Platelet dysfunction in Uremia

In ICU, sometimes we have to refer our critically ill patients for surgical tracheostomy. The majority of these patients is suffering from MODS which include acute kidney injury. Very often, the level of urea varies from day to day, and also related to the frequency of dialysis in ICU. This is where we have a problem, since quite often the ENT surgeons request for a single digit of urea level. Their concern is bleeding associated with renal failure. Many times the procedure is delayed due to this request. This is what I read from uptodate.com:

The association between renal failure and bleeding was recognized more than 200 years ago. Impaired platelet function is one of the main determinants of uremic bleeding.

Clinical and Lab manifestations

1. Bleeding may involve the skin, oral and nasal mucosa, gingiva, gastrointestinal, urinary tracts and respiratory system. Excessive bleeding may also occur in response to injury or invasive procedures.

2. Although an association between bleeding time prolongation and uremia has long been suggested, there are no good studies demonstrating an increase risk of either spontaneous bleeding or bleeding with a procedure that is associated with prolonged bleeding time among patients with chronic kidney disease.

3. Degree of azotemia (elevation of BUN or creatinine) does not correlate with bleeding risk.

4. Patients may display increased sensitivity to aspirin. The platelet count is usually normal. Generally  levels of circulating coagulation factors are normal and there is no prolongation of the PT or APTT unless there is coexisting coagulopathy.

Pathogenesis - the cause of uremic bleeding is multifactorial.

Causes of platelet impairment include intrinsic platelet defects, abnormal platelet-endothelial interaction, uremic toxins and anemia.

1. The most important factor is platelet dysfunction which is due to decreased platelet aggregation and impaired platelet adhesiveness.Contributing factors extrinsic to platelets include the action of uremic toxins, anemia, increased NO production, von Willebrand factor abormalities, decreased platelet production and abnormal interaction between the platelet and the endothelium of the vessel wall.

2. Uremic toxins:

Consistent with this postulate is the observation that mixing uremic plasma with normal platelets impairs platelet function. However urea is not the major platelet toxin and there is no predictable correlation between the BUN and the bleeding time in patients with renal failure. The addition of urea, guanidinoacetic acid or creatinine to the plasma did not affect platelet function. High levels of guanidinosuccinic acid and methylguanidine have been suggested as potential contributors to uremic platelet dysfunction, likely through simulation of NO production.

3. Anemia

Is common in patients with CKD and is primarily due to decreased renal erythropoietin production. Correction of anemia with blood transfusions or erythopoietic stimulating agents often improves platelet dysfunction. It has been proposed that rheologic factors play an important role in the overall relationship between anemia and platelet function.

4. Nitric oxide

NO is an inhibitor of platelet aggregation that is produced by endothelial cells and platelets. Studies have shown that platelet NO synthesis is increased, may be due to elevated levels of guanidinosuccinic acid (uremic toxin).

Treatment:

No specific therapy is required in patients without bleeding even in the setting of severe azotemia. Correction of platelet dysfunction is warranted in patients who are actively bleeding or who are about to undergo a surgical procedure. It is important to identify any sources of bleeding.

 

A number of modalities to improve platelet function and reduce bleeding, which vary in their onset and duration of action.

 

1. Dialysis:

Hemodialysis can partially correct the bleeding in about two thirds of uremic patients. It should be done without systemic anticoagulation.

2. Desmopressin

It is the simplest and most rapidly acting of acute treatment for platelet dysfunction in uremic patient. dDAVP is effective in at least one-half of patients and appears to act by increasing the release of large factor VIII: von Willebrand factor multimers from endothelial cells. Other factors may include increases in platelet membrane glycoprotein expression. dDAVP can be given intravenously at a dose of 0.3 mcg/kg (in 50 ml of saline over 15 to 30 minutes if IV) or 3 mcg/kg if intranasally. The improvement in bleeding time begins within one hour and lasts 4 to 8 hours. Tachyphylaxis typically develops after the second dose, perhaps due to depletion of endothelial stores of the factor VIII: von Willebrand factor multimers. Reduced urine volume and hyponatremia may occur in patients who have urine output.

 

3. Correction of anemia

Raising the Hb to about 10g/dL or higher will reduce the bleeding time in many patients, occasionally to a normal level. This can be achieved by RC transfusions or via administration of recombinant erytrhopoietic stimulating agents (ESAs). The improvement in platelet function persists for as long as the Hb remains elevated. ESAs may also have a direct beneficial effect on platelet function.

