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JOURNAL CLUB DECEMBER 2011

Chief : Dr.Bagialakshmi.MD

Asst : Dr.Peer Mohamed.MDDr.Premkumar.MD

VI MU

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High frequency oscillations in patientswith acute lung injury and acute

respiratory distress syndrome(ARDS):

systematic review and meta-analysis.

BMJ 2010;340:c2327

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INTRODUCTION

ALI and ARDS life threateningconditions

Acute lung inflammation characterised

by pulmonary congestion, hypoxemiaand decreased pulmonary compliance

Substantial mortality and morbidity

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EXISTING MODALITIES OFMECHANICAL VENTILATION

Conventional mode

Nitric oxide inhalation

Prone position ventilation

Extra corporeal membraneoxygenation

High frequency oscillation

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HIGH FREQUENCY OSCILLATION

Mode of mechanical ventilation

Small tidal volumes delivered at highfrequencies (3-15 hz) with an

oscillatory pump Lung protective ventilation with

extremely small tidal volumes (1-4

ml/kg) Constant lung recruitment

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OBJECTIVE

Systematic review and meta-analysis wasdone for 8 RCTs of high frequencyoscillation compared with conventionalmechanical ventilation for adults and

children with ACUTE LUNG INJURY andARDS

To determine effects on

MortalityClinical outcomes

Physiological outcomes

Adverse effects

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METHODS

SYSTEMATIC REVIEW PROTOCOLWITH PRE SPECIFIED CRITERIA

FOR STUDY SELECTION,OUTCOME MEASUREMENT ANDANALYSIS

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METHODS CONTD

Study identification

Study eligibility

Data extraction and study quality

Outcomes

Statistical analysis

Subgroup analysis

Results

Adverse events

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STUDY ELIGIBILITY

Adults

Children (over 4wks and over 42 wksafter conception)

With ALI or ARDS

On conventional mechanicalventilation

Randomly assigned to experimentaland control groups

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Inclusion criteria :

Both adults and children

Primary ventilation strategy till

resolution of ARDS Secondary intervention- tracheal gas

insufflation, recruitment manuovers

High frequency oscillation for 24 hrs orless for physiological outcomes

Exclusion : cross over trials

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DATA EXTRACTION AