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Ronald V. Maier, M.D.

harborview injury prevention and research center

clinical trials in the surgical intensive care unit at harborview
medical center
modulation of the excessive inflammatory response to biomaterials
modulation of the trauma-related macrophage inflammatory response
to prevent ards, mofs, and death
awards: funding:
National Institutes of Health Centers for Disease Control
NIGMS Institutional NRSA National Center for Injury Prevention and Control
Shock Society National Institutes of Health
Young Investigator of the Year National Heart, Lung, and Blood Institute
American Trauma Society National Institute of General Medical Sciences
William S. Stone Award Institutional National Research Service Award
National Science Foundation

T rauma remains a major cause of death and

morbidity in America. It is the number one
cause of mortality among 1-45 year olds, and is
the overall number one contributor to loss of productive
years of life in America. Death due to injury occurs in
Current projects include identifying the risk
factors for injury while developing new techniques for
the application of epidemiology in the field of trauma
research. Further goals are to develop and utilize
systematic, high-quality data systems to document the
three peaks: 1) at the scene; 2) during the acute resusci- types, causes, treatment and consequences of injuries in
tation phase, and 3) late, after one to two weeks of ICU a wide variety of settings. A particular focus is on
support, secondary to multiple organ failure and sepsis. assessment of outcomes and the impact of trauma system
My research focuses on each of these phases. Prevention development. In addition, development and assessment
provides the best means to minimize deaths at the scene. of new, more effective means to resuscitate and treat
Trauma system development and improvements in acute injured patients along the entire spectrum of care from
care including resuscitation will reduce early deaths and pre-hospital to rehabilitation is ongoing. Following are
minimize subsequent morbidity. Finally, elucidation of examples of current investigations:
the basic pathophysiology of severe injury will identify 1. Evaluation of the Washington Pre-hospital Trauma Triage
treatment modalities to prevent the autodestructive Instrument in a Population-Based Study: Triage decisions are
inflammatory response causing organ dysfunction and made by emergency medical care providers to distin-
death following trauma. guish patients who require care at a fully equipped
trauma center from those whose injuries are less exten-
Harborview Injury Prevention and Research Center sive. Excessive triage assignment to a major trauma
Dr. Maier is Associate Director of the Harborview center overburdens such centers with victims who could
Injury Prevention and Research Center (HIPRC). be effectively treated at a facility closer to their home.
HIPRC is linked closely with the Northwest Regional On the other hand, triage which underutilizes the major
Trauma Center at Harborview Medical Center. The trauma centers in favor of local hospitals may place
goal of HIPRC is to diminish the impact of trauma on patients in facilities with inadequate resources and
peoples lives and to draw on the effectiveness of the increased risk of poorer outcomes. Using selected
Northwest Regional Trauma Centers injury prevention population-based trauma registry data consisting of pre-
and trauma treatment programs. Established at HMC hospital and hospital records, we will determine the
in 1985, HIPRC is a component of the University of accuracy of the state trauma triage instrument for distin-
Washington and the Schools of Medicine and Public guishing major trauma patients for care in major trauma
Health. centers, and modify patient distribution as appropriate.

hmc/trauma surgery

2. Relationship Between Trauma Center Volume and tion use tidal volumes of 10-15 ml/kg of body weight.
Outcome: The premise underlying regionalization of These volumes are much larger than those in normal
trauma care is that optimal outcomes can be achieved at subjects at rest, but are frequently necessary to achieve
greatest efficiency if care is restricted to relatively few normal values for partial pressure of arterial carbon
dedicated trauma centers. Implicit in this premise is dioxide and pH. Since atelectasis and edema reduce
that higher patient volumes will lead to greater experi- aerated lung volumes, inspiratory airway pressures are
ence, and this experience translates into better out- often excessively high to achieve these parameters,
comes. This relationship appears to hold for other areas suggesting the presence of excessive distension or
of surgical care involving complex procedures, but in stretch of the remaining aerated lung.
contrast, there is no such relationship when less Thus, this traditional approach to mechanical
complex procedures are evaluated. Previous studies ventilation may exacerbate or perpetuate lung injury,
evaluating the relationship between institutional volume and in contrast, the use of lower tidal volumes during
and outcomes in trauma patients are difficult to ventilation may reduce or prevent this deleterious
interpret because of multiple logistic issues. We are process. Previous uncontrolled studies suggest that

