICUs worldwide has
improved, and we are providing compassionate care with augmented
monitoring capabilities. However, we still have a "ways to go"
regarding the prevention and treatment of serious infections that lead
to sepsis and septic shock.
|
References
|
|---|
- Block, AJ (1998) Opinions/hypotheses: a new department in CHEST. Chest 113,855[Free Full Text]
- Drinker, P, McKhann, CF The use of a new apparatus for the prolonged administration of artificial respiration. JAMA 1929;92,1658-1660
- Kouwenhoven, WB, Jude, JR Closed-chest cardiac massage. JAMA 1960;173,1064-1067[ISI][Medline]
- Lown, B, Amarasingham, R, Neuman, J New method for terminating cardiac arrhythmias: use of synchronized capacitor discharge. JAMA 1962;182,548-555[ISI][Medline]
- Michie, HR, Manogue, KR, Spriggs, DR, et al Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988;318,1481-1486[Abstract]
- Suffredini, AF, Fromm, RW, Parker, MM, et al The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989;321,280-287[Abstract]
- Marano, MA, Fong, Y, Moldawer, LL, et al Serum cachectin/tumor necrosis factor in critically ill patients with burns correlates with infection and mortality. Surg Gynecol Obstet 1990;170,32-38[ISI][Medline]
- Fisher, CJ, Jr, Agosti, JM, Opal, SM, et al Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. N Engl J Med 1996;334,1697-1702[Abstract/Free Full Text]
- Bernard, GR, Wheeler, AP, Russell, JA, et al The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med 1997;336,912-918[Abstract/Free Full Text]
- Abraham, E, Glauser, MP, Butler, T, et al p55 tumor necrosis factor receptor fusion protein in the treatment of severe sepsis and septic shock. JAMA 1997;277,1531-1538[Abstract]
- Opal, SM, Fisher, CJ, Jr, Dhainaut, J-FA, et al Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med 1997;25,1115-1124[CrossRef][ISI][Medline]
- Quartin, AA, Schein, RMH, Kett, DH, et al Magnitude and duration of the effect of sepsis on survival. JAMA 1997;277,1058-1063[Abstract]
- Executive Summary of an American College of Chest Physicians, National Institute of Allergy and Infectious Disease, and National Heart, Lung, and Blood Institute Workshop. From bench to bedside: the future of sepsis research. Chest 1997; 111:744–753
- Fekade, D, Knox, K, Husssein, K, et al Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor N Engl J Med 1996;335,311-315[Abstract/Free Full Text]
- Moreland, LW, Baumgartner, SW, Schiff, MH, et al Treatment of rheumatoid arthritis with a recombinant tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997;337,141-147[Abstract/Free Full Text]
- Zisman, DA, Kunkel, SL, Strieter, RM, et al MCP-1 protects mice in lethal endotoxemia. J Clin Invest 1997;99,2832-2836[ISI][Medline]
- Sevransky, JE, Shaked, G, Novgrodsky, A, et al Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis. J Clin Invest 1997;99,1966-1973[ISI][Medline]
- Böhrer, H, Qiu, F, Zimmermann, T, et al Role of NF
B in the mortality of sepsis. J Clin Invest 1997;100,972-985[ISI][Medline] - Beg, AA, Baltimore, D An essential role for NF-B in preventing TNF--induced cell death. Science 1996;274,782-784[Abstract/Free Full Text]
- Barnes, PJ, Karin, M Nuclear factor-B—a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997;336,1066-1071[Free Full Text]
- Adams, DH, Lloyd, AR Chemokines: leucocyte recruitment and activation cytokines. Lancet 1997;349,490-495[CrossRef][ISI][Medline]
- Luster, AD Chemokines—chemotactic cytokines that mediate inflammation. N Engl J Med 1998;338,436-445[Free Full Text]
- Chen, Q, Kirsch, GE, Zhang, D, et al Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392,293-296[CrossRef][Medline]
- Westendorp, RGJ, Langermans, JAM, Huizinga, TWJ, et al Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997;349,170-173[CrossRef][ISI][Medline]
- van Dissel, JT, van Langevelde, P, Westendorp, RGJ, et al Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998;351,950-953[ISI][Medline]
- Stüber, F, Petersen, M, Bokelmann, F, et al A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor- concentrations and outcome of patients with severe sepsis. Crit Care Med 1996;24,381-384[CrossRef][ISI][Medline]
