Procedure

Left Ventricular Assist Device

search

Left Ventricular Assist Device, LVAD, Biventricular Assist Device, BiVAD, Artificial Ventricle, Ventricular Assist Device

  • See Also
  1. Implantable Defibrillator
  2. Pacemaker
  3. Cardiac Resynchronization Implantable Device
  • Epidemiology
  1. LVADs were implanted in over 22,000 patients between 2006 and 2016 in U.S.
  1. Criteria
    1. NYHA Class 4 Heart Failure
    2. Ejection Fraction <25%
    3. VO2 Max <15
    4. Poor response to optimal medical management (e.g. Beta Blockers, ACE Inhibitors)
    5. Life Expectancy <2 years
  2. Scenarios (three possible)
    1. Bridge to Heart Transplant
    2. Destination therapy (Palliative Care)
      1. Primary treatment for those not candidates for Heart Transplant
    3. Reversible disease (e.g. severe Myocarditis)
      1. Bridge to recovery (remodeling of heart allows for LVAD removal)
  • Types
  • Ventricular Assist Devices
  1. Left Ventricular Assist Device (LVAD)
    1. Shunts blood from inflow cannula at the left ventricle apex via external pump
    2. Transfers blood to outflow cannula in the proximal aorta
  2. Biventricular Assist Device (BiVAD)
    1. Shunts blood from both ventricles via external pump
  • Mechanism
  • LVAD
  1. Blood pathway with Intracorporeal pump unit
    1. Blood is shunted from left ventricle to inflow cannula
    2. Inflow cannula to external pump
    3. Pump Blood Flow capacity up to 10 L/min
    4. External pump to outflow cannula
    5. Outflow cannula to aorta
  2. Controller
    1. Worn externally, and plugs into the implanted pump via drive line protruding from skin
    2. Controller manages speed of pump and monitors patient parameters
    3. Controller will issue audible alarms when problems arise
    4. LED indicators on controller indicate status (e.g. on status)
    5. One button on LVAD indicates battery life
    6. Button on display cycles through alerts (suction event, low battery, driveline disconnected)
    7. LVAD is preprogrammed and can not be modified by controller device without LVAD coordinator assistance
  3. Driveline
    1. Percutaneous Driveline exits implanted pump and is tunneled via skin
    2. Driveline connects to external controller
  4. Power
    1. Controller connects to AC power base unit or to two batteries
    2. Allows for battery to be changed without device interruption
    3. One battery or AC power base unit must be connected at all times
    4. Patient wears batteries on suspenders (one on each side)
  • Precautions
  1. Patients receive backup components
  2. Patients receive education on alarms and response
  3. Patients are assigned an LVAD coordinator
  4. Patients are instructed to carry emergency supplies with them
    1. Backup controller
    2. Charged spare batteries
    3. Cords to connect the battery packs to a charger
    4. Emergency card with device information and VAD treatment team (e.g. VAD coordinator, cardiologist, CV surgeon)
  • Preparations
  • LVAD
  1. First Generation LVAD
    1. Pulsatile-flow mechanism
    2. Bulky and less durable
  2. Second Generation LVAD
    1. Continuous-flow mechanism (via centrifugal or axial flow pump)
    2. Smaller, more durable and quieter than first generation pumps
    3. Pump implanted in Abdomen (HeartMate II) or chest (HeartWare)
  • Symptoms
  1. Maintain a high level of suspicion for serious underlying cause in LVAD patients
  2. Patients with LVAD malfunction may present nonspecifically despite potentially lethal impending decompensation
    1. Weakness
    2. Malaise
  • Exam
  • Continuous Flow LVAD
  1. See LVAD evaluation under the Approach Emergency Department section below
  2. LVAD parameters
    1. Power
      1. Electrical current being drawn from the device
      2. High power suggests vasodilation (e.g. Sepsis, Anaphylaxis, Adrenal Insufficiency)
      3. Low power suggests device malfunction or battery failure
    2. Flow Rate
      1. Estimated Blood Flow through the pump
      2. Calculated from power level and pump speed (rpm)
      3. Flow is altered by Preload and Afterload
