Amantadine to Stimulate Wakefulness Following Post-Anoxic Encephalopathy

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Description

Principal Investigator:

Michael Donnino MD

Status of Study:

Ongoing

Purpose of Protocol:

The overall aim of this study is to determine if amantadine (a neurostimulant) will improve the rate of awakening in comatose post-cardiac arrest patients. In order to achieve this goal, we will perform a randomized, controlled, double-blind trial of amantadine for patients who remain comatose 72 hours after cardiac arrest.  The primary aim of the study will be rate of awakening in this comatose population. This short-term primary outcome is selected to test for safety and signal of efficacy that would justify a large trial powered to measure long-term outcomes.

Specific aim #1: Determine if amantadine administration to patients who remain comatose 72 hours after resuscitation from cardiac arrest promotes awakening compared to placebo.

Specific aim #2: Determine if the number of serious adverse events differ between subjects randomized to amantadine and subjects randomized to placebo. The null hypothesis is that adverse events do not differ between groups

Significance and Background:

Cardiac arrest results in approximately 382,000 deaths per year in North America. After

resuscitation from cardiac arrest, the majority of deaths in-hospital are secondary to brain injury.

Standardized post arrest care plans, including temperature management, early coronary

revascularization and delayed neurologic prognostication improve outcomes.  Despite these

advances, the most common cause for withdrawal of life sustaining therapy is failure to awaken. In many cases, decisions to withdraw life sustaining treatment may occur earlier than accurate

prognosis is possible.

 

One method to accelerate awakening from coma is the use of neurostimulant medications, such as

amantadine. Neurostimulant medications stimulate consciousness in comatose traumatic brain injury patients. We have previously demonstrated these medications are tolerated and are associated with awakening in cardiac arrest patients.

The results of this work are significant and will directly influence care and outcomes for 120,000 post-cardiac arrest patients admitted to hospitals each year. The approach is innovative and provides a pragmatic approach to enrollment. The investigative group is expert in clinical care and regularly uses a standardized post-arrest care bundle including multimodal neurologic prognostication. This will be the first trial to accelerate awakening and to compare awakening with neuroanatomic injury patterns.

Design:

Multicenter, randomized-controlled, double-blinded trial to test whether early neurostimulant administration increases the rate of awakening after resuscitation from cardiac arrest.

Inclusion Criteria:

1. Non traumatic cardiac arrest
2. Age 18 and older
3. Defibrillation and/or chest compressions by healthcare providers
4. Return of spontaneous circulation
5. Comatose, e.g. unresponsive to verbal stimuli and no purposeful response to pain

 

Exclusion Criteria:

1. Written do not attempt resuscitation (DNAR) reported to providers before randomization
2. Known prisoner or pregnancy
3. Lack of motor response to pain and absent N20 response on SSEP prior to randomization
4. Initial CT demonstrating brain edema (defined as grey white ratio <1.2)
5. Presence of malignant pattern on EEG at time of randomization. (Including those with a history of seizures)
6. Next of kin/LAr unwilling to provide supportive care for at least one week after enrollment
   1. At 72 hours after cardiac arrest, neuroprognostication and a family meeting to determine goals of care are the typical approach.  If a family determines that care will be withdrawn and/or unwilling to consider continuation of care for at least a week after enrollment, then the patient will be excluded.  Note, that if a family changes their mind during the protocol and wishes to withdraw support on a patient, the study team will not intervene in this decision or discussion.
7. Creatinine clearance <50mL/min
8. Presently using other dopaminergic agent

 

Treatment Protocol:

• The trial will have 2 arms: one enteral control and one active 100mg enteral amantadine treatment arm, each administered over approximately 15 minutes twice daily (0600 and 1200) for up to seven days beginning 72 hours of resuscitation.

 

• Neither the investigators nor the research participants will know to which arm the participant has been assigned. The pharmacist who mixes the treatment solution will not be blinded; however, this individual will have no study-related contact with the study participants.

 

Subjects will continue to undergo clinical routine procedures such as EEG testing. A study physician will complete a neurologic examination upon hospital arrival and again once the subject has rewarmed to a core temperature of >36°C.

Primary Outcome:

Awakening during hospitalization is the primary outcome for this trial to determine whether there is any potential signal of benefit that is meaningful to patients from early neurostimulant administration.

Measurements:

Blood samples will be collected at 8 timepoints (5 mLs each time for a total of 40 mL):

1. Daily “peak” levels 1-2 h following the afternoon dose on days 1-4
2. “Trough” levels immediately prior to 6 AM dose on days 2-5

ASCORBIC ACID, CORTICOSTEROIDS AND THIAMINE IN SEPSIS (ACTS)

Please click here for full details on the trial

Description: a randomized, double-blind, placebo-controlled trial of ascorbic acid, hydrocortisone, and thiamine to improve outcomes in septic shock.

Steering Committee:

Michael W. Donnino (Principal Investigator)

Ari Moskowitz MD

Katherine M. Berg MD

Michael N. Cocchi MD

Anne V. Grossestreuer PhD

Paul Marik, MD

Lars W. Andersen, MD, MPH, PhD

Funding Source:

Open Philanthropy

Status of Study:

Enrolling

Purpose of Protocol:

Our overall hypothesis is that the administration of ascorbic acid, hydrocortisone, and thiamine in septic shock patients will mitigate organ injury through improvement in free radical reduction, immune function, endothelial integrity, and mitochondrial energy production.

Specific Aim – To determine whether the combination of thiamine/ascorbic acid/hydrocortisone administered to patients with shock septic mitigates organ dyfunction as compared to placebo. 

Significance and Background:

Septic shock is a common and highly morbid condition affecting over 200,000 patients in the United States each year and resulting in upwards of 40,000 deaths. In-hospital mortality for patients admitted with septic shock has been has been estimated to be as high as 40%. While there is presently no recommended pharmacologic therapy specifically targeted at attenuating organ injury in septic shock, recent observational studies have found promising results using the combination of ascorbic acid (vitamin C), corticosteroids, and thiamine (vitamin B1). This medication combination has gained traction in the lay-media and is already being used by some hospitals to treat patients with sepsis and septic shock. Prospective testing in a randomized controlled trial, however, is needed prior to the widespread implementation of this therapy for victims of septic shock.

