VASST trial

VASST trial

- Evaluate the role of vasopressin in septic shock being treated with conventional vasopressors.

What they did? Read it here
http://www.nejm.org/doi/full/10.1056/NEJMoa067373

Refractory septic shock in this study was defined as
- septic shock resistant to 500 mL of fluid and low dose norepinephrine (and required other vasopressors).

So are these patients really having REFRACTORY septic shock?
From http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/infectious-disease/sepsis/ : Refractory septic shock is a persistently low mean arterial blood pressure despite vasopressor therapy and adequate fluid resuscitation

Look at their mean MAP: it is about 70 mmHg (River's protocol MAP is 65 mmhg)
Look at their lactate: mean is 3.5

My opinion is: these patients were quite well resuscitated prior to randomization. They responded to whatever pressors given to them. So this is a study of vasopressin's role in septic shock in which you are considering to take off norepinephrine early, not really a study of vasopressin in REFRACTORY shock.

BUT, after patients achieved the target MAP, they were started on studied drugs. Open-label pressors were only given if the MAP could not be maintained. Based on the dosage of pressors use, they subdivided the patients into severe vs less severe groups.
- They did not specifically mentioned what the pressors they have used. But I think they just continued what the patients were using prior to randomization.
- Almost 60% only required one vasopressor, 30% required two vasopressors and 10% did not need any vasopressors (in addition to the studied drugs) to maintain MAP. The proportions were divided equally among two groups.
- And they were evaluating whether vasopressin has any role in severe vs less severe septic patients in comparison to NE

Another thing to consider is, they only received 0.5 cc of fluid and if they did not respond, pressors were started. 0.5 cc was perhaps too less, maybe pressors were given at higher doses that these patients really required.
- NE were given at mean dose of 20.7 mcg/min before randomization.
- Epinephrine were given at a mean dose of 8.6 mcg/min in NE group vs 14.6 mcg/min in vasopressin group.

How many of these patients ended in severe vs less severe septic group?
- 200 each from NE and vasopressin group were in severe group
- 182 vs 196 were in less septic group.
- So basically, whatever the patients received. around 200 ended up in severe vs less severe septic group (the drugs used weren't really important); BUT the drug used was important in determining whether the patients survived.
- In less severe group, vasopressin was better (reached statistical significance). In more severe group, neither was superior. However, test of interaction and post-hoc analysis did not find significant p-value between vasopressin and sepsis severity.

Anyway, what they found ?
Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressor

My thoughts:
- This study did not tell us the role of vasopressin if septic shock didnt respond to catecholamines.

- The mortality in this study was lower than expected. Perhaps reflecting the better care nowadays.

- Epinephrine was of higher dose in vasopressin group. Perhaps this affected the mortality at 28 days. Perhaps this is why NE infusion doses were lower in vasopressor group.

- In less severe septic shock, perhaps vasopressin is better (better vasoconstriction). But role within 6 hours is not known. Role substituting catecholamines is not known.

- In severe septic shock, NE is better. In fact, mortality was marginally better in the study in NE group. Perhaps related to its effect to improve microperfusion

TRANSFER-AMI trial

TRANSFER AMI study

Evaluate role and optimal timing of routine PCI after fibrinolysis (role of rescue PCI).

1059 patients with STEMI who were receiving fibrinolytics were assigned to standard treatment (rescue PCI or delayed angio if needed) or early PCI group (transfer to PCI facility within 6 hours). 

All groups received standard medical treatments.

Primary end point was the composite of death, reinfarction, recurrent ischemia, new or worsening CHF, or cardiogenic shock within 30 days

Study found that early PCI group had better outcome than standard treatment group. (17.2% vs 11.0%, Relative risk reduction of 0.64, p = 0.004)

Definition of terms:

1) Facilitated PCI : PCI done RIGHT AFTER fibrinolysis within 2 hours window. In this study, the median time from lysis-balloon inflation was about 4 hours.

2) Rescue PCI : life-saving PCI done if lysis has failed/contraindicated/cardiogenic shock.

- This is what this study was about, comparing rescue PCI vs patients who got routine PCI after fibrinolysis.

My conclusion:

- Group with routine PCI after fibrinolysis had significantly lesser primary end points, but mostly driven by lesser recurrent ischemia and to a lesser extent new/worsening CHF. Death and re-infarction did not reach statistical significance.

• But perhaps if more patients were enrolled, re-infarction would reach statistically significant reduction in early PCI group.

Take note that:

- Note that most of them had Killip class I. So this did not apply to patients who had cardiogenic shock as the initial presentation (in fact these patients were excluded).

- They also presented early (median time of 2 hours from symptom onset) and received fibrinolysis within 30 minutes of hospital presentation.