      4. High flow rates suggest vasodilation (e.g. Sepsis, Anaphylaxis, Adrenal Insufficiency)
      5. Low flow rates have many potential causes
        1. Decreased Preload (e.g. Hypovolemic Shock, Cardiogenic Shock, Tension Pneumothorax, tamponade)
        2. Pump obstruction (e.g. pump thrombosis, malpositioned inflow or outflow cannula)
        3. Increased Afterload (e.g. Hypertension)
    3. Pulsatility Index
      1. Degree of pulsatile flow from native heart function in comparison to LVAD function
      2. High pulsatility suggests volume overload
      3. Low pulsatility suggests Dysrhythmia, pump thrombosis, decreased native heart contractility
    4. Suction Events
      1. Left ventricular wall pulled into LVAD inflow cannula (due to low LV volume)
      2. Suction events risk ventricular Dysrhythmia
    5. Alarms
      1. Red hazard alerts (current or impending pump failure)
      2. Yellow advisory alert
  3. Signs of adequate perfusion
    1. Intact mental status
    2. Normal Capillary Refill
    3. Warm distal extremities
  4. Auscultation
    1. A working continuous flow LVAD should emit a continuous, low pitched hum (dish washer)
  5. Arterial Pulses are weak or absent and Pulse Pressure is decreased
    1. If pulses present, standard Blood Pressure may be obtained
    2. Pulses are typically absent with normally functioning continuous flow LVADs
  6. Mean arterial pressure (MAP) approximation (in place of standard BP)
    1. Apply manual cuff to arm and apply handheld doppler over brachial artery
    2. Slowly lower cuff pressure
    3. Listen for start of Karotkoff sound (will not be pulsatile with continuous flow LVAD)
    4. Onset of Karotkoff sound approximates mean arterial pressure (MAP)
    5. Goal MAP: 70-90 mmHg
      1. Hypertension (increased Afterload) puts the LVAD patient at risk for pump malfunction and failure
    6. Consider Arterial Line for MAP monitoring
  7. Oxygen Saturation
    1. Typically unreliable with continuous flow LVAD and decreased Pulse Pressure
    2. Consider cerebral oximetry instead
  • Labs
  1. Basic metabolic panel (Chem8)
    1. Electrolytes
    2. Renal Function tests (BUN and Serum Creatinine)
  2. Complete Blood Count
    1. Evaluate for Anemia and Thrombocytopenia
  3. INR
    1. Typical goal for LVAD: 1.5 to 2.5 (ideally 1.8 to 2.3)
  4. Other labs as indicated
    1. Serum Troponin
    2. Type and Screen
    3. Infection suspected
      1. Serum Lactate
      2. Blood Cultures
    4. Significant Hemolysis suspected
      1. Lactate Dehydrogenase (LDH) increased
      2. Haptoglobin
  • Diagnostics
  • As Indicated
  1. Electrocardiogram (EKG)
  • Imaging
  • As Indicated
  1. Chest XRay
  2. Echocardiogram (or Bedside Ultrasound)
    1. See Inferior Vena Cava Ultrasound for Volume Status
    2. See Inflow cannula obstruction or malposition (below)
  • Management
  • Approach Emergency Department
  1. Contact VAD team on patient arrival (LVAD coordinator or cardiothoracic surgeon)
    1. Consult for all significant management decisions
    2. Arrange transfer to LVAD center if evaluating at non-LVAD center
  2. Approach with a modified ABC Management
    1. Airway and Breathing are evaluated with the same standard ABC Management for any patient
    2. Circulation evaluation is of course modified to address LVAD specific concerns
      1. See exam above regarding pulse and perfusion markers
  3. Evaluate device power (interruption of power even briefly is an emergency)
    1. Check driveline skin exit (for Trauma) and its connection to controller
    2. Check controller connection to batteries
    3. Check for green light on controller (indicates device is powered)
    4. Plug driveline into AC power base unit if available (to conserve battery power)
    5. Feel the controller for excessive heat
      1. Suggests increased circuit resistance
      2. May indicate device malfunction, pump thrombosis or increased Afterload
  4. Evaluate that device is functioning
    1. Check for warning lights or alarms on device
    2. Auscultate for the hum or blender-like sound of an operating LVAD