Until now, therapeutic approaches have focused on control or inhibition of single components
of the overall inflammatory response.

currently investigating two distinct cohorts of trauma lower tidal volumes may improve survival. However, this
patients to evaluate whether there is an institutional approach may necessitate acceptance of significant
volume threshold at which optimal outcomes can be acidosis and decreased arterial oxygenation or increased
achieved for critically injured patients. levels of PEEP. Currently, our clinical trial in conjunc-
tion with the ARDS Network is testing whether lower
Clinical Trials in the Surgical Intensive Care Unit at tidal volumes during mechanical ventilation in patients
Harborview Medical Center with acute lung injury will improve ARDS severity and/
We are performing multiple ongoing trials based or survival.
on the pathophysiologic response of the severely injured 2. Modulation of the Inflammatory Response: The
patient, many in conjunction with the Division of potentially auto-destructive excessive immunoinflam-
Pulmonary and Critical Care in the Department of matory response is thought to contribute to the initia-
Medicine. In particular, clinical studies and associated tion and progression of ARDS and to ultimately affect
basic investigations are focused on the acute respiratory patient outcome. Preliminary work at Harborview
distress syndrome (ARDS) which affects critically ill and Medical Center (HMC) has shown a high incidence of
injured patients. Vitamin C and potential Vitamin E deficiency in trauma
ARDS is largely responsible for the prolonged patients admitted to the HMC intensive care unit. A one
intensive care unit and hospital stay, and contributes month study of new patient admissions to Harborview
significantly to mortality in these patients. Management Medical Center found that 64% of patients had plasma
is primarily supportive while the underlying disease Vitamin C levels below the reference range, and 23% of
process stabilizes and resolves. Attempts to reduce the patients had plasma Vitamin C levels less than 0.20mg/
consequences of ARDS have focused upon 1) pharmaco- dL, indicating Vitamin C deficiency as defined by the
logic manipulation of the inflammatory response and 2) World Health Organization. Reports from other
modifying positive pressure ventilation techniques to institutions document a low plasma Vitamin C concen-
reduce the potential iatrogenic ventilator-associated tration in 28%-83% of select hospitalized patient
lung injury. Examples of current studies are: populations, and 12%-21% in a random sample of all
1. Low Tidal Volume Ventilation in ARDS: The mortality new hospital admissions.
rate from acute lung injury and ARDS is approximately An HMC study demonstrated that supplementing
40-50%. Traditional approaches to mechanical ventila- 3 gram/day of Vitamin C and 3 gram/day of Vitamin E