4. Estrogen
Most chronic control of bleeding can be achieved in many uremic patients by the administration of conjugated estrogens. The long term use is limited by estrogen related side effects. The mechanism is not well understood but may be due to decreased generation of NO.

5. Cryoprecipitate
The infusion of cryoprecipitate (10 units intravenously every 12 - 24 hours) can shorten the bleeding time in many uremic patients. The improvement in BT begins within one hour and lasts 4-24 hours;  it is presumably mediated by the presence in cryoprecipitate of a substance that enhances platelet aggregation, such as factor VIII: von Willibrand factor multimers. The potential risk of infectious complications of this modality limit its use to patients with life threatening bleeding who are resistant to treatment with dDAVP and blood transfusions.

In my opinion, the surgeons (esp ENT surgeon in my case) should understand about the multifactoral causes of platelet dysfunction in uremia. There is no correlation in between the  value of BUN and the risk of bleeding. If the patient is on regular dialysis, have a good Hb and no evidence of spontaneous bleeding there are no reasons to postpone the tracheostomy. If intermittent HD is done, anticoagulation should be avoided especially after the procedure. I should do more PDT in my ICU to overcome this problem.

 

D-dimer in diagnosing of PE

There were five trauma cases this morning in the ICU. The ICU 2 was admitted during the weekend. Another polytrauma case (without TBI), who developed acute respiratory failure and required ventilatory support. The injuries are fracture  right ribs from 2nd to 5th, lung contusion, open book fracture and fracture femur. The C-spine was cleared clinically. There were bilateral pulmonary infiltrates on both sides of the lungs. He has moderate increased in A-a gradient. I start to go thru few differential diagnoses in my mind which include fat embolism syndrome, PE, aspiration pneumonia, worsening lung contusions and finally TRALI. Suddenly I was distracted by the MO's comment: Since the D-dimer was positive, this patient has been treated for pulmonary embolism and 'they' have started him on fondaparinux...I asked, what was the next plan? She said, the orthopedic team is planning for ILN once this patient is more 'stable'..Actually, I raised few issues, first of all the safety of fondaparinux in this pelvic injury and secondly since when D-dimer was used as a confirmatory test for PE??

"D-dimer assays for the diagnosis of PE have been extensively studied. They are best characterized as having good sensitivity and negative predictive value but poor specificity and positive predictive value."

Sensitivity: D-dimer levels are abnormal in about 95% of all patients with PE when measured by ELISA, quantitative rapid ELISA or semi-quantitative rapid ELISA. This falls to about 90% when measured by qualitative rapid ELISA or quantitative latex agglutination, 86% measured by semiquantitative latex agglutination and 82% measured by erythrocyte agglutination. Among patients who have subsegmental PE, d-dimer levels are abnormal in only 50% when measured by quantitative latex agglutination.

Specificity: D-dimer levels are normal in only 40-68% of patients without PE, regardless of the assay used. This is a consequence of abnormal D-dimer levels being common among hospitalized patients, especially those with malignancy or recent surgery. The specificity decreases even further in the setting of severe renal dysfunction and increased patient age.

NPV: The ability of a normal or negative D-dimer assay to exclude acute PE  depends on both the type of D-dimer assay and the clinical pretest probability that a patient has acute PE.

Taken together, the evidence indicates that a D-dimer level less than 500ng/ml by quantitative ELISA or semiquantitative latex agglutination is sufficient to exclude PE in patients with a low or moderate pretest probability of PE.
source: uptodate.com



 

BLUNT AORTIC INJURY

Today, during the morning handover, there was a polytrauma case. Very interesting, since he has thoracic aorta dissection,, open book fracture of pelvis, liver laceration and fracture femur. Another striking findings were rhabdomyolysis and acute kidney injury. This is a very interesting case since there are a few possible causes of acute kidney injury which include hypovolemia, contrast induced nephropathy, rhabdomyolisis, and trauma to the genitourinary tract.

I asked the MO, was the dissection due to blunt aortic injury?? Well, she didn't have a clue.

Blunt aortic injury usually occur at the junction between the mobile arch and the fixed descending aorta, just distal to the origin of the left subclavian artery, as a result of severe deceleration injury. Less frequently, the ascending aorta or arch vessels are injured by direct trauma.