  5. Evaluate for signs infection
    1. Evaluate skin overlying driveline (or sternal incision if recent implantation)
    2. Consider evaluating pump pocket or device endocarditis with Echocardiogram
    3. Consider other infection sites (e.g. Urinary Tract Infection, Pneumonia) with risk of seeding the device
    4. When empiric Antibiotics are indicated in a septic patient cover broadly
      1. See Infection as below
  6. Evaluate for signs of Fluid Overload (e.g. rales, edema, JVD)
  7. Evaluate for Hypertension (MAP >90 mmHg)
    1. MAP over 90 mmHg is a risk of CVA and impaired Cardiac Function
    2. Consider Fluid Overload or missed Antihypertensive dose
    3. Consider Beta Blocker or ACE Inhibitor (consult cardiology)
  8. Evaluate for Hypotension (MAP <60 mmHg)
    1. Approach
      1. Consider causes (see each described in detail below under complications)
      2. Obtain Bedside Ultrasound or formal Echocardiogram, CBC and coagulation panel
      3. Initiate fluid bolus 500 to 1000 ml
    2. Dehydration
    3. Gastrointestinal Bleeding
    4. Infection (Sepsis)
    5. Right ventricular dysfunction with Heart Failure exacerbation
    6. Inflow cannula obstruction or malposition
    7. Pump thrombosis (increased risk when MAP <60)
      1. See below
  9. Evaluate for Arrhythmia
    1. See Tachyarrhythmia below (VF, VT, a fib with RVR, SVT)
    2. See Cardiac Arrest below
  10. Consider other LVAD complications
    1. Pulmonary Embolism
  • Complications
  • Infection
  1. Infection occurs in 18-36% of LVAD implantations
    1. Infection is less common with continuous-flow devices by more than 2.5 fold
    2. May present non-specifically (e.g. weight loss, Fatigue, low-grade fever)
    3. Highest risk of infection is in first 3 months of LVAD implantation
    4. Higher risk with comorbid Diabetes Mellitus and Chronic Kidney Disease
    5. Primary cause of death for LVAD patients
      1. First month: 8.6% of deaths
      2. After the first month: 20.5% of deaths
  2. Sites
    1. Non-LVAD related infections (UTI, Pneumonia, Cellulitis)
    2. Sternal incision infection (mediastinitis)
    3. LVAD pump pocket or pump infection
      1. Presents with vague symptoms (weight loss, malaise and low grade fever)
      2. Consider Echocardiogram or CT to evaluate device or pocket for infection
      3. Pump pocket infection
        1. Introduced in perioperative period (near the time of pump insertion)
      4. LVAD Endocarditis
        1. Pump may be seeded with Bacteria or fungus resulting
    4. Driveline infection
      1. Most common site of infection
      2. May occur during surgical implantation or via hematogenous spread
      3. Often responds to Antibiotics alone (without surgical drainage), covering for organisms listed below
      4. May result if driveline wire fails to adhere well to surrounding tissue (excessive manipulation)
        1. Allows for pocket to form along the driveline, in which infection can develop
      5. Presents with driveline exit site signs of infection
        1. Purulent drainage
        2. Erythema, warmth, tenderness or persistent serous drainage
        3. Wound dehiscence
      6. Prevention
        1. Avoid excessive manipulation of the driveline after insertion
        2. Daily cleaning of the driveline skin exit site
  3. Organisms (high risk of nosocomial organisms and Gram Negative infections)
    1. Gram Positive Bacteria (>50% of cases)
      1. Staphylococcus aureus (including MRSA)
      2. Staphylococcus epidermidis
      3. Enterococcus
    2. Gram Negative Bacteria
      1. Pseudomonas aeruginosa
      2. Klebsiella
      3. Enterobacter
    3. Fungal organisms (<10% of infections)
  4. Evaluation and Management
    1. See Sepsis
    2. Similar evaluation as for Sepsis (CBC, chemistry, Blood Cultures, Urinalysis and Urine Culture, Chest XRay)
    3. Consider CT chest and CT Abdomen if mediastinitis, LVAD pump or pump pocket infection is suspected
    4. Consultation with cardiothoracic surgery
    5. Aim for MAP >65 mmHg in Sepsis via IV fluids (caution related to Right Heart Failure risk)