Design:

This prospective, randomized, blinded, placebo-controlled multi-center trial will investigate the effect of ascorbic acid, hydrocortisone, and thiamine vs placebo on organ function in patients with septic shock. We will also evaluate other outcomes including mortality.

Study Sites

Hospital Name	Location
BIDMC	Boston, MA
Henry Ford Hospital	Detroit, MI
DMC-Detroit Receiving Hospital	Detroit, MI
DMC-Sinai-Grace Hospital	Detroit, MI
Harper Hospital	Detroit, MI
UT Health, The University of Texas Health Science Center	Houston, TX
Mayo Clinic	Phoenix, AZ
Beaumont Hospital	Royal Oak, MI
Brigham and Women’s Hospital	Boston, MA
Long Island Jewish Hospital Center - Queens	New York, NY
Long Island Jewish Hospital Center – Hyde Park	New York, NY
Mount Auburn Hospital	Cambridge, MA
University of Pittsburgh	Pittsburgh, PA
South Shore Hospital	South Shore, MA

 

Inclusion Criteria:

1.  Adult (≥ 18 years)
2. Suspected (blood cultures drawn and antibiotics given) or confirmed (via culture results) infection
3. Receiving vasopressor support (norepinephrine, phenylephrine, epinephrine, dopamine, or vasopressin)*Sepsis/Infection should be the suspected precipitant of hypotension requiring vasopressor support.

Exclusion Criteria:

1. Known kidney stones within the past 1 year (not including incidentally noted stones)
2. End Stage Renal Disease requiring renal replacement therapy
3. Known G6PD deficiency or hemochromatosis
4. Comfort Measures Only status or anticipated death within 24-hours despite maximal therapy
5. Clinical indication for steroids, thiamine, or Vitamin C as determined by clinical teams
6. Known allergy to vitamin C, hydrocortisone, or thiamine
7. Protected Population (prisoner, pregnant)

Study Protocol:

All patients will receive standard septic shock care per their clinical team, whether or not they enroll in the study. After consent/enrollment, patients will have baseline labs drawn, and will be administered the study drug or placebo four times daily for four days (or until they leave the ICU).

Blood and Urine sample collection: All patients will have blood samples collected at 0, 24, 72, and 120 hours, with testing as detailed below.

Primary Outcome: The primary outcome will be the Sequential Organ Failure Assessment (SOFA) score. The SOFA score is a measure of organ dysfunction.

Secondary Outcomes:

• Need for renal replacement therapy
• Incidence of delirium
• Vasopressor-free days
• Ventilator-free days
• ICU LOS
• 30-day Mortality
• 90-day cognitive outcomes
• Measurements of other blood and urine marker of organ dysfunction

 

Esmolol to Treat the Hemodynamic Effects of Septic Shock

Description

Principal Investigator:

Michael Cocchi

Status of Study:

Enrolling

Purpose of Protocol:

We hypothesize that the provision of beta blockade to tachycardic patients in vasopressor-dependent septic shock will lower the heart rate, thereby improving diastolic filling time and improving cardiac output, resulting in a reduction in need for vasopressor support.  To test our hypothesis, we propose a Phase II randomized trial to determine if esmolol decreases vasopressor requirements (primary endpoint) and alters the inflammatory cascade as well as oxygen consumption in patients with septic shock.  Given that the compelling finding of a 30% reduction in mortality was the result of a single center European study, we submit that a Phase II pilot study is needed in a U.S. critical care environment, to validate this concept, before a larger, multicenter U.S. trial could be justified.  If we find that esmolol does allow for more rapid decrease of vasopressor need over time, without evidence of harm, we will have the necessary and sufficient data upon which to design a larger Phase III investigation aimed at addressing clinical patient-related outcomes.

Specific Aim #1: To determine if continuous infusion of esmolol improves the hemodynamic profile in septic shock by decreasing the need for vasopressor support.

Specific Aim #2: To characterize the effects of esmolol infusion on the pathophysiology of septic shock.

Specific Aim #2a:  To characterize the effects of esmolol infusion on total body oxygen consumption (VO₂) in patients with vasopressor-dependent septic shock.

Specific Aim #2b:  To characterize the effects of esmolol on inflammatory markers in patients with vasopressor-dependent septic shock.

Significance and Background:

Severe sepsis and septic shock are the cause of significant morbidity and mortality worldwide.  An estimated 751,000 cases (3.0 per 1,000 population) of severe sepsis occur in the U.S. each year, resulting in approximately 215,000 deaths. Septic shock is characterized by cardiovascular dysfunction (most typically systemic arterial hypotension), a hypermetabolic state, and lactic acidosis, potentially leading to death. In addition, the economic burden on the health care system for patients suffering from severe sepsis is striking.  Weycker et al. report that patients suffering from severe sepsis will require an average of $45,000 dollars of medical care cost on their index admission and up to $78,500 dollars in the first year post-diagnosis. These figures rival such entities as acute myocardial infarction, trauma, and stroke.

Despite advances in critical care and increased awareness of the need for early identification and aggressive treatment of sepsis, morbidity and mortality for septic shock remains unacceptably high.  The downstream cardiovascular effects of septic shock, beyond the shock period itself, are not trivial: myocardial depression, tachycardia-induced cardiomyopathy, and direct myocyte toxicity.  Novel therapies for septic shock are continually being sought, with a long history of agents which have failed to improve outcomes for these patients, and in some cases, have actually conferred harm. Currently, there is no adjunctive therapy for the treatment of septic shock that has adequately demonstrated an ability to reduce morbidity and mortality.  Furthermore, beyond the use of vasopressors and inotropes to support failing hemodynamics, there is currently no specific therapy targeted at the cardiovascular effects of septic shock.  Identification of a therapy which could improve outcomes for patients with septic shock, specifically related to cardiovascular dysfunction, would be a major advancement in a field plagued by a history of therapeutic failures.  While a recent single-center European trial has shown promise for the use of beta blockade in septic shock, further evaluation is necessary before widespread application of this therapy could be safely and responsibly advocated.  However, there are reasonable existing data available to justify moving forward with this line of investigation.

Design:

Prospective, randomized, double-blind, human clinical trial.

Inclusion Criteria:

1. Adult (≥ 18 years)
2. Sepsis defined as suspected or confirmed infection with at least two systemic inflammatory response syndrome (SIRS) criteria
3. Norepinephrine (minimum 0.1 mcg/kg/min) support to maintain a mean arterial pressure ≥ 65 mmHg despite appropriate volume resuscitation (as defined by the clinical team, however at least 30mL/kg intravenous fluid
4. Heart rate ≥ 95 per minute for at least 2 hours prior to enrollment
5. >6hours since admission

Exclusion Criteria:

1. Intravenous β-blocker therapy prior to randomization
2. Pronounced cardiac dysfunction (i.e. cardiac index [CI] ≤ 2.2 L/min/m²)
3. Known significant valvular heart disease
4. Research-protected populations (pregnant women, prisoners, intellectually disabled)
5. Known “Comfort Measure Only” or “do-not-intubate” order at the time of enrollment
6. Infusion of epinephrine , dobutamine or milrinone at time of enrollment
7. Known allergy/sensitivity to esmolol or history of asthma/COPD that would preclude administration of a beta blocker medication; this would be determined by the clinical team caring for the patient so as to not create a conflict of interest.  For example, a patient may have a history of COPD but is already on a beta blocker medication as an outpatient; that patient should not be excluded for consideration of enrollment in this trial.

Treatment Protocol:

The randomization will be done in a 1:1 ratio between treatment and control groups in varying blocks of two to six using SAS software. This main list of group assignment will be maintained in the hospital research pharmacy. After randomization as described above, patients will be assigned to one of the following two arms: esmolol for 24 hours or standard care (no esmolol).

Primary Outcome:

The primary endpoint will be improvement in the hemodynamic profile as measured by a decrease in the need for norepinephrine support. This will be defined as the difference in norepinephrine dose between groups at 6 hours after onset of study drug.

Measurements:

Hemodynamics: Heart rate and blood pressure will be measured hourly for all patients for the full study period. Cardiac index and stroke volume will be measured continuously with the use of the Non-invasive Cardiac Output Monitor (NICOM) (Cheetah Medical, Oregon, USA) which is a validated tool for hemodynamic measurements in the critically ill.

Vasopressors: Vasopressor doses will be recorded hourly for the full study period.

Additional measurements: At baseline we will collect pertinent variables such as demographics and past medical history. At baseline, 6, 12 and 24 hours after, trained research assistants will collect information on laboratory values and interventions performed by the clinical team (including but not limited to fluid administration, procedures, pharmacological intervention etc.), ventilator settings, results of cultures, etc. Patients will be followed to hospital discharge and time on mechanical ventilation, length of ICU stay, length of hospital stay and mortality will be recorded. SOFA scores will be calculated at all time points.  In a subset of patients who are mechanically ventilated, we will also continuously measure oxygen consumption for these patients via continuous VO2 monitor connected to the ventilator circuit.

Nivolumab in Septic Shock Phase Ib

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Description

Principal Investigator:

Michael Donnino

Status of Study:

Completed

Purpose of Protocol:

The purpose of this Phase 1b study is to evaluate the safety, tolerability, and pharmacokinetics of single doses of BMS-936558 (nivolumab) in participants with severe sepsis or septic shock to inform feasibility of further study of nivolumab in his population. Data from a mouse model of sepsis and form samples from septic patients support a role for the PD-1/PD-L1 pathway in sepsis. Taking these data together with evidence of an immunosuppressive phase in severe sepsis associated with poor clinical outcomes, interventions with the potential to improve host immune function, such as nivolumab, should be studied.

The primary objectives are:

• To assess the safety and tolerability of a single dose of nivolumab 480 mg or 960 mg in participants with severe sepsis or septic shock
• To assess the pharmacokinetics of BMS-936558 in participants with severe sepsis or septic shock

The secondary objectives are:

• To assess receptor occupancy of nivolumab following single dose administration
• To assess the effect of a single dose of nivolumab on monocyte HLA-DR expression and absolute lymphocyte count
• To assess the immunogenicity of nivolumab following single dose administration

Significance and Background:

Severe sepsis, defined as a systemic, deleterious host response to infection complication by acute organ dysfunction is a major health problem. In the US, severe sepsis is increasing in incidence, occurs in greater than 1,000,000 individuals annually, is recorded in 2% patients admitted to the hospital – half of whom are treated in the intensive care unit (ICU), and contributes to 1 in every 2 to 3 hospital deaths. Despite advances in early detection, ICU care, and implementation of guidelines-based care, for patients with severe sepsis, 90-day mortality rates remain close to 40%. Moreover, patients who survive their acute episode of severe sepsis have considerable incidence of re-hospitalization and ongoing morbidity and mortality beyond short-term endpoint.

Historically, organ dysfunction in patients with severe sepsis was thought to result from an exaggerated pro-inflammatory response. Accordingly, numerous randomized clinical trials examined therapies aimed at decreasing the pro-inflammatory response. With few exceptions, the results from these trials have been disappointing, and currently no specific therapeutic agent is approved for the treatment of patients with severe sepsis.

It is now appreciated that patients with severe sepsis mount simultaneous pro- and anti-inflammatory responses that perturb immune homeostasis. For many patients, an imbalance between these responses, with a predominant and/or protracted anti-inflammatory component, leads to a state of net immunosuppression. This immunosuppression is mediated by multiple mechanisms including reduction in the number of circulating lymphocytes and dendritic expression of negative co-stimulatory molecules, an increase in the numbers of regulatory T-cells and myeloid-derived suppressor cells, and a shift from a phenotype of pro-inflammatory type 1 helper T-cells to an anti-inflammatory phenotype of type 2 helper T cells. This immunosuppression has important clinical consequences including increased risk of secondary infection, viral reactivation, organ dysfunction, and mortality.

Design:

Prospective, randomized, double-blind, human clinical trial.

Treatment Protocol:

Nivolumab will be administered as a single dose infused using a volumetric pump at the protocol specific doses and rate through an intravenous solution infusion set with a sterile, non-pyrogenic, 0.2-micron pore size, low protein binding in line filter. Nivolumab will be infused at a rate of 2mL/min  over 90 minutes followed by a flush.

