Research

Learn more about the Alam Lab's work and impact.

Lab member looking through microscope
Dr. Alam
Lab materials

Alam Lab Overview

Our team has adopted a multifaceted, collaborative, and comprehensive approach towards tacking these complex problems. Our team and collaborators include computational and molecular biologists, surgeons, emergency medicine physicians, cardiologists, critical care specialists, engineers and other experts that are interested in lethal injuries.

Our work centers on four key areas:

  • Hemostasis, or hemorrhage control, and resuscitation, including the use of pre-hospital plasma and blood products to restore normal clotting
  • Novel cytoprotective strategies, including pharmaceuticals and induced hypothermia, for treating hemorrhage, hemorrhagic shock, traumatic brain injury (TBI) and sepsis
  • Infections and sepsis, including rapid diagnosis and novel treatments
  • New tools and devices for use alone or in combination with other approaches to treating trauma, preventing infection and expanding the pre-hospital survival window.  

Our findings have led to a number of discoveries, strategies and protocols, and inventions, all aimed at creating a "pro-survival phenotype." 

Strategies

Our research group uses many strategies to improve survival and reduce disability following trauma.

Activating Pro-Survival Mechanisms

Building on earlier work that identified damaging changes in cardiac and other cells from conventional crystalloid resuscitation fluids, we're currently focused on activating pro-survival genes and proteins using histone deacetylase inhibitors (HDACIs). These include but aren't limited to valproic acid (VPA), a commonly used anti-seizure medication that has been FDA-approved for decades. We have also investigated other novel agents such as mesenchymal exosomes to attenuate cellular injury and to promote recovery.

We've been investigating the effectiveness and optimal dosing of VPA in hemorrhage control, TBI, sepsis and in combined models. These findings have broader applications that extend beyond trauma care, for example we have discovered that VPA treatment can minimize cardiac damage following myocardial infarction, and kidney damage after ischemia-reperfusion. And we're further investigating targeted, isoform-specific HDACIs for patient-, organ-, and injury-specific uses. Eighteen HDACs have been identified in humans to date, each with distinct effects, which give us many potential new therapeutic targets.

Alternatives to Fresh Frozen Plasma

Problems with blood clotting, or coagulopathy, is ubiquitous in severely injured patients, and its presence correlates with high mortality. Administering fresh frozen plasma soon after injury can improve survival rates, but it needs refrigerated storage, which makes its use logistically impossible in the pre-hospital phases of care, especially in combat settings. Our lab continues to develop and test freeze- and spray-dried plasma and other blood products that don't require refrigeration -- alone and in combination with other strategies -- to treat trauma-induced coagulopathy.

Intra-aortic Balloon Pump to Stop Bleeding & Prevent Arrest

In this project that is funded by the DoD, we plan to combine two innovative strategies that have emerged in the recent years. The first is resuscitative endovascular balloon occlusion of the aorta (REBOA) that can control internal bleeding by stopping the blood flow below the level of the inflated balloon. The second, is Valproic acid (VPA), which is a drug that can sustain life despite massive blood loss. Both of these interventions have limitations, which we believe can be overcome by using them together to achieve synergistic effects. Limitation for standard REBOA is that it stops the blood flow below the level of balloon occlusion (complete or cREBOA), which can have serious consequences due to ischemia-reperfusion. This limits its use to less than 30 minutes. VPA, on the other hand, can make the cells/organs tolerant to ischemia but lacks the ability to actually stop the bleeding. We are testing a dual pronged approach which can significantly extend (6 fold or more) the safe ischemia time for REBOA, while minimizing its adverse consequences. As both the REBOA and VPA are in clinical use, these refinements, if successful, can easily be translated into clinical domain. By significantly increasing the safe duration of REBOA, we can make the technology suitable for military field-hospitals (and for the smaller civilian hospitals), where aortic balloons may have to be kept inflated for hours while the patients are transferred to other facilities for definitive care.