    6. Vasopressors may be needed for refractory Distributive Shock
    7. Most LVAD patients will be hospital admitted for infection (other than superficial infection in well-appearing patient)
    8. Cover for Bacteria listed below with broad spectrum Antibiotics for deep space infection or Sepsis
      1. Vancomycin (preferred) or Daptomycin AND
      2. Cefepime (preferred) or Ciprofloxacin or Levofloxacin or Piperacillin-Tazobactam (Zosyn) AND
      3. Fluconazole (preferred) or Voriconazole, Caspofungin, Micafungin, Anidulafungin
  5. References
    1. (2016) Sanford Guide, accessed 4/8/2016
    2. Gordon (2006) Lancet Infect Dis 6(7): 426-37 [PubMed]
    3. Pereda (2011) Cardiol Clin 29(4): 515-27 [PubMed]
    4. Topkara (2010) Ann Thorac Surg 90(4): 1270-7 [PubMed]
  • Complications
  • Bleeding
  1. Anticoagulation
    1. Most patients with LVAD or BiVAD are dual anticoagulated (e.g. Coumadin and Aspirin)
    2. LVAD itself is also associated with Platelet Dysfunction and von Willebrand dysfunction
  2. Small bowel Angiodysplasia (Intestinal Arteriovenous Malformation)
    1. Unclear etiology, although postulated to result from decreased intestinal mucosal perfusion
    2. Most common cause of Gastrointestinal Bleeding in LVAD patients
  3. Mechanical lysis of blood factors
    1. Acquired Von Willebrand's Disease (mechanical lysis of vwF)
    2. LVAD pump related Hemolysis (mechanical lysis of Red Blood Cells)
    3. Platelet Dysfunction
  4. Presentations
    1. Gastrointestinal Bleeding is the most common presentation (25% of LVAD patients)
      1. Gastrointestinal Bleeding is the most common cause for LVAD patient rehospitalization
    2. Epistaxis
      1. Second most common site for LVAD patient bleeding
  5. Labs
    1. Complete Blood Count (Hemoglobin, Platelet Count)
    2. Coagulation tests (PT/INR, PTT)
    3. Type and Screen
  6. Management
    1. Consult LVAD team (LVAD coordinator or cardiothoracic surgery)
      1. Discuss temporary Anticoagulant Reversal (risk of pump thrombosis)
      2. May transiently stop Warfarin for major bleeding without serious risk of short-term Thromboembolism
      3. Reverse Coagulopathy in serious bleeding events (e.g. Vitamin K, FFP, Platelet Transfusion, DDAVP)
      4. Avoid Prothrombin Complex Concentrate (PCC) if possible (higher risk of pump thrombosis)
    2. Evaluate and treat for Hemorrhagic Shock
    3. Manage Acute Gastrointestinal Hemorrhage
      1. Consult gastroenterology
      2. Consider Octreotide (Somatostatin Analog)
    4. Manage Epistaxis
    5. Keep Mean Arterial Pressure >70 mmHg
      1. Hypovolemia may result in increased suction events (see above) and low flow alarms
    6. Transfuse for Hemoglobin <7 mg/dl (higher Hgb for active bleeding)
      1. Cross-match blood to Leukocyte-reduced blood
      2. Prevents Antibody formation (risk for future Heart Transplant)
  • Complications
  • Pump failure
  1. Presents with a pulseless patient in extremis
  2. Pump failure results in blood backflow into ventricle, and resistance to forward flow
    1. LVAD dependent patients (e.g. severe Aortic Stenosis) will have no forward systemic flow
  3. Auscultate chest (or Abdomen) to confirm that the pump is working (hum or blender-like sound)
  4. Check tubes, cables and controller
  5. Assess if the LVAD controller is over-heating (see above)
  6. Check battery power remaining (press button on battery)
    1. Patient should have extra batteries with the pump
    2. Patient may have power pack that allows for AC plug-in
    3. EMS may also have available AC base power supplies
  7. Evaluate pump output
    1. Obtain mean arterial pressure via Doppler Ultrasound
    2. Obtain EKG to assess for acute Myocardial Infarction or Arrhythmia
    3. Obtain Echocardiogram to assess for interval changes from prior Echocardiogram
  8. Assess alarms
    1. Red lights or audible alarms suggest impending pump failure (address emergently)
  9. Restarting a stopped pump
    1. Press "Test Select" or "Alarm Reset" buttons may restart the LVAD