2002 research in the department of surgery

in patients with initially low levels resulted in plasma biomaterials and that cause the subsequent chronic
levels within the normal reference range within seven inflammatory response that leads to non-healing and
days. Patients not receiving supplements remained in the extrusion of biomaterials.
low reference range. The significance of Vitamin C Preliminary experiments have demonstrated that
deficiency in these patients is illustrated by a study of 78 adherence by the macrophage to various surfaces primes
patients with 105 fractures of the mandible treated at the macrophage for activation. Subsequent steps in the
HMC: those patients who had fracture complications inflammatory response lead to multi-nucleated giant cell
(infection, malunion) had significantly lower serum formation and subsequent capsule formation, secretion
Vitamin C concentration than those with a good fracture of extracellular matrix, vascular budding, and fibroblast
outcome. In addition, patients with ARDS have been proliferation with thick collagen deposition. Prevention
shown to have high levels of oxidants and suppressed of the proinflammatory phenotype may well equate with
levels of antioxidants, such as Vitamin C and Vitamin E, prevention of foreign body reaction. In current studies
in bronchoalveolar lavage (BAL) specimens. we are investigating coating biomaterials with various
We hypothesize that plasma and tissue Vitamin C molecules. These include ostepontin and various anti-
and E concentrations are significantly low in patients inflammatory agents such as antioxidants including
admitted to the intensive care units at HMC, and that Vitamin E, and components of the extracellular matrix,
routine supplementation of Vitamin C and E will elevate such as hyaluronic acid derivatives, to test the subsequent
levels. Elevated levels of these two potent antioxidants response of adherent macrophages to inflammatory
may well protect against oxidant-induced injury in these stimuli such as endotoxin.
severely injured and stressed patients and avoid the In addition, we are studying materials of various
diffuse insult predisposing to ARDS and other organ selected pore sizes, to minimize cell spreading and to test
dysfunction, and also to secondary nosocomial infec- environmental structural impact on macrophage
tions such as ventilator associated pneumonia and response to inflammatory stimuli. End product analysis
wound infections. of inflammatory mediators such as TNF, procoagulant
The study design is a prospective, observational activity, and IL-8 along with the normally produced
study in which all trauma admissions to HMC ICU will anti-inflammatory mediators IL-10 and PGE2 are
have plasma Vitamin C and E levels determined at time monitored. These mediators exist in a delicate balance
of admission. Patients are randomized to receive and time sequence to produce normal, as opposed to
standard care or antioxidant supplemented care with 1 abnormal, wound healing and chronic inflammation.
gm q 8h orally Vitamin E and 1 gm q 8h IV of Vitamin In additional experiments, we will test the effect of
C. These populations will be followed to determine their end products of macrophage activation and modulation
incidence of ARDS, duration in the ICU, mortality and of macrophage activation. Using a chorioallantoic
infectious complications. In addition, BAL samples will membrane fractal dimension and grid intersection assay
be obtained to determine the effect on oxidant levels, we will monitor angiogenesis as a crucial component of
cytokine production and activation state of the alveolar both normal and abnormal wound healing and incorpo-
macrophage regarding intracellular signal transduction ration, or healing, of biomaterials. The ultimate goal
pathways. is to modulate the surface characteristics of biomaterials
so that they may be adapted as compatible and elicit a
Modulation of the Excessive Inflammatory Response normal host response and normal wound healing with
to Biomaterials incorporation of the biomaterial true healing.
The production and release of potent inflamma-
tory mediators by tissue-fixed macrophages coordinate Modulation of the Trauma-Related Macrophage
and orchestrate a series of biologic events that lead to Inflammatory Response to Prevent ARDS, MOFS,
either normal wound healing or abnormal chronic and Death
granulation and typical foreign body reaction. The The last major area of investigation is based on the
goal of the experiments performed in conjunction with aberrant host immunoinflammatory response to trauma
the University of Washington Engineered Biomaterials and sepsis. This auto-destructive response is thought to
(UWEB) program funded by the NSF is to define the be responsible for the induction and persistence of the
cell signaling processes that control the pro-inflamma- malignant systemic inflammatory response underlying
tory phenotype of the macrophage in response to various ARDS and multiple organ failure syndrome (MOFS).

hmc/trauma surgery

ARDS and MOFS are the major determinants of late production of multiple inflammatory cytokines.
death following trauma. The goal is to develop therapeutic interventions
The primary etiology of ARDS and MOFS leading based on controlling these intracellular transduction
to late mortality following trauma is the clinical sepsis pathways and to modulate the over-aggressive macroph-
syndrome or systemic inflammatory response syndrome age response and the subsequent auto-destructive
(SIRS). This diffuse inflammatory response causes immunoinflammatory response. Currently we are
disseminated tissue injury and subsequent organ studying the manipulation of cellular signal transduc-
dysfunction. The long-lived, highly diverse tissue fixed tion mechanisms that control inflammatory mediator
macrophage is a crucial central coordinator of both genes by altering the intracellular levels and release of
the normal and the aberrant host immunoinflamma- calcium, the regulation of levels of cyclic AMP, and the
tory response. The macrophage is both primed and delineation of regulatory protein kinase signal transduc-
activated by a multitude of stimuli during the inflam- tion pathways, particularly the MAP kinase family,
matory response. including ERK1/2, SAPK, and r38. In addition, we are
Until now, therapeutic approaches have focused on investigating signaling processes activated through
control or inhibition of single components of the over- for-mation of focal adhesion complexes induced by
all inflammatory response. However, since the inflam- adherence of the monocyte/macrophage as critical to
matory response is replete with redundancy and feedback the host inflammatory cell response. A major focus is
amplification mechanisms, it is appealing to take a on the ability of antioxidants, such as vitamin E, or
broader approach to control the inflammatory response cytoskeletal inhibitors, such as cytochalasin D, to modify
and subsequent injury to multiple diffuse organ beds. the cellular response to inflammatory stimuli. Elucida-
To achieve this goal in these basic laboratory investiga- tion and control of these macrophage cellular mecha-
tions, we are focusing on the cellular and molecular nisms will permit development of future safe therapies
mechanisms involved in macrophage signaling and to prevent ARDS, MOFS, and death in the critically
activation by inflammatory stimuli and the subsequent ill surgical patient.