Primary Outcome:

For each subject, the study consists of four periods: (1) a screening period of up to 10 days, (2) baseline assessments within 24 hours prior to study treatment, (3) treatment with a single dose of nivolumab, and (4) a clinical study assessment period of up to 90 days. The total study duration is approximately 100 days for an individual subject. AE and SAE will be collected up to Day 90. The end of the study is defined as the last subject’s last assessment, or 90 days after last subject’s first dose, whichever is later.

Measurements:

Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG), and clinical safety laboratory assessments will be performed at selected times. Serial blood samples for pharmacokinetics, receptor occupancy, pharmacodynamics, biomarker, and immunogenicity analyses will be collected pre-dose and at selected time points post-dose.

Neuromuscular Blockade for Post-Cardiac Arrest Care

 

Description

Principal Investigator:

Michael Donnino

Status of Study:

Ongoing

Purpose of Protocol:

The overall aim of this study is to determine whether the continuous use of neuromuscular blockade (NMB) can improve lactate clearance and clinical outcomes in comatose patients following in-hospital and out-of-hospital cardiac arrest (OHCA).

Aim #1:  Determine whether 24 hours of continuous use of NMB will attenuate 24 hour lactate levels in post-OHCA patients.

Aim #2: Determine whether 24 hours of continuous use of NMB will improve clinical outcomes (length of stay, neurological outcome and in-hospital survival) in post-OHCA patients.

Aim #3: Determine the effect 24 hours of continuous use of NMB has on global and cellular oxygen consumption as well as hemodynamics parameters.

Aim #4: Determine the effect 24 hours of continuous use of NMB has on markers of systemic inflammation.

Significance and Background:

Cardiac Arrest (CA) is a devastating disease process with high mortality and neurological morbidity. Unfortunately, we currently have little to offer other than supportive care. Specific to this proposal, the use of neuromuscular blockade (NMB) remains controversial and additional data is desperately needed to inform practice. The current study will provide necessary preliminary data for a larger phase III trial aimed at reducing mortality in post-CA patients. This intervention is already used in clinical practice and therefore the findings will be highly translatable and could easily be incorporated into clinical practice.

Recently Nielsen et al. evaluated patients cooled to 33 °C vs. 36 °C and found no difference in survival or neurological outcome. This contradicted findings from two widely implemented 2002 trials showing an improvement in outcome in OCHA patients treated with 32-34 °C. The use of NMB was minimized in both arms of the Nielsen et al. study, (verbal communication with author) while NMB was used as boluses or infusions in both of the 2002 trials that found a benefit from therapeutic hypothermia TH. Thus, differences in NMB use in the treatment compared to control arms may have contributed to overall outcome differences.

Newer studies provide evidence for a benefit of NMB, which will be clarified further by the current trial. Papazian et al. recently published a trial in which they randomized heavily sedated patients with early severe Acute Respiratory Disease Syndrome (ARDS) to cisatracurium vs. placebo for 48 hrs. The cisatracurium group had improved adjusted survival (41% vs. 32%) and more ventilator-free days (p < 0.05) without an increase in intensive  care unit (ICU)-acquired myopathy. Alhazzani et al. conducted a meta-analysis of three trials using cisatracurium early in ARDS, and found an overall mortality benefit and no increase in ICU-acquired myopathy. Furthermore, the use of NMB has been associated with a decrease in pulmonary and systemic inflammation. In severe sepsis, Steingrub et al. found that administration of NMB was associated with lower hospital mortality in a retrospective cohort study of 7,864 patients on mechanical ventilation where 1,818 (23%) were treated with NMB. Based on this emerging evidence as well as our preliminary data we hypothesize that NMB will be beneficial in post-CA patients.

Design:

Prospective, randomized, human clinical trial.

Inclusion Criteria:

1. Adult (≥ 18 years)In hospital and Out-of-hospital cardiac arrest with sustained return of spontaneous circulation (ROSC)
2. Comatose (i.e., not following commands) following ROSC
3. Undergoing targeted temperature management (TTM)
4. Time of enrollment ≤ 6 hours from initiation of TTM
5. Lactate ≥2mmol/L

Exclusion Criteria:

1. Pre-existing dementia, severe brain injury, or dependence on others for activities of daily living  (i.e. a modified Rankin scale score of 4 or higher)
2. Traumatic etiology of the cardiac arrest
3. Protected population (pregnant, prisoner)

Treatment Protocol:

1) NMB for 24 hours: Patients in this arm of the study will have NMB for 24 hours utilizing rocuronium as described below.  At present clinicians at BIDMC arbitrarily sometimes use NMB and other times do not.  Thus, the provision of NMB does not fall outside of current practice.

2) “Usual Care”: Patients will receive 100 mL of normal saline over 5-10 minutes at the beginning of the study in addition to usual care. When patients are enrolled in a clinical trial there is a time period from consent to study drug administration that depends on the investigative team, the research pharmacy, and the available nursing staff. In order to guarantee that this time interval is similar between the two groups the control arm will receive a small bolus of saline at the beginning of the trial. This will ensure that “time zero” is similar between the two groups which is essential in a trial evaluating a metabolic marker (lactate) that may change rapidly. Patients in this arm of the study will not be mandated to have NMB and the choice of whether to utilize will be per usual care.  The decision for a “usual care” arm as opposed to mandated lack of NMB is for patient safety reasons.  We do not wish to have a clinical scenario arise in which a patient should receive NMB but cannot because of being entered into this study.  Therefore, while we anticipate the majority of patients in this arm will not have NMB, we recognize that some conditions may require NMB and they will receive them.

Primary Outcome:

The primary outcome will be blood lactate at 24hrs after treatment protocol

Measurements:

Research blood will be used in the isolation of peripheral blood mononuclear cells (PBMCs) from blood: Plasma will be separated by centrifugation at 800g for 15min at 4°C and saved without disturbing the buffy coat. Then plasma will be replaced with the same volume of phosphate buffered saline (PBS). The cell pellets will then be mixed by gently pipetting up and down several times to disperse the cells. Next, PBMCs will be isolated from the PBS substitute blood samples using density gradient, Ficoll-Paque premium (GE Healthcare Bio-Sciences Corp).