  • Complications
  • Inflow cannula obstruction or malposition
  1. Evaluate with Bedside Ultrasound
    1. Evaluate left ventricular and right ventricular function
    2. Small right ventricle and left ventricular collapse may suggest Hypovolemia (see below)
  2. Hypovelemia allows left ventricle to collapse over the LVAD inflow cannula (suction event, suck-down phenomenon)
    1. Obstructs Blood Flow into the pump, reducing Cardiac Output
    2. Fluid bolus may re-expand left ventricle and relieve obstruction
  3. Inflow cannula may also be malpositioned
    1. Urgent cardiovascular surgeon Consultation
  • Complications
  • Pump thrombosis
  1. Occurs in up to 10% of LVAD patients
  2. Causes
    1. LVAD heat production
    2. LVAD friction sites
    3. Foreign material within LVAD serves as nidus of thrombosis
  3. Pump may become clogged with clot, impeding forward flow
  4. Emergent condition typically presenting with MAP <60 mmHg
  5. Evaluate pump parameters
    1. Pump parameters are available when the pump is on external power
    2. High pump power, high pump speed despite decreased flow may suggest pump thrombosis
      1. High pump power may falsely report a calculated high flow rate despite Occlusion
    3. Pump may sound choppy or harsh, instead of typical constant hum
    4. Controller display may show alert "low flow alarm"
    5. Acute pulsatility index changes
  6. Bedside Ultrasound or Echocardiogram
    1. Left ventricle small and right ventricle large
  7. Exam
    1. Paradoxically increased palpable pulse
    2. Findings suggestive of right ventricular Heart Failure
    3. Hemolytic Anemia
      1. Fatigue or Dizziness
      2. Jaundice or Dark Urine
    4. Complete or near-complete Occlusion
      1. Hypotension to circulatory collapse
      2. Altered Mental Status
  8. Labs: Hemolysis due to thrombus related turbulent flow
    1. PTT, PT/INR to confirm Anticoagulation in target range
    2. Hemolytic Anemia
    3. Decreased Hemoglobin
    4. Increased Serum Bilirubin (Total Bilirubin and Indirect Bilirubin)
    5. Increased Lactate Dehydrogenase (LDH) >600 mg/dl (or >2.5x normal)
    6. Increased plasma free Hemoglobin >40 mg/dl
    7. Decreased Haptoglobin
    8. Hemoglobuniuria may occur
    9. Serum Creatinine (evaluate for Acute Kidney Injury)
  9. Management
    1. Initiate intravenous Heparin
    2. Stabilize Unstable Patients with inotropic medications
    3. Consider intravenous Thrombolytics in persistently Unstable Patients
      1. Consult LVAD coordinator and cardiac surgeon
  10. Prevention
    1. Most LVAD patients are on Anticoagulation (e.g. Warfarin with INR target 2 to 3)
  • Complications
  • Heart Failure exacerbation despite pump operating
  1. Right ventricular dysfunction is common after LVAD insertion
    1. LVAD patients depend on the right ventricle for Preload
  2. Obtain Bedside Ultrasound or Echocardiogram to evaluate right ventricle
  3. Consider Endotracheal Intubation
    1. May decrease Pulmonary Hypertension
    2. May improve Respiratory Acidosis and Metabolic Acidosis
  4. Consider Vasopressors
  • Complications
  • Tachyarrhythmia
  1. Common Arrhythmias
    1. Ventricular Tachycardia or Ventricular Fibrillation
      1. Sustained VT or VF occurs in up to 52% of LVAD patients
      2. May be asymptomatic for days in some LVAD patients
      3. Those with AICD may fire repeatedly
    2. Atrial Fibrillation or Atrial Flutter
    3. Supraventricular Tachycardia
  2. Presentation
    1. Right-sided Heart Failure
      1. Decreased left Ventricular Preload
      2. Results in Syncope, Light Headedness or weakness
  3. Management
    1. AICD may fire repeatedly if present
    2. Consult with VAD team when able
    3. Cardioversion is critical if this affects the right ventricle and Preload of the left ventricle
      1. Attempt chemical cardioversion (e.g. Procainamide, Amiodarone) in stable patients
      2. Electrical cardioversion if unstable or refractory tachyarrhythmia
        1. Avoid overlapping conductor pads over the LVAD (or AICD) if possible