Hypothermia and Hibernation Strategies

Induced hypothermia, or emergency preservation and resuscitation (EPR), can help brain, heart and other cells survive while patients are treated for hemorrhage, hemorrhagic shock and TBI. We investigate approaches to inducing hypothermia and to controlled resuscitation to preserve neurologic and organ function after traumatic injury. 

Biomarker Identification

Since the clinical signs of infection and inflammatory responses to hemorrhagic shock overlap, we're working to identify biomarkers to more effectively discern patients developing sepsis — who need rapid antibiotic administration — from those with a systemic inflammatory response to injury. We're also working toward a point-of-care device to measure protein and metabolite biomarkers in the brain to help monitor and treat TBI.

A number of clinical trials and other studies in these areas are currently underway or forthcoming, including:

  • Phase 2 and 3 trials of the HDAC inhibitor VPA
  • Phase 1 trial of VPA (recently completed)
  • Dose optimization study of VPA in large animal models of combat injuries
  • Prolonged field care (72 hours) in hemorrhage and TBI with VPA and other strategies, including freeze-dried plasma in large animal models of combat injuries
  • Studies of isoform-specific HDACIs in clinically relevant large animal models
  • Administration of high dose intra-nasal insulin and light therapy as novel treatments for TBI in larege animal models
  • Preclinical studies of mesenchymal stem cell-derived exosomes in in clinically relevant large animal models of TBI

Results

  • Funded by the Office of Naval Research, we developed new a battlefield dressing that was widely deployed by the US Military during the conflicts in Iraq and Afghanistan .
  • Ours was among the first group to identify the proinflammatory pathways activated by conventional resuscitation strategies using crystalloid fluids, including changes in cell function, clotting profiles, organ injury and inflammation. 
  • We've identified and clarified trauma-induced epigenetic changes, which led us to investigations of valproic acid (VPA) and other histone deacetylase inhibitors (HDACIs) to activate pro-survival and anti-inflammatory pathways, attenuate cellular injury, mitigate brain injury as improve neurological recovery, as well as protect against the consequences of septic insults. 
  • Subsequent studies have identified the mechanisms underlying HDAC inhibitors and how they improve trauma outcomes across hemorrhage, hemorrhagic shock, traumatic brain injury and, more recently, in the critical care setting, myocardial infarction. To carry out this work, we have created numerous small and large animal models of hemorrhage, poly-trauma, TBI, sepsis, and combined insults.  Further work has clarified timing and optimal dosing of VPA and other HDAC inhibitors. 
  • We've discovered a number of biomarkers, such as citrullinated H3 (CitH3), to distinguish patients with infections and those with inflammatory responses to injury. Other biomarkers we have discovered can help clinicians monitor TBI, and we're currently developing a point-of-care device to facilitate this.
  • Our group has reinvigorated the idea of using alternative forms of fresh frozen plasma, particularly in austere environments. We've developed and tested the use of freeze- and spray-dried plasma, demonstrating equivalent effectiveness as fresh frozen plasma while reducing logistical challenges, such as weight and refrigeration.
  • Identified a number of pathways that are altered in sepsis, and have created new knock out animals to fully define these underlying mechanisms.  This has allowed us to develop a new monoclonal antibody that significantly improves survival in animal models of lethal sepsis.  We are currently humanizing this antibody for potential clinical testing.
  • Refined the EPR approach to a level where it is now being tested in a clinical trial  

Clinical Relevance & Impact

Our work is brightening the outlook for individuals who sustain life-threatening injuries, on the battlefield and off. Our contributions have changed battlefield resuscitation policies and protocols, saving lives and limbs and lengthening the survival window in austere environments. The hemorrhage control dressing we developed, QuickClot was widely used by the US Marines, and its next-generation product, QuikClot Combat Gauze, has become the first line of treatment for the US Military. Work with epigenetic, cell-protecting therapies as well as freeze- and spray-dried plasma has created a new paradigm in trauma care, "damage control resuscitation," which has now become standard practice. Biomarkers we are identifying, and related point-of-care testing platforms we're developing, are speeding diagnosis – and therefore treatment – and monitoring of sepsis and traumatic brain injury while avoiding overtreatment.