The isolated PBMCs will be used in the cellular metabolism and mitochondrial function analysis. Using the XF24 Extracellular Flux Analyzer (Seahorse Bioscience) we will simultaneously measure the oxygen consumption rate (an indicator of mitochondrial respiration), and the extracellular acidification rate (an indicator of the lactate produced e.g. anaerobic metabolism). First, PBMCs will be re-suspended in Dulbecco's modified Eagle's medium and seeded in a 24-well assay plate pre-coated with CellTak (BD Biosciences) and incubated at 37°C for 30 min to allow cells to attach to the bottom of the plate. Then the wells will be washed and 675uL of fresh XF assay buffer will be added to each well. The plate will be incubated at 37°C without Carbon Dioxide (CO2) for 1 hour prior to assay start.

VO2 (volume oxygen or oxygen consumption) monitoring: VO2 will be measured using the General Electric Compact Anesthesia monitor with gas exchange module, which will be connected to the ventilator tubing via a ventilator adapter with an attached gas sampling line.  This device measures VO2 continuously on a breath-by-breath basis, using an incorporated pneumotachograph to measure the volume of gas being exchanged and a paramagnetic analyzer to detect differences in inspired and expired oxygen. The patient’s ventilator settings with not be changed by our team, and a respiratory therapist will be present to connect and disconnect the monitor from the ventilator for the research physician or research assistant. Measurements will be carried out in the ICU where the patient is located.  We will also measure cardiac output through the Cheetah Reliant Bioreactance-based non-invasive cardiac output monitor.

Neurological outcome: We will use the modified Rankin scale to assess neurological outcome at discharge as recommended per recent  American Heart Association (AHA) outcome guidelines. This is a validated scale, ranging from 0 to 6, commonly used in CA. Good and bad neurological outcome will be defined as a score of 0-3 and 4-6.

Statins in Influenza

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Description

Principal Investigator:

Maureen Chase MD, MPH

Status of Study:

Ongoing

Purpose of Protocol:

Influenza is a large-scale public health issue for which considerable focus has been placed on vaccination programs and on the development of antiviral therapies.

The objective of this study is to determine the potential effect of statin therapy for the treatment of acute influenza infection.  In addition, we will evaluate the mechanism by which statin therapy attenuates the host inflammatory response and the effect on clinical outcomes as follows:

Specific Aim #1: To determine if the administration of statin therapy to patients with acute influenza will attenuate the inflammatory cascade.

Specific Aim #2: To determine if the administration of statin drugs attenuates disease severity and improves time to clinical resolution of symptoms in patients with confirmed influenza.

Specific Aim #3: To determine the effect of influenza on host metabolic response to disease.

Significance and Background:

Influenza is associated with a high level of morbidity and mortality worldwide: The World Health Organization still estimates 3 to 5 million severe cases of influenza illness worldwide and attributes 250,000-500,000 deaths to seasonal influenza outbreaks each year. While a reported 90% of influenza-associated deaths occur among adults aged ≥65 years, the morbidity associated with 2009 swine-origin influenza A (H1N1) resulted in a shift in the ages and baseline health of patients who became ill and died. One epidemiologic study found that two-thirds of hospitalized patients and 40% of those who died had no pre-existing medical conditions. In addition, mortality rates in other major diseases also peak when influenza is circulating.

No universal influenza vaccine exists: The best means of controlling influenza outbreaks is the development of protective vaccines. Because it takes months to generate, produce and distribute a strain-specific vaccine, populations with no prior immunity may be left vulnerable in the event of pandemic-associated vaccine shortages.

Antivirals are currently the only primary defense: In the setting of inadequate vaccine supplies, the only line of treatment will be existing antiviral agents. There are challenges to using these agents including cost, utility late in disease, limited supplies and, perhaps most concerning with regard to using antivirals as a singular defense in influenza infection is emerging resistance.

Statins are inexpensive and widely available; if effective, statins may have a profound effect on the morbidity, mortality and economic burden associated with influenza worldwide. Thus, our investigation could lead to a practice-changing therapeutic intervention that complements the current strategies of prevention (vaccination) and direct antiviral therapy.

Design:

Prospective, double-blind, randomized clinical trial.

Inclusion Criteria:

1. Adult patient (age > 18 years)
2. Positive influenza DFA/RAT test result
3. <12 hours from positive influenza test result

Exclusion Criteria:

1. Prior statin medication use (within 30 days of positive influenza test result)
2. Comfort measures only designation or anticipated withdrawal of life-support
3. Atorvastatin specific exclusions:
   1. Documented liver cirrhosis or liver dysfunction (AST or ALT greater than 240)
   2. Known allergy or intolerance to statins
   3.    Rhabdomyolysis (CPK elevation > 6x normal)
   4. Patients taking the following medications:  cyclosporine, HIV protease inhibitors, hepatitis C protease inhibitor telaprevir, fibric acid derivatives (gemfibrozil), niacin, azole antifungals (itraconazole, ketoconazole) clarithromycin and colchicine
4. Patients unable to take oral or nasogastric medications or plan for no oral intake as part of medical course (eg. emergent surgical intervention)
5. Known pregnancy or active breastfeeding
6. Inability to provide written informed consent for any reason

Treatment Protocol:

• Patients will be administered study medication (either atrovastatin 40 mg or placebo) orally once daily for 5 days or  or for a maximum of 7 days for those remain hospitalized:
  • Patients seen in the ED will receive a 5 day supply of the study medication.
  • Patients who are hospitalized will receive a minimum of 5 day supply (7 days maximum for those who remain hospitalized after 5 days)
• We will ask patients to provide an email address and telephone number for follow-up.
• For patients who are in hospital study staff will go over the online diary at the bedside each day of the interventional period.
• For patients who are not admitted to the hospital or discharged before Day10, they will receive email or telephone reminders daily up to Day 10 to complete the diary online. If internet access is not available, study stuff will fill out the diary with patients over the phone.
• A 14-day telephone follow up interview will be conducted and patients will be asked about relapse, recurrence of symptoms or re-hospitalization.
• Female patients of child bearing potential and males capable of fathering children will be asked to provide a method of contraception and advised to continue for 2 weeks after finishing the study drug.

Primary Outcome:

Specific Aim 1: To determine if the acute administration of statin drugs to patients with confirmed influenza will attenuate the inflammatory cascade.

• The primary endpoint for this study is change in inflammatory biomarker IL-6 from the time of enrollment to 72 hours.
• Secondary endpoints will include change on additional markers of inflammation including VegF and TNFa.