- Tan, S, Hall, IP, Dewar, J, et al Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 1997;350,995-999[CrossRef][ISI][Medline]
- Nygård, O, Nordrehaug, JE, Refsum, H, et al Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337,230-236[Abstract/Free Full Text]
- Bennett-Guerrero, E, Ayuso, L, Hamilton-Davies, C, et al Relationship of preoperative antiendotoxin core antibodies and adverse outcomes following cardiac surgery. JAMA 1997;277,646-650[Abstract]
- Goldie, AS, Fearon, KCH, Ross, JA, et al Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome. JAMA 1995;274,172-177[Abstract]
- Bone, RC Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIDS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 1996;125,680-687[Abstract/Free Full Text]
- Pellegrini, JD, Puyana, JC, Lapchak, PH, et al A membrane TNF-/TNFR ratio correlates to MODS score and mortality. Shock 1996;6,389-396[ISI][Medline]
- Donnelly, SC, Strieter, RM, Reid, PT, et al The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome. Ann Intern Med 1996;125,191-196[Abstract/Free Full Text]
- Zelllweger, R, Wichmann, MW, Ayala, A, et al Females in proestrus state maintain splenic immune functions and tolerate sepsis better than males. Crit Care Med 1997;25,106-110[CrossRef][ISI][Medline]
- Ben-Jonathan, N, Mershon, JL, Allen, DL, et al Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocr Rev 1997;17,639-669[CrossRef][ISI][Medline]
- Houston-Bolze, MS, Downing, MT, Sayed, AM, et al Gender differences in the responses of serum insulin-like growth factor-1 and transthyretin (prealbumin) to trauma. Crit Care Med 1996;24,1982-1987[CrossRef][ISI][Medline]
- Angele, MK, Ayala, A, Monflils, BA, et al Testosterone and/or low estradiol: normally required but harmful immunologically for males after trauma-hemorrhage. J Trauma 1998;44,78-84[ISI][Medline]
- Van Cauter, E, Leproult, R, Kupfer, DJ Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 1996;81,2468-2473[Abstract]
- Malacrida, R, Genoni, M, Maggioni, AP, et al A comparison of the early outcome of acute myocardial infarction in women and men. N Engl J Med 1998;338,8-14[Abstract/Free Full Text]
- Fitzpatrick, LA Coronary artery disease in women—an equal opportunity killer [editorial]. J Clin Endocrinol Metab 1998;83,719-720[Free Full Text]
- Gui, D, Spada, PL, De Gaetano, A, et al Hypocholesterolemia and risk of death in the critically ill surgical patient. Intensive Care Med 1996;22,790-794[ISI][Medline]
- Weverling-Rijnsburger, AWE, Blauw, GJ, Lagaay, AM, et al Total cholesterol and risk of mortality in the oldest old. Lancet 1997;350,1119-1123[CrossRef][ISI][Medline]
- Gordon, BR, Parker, TS, Levine, DM, et al Low lipid concentrations in critical illness: implications for preventing and treating endotoxemia. Crit Care Med 1996;24,584-589[CrossRef][ISI][Medline]
- DiPiro, JT, Cue, JI, Richards, CS, et al Pharmacokinetics of reconstituted human high-density lipoprotein in pigs after hemorrhagic shock with resuscitation. Crit Care Med 1996;24,440-444[CrossRef][ISI][Medline]
- Netea, MG, Demacker, PNM, Kullberg, BJ, et al Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe Gram-negative infections. J Clin Invest 1996;97,1366-1372[ISI][Medline]
- Muldoon, MF, Flory, JD, Marsland, A, et al Effects of lovastatin on the immune system. Am J Cardiol 1997;80,1391-1394[CrossRef][ISI][Medline]
- Sessler, CN, Windsor, AC, Schwartz, M, et al Circulating ICAM-1 is increased in septic shock. Am J Respir Crit Care Med 1995;151,1420-1427[Abstract]
- Boldt, J, Muller, M, Heesen, M, et al Does age influence circulating adhesion molecules in the critically ill? Crit Care Med 1997;25,95-100[CrossRef][ISI][Medline]
- Ryan, CM, Schoenfeld, DA, Thorpe, WP, et al Objective estimates of the probability of death from burn injuries. N Engl J Med 1998;338,363-366
- Kober, L, Torp-Pedersen, C, Ottesen, M, et al Influence of age on the prognostic importance of left ventricular dysfunction and congestive heart failure on long-term survival after acute myocardial infarction. Am J Cardiol 1996;78,156-162