- More important is the study did not recruit enough patients and was underpowered to detect any difference in mortality.

- More patients in early PCI group had stroke/TIA, while more in standard tx group has prior CHF. 

- More patients in early PCI group received clopidogrel.

- There was higher rate of bleeding in early PCI group, but mostly were mild bleeding.

My opinion is:
If you can transfer AMI patients from non-PCI to a PCI facility within 6 hours of fibrinolysis, there maybe a benefit.

• Within 6 hours is the key, not sure if there is a benefit after 6 hours.
• PCI should be done after at least 3 hours of fibrinolysis.

Pathophysiologically, it makes sense, you are trying to save heart muscles which are not yet necrotic if you do early PCI.

References

Routine Early Angioplasty after Fibrinolysis for Acute Myocardial Infarction, NEJM 2009

Tips and Pearls for Chest X Ray part II

- Air fluid level

• Air fluid level in esophagus = esophageal stasis
• Intrapulmonary cavity with air fluid level - upper walls must be visible
• Hydropneumothorax = indistinct upper walls with different 'shape' of air fluid levels in PA and lateral view ( lower level can be outlined by the curved minor fissure )

- Thymoma can regularly metastasize to pleural layers

- Any opacity in diaphragm may arise below

- Lymph node with hypodense center - think about TB

- Ivory vertebrae ddx - adult - malignancy, lymphoma, Paget's disease of bone; kids - lymphoma, neuroblastoma, osteoblastoma, Ewing's sarcoma, osteosarcoma

- When the undersurface of the rib is eroded, the mass arises from the structure below the rib when it is found beneath the eroded rib

- There are 3 knobs on PA view in normal person - aortic knob, pulmonary arch and LV

• In MS, left auricle can be seen between pulmonary arch and LV
• A bulging pulmonary arch suggests PAH

- 3 ddx of bulging pulmonary arch

• Enlarged hilum + abrupt tapering of the vessels - PAH due to lung diseases or heart failure
• Enlarged hilum + increased vascularity seen in PA film - left to right shunt
• Normal or decreased vascularity without enlarged hilum - congenital pulmonic stenosis

- Kerley lines - A line, B line and C line

• Look for Kerley lines when u see reticular pattern 
• If CHF can be excluded, another ddx for Kerley line is lymphagitis carcinomatosis

- Aspiration due to achalasia normally goes to right apical lobe !!

- Upper lobe redistribution in hemithorax - CHF, MS or PE

- Hematoma can be suspected by seeing increased density of the mass in CT scan ( same as blood in LV )

- ABPA - tree in a bud pattern, can cause mucous impaction and lobar collapse

- PseudoPTX - the vessels will cross the pseudopleural line !!

- Oreo cookie sign - first layer - lung, second layer - fluid, third later - epicardial fat pad, diagnostic of effusion

- Lytic lesion in lung - MM, renal and thyroid cancer, blastic lesion ( Ivory rib ) - prostate cancer

- Air crescent sign - aspergilloma; water lily sign - hyatid cyst

- Know how to differentiate bullae vs pneumothorax

- Double density sign on aortic arch suggests a posterior mediastinal mass hiding behind the aorta

- Bronchiectasis can be cystic or cylindrical lesion

- Air below right diaphragm - pneumoperitoneum, pneumobilia ( Rigler's triad ), emphysematous cholecystitis and Chilaidit's syndrome

Tips and Pearls for Chest X Ray part I

- Humane approach to CXR interpretation : be curious, satisfy the need for search, KISS ( keep it simple, stupid !! )

- When assessing for airway position, do not forget to look at the esophagus !! Air fluid level + thickened retrotracheal line and displaced trachea to front is suspicious of esophageal stasis

- Rib notching w/o hypertension - do not diagnose coarctation of aorta

- If a mass overlies the ribs, assess whether there is any lytic lesion. You are done with your diagnosis if you could identify any bony involvements

- Pay attention to the spine and intervertebral disc when you are suspecting bone metastasis. Ivory vertebrae, collapsed disc are your clues that metastasis has happened

- Extrapulmonary mass must have distinct borders and forms obtuse angle with the lung. Another important sign is incomplete border sign.

- Pleural mass has in addition peripheral location and blunted costophrenic angle if located inferiorly

- A rounded atelectasis can be suggested if there is volume loss and the mass is located peripherally, pleural thickening and curvilinear vessels leading to it

- 3 complications of chronic pleural disease : malignancy, empyema necessitantis and bronchopleural fistula. 

• Malignancy can be distinguished by being a solid in CT scan. 
• Empyema necessitantis is a condition characterized by pus boring its way to the chest wall. 
• Bronchopleural fistula is characterized by an abnormal connection between the visceral pleura and the lung

- 3 subtle areas that can hide the mass - behind first rib, retrocardiac areas and subdiaphragmatic areas

- Always look in costophrenic angle and along the diaphragm for any nodular lesion ( in addition for effusion )

- A calcified nodule is likely to be benign

- A localized mass with air fluid level is highly suggestive of malignancy ( Squamous cell carcinoma )

- Always compare the position of left and right hilum. Left hilum usually is located between aortic knob and superior border of heart; right hilum just at the level of superior border of heart. A pulled up/down hilum suggests volume loss in that lung

- LLL collapse - sail sign, flat waist sign; LUL collapse - juxtaphrenic peak sign; Lufsichel sign

- Lufsichel sign is not only found around aortic knob, it can be a band of hyperlucency anywhere in the upper lobe of left lung

- If inspiratory and expiratory films are done, it is important to know before interpretation, which phase is pathological !!

- Congenital bronchial atresia is not uncommon. An area of hyperlucency with tubular density ( mucous impaction ) is suggestive

- Only 3 things cause tubular densities in lung - mucous, vascular lesions and herniated bowel loops

- The most common cause of lung collapse is cancer !!

- Fibrous dysplasia is not uncommon, seen as solitary lesion in a rib in a young patient

- Bulging of any of the mediastinal lines suggest mediastinal mass. Confirm with lateral X ray

- Always consider vascular pathology in ANY of the mediastinal mass ( mediastinum is made up of basically vessels )

- Look at the anterior clear space at lateral X ray for anterior mediastinal mass

- Superior mediastinal mass can be in anterior or posterior compartment. A superior mediastinal mass located posteriorly is likely a vascular lesion. It will show what is called cervicothoracic sign ( the mass will extend above clavicle )

- Always assess the centrality of the trachea. A displaced trachea in a S shaped manner suggests mass effect. Remember a trachea usually ends just at the beginning of the aortic arch. A displaced trachea at lateral film suggests mass effect

- Ddx of middle mediastinal mass depends on the location of the mass.

• A superiorly located - vascular mass; the most common is aortic aneurysm ; aortic aneurysm is also the most commonly mass that calcifies
• A middle-ly located - lymph nodes or duplication cyst ; look for bulging in azygoesophageal fissure
• An inferiorly located - esophageal pathology ( achalasia, stricture that leads to esophageal stasis )
• Always include esophageal pathology in ANY of the middle mediastinal lesions

- We only see the outer contour of aorta and  it's impossible to see the inner wall because it blends with mediastinal structures; a dilated aorta may not be dilated !!

- A dilated descending aorta + normal ascending aorta suggests type B aortic dissection

- Look in aortopulmonary window. A bulging window is suggestive of mass

- Unilateral lymph node and cavity - the top two ddx is TB and carcinoma

- Lymphoma causes anterior mediastinal lymphadenopathy as seen on CT

What I got from reading the slides " HIV update 2014 "

1) Dx of HIV - 

• Traditional - ELISA screening -> Western bot
• Now - 2 positive immunologic tests that are orthogonal ( different antigens or principles )
  - Ag/Ab test followed by Ab ONLY test
  - Ab test -> viral load assay
  - RAPID Ab test -> conventional immunoassay
  - A single non antibodies test ( p24, viral load ) is also diagnostic

2) Monitoring - viral load is better

3) Inclusion of stage 0

• Indicate very early infection, when seroconversion is taking place
• A sequence of discordant test results indicative of early HIV infection in which a negative or indeterminate result was within 180 days of a positive result
• Negative or indeterminate ab, ab/ag or NAT within 6 months BEFORE a positive test of any type or
• Positive test of viral specific markers within 6 mths of a negative / indeterminate antibody type
• If > 180 days after stage 0 has been diagnosed, the stage is classified at stage 1,2,3 or unknown
• Exception - stage 0 is NOT diagnosed if the negative / indeterminate HIV test was preceded > 60 days by a confirmed positive HIV test, a clinical dx of HIV, CD4 or opportunistic infection indicative of stage 3 infection

HIV and TB

1) Look out for 4 sxs of TB - fever, cough, night sweats and LOW - absence of 4 combos have high NPV

2) LTBI = TST/IGRA +ve but CXR and smear negative

- Daily INH for 9 months

3) TB tx in HIV

- EHRZ DAILY instead of 3X weekly

- Bactrim prophylaxis ( protect against toxoplasmosis and PCP ), at least for 6 months

4) When to start ART in TB

A new RCT suggests starting ART early in CD4 > 220 does not give any advantage over late ART

5) DIH ( Drug induced hepatitis )

- Dx if

• Sxs + AST/ALT > 3X ULN
• No Sxs + AST/ALT > 5X ULN

- Hepatotoxic anti TB drugs - INH and pyrazinamide are the most potent

• Less - rifampin
• Least -  ethambutol, streptomycin and FQ

6) Options to DIH

• Stop it - if patient has less bacilli burden
• Change to SEF ( least toxic ) combination if high bacilli burden ( disseminated, miliary or cavitation )

7) Overlapping toxicities

- Notice that NNRTIs have many overlapped toxicities with anti TB drugs

- Basically ALL ARV drugs are hepatotoxic

Change of HAART

1) Efavirenz

- Avoid in people working in night shifts

- Avoid in depression

2) Tenofovir - avoid in kidney disease, osteoporosis

    Zidovudine - can cause macrocytic anemia, so avoid in anemia

    Abacavir - avoid in heart disease

    

3) Avoid NVP and abacavir in very high viral load ( > 100,000 )

4) Tx failure - ask about adherence and potential side effects ( reasons of stopping )

5) Efavirenz and Nevirapine can BOTH cause rash

6) Algorithm

7) Early vs late switch

• Less resistance developed in early switch, but more pricey
• More resistance in late switch, but cheaper

8) NNRTI resistance is more common

• Takes longer time to peak, so virus has time to adapt

9) NRTI resistance - common in 3TC based regimen ( + AZT or TNF ) 

• NRTIs are structurally similar to purines and pyrimidines, so RT will not be able to differentiate between NRTIs and their natural counterparts -> so is incorporated into the synthesis of viral DNA -> NRTIs prevent the elongation of the DNA chain
• Resistance can develop when the RT has reduced ability to incorporate the drug

HIV and CNS

1) HIV is neutropic drug

2) Toxoplasmosis can present with focal CNS lesions or encephalitis

• IgM is not useful is dx, 90% is IgG
• Rx and evaluate response after 2 weeks
• Prophylaxis - Bactrim

3) Cryptococcosis

- Rx - liposomal amphotericin B + flucytosine and maintenance by fluconazole untol CSF fungal C and S is negative

- For high ICP, repeat LP or CSF shunt ( mannitol/ steroids NOT effective )

4) Timing of HAART after OI

Drug-drug interactions

1) Important rxns to note

• CYP 3A4
  - Inducers - NVP, EFV
  - Inhibitors - PIs ( Ritonavir )
• CYP 1A2
  - INDUCED by ritonavir
• CYP 2C19
  - INDUCED by ritonavir 

Ritonavir INHIBITS CYP 3A4 but INDUCES other CYPs

2) AZT and d4T not to be used tgt - binding competition

3) AZT and ganciclovir NOT to be used tgt - bone marrow toxicity

4) Important DDIs

Credit to all the people that prepare these nice and beautiful figures !!

Breathing patterns

Blalock-Taussig shunt, Norwood and Fontan surgery

Have always bee confused how do these all work up here i hope to simplify them

BTS
- Simply to connect left pulmonary artery and left subclavian artery
- Reason : there is limited pulmonary blood flow as in TOF or to become another source of pulmonary circulation ( as in Norwood procedure )

Bottom line
- We use BTS if there is not enough blood in pulmonary circulation
- Without blood going through lung, there will be no oxygenation of the blood and the kid will be in cyanosis ( as the circulating blood is deoxygenated blood )

Norwood
- BTS + Atrial septectomy + Anastomosis between MPA and aortic arch
- Reason to do this - only RV is working
- Distal MPA is transected and proximal MPA is anastomosed to aortic arch -> so now all blood is delivered to systemic circulation by RV
- Now the problem arises : from where pulmonary circulation gets the blood ? As MPA has already been transected....We use a BTS !!!
- To make sure the blood from LA gets to RV, atrial septectomy is done for shunting to right chambers to occur

Bottom line
- Norwood is done if we want temporary RV function to pump blood to systemic circulation

Fontan
- 2 stages - 1st stage - redirect all SVC blood to pulmonary circulation; 2nd stage, redirect IVC blood to pulmonary circulation BYPASSING RV
- Purpose - when ONLY one ventricle is working
- Done after Norwood
- By shunting all venous blood to pulmonary circulation, we spare RV

Now then RV is either not working ( Tricuspid atresia ) so the atrial septectomy done in Norwood can be used to shunt the blood to LV
If LV is not working, blood is shunted to right and RV is used to pump blood to systemic circulation

Note that
In Norwood, the blood in RV is mixed
In Fontan, RV is separated from vena cava by a tube - so ALL the blood in RV/LV is OXYGENATED blood