It is divided into two:
1. Significant aortic injury: with disruption of the intima and full thickness of the media. There is a high risk of rupture

2. Minimal aortic injury: with laceration limited to the intima and inner media.  Radiologically this manifests as an intimal flap< 1 cm with minimal periaortic hematoma. There is a low risk of rupture

Clinical signs include unequal upper limb pulses, pseudocoarctation or interscapular murmur. The aortic injury should be suspected if the mechanism of injury is suggestive of rapid deceleration such as high speed (greater than 90 km/hr) motor vehicle or motorcycle crashes or a pedestrian hit by a vehicle.
CT and transesophageal echocardiography have been used for screening and diagnostic purposes.
Limitation of TOE : it provides high diagnostic accuracy for aortic injury and also allows examination for blunt cardiac injury. Imaging of distal aorta, proximal arch and major branches are limited.

Chest radiograph signs of blunt aortic injury:
1. Signs of periaortic hematoma:
-Widened mediastinum > 8 cm at the level of aortic knuckle
-Obscured aortic knuckle
-Opacification of aortopulmonary window
-Deviation of trachea, left main bronchus or nasogastric tube
-Thickened paratracheal stripe

2. Indirect signs:
-left haemothorax
-Left pleural cap
-Fractured first or second ribs


Significant aortic injury requires prompt surgical or endoluminal stent repair. Surgery should be deferred sometimes indefinitely if severe associated injuries or comorbidities make the operative risk unacceptably high.
Options for surgery: direct repair (clamp and sew), endoluminal stent repair.
Conservative management includes antihypertensive therapy (B-blockers +/- vasodilators) and serial imaging to assess for expanding pseudoaneurysm that will require intervention.

reference: Oh's intensive care manual 5th edition pg 794













 

Tumor Lysis Syndrome

It is caused by massive lysis of malignant cells and leads to release of large amounts of potassium, phosphate and uric acid into the systemic circulation with secondary hypocalcemia. Acute kidney injury can result from precipitation of uric acid and/or calcium phosphate in the renal tubules.

Most commonly encountered after initial chemotherapy for

a) High grade lymphomas (particularly Burkitt subtype)

b) Acute lymphoblastic leukemia (mature B cell acute lymphoblastic leukemia)

c) May occur spontaneously in high grade lymphoma or ALL

d) May occur in other tumor types with a high proliferative rate, large tumor burden or high sensitivity to cytotoxic therapy.

Diagnosis: Cairo-Bishop Definition of TLS

Laboratory tumor lysis syndrome is defined as any 2 or more of the following metablic abnormalities and presents within 3 days before or 7 days after instituting chemotherapy.

a) Uric acid > 476 micromol/L or 25% increase from baseline

b) Potassium > 6 mmol/L or 25% increase from baseline

c) Phosphate > 1.45 mmol/L in adults (> 2.1 in children) or 25% increase from baseline

d) Calcium < 1.75 mmol/L or 25% decrease from baseline

Clinical TLS: is defined as laboratory TLS plus one or more of the following that was not directly or probably attributable to a therapeutic agent

a) Increased serum creatinine > 1.5 from the upper limit normal

b) Cardiac arrythmias/sudden death

c) Seizure

Treatment

Best management is prevention
 

1. Key components are

a) Aggressive fluid hydration prior to therapy in all patients at intermediat or high risk for TLS. Children and adult should initally receive 2 to 3 L/m2 per day of IV fluid (or 200ml/kg per day in children weighing less than 10 kg). Urine output should be monitored closely and maintained within a range of 80 to 100 ml/m2 per hour (2 ml/kg for both children and adults, 4-6ml/kg in children less than 10 kg). Diuretics can be used to maintain the urine output, if necessary but should not be required in patients with relatively normal renal and cardiac function.
 

b) Diuresis
 

c) Administration of hypouricemic agents

Purine catabolism results in the production of hypoxanthine and xanthine which are metabolized to uric acid via the enzymatic action of xanthine oxidase. Allopurinol inhibits xanthine oxidase: blocking  hypoxanthine and xanthine to uric acid. After two to three days, allopurinol therapy results in increased excretion of both hypoxanthine which is more soluble than uric acid and xanthine which is less soluble than uric acid. A marked increase in xanthine excretion can occur when allopurinol is given for prevention of TLS and may lead to acute renal failure or xanthine stones. Allopurinol does not reduce the serum uric acid concentration before treatment is initiated. Thus for patients with pre-existing hyperuricemia, rasburicase is the preferred hypouricemic agent. Urate oxidase (which in not present in human) oxidizes preformed uric acid to allantoin which is 5 to 10 times more soluble than uric acidin acid urine. When exogenous urate oxidase (rasburicase) is administered, serum and urinary uric acid levels decrease markedly within approximtely four hours.