- Shapira, OM, Kelleher, RM, Zelingher, J, et al Prognosis and quality of life after valve surgery in patients older than 75 years. Chest 1997;112,885-894[Abstract/Free Full Text]
- Battistella, FD, Din, AM, Perez, L Trauma patients 75 years and older: long-term follow-up results justify aggressive management. J Trauma 1998;44,618-624[ISI][Medline]
- Lazarou, J, Pomeranz, BH, Corey, PN Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279,1200-1205[Abstract/Free Full Text]
- Bates, DW, Spell, N, Cullen, DJ, et al The costs of adverse drug events in hospitalized patients. JAMA 1997;277,307-311[Abstract]
- Classen, DC, Pestotnik, SL, Evans, RS, et al Adverse drug events in hospitalized patients: excess length of stay, extra costs, and attributable mortality. JAMA 1997;277,301-306[Abstract]
- Vincent, J-L, Bihari, DJ, Suter, PM, et al The prevalence of nosocomial infection in intensive care units in Europe: results of the European Prevalence of Infection in Intensive Care (EPIC) Study. JAMA 1995;274,639-644[Abstract]
- Maki, DG, Stolz, SM, Wheeler, S, et al Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnated catheter: a randomized, controlled trial. Ann Intern Med 1997;127,257-266[Abstract/Free Full Text]
- Mimoz, O, Pieroni, L, Lawrence, C, et al Prospective, randomized trial of two antiseptic solutions for prevention of central venous or arterial catheter colonization and infection in intensive care unit patients. Crit Care Med 1996;24,1818-1823[CrossRef][ISI][Medline]
- Cook, D, Randolph, A, Kernerman, P, et al Central venous catheter replacement strategies: a systematic review of the literature. Crit Care Med 1997;25,1417-1424[CrossRef][ISI][Medline]
- Insel, PA Adrenergic receptors—evolving concepts and clinical implications. N Engl J Med 1996;334,580-585[Free Full Text]
- Huang, M-H, Griend, DS, Sunday, ME, et al An intrinsic adrenergic system in mammalian heart. J Clin Invest 1996;98,1298-1303[ISI][Medline]
- Gauthier, C, Tavernier, G, Charpentier, F, et al Functional β3-adrenoceptor in the human heart. J Clin Invest 1996;98,556-562[ISI][Medline]
- Niebauer, J, Coats, AJS Treating chronic heart failure: time to take stock. Lancet 1997;349,966-967[CrossRef][ISI][Medline]
- Wallace, A, Layug, B, Tateo, I, et al Prophylactic atenolol reduces postoperative myocardial ischemia. Anesthesiology 1998;88,7-17[CrossRef][ISI][Medline]
- Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease Lancet 1997;349,375-380[CrossRef][ISI][Medline]
- Mangano, DT, Layug, EL, et al Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med 1996;335,1713-1720[Abstract/Free Full Text]
- Soumerai, SB, McLaughlin, TJ, Spiegelman, D, et al Adverse outcomes of underuse of β-blockers in elderly survivors of acute myocardial infarction. JAMA 1997;277,115-121[Abstract]
- Barron, HV, Viskin, S, Lundstrom, RJ, et al of β-Blocker dosages and mortality after myocardial infarction. Arch Intern Med 1998;158,449-453[Abstract/Free Full Text]
- Constant, J A review of why and how we may use β-blockers in congestive heart failure. Chest 1998;113,800-808[Abstract/Free Full Text]
- Cullen, DJ, Sweitzer, BJ, Bates, DW, et al Preventable adverse drug events in hospitalized patients: a comparative study of intensive care and general care units. Crit Care Med 1997;25,1289-1297[CrossRef][ISI][Medline]
This article has been cited by other articles:
|
|
|
|
 
M. A. M. Rogers, K. M. Langa, C. Kim, B. K. Nallamothu, L. F. McMahon Jr, P. N. Malani, B. E. Fries, S. R. Kaufman, and S. Saint
Contribution of infection to increased mortality in women after cardiac surgery.
Arch Intern Med,
February 27, 2006;
166(4):
437 - 443.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. B. Fessler, P. G. Arndt, S. C. Frasch, J. G. Lieber, C. A. Johnson, R. C. Murphy, J. A. Nick, D. L. Bratton, K. C. Malcolm, and G. S. Worthen
Lipid Rafts Regulate Lipopolysaccharide-induced Activation of Cdc42 and Inflammatory Functions of the Human Neutrophil
J. Biol. Chem.,
September 17, 2004;
279(38):
39989 - 39998.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
Abstract
Introduction