2002 research in the department of surgery

related publications:
1. Arbabi S, Rosengart M, Garcia I, Jelacic S, Maier R: Priming Interleuken-8 production The role of platelet-activating factor and p38.
Arch Surg, Dec 1999; 134(12):1348-53.
2. Nathens A, Jurkovicj J, Rivara F, Maier R: Effectiveness of state trauma systems in reducing injury-related mortality: A national evaluation.
J Trauma, 2000; 48(1):25-31.
3. Rosengart MR, Arbabi S, Garcia I, Maier RV: Interactions of calcium/calmodulin-dependent protein kinases (CaMK) and extracellular-regulated kinase
(ERK) in monocyte adherence and TNFa production. Shock, 2000; 13(3):183-189.
4. Bulger EM, Jurkovich GJ, Gentilello LM, Maier RV: Current clinical options for the treatment and management of ARDS. J Trauma, 2000; 48(3):562-572.
5. Nathens A, Jurkovich G, Cummings P, Rivara F, Maier R: The effect of organized systems of trauma care on motor-vehicle crash mortality.
JAMA, 2000; 283(15):1990-1994.
6. Steinberg KP, Maier RV, Schoenfeld D, Thompson BT: Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome:
The ARDS Clinical Trials Network. JAMA, 2000; 283(15):1995-2002.
7. Bulger EM, Maier RV: Lipid Mediators in the pathophysiology of critical illness. Critical Care Medicine, 2000; 28(4) (Suppl.) N27-N36.
8. Brundage SI, McGahn R, Jurkovich J, Mack C, Maier RV: Incidence of adult respiratory distress syndrome as a function of the timing of femur fixation.
Proceedings: 5th International World Congress on the Pathophysiology, Immune Consequences and Therapy of Trauma, Shock and Sepsis, Munich,
Germany March 2000. Monduzzi Editore S.p.A, Bologna, Italy, pp. 113-118, 2000.
9. The ARDS Network: A trial of traditional tidal volume versus lower tidal volume ventilation in acute lung injury and acute respiratory distress
syndrome. NEJM, 2000; 342(18):1301-1308.
10. Arbabi S, Rosengart R, Garcia, I, Maier R: Hypertonic saline induces prostacyclin production by increasing cyclooxygenase-2 expression.
Surg, 2000; 128(2) 198-205.

department co-investigators:
Sam Arbabi, M.D. / Michael K. Copass, M.D. / Joe Cushieri, M.D. / Iris Garcia / Lawrence Gentilello, M.D. / David Gourlay, M.D. / Gregory Jurkovich, M.D. /
Timothy Pohlman, M.D. / Nicholas Vedder, M.D. / Robert Winn, Ph.D.

other co-investigators:
Cecelia M. Giacelli, Ph.D.; UW Department of Bioengineering / David P. Grossman, M.D.; UW Department of Pediatrics and HIPRC Co-Director /
Tom Horbett, Ph.D.; UW Department of Bioengineering / Leonard Hudson, M.D.; UW Department of Pulmonary Critical Care Medicine /
Terrance Kavanagh, Ph.D.; UW Department of Pulmonary and Critical Care Medicine / Tom Koepsell, Ph.D.; Chair, UW Department of Epidemiology /
Frederick T. Rivara, M.D., M.P.H.; UW Department of Pediatrics and HIPRC Director / Patrick S. Stayton, Ph.D.; UW Department of Bioengineering /
Kenneth Steinberg, M.D.; UW Department of Pulmonary and Critical Care Medicine