 

d) Urinary alkalinazion: generally not recommended. Benefit in increasing uric acid excretion is unproven. Potential harms, particularly in the setting of hyperphosphatemia.

e) Indications for dialysis are oliguria, persistent hyperuricemia, hyperphosphatemia and hypocalcemia.

Indications for renal replacement therapy include:

-Severe oliguria and anuria

-Persistent hyperkalemia

-Hyperphosphatemia induced symptomatic hypocalcemia

PERCUTANEOUS TRACHEOSTOMY

Important summary of my presentation:

Since Ciaglia et al. described the percutaneous dilatational tracheostomy (PDT) in 1985, PDT has gained popularity over surgical  tracheostomy in the intensive care setting. Percutaneous tracheostomy (PCT) requires less time to perform, it is less expensive and it is typically performed sooner (because an operating room does not have to be scheduled).  In a meta-analysis of 17 randomized control trials, PDT offers several advantages such as decreased wound infections, decreased bleeding and mortality compared to surgical technique. Indications for PCT are the same as those for standard open tracheostomy. Established contraindications against PCT are unstable fractures of cervical spine, severe local infection of anterior neck and uncontrolled coagulopathy. Relative contraindications are high PEEP or oxygen requirements, difficult anatomy, proximity to extensive burns or surgical wounds, elevated intracranial pressure, haemodynamic instability and previous radiotherapy to the neck.  In experienced hands, PDT seems to be a safe procedure. The number of relative contraindications to PDT declines with increasing operator experience. Overweight patients have a five times higher risk of perioperative complications with PDT than normal weight patients.

Percutaneous tracheostomy using the dilator (or Ciaglia) technique is superior to other percutaneous approaches including the single-forceps (Griggs) technique. Several commercial kits are available for PDT. Eventhough procedure differs slightly with choice of kit, the basic steps remain common. No strong evidence supports one specific kit or technique. To minimize complications, it is recommended that each institution chooses one kit and gain familiarity to appreciate its advantages and drawbacks. With bronchoscope guidance, the operator can ascertain correct tracheostomy site, intratracheal guidewire placement, intratracheal dilator placement without tracheal damage, proper partial withdrawal of the endotracheal tube and placement of tracheostomy tube. If ultrasound machine is available, a skilled operator can evaluate the anatomy of major vessels and the thyroid gland in relation to tracheostomy site. It helps in localize the level of tracheal rings and indentify midline puncture, depth etc. Following PDT, a routine chest radiograph is probably unnecessary, provided the procedure had been uncomplicated. In a retrospective review of 60 patients undergoing tracheostomy with bronchoscopic guidance, a post-procedure chest radiograph was only useful in detecting complications following procedures deemed difficult by and experienced operator.

 

Vancomycin in ICU

I am writing this today because someone is confused on prescribing vancomycin in critically ill patients. I hope this comment is useful, at least for my revision.

 

Vancomycin is a glycopeptide antibiotic, used for suspected or proven gram-positive infections.  Vancomycin's primary route of elimination is by renal excretion of unchanged drug. The rate of elimination is directly related to creatinine clearance.

 

The rate of killing depends primarily on time of concentration exceeding the organism's MIC (concentration dependent with time dependence). The ratio of area under the time concentration curve  during a 24 hour period to MIC(AUC0-24h/MIC ratio) is the best predictor of efficacy in this model.

Adverse effects:

1. Red man syndrome: is anaphylactoid reaction during or immediately following rapid infusion of large doses of vancomycin. Flushing usually involves face and neck, but can affect the whole body. It may be eliminated by avoiding massive doses and prolonging the infusion time e.g. no more than 500mg/hour or a maximum of 15 mg/min should prevent most infusion related reactions.