  1. See Unresponsive Altered Level of Consciousness management as below
  2. Precautions
    1. Absent pulse or Blood Pressure does not equate to Cardiac Arrest in the LVAD patient (see exam above)
    2. Chest Compressions may dislodge left ventricle LVAD inflow cannula
      1. Start Chest Compressions as a last resort, but do not withhold if indicated
      2. Abdominal only CPR has been suggested as possible option (experimental only)
      3. Some studies have demonstrated safety of CPR in LVAD patients
        1. Shinar (2014) Resuscitation 85(5):702-4 +PMID:24472494 [PubMed]
    3. Avoid overlapping electrical Defibrillation conductor pads over the LVAD (or AICD) if possible
  3. Diagnostics
    1. Auscultate the chest for hum, and if present, measure mean arterial pressure
    2. Bedside Echocardiogram to evaluate assess left and right ventricles
    3. Confirm that LVAD is operational (see above under pump failure)
      1. Pump disconnected from driveline, battery disconnected or discharged
  4. Management
    1. Follow ACLS protocol (including electrical Defibrillation)
    2. Address pump failure, pump thrombosis, and inflow cannula obstruction (see above)
    3. Consider Intravenous FluidResuscitation if left ventricular collapse suspect (with inflow cannula obstruction)
  5. References
    1. Shinar (2014) Resuscitation 85(5): 702-4 [PubMed]
  1. See CVA Management
  2. Cerebrovascular Accident (CVA) occurs in as many as 20% of LVAD patients at one year
  3. CVA is the most common cause of death in LVAD patients
  4. Ischemic Cerebrovascular Accident
    1. Associated with LVAD related thromboembolic events (esp. pump thrombosis)
      1. Acute Ischemic CVA in LVAD patients is often associated with pump thrombosis
    2. Associated with Cardiovascular Risk Factor comorbidities (e.g. Hypertension, Hyperlipidemia, diabetes)
    3. Typically avoid CVA Thrombolysis (risk of hemorrhagic conversion)
    4. Consider endovascular retrieval for large vessel Occlusion
  5. Hemorrhagic Cerebrovascular Accident
    1. Increased risk related to Anticoagulants and Antiplatelet Therapy
    2. Consult neurosurgery
    3. As always, consult LVAD team regarding stopping Anticoagulation and Anticoagulation Reversal
    4. Manage as Hemorrhagic CVA
  1. See Altered Level of Consciousness
  2. ABC Management
    1. See Cardiac Arrest management above
    2. Airway Management (including Endotracheal Intubation as needed)
    3. Assist Ventilation
    4. Assess perfusion (Skin Color, Temperature, Capillary Refill)
  3. Decreased perfusion evaluation and management
    1. Evaluate LVAD function (alarms, hum)
      1. See emergency evaluation as above
      2. See pump failure as above
    2. External Chest compression Indications despite risk of device displacement (at least one of 2 criteria present)
      1. MAP <50 mmHg
      2. PETCO2 <20 mmHg (only if Endotracheal Tube in place)
      3. See Cardiac Arrest management described above
      4. See Cardiac Dysrhythmia management above (including Defibrillation and cardioversion)
    3. Manage post-arrest in similar fashion to other patients
      1. See Post-Cardiac Arrest Care
  4. Consider Non-LVAD related causes of Altered Level of Consciousness
    1. Bedside Glucose for Hypoglycemia
    2. Consider Naloxone (and consider other drug Overdose or Unknown Ingestion)
    3. Supplemental Oxygen for Hypoxia
    4. Consider Cerebrovascular Accident (see above)
  • Efficacy
  1. Device malfunctions occur in 10-15% of patients
  2. Survival rates (continuous flow devices)
    1. Year 1: 80% (compared with 25% on medical therapy)
    2. Year 2: 70% (compared with 8% on medical therapy)
    3. Kirklin (2013) J Heart Lung Transplant 32(2):141-56 [PubMed]
  • References
  1. Lo and Devine (2014) Crit Dec Emerg Med 28(7): 2-9
  2. Mallemat, Swaminathan and Egan in Herbert (2014) EM:Rap 14(10): 3-5
  3. Pokrajac (2021) Crit Dec Emerg Med 35(6): 3-11
  4. Swadron and Shinar in Majoewsky (2012) EM:RAP 12(4): 4-5
  5. Vanlandingham (2015) Crit Dec Emerg Med 29(10): 2-14
  6. Klein (2012) Cardiol Clin 30(4): 673-82 [PubMed]