Other inventions we've devised, including a portable hand pump to evacuate blood from body cavities during field care has yielded unanticipated benefits away from the battlefield. This has been incorporated into a pleural drainage system to improve home care for patients with cancer who would otherwise endure repeated hospitalizations for pleural effusions. Many of our strategies have wider application beyond trauma, including in organ preservation for transplant and in any resource-constrained setting that lacks specialized trauma care and facilities.

Future Directions

Our team continues to work towards optimizing the delivery of life saving treatments for the most critically ill patients, in civilian and military settings. In the not too distantfuture, trauma resuscitation will be very different from what we currently practice.  In addition to early hemorrhage control and “Damage Control Resuscitation”, we are also likely to see many new strategies.  Many of these novel treatments are already at the cusp of clinical reality:

  • Use of specific pro-survival drugs that can be given in the pre-hospital setting to keep the injured alive long enough to get evacuated to higher levels of care (“bridge to definitive care”).
  • Early use of preserved plasma products, platelets and red blood cells.
  • Availability of manufactured blood to eliminate the logistical barriers to supply.
  • Development of safe and effective non-blood oxygen carrying fluids that can be easily administered.
  • Ability to temporarily “suspend” life using hypothermia or hibernation strategies for patients that have potentially survivable injuries, but need more time for surgery or transfer.
  • Individualized therapy (“precision medicine”) with administration of agents based upon the individual’s specific needs.
  • Monitoring of response to therapy that goes beyond measurement of basic physiology by looking at the key cellular disturbances.
  • Reliable methods to diagnose complications, such as sepsis, and availability of effective and specific therapies to mitigate sepsis-induced cellular damage.

Collaborations

Internal Collaborators

  • Amit Pai, PhD, Clinical Pharmacy
  • Kathleen A. Stringer, PHARMD, Clinical Pharmacy
  • Gerry Higgins, PhD, Computational Medicine and Bioinformatics
  • Brian D. Athey, PhD, Computational Medicine and Bioinformatics
  • Mark Hemmila MD, Michigan Trauma Quality Improvement Program
  • Theodore J. Standiford, MD, Pulmonary Critical Care
  • Matthew Delano, MD, Surgical Critical Care
  • Krishnan Raghavendran, MBBS, Surgical Critical Care
  • Mohammed Islam, PhD, College of Engineering
  • Katsuo Kurabayashi, PhD, College of Engineering
  • Kevin Ward, MD, MCIRCC
  • Robert Neumar, MD, PhD, Emergency Medicine
  • M. Hakam Tiba, MD, MS, Emergency Medicine
  • Thomas H Sanderson, PhD, Emergency Medicine
  • Cindy Hsu, MD, PhD, Emergency Medicine
  • Kayvin Najarian, PhD, Emergency Medicine

External Collaborators

  • Xiuzhen Duan, MD, PhD, Loyola, Louisiana
  • John B. Holcomb, MD, UTHealth, Texas
  • Michelle McNutt, MD UTHealth, Texas
  • Walter Biffl, MD, Scripps, California
  • Clay Burlew, MD, Denver Health,Colorado
  • Tianbing Wang, MD, China
  • Baoguo Giang, MD, China
  • Martin Sillesen, MD, Europe
  • National Institutes of Health
  • U.S. Department of Defense
    • Office of Naval Research
    • U.S. Army Medical Research Acquisition Activity
    • DARPA
  • Medical Technology Enterprise Consortium and Department of Defense, Dept. of the Army
  • Massey Foundation
  • Surgical Infection Society
  • MCRN SCIP in conjunction with Hayes Innovations
  • Coller Surgical Society
  • Westat and Department of Defense, Dept. of the Army
  • Innovative Biotherapies and Department of Defense, Dept. of the Army
  • PCORI