2. Nephrotoxicity: in monotherapy is not fully understood since early preparations were associated with nephrotoxicity. Only 20 cases reported in the medical literature in the years 1956-1984 despite the incessant use. Most of these cases were complicated by concomitant aminoglycoside therapy and pre-existing renal problems as well as investigator discrepancies in interpreting serum levels. Renal insufficiency due to vancomycin administered concomitantly with an aminoglycosides is well established. The incidence of acute renal failure in this setting may be as high as 20 to 30 percent.

3. Ototoxicity: has been described but it is the incidence is < 2%. Only approximately 40 cases of oto- and nephrotoxicity were reported in medical literature in the years 1956-1984.

Dosing

Vancomycin doses of 15 to 20 mg/kg should be administered q12h in patients with normal renal function, not to exceed 2g per dose. In settings where rapid clearance is anticipated, the intervals may be increased to q8h. For rapid achievement of target concentrations in seriously ill patients, a loading dose of 25 to 30 mg/kg may be administered. This may be appropriate for patients with critical illness in the setting of high anticipated Vd (e.g. burns, fluid overload).

 

Vancomycin dosing is based on actual BW (even in the setting of obesity), and doses are rounded to the nearest 250 mg. In general, the drug should b infused over 0.5 hours for each 500mg increment (e.g. 500mg over 0.5 hours, 1g over 1 hour etc). In the setting of the red man syndrome, the rate of infusion may be reduced to 500mg over 1 hour.

 

In recent RCT of continuous infusion regimens have not shown substantial improvement in patient outcomes compared with intermittent dosing.

 

In obesity, to avoid individual doses greater than 2g, the total daily dse can be divided into 3 administrations (q8h). In patients with renal insufficiency, doses in the range of 15-20mg/kg (based on target trough concentration) rounded to the nearest 250mg should be administered at frequencies based on estimations of creatinine clearance.

 

Serum concentration monitoring

Troughs versus peaks: Trough concentrations are useful as surrogate to AUC and are generally considered the most accurate and practical method to monitor vancomycin. Therefore, optimal dosing is guided by knowledge of both susceptibility and trough concentration.

There is little role for the routine monitoring of peak vancomycin concentrations, given the concentration independent pd properties and lack of data correlating peak concentrations with either efficacy or toxicity. IDSA 2005 guidelines for endocarditis endorsed target peak of 30-45 mcg/ml, the opinion was based on animal models and invitro susceptibility data rather than clinical evidence.

 

Target trough

At least 10 mcg/ml, may reduce emergence of isolates with elevated MIC. In the setting of invasive infections (e.g. bacteremia, endocarditis, osteomyelitis, prosthetic joint infections, HAP, infections of CNS) aim trough of 15-20 mcg/ml. Such concentrations generally achieve an AUC/MIC of > 400 for isolates with vancomycin MIC < 1. If MIC is > 2 mg/ml, alternate therapies should be considered.

 

Timing of levels: trough concentrations should be measured within 30 minutes prior to infusion of the fourth or fifth dose following the inital dose or dose adjustment. Trough concentration monitoring should be performed in patients receiving vancomycin therapy longer than 3 days. Once target concentrations are achieved, the trough should be monitored at least weekly for patients who receive longer therapy.

Serum creatinine concentration should be determined daily until stable,the weekly. More intensive monitoring may be considered if renal function unstable, if nephrotoxic drugs are administered concomitantly.

For patients on RRT via the newer, more permeable high flux membranes, repeat vancomycin is often required following each session. Many favour supplemental doses of at least 500 mg following each hemodialysis session.

Whenever practical, serum concentrations assessed immediately prior to hemodialysis may be used to guide subsequent dosing.

 

Pulmonary Disease in Chronic Liver Failure

Portal hypertension is responsible for:
1. Gastrointestinal bleeding
2. Ascites
3. Portosystemic encephalopathy
4. Hepato-renal syndrome
5. Pulmonary disease:
    a. Hepato-pulmonary syndrome
    b. Porto-pulmonary hypertension

A. Hepatopulmonary syndrome
It is characterized by:
i. Portal hypertension (with or without cirrhosis)
ii. Hypoxaemia (A-a gradient > 15 mmHg on room air)
iii. Evidence of pulmonary vascular dilatation

Diagnosis: Contrast enhanced echocardiography demonstrates delayed  visualization of microbubbles (more than 3 cardiac cycles) into the left heart of injected agitated saline bubbles intravenously. This suggests intrapulmonary shunt, whereas immediate visualization would suggest intracardiac shunting.