Specific Aim 2:  To determine if the administration of statin drugs attenuates disease severity and improves time to clinical resolution of symptoms in patients with confirmed influenza.

• The primary endpoint in this aim will be the time to clinical resolution based on a daily composite score of recorded major influenza symptoms. Study subjects will record a diary of symptom severity, temperature, ability to perform normal activities, and use of relief medication twice daily for 10 days. The diary will be used to create a composite score for each of 5 major symptoms (fever, cough, sore throat, headache, myalgia) ranked from 0 to 3 (none, mild, moderate, severe) for a score ranging from 0 to 15.⁸⁰Clinical resolution of symptoms will be defined as time to alleviation in major symptoms recorded as no more than mild x 24 hours.
• Secondary endpoints will be:

1.) Change in severity of illness (APACHE II) from enrollment to 24-hour follow-up

2.) Hospital and ICU lengths of stay

3.) Rates of progression to vasopressor-dependent shock

4.) In-hospital mortality

Specific Aim 3(Exploratory): To determine the effect of influenza on host metabolic response to disease.

• The first exploratory endpoint (3a) will be to determine if influenza host response consists of a unique metabolic fingerprint for diagnostic or prognostic purposes. We will obtain a “metabolomic” fingerprint of all patients at baseline which will consist of over 250 metabolites. We will evaluate the association of the metabolic profiles to outcome measures including need for hospital or ICU admission and mortality. We will then evaluate the metabolomic profile as a prognostic indicator in comparison to other biomarker indices and severity of illness scoring.
• The second exploratory endpoint (3b) will be to identify metabolic derangements and deficiencies that can serve as adjunctive therapies. Specifically, we will examine whether CoQ10 and other metabolic derangements may lead to adjunctive interventional therapies in influenza infection.

Measurements:

We will perform CoQ10 and metabolomic assessments on the first 50 patients enrolled in the trial. We will compare these results to those of controls in our data repository. A sample size of 50 patients per group will allow us to detect an effect size of 0.5 with 80% power (two-sided alpha 0.1).

UBIQUINOL AS A METABOLIC RESUSCITATOR IN POST-CARDIAC ARREST

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Description

Principal Investigator:

Michael Donnino

Status of Study:

Ongoing

Purpose of Protocol:

To study the effects of ubiquinol as a “metabolic resuscitator” in post-CA patients and to provide additional preliminary data for a large-scale phase II/III trial

Specific Aim #1: To determine whether oral ubiquinol is absorbed in post-CA patients and to evaluate potential biochemical effects of ubiquinol

Specific Aim #2: To determine if in vivo and in vitro administration of ubiquinol improves mitochondrial function and cellular oxygen consumption

Significance and Background:

Cardiac arrest (CA) occurs in more than 400,000 patients in the United States each year with an estimated mortality of greater than 90%. The majority of patients who are resuscitated from CA will succumb to the neurologic morbidity associated with the post-CA syndrome and ischemic-reperfusion injury. Currently, there are no pharmacologic agents known to offer survival benefit or to prevent devastating neurologic injury in post-CA patients. A potential therapeutic target following ischemia-reperfusion injury is mitochondrial function in the injured cell and/or reduction of oxygen free radicals. Coenzyme Q10 (CoQ₁₀) is an essential mitochondrial co-factor and free radical scavenger that has been proposed as a neuroprotective agent in various neurodegenerative disorders as well as a cardioprotective agent. CoQ₁₀ have furthermore shown exciting preliminary results as a potential therapy in post-CA.

Design:

Prospective, randomized, double-blind, placebo-controlled phase II human clinical trial.

Inclusion Criteria:

1. Adult (age ≥ 18 years)
2. Cardiac arrest defined by cessation of pulse requiring chest compressions
3. Not following commands after ROSC
4. Admission to the ICU
5. Nasogastric tube

Exclusion Criteria:

1. Protected populations (pregnant women, prisoners)
2. Current CoQ10 supplementation
3. Unable to receive enteral medications

Treatment Protocol:

Patients will be administered the study drug (placebo or 300 mg ubiquinol) and will receive two daily doses for one (1) week, the remainder of the in-hospital course, or until the patient has a normal neurologic examination. Neurological status will be assessed using the CPC-E score by the Principal Investigator and may be performed at any time prior to hospital discharge. Normal neurological examination is defined by a perfect CPC-E score of 30. The placebo will be pure Ensure (food/dietary supplement commonly provided to critically ill patients) and the ubiquinol will be mixed with Ensure for delivery and to allow for matching groups.

Outcomes:

The primary outcome will be blood CoQ₁₀ parameters (total CoQ₁₀, reduced CoQ₁₀ and CoQ₁₀ /cholesterol).

Secondary outcomes will include biomarker measurements including but not limited to: cytokines, vascular endothelial markers, markers of neurological injury (NSE, S100B), oxygen consumption rates, and metabolomics markers.  We will measure oxygen consumption and utilize in vitro inhibitors and stimulators of metabolism to further characterize samples including additional ubiquinol for the placebo arm samples.

Measurements:

All patients enrolled in the study will have blood drawn at time 0 hours, 24 hours, 48 hours, and 72 hours.  We will measure lactate at each time point through the clinical lab.  In addition, blood samples will be analyzed for CoQ₁₀ parameters either locally or by sending to an outside commercial lab likely the Department of Pathology and Laboratory Medicine at Cincinnati Children’s Hospital Medical Center (Cincinnati, Ohio, USA) using high-performance liquid chromatography.

Thiamine After Cardiac Arrest

Description: a randomized, double-blind, placebo-controlled trial of thiamine to decrease lactate and improve outcomes after cardiac arrest:

Study Team:

Michael W. Donnino MD (Principal Investigator)

Katherine M. Berg MD

Michael N. Cocchi MD

Anne V. Grossestreuer PhD

Xiaowen Liu PhD

Mathias J. Holmberg MD

Why are we doing this study?

Cardiac arrest is an emergent condition in which the heart completely stops. The chances of survival are low, even with CPR. Over 200,000 people per year experience an out-of-hospital cardiac arrest in the United States. Survival rates are low, and even those who survive often have significant brain injury. Unfortunately there are no medicines available to treat this condition. Our prior work suggests that a simple vitamin (Vitamin B1, or thiamine) may help improve outcomes in these patients. Based on our work, the National Institutes of Health has funded a study to test whether thiamine decreases lactate (a chemical that increases in the blood when a patient is in shock from lack of blood flow or inability to process oxygen). We will also test whether thiamine improves the ability of patient’s cells to use oxygen normally, and other blood tests that are markers for brain and other organ injury.

This is a randomized, double-blind, placebo-controlled study. This means that when a patient starts the study neither the patient, family nor the research team will know if the patient is getting thiamine or a placebo (an inactive substance, in this case simple salt water).

Who is eligible to be in this study?

We will include adult patients who are brought to the hospital after a cardiac arrest requiring CPR.

How is this study different from many research studies?

Because of the importance of administering Vitamin B1 (Thiamine) as soon as possible after cardiac arrest in order to maximize the chance of finding a benefit, this study will be conducted under exception from informed consent (EFIC) in accordance with the federal Food and Drug Administration (FDA) regulations. EFIC is allowed only when testing possible treatments for life-threatening conditions for which there is no alternative proven treatment, when obtaining consent is not possible because the study treatment must be administered quickly and family or healthcare proxy is not reachable.

When someone is reachable to provide consent, research staff will obtain consent prior to enrollment.  For participants enrolled under EFIC, they or their representatives will be notified of enrollment as soon as possible and asked if they would like to continue participation, with the option to withdraw from the study at any time. All patients will receive standard post-cardiac arrest care per their clinical team, whether or not they enroll in the study.

When research is done under EFIC, the study must conduct outreach to the surrounding community to inform them of the study, get feedback on the proposed study and EFIC, and provide a way for individuals to opt out of the study.  Based on this response, the IRB has determined that we can move forward. We will continue to take feedback and questions from anyone in the community leading up to and during the trial.

Opting out: Any member of the community has the right to opt out if they do not wish to be enrolled in the event that they suffer a cardiac arrest. In order to opt out, a person simply needs to contact our team at Vitaminstudy@bidmc.harvard.edu, or (617) 754-2885, and provide their name and date of birth. A bracelet indicating their wish to opt out of the BIDMC THACA trial will be provided either by being mailed to their home or picked up at the medical center, according to their preference.

Results: The THACA study is now complete. Results can be found at clinicaltrials.gov (https://clinicaltrials.gov/study/NCT03450707?term=donnino&rank=1&tab=results) and in the manuscript.

Thiamine After Cardiac Arrest

Thiamine After Cardiac Arrest (THACA): a randomized, double-blind, placebo-controlled trial of thiamine to decrease lactate and improve outcomes after cardiac arrest:

Study Team:

Michael W. Donnino MD (Principal Investigator)

Katherine M. Berg MD

Michael N. Cocchi MD

Anne V. Grossestreuer PhD

Xiaowen Liu PhD

Mathias J. Holmberg MD

Funding Source:

National Institutes of Health

Status of Study:

Enrolling

Purpose of Protocol:

The study will include all adult out of hospital cardiac arrest (OHCA) survivors admitted to a BIDMC ICU with a lactate above 3 mmol/L. Our overall hypothesis is that the administration of thiamine in post-arrest patients will mitigate lactate acidosis, improve cellular oxygen consumption, and improve clinical outcomes. Lactate change will serve as the primary endpoint for this study.

Specific Aim 1: To determine whether thiamine attenuates lactic acidosis, improves cellular oxygen consumption, and increases pyruvate dehydrogenase (PDH) activity in post-arrest patients.

Specific Aim 2: To evaluate whether the administration of thiamine will attenuate biomarkers indicative of neurological injury

Specific Aim 3: To determine whether intravenous thiamine improves clinical outcomes in post-arrest patients.

Significance and Background:

Cardiac arrest is an emergent condition in which the heart completely stops and the chances of survival are low. Over 200,000 people per year experience an out-of-hospital cardiac arrest in the United States. Survival rates are low, and even those who survive often have significant brain injury. Unfortunately, despite the high mortality, there are no medicines available to treat this condition. Our prior work suggests that a simple vitamin (Vitamin B1, or thiamine) may help improve outcomes in these patients. Based on our work, the National Institutes of Health has approved funding for a clinical trial to test whether thiamine decreases lactate and improves other outcomes after cardiac arrest.

Thiamine is a co-factor of PDH. Inadequate PDH function and/or thiamine deficiency limits pyruvate from entering the Krebs Cycle and results in lactic acidosis (anaerobic metabolism). We have shown that PDH is inhibited in post-cardiac arrest patients. Lactic acidosis is common, and failure to clear lactate is associated with worse outcome. While we anticipate the benefit of thiamine will be greater in cardiac arrest because of neuroprotection, we note that in a randomized trial in septic shock, thiamine decreased lactate over time compared to placebo and survival over time was improved for those with thiamine deficiency. Thiamine also improved survival and neurologic function in a mouse model of cardiac arrest. We hypothesize that the administration of thiamine in post-cardiac arrest patients will mitigate lactic acidosis, improve cellular oxygen consumption, and improve clinical outcome.

Design:

This phase II prospective, randomized, blinded, placebo-controlled single-center trial will investigate the effect of thiamine vs placebo on lactic acidosis and PDH in patients who achieve ROSC after OHCA.

Inclusion Criteria:

1. Adult patient (age ≥ 18 years)
2. Cardiac arrest with sustained (> 20 minutes) return of spontaneous circulation (ROSC)
3. Within 6 hours of cardiac arrest event
4. Lactate >/=3
5. Not following commands after ROSC

Exclusion Criteria:

1. Clinical indication for thiamine administration (alcoholism, known or highly suspected deficiency) or treatment with thiamine beyond the amount found in a standard multivitamin within the last 10 days
2. Traumatic etiology of arrest
3. Comfort measures only or anticipated withdrawal of support within 24 hours
4. Protected populations (pregnant women, prisoners)
5. Known allergy to thiamine

Consent Protocol and Exception from Informed Consent:

An attempt to consent a patient’s legally authorized representative will always be made by our study team. Clinical trials for cardiac arrest are very difficult to conduct since patients are too ill to be able to consent for themselves, and it is not always possible to reach family members immediately. To address this problem and allow for ongoing studies to potentially help individuals and communities, the FDA developed a mechanism to conduct research in these types of scenarios. This mechanism, termed “Exception From Informed Consent (EFIC)” allows the study to proceed if the investigators are unable to reach family members for consent. If no one can be reached for consent and a patient is enrolled, repeated attempts to contact family will be made. If the patient becomes able to consent or family is reached after enrollment, they have the option of withdrawing from the study at any time.

EFIC requires not only approval from the BIDMC Institutional Review Board (IRB) as standard for all research studies but also requires input from the community through focus groups, surveys, and other community meetings. We have done this community outreach and received overwhelmingly positive feedback. Based on this response, the IRB has determined that we can move forward. The final phase of the process is public disclosure and this is currently being performed through both traditional media and social media outreach. We will continue to take feedback and questions from anyone in the community leading up to and during the trial.

Opting out: Any member of the community has the right to opt out if they do not wish to be enrolled in the event that they suffer a cardiac arrest. In order to opt out, a person simply needs to contact our team at Vitaminstudy@bidmc.harvard.edu, or (617) 754-2885, and provide their name and date of birth. A bracelet indicating their wish to opt out of the BIDMC THACA trial will be provided either by being mailed to their home or picked up at the medical center, according to their preference.

 

Study Protocol:

All patients will receive standard post-cardiac arrest care per their clinical team, whether or not they enroll in the study. After consent/enrollment, patients will have baseline labs drawn, and will be administered the study drug (placebo or 500mg thiamine) twice daily for 2 days.

Blood sample collection: All patients will have blood samples collected at 0, 6, 12, 24, 72 and 168 hours, with testing as detailed below.

Primary Outcome: The primary outcome will be the difference in lactate between the thiamine and placebo group.

Secondary Outcomes:

PDH activity: We will compare PDH quantity and activity between groups.

Cellular metabolism measurements: we will compare quantitative, real-time, tissue specific cellular metabolism and mitochondrial function between groups, using the XFe96 instrument (Seahorse Biosciences).

Measurements of neuron specific enolase (NSE) and S-100B: Serum NSE levels and plasma S100 levels (both markers of neurologic injury) will be compared between groups at various time points.

Global VO2 measurements: VO2 will be measured using a General Electric VO2 monitor with gas exchange module, which will be connected to the ventilator tubing via a ventilator adapter with an attached gas sampling line.

CPC-E score: The Cerebral Performance Category-Extended (CPC-E) score is a validated, clinically-feasible robust assessment of function and disability, providing more granular detail than the original CPC score.

The Effect of Thiamine after In-hospital Cardiac Arrest

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Description

Thiamine for Renal Protection in Septic Shock

Description

TRPPS: a randomized, double-blind, placebo-controlled trial of thiamine to improve renal outcomes in septic shock.

Study Team:
Ari Moskowitz MD (Principal Investigator)
Michael W. Donnino MD
Katherine M. Berg MD
Michael N. Cocchi MD
Anne V. Grossestreuer PhD

Funding Source:
National Institutes of Health

Status of Study:
Enrolling

Purpose of Protocol:

Our overall hypothesis is that the administration of thiamine in septic shock patients will mitigate renal injury through improvement in mitochondrial energy production.

Specific Aim #1 – To determine whether thiamine administered to patients with shock septic mitigates renal injury as compared to placebo.

Specific Aim #2 – To evaluate the effect of thiamine on mitochondrial respiration during septic shock and to evaluate the relationship between mitochondrial respiration and biomarkers of renal injury.

Significance and Background:
Septic shock is a common and highly morbid syndrome that affects over 200,000 patients in the United States annually and results in over 40,000 deaths. Renal failure is a frequent sequela of septic shock that is associated with notably worse outcomes. Thiamine (vitamin B1) is a critical component of aerobic respiration that may attenuate renal injury during septic shock. In a randomized trial, our research group has previously shown that thiamine deficiency is common in septic shock (35% of patients) and that the administration of thiamine to thiamine deficient patients with septic shock leads to reduced lactate at 24-hours. In a post-hoc analysis of that study, we have demonstrated that patients (both thiamine replete and thiamine deficient) who received thiamine had lower creatinine levels and were less likely to require renal replacement therapy.

Thiamine, a key cofactor of pyruvate dehydrogenase, is a critical component of mitochondrial respiration without which a shift towards anaerobic energy production occurs. Thiamine is also a necessary component of the pentose phosphate pathway, which plays a role in reducing oxidative stress. Given the above, we hypothesize that the administration of thiamine to patients with septic shock will mitigate renal injury through resuscitation of mitochondrial function.

Design:
This phase II prospective, randomized, blinded, placebo-controlled single-center trial will investigate the effect of thiamine vs placebo on renal function in patients with septic shock.

Inclusion Criteria:

1.  Adult (≥ 18 years)
2. Suspected (blood cultures drawn and antibiotics given) or confirmed (via culture results) infection
3.  Serum lactate >2mmol/L
4.  Serum Creatinine >1.0mg/dL
5.  Receiving vasopressor support (norepinephrine, phenylephrine, epinephrine, dopamine, or vasopressin)

Exclusion Criteria:

1.  Renal replacement therapy in past 30-days
2. Comfort Measures Only status or anticipated death within 24-hours despite maximal therapy
3.  Clinical indication thiamine
4.  Known allergy to thiamine
5.  Protected population (prisoner, pregnant)

Study Protocol:

All patients will receive standard septic shock care per their clinical team, whether or not they enroll in the study. After consent/enrollment, patients will have baseline labs drawn, and will be administered the study drug (placebo or 200mg thiamine) twice daily for 3 days.

Blood sample collection: All patients will have blood samples collected at 0, 24, 48, and 72 hours, with testing as detailed below.

Primary Outcome: The primary outcome will be the difference in creatinine (a marker of renal function) between the thiamine and placebo group.

Secondary Outcomes:

Cellular metabolism measurements: we will compare quantitative, real-time, tissue specific cellular metabolism and mitochondrial function between groups, using the XFe96 instrument (Seahorse Biosciences).

Measurements of other blood and urine marker of renal injury

Global VO2 measurements: VO2 will be measured using a General Electric VO2 monitor with gas exchange module, which will be connected to the ventilator tubing via a ventilator adapter with an attached gas sampling line.