Treatment: Oxygen therapy, exclusion of other causes of hypoxaemia (shunt) and liver transplant

B. Portopulmonary hypertension

It is characterized by:
i. Portal hypertension
ii. PCWP < 15 mmHg
iii. Pulmonary hypertension (mPAP > 25 mmHg at rest)
iv. Pulmonary vascular resistance > 120 dynes per m-5 (3 Woods units)

Diagnosis: Right heart catheterization with measurement of PAP is the 'gold standard for diagnosis.

Treatment is a liver transplant (LT). In appropriately selected subjects, LT can effectively treat all the complacations of endstage CLD. LT can be determined by calculation of the model for end-stage liver disease (MELD) score. It is contraindicated in severe pulmonary hypertension (mPAP > 50 mmHg) but can be considered in those who respond to treatment with oral or IV vasodilator therapy.

Reference: Manual of Intensive Care by Irwin and Rippe.

Questions: Forty year old man with history of hepatitis C presents with dyspnoea. On examination he is jaundiced, with spider naevi and ascites. Chest X-Ray and spirometry are normal. Pulse oximetry is performed: Standing 88% and Supine 97%. (From data interpretation in critical care medicine)

1. What is the likely diagnosis?
     Answer: Hepatopulmonary syndrome in end-stage Hep C cirrhosis.

2. What is the postulated pathophysiological mechanisms?
     Answer: Intrapulmonary vasodilation with right to left shunting. The process affects mainly the bases. Changes in posture that increase basal pulmonary blood flow (upright position) worsen gas exchange.

Orthodeoxia is hypoxaemia accentuated in the upright position.
Platypnoea is increased dyspnoea in upright position, improved by assuming the recumbent position. Causes are: a. Intracardiac shunts (intra-atrial shunt) with or without lung disease and b. Pulmonary vascular shunts (pulmonary artery-pulmonary vein communications) either anatomical or parenchymal.

3. What further investigation is indicated?
     Answer: see above

4. Is liver transplantation likely to help?
    Answer: Yes, over 80% of patients with hepatopulmonary syndrome have resolution or marked improvement in intrapulmonary vasodilatation with LT. This contrasts with portopulmonary hypertension which is considered a contraindication (see comment above).




 

stroke- imaging

A 55 year old man presented to the department of emergency medicine after developing right sided weakness and inability to speak. He has a history of hypertension on ACEI.

Q1: List CT head abnormalities seen in an acute ischemic stroke.
A:
1. Hyperdensity within an intracranial vessel owing to intraluminal thrombus.
2. Parenchymal hypoattenuation owing to cytotoxic oedema. Hypoattenuation on CT is highly specific for irreversible ischemic brain damage.
 3. Obscuration of gray white matter contrast and effacement of sulci owing to edema
 4. Insular ribbon sign. Hypodensity and swelling of insular cortex. Located between the Sylvian fissure and the basal ganglia, it is supplied by small perforating branches of the MCA.
5. Obscuration of the lentiform nucleus. Also called blurred basal ganglia - early and frequent sign in MCA infarction.

Q2: List the abnormalities you might expect to see in an MRI done in a patient with an acute ischaemic stroke.
Answer:

1. Subtle low signal (hypointense) on T1 - often difficult to see at this stage
2. High signal (hyperintense) on T2 - comparable to hypodensity on CT
3. High intensity on DWI - the most sensitive sequence for stroke imaging. DWI sensitive to restriction of Brownian motion of extracellular water due to imbalance caused by cytotoxic edema.

Reduction in the ADC. DWI is sensitive to the microscopic random motion of the water molecule protons, a value known as the apparent diffusion coefficient (ADC), which is measured and captured by this type of imaging. ADC maps allow us to assess the extent of ischaemic disease. Measuring the ADC allows us to get an idea about the depth of ischemia in the penumbra itself and to obtain data regarding tissue viability.

MRI is commonly used method for assessment of the ischemic core and penumbra. The diffusion weight MRI (DWI) lesion is generally assumed to reflect the ischemic infarct, whereas the PWI perfusion weighted MRI (PWI) which uses gadolinium contrast lesion includes both infarct and penumbra hence the potential for perfusion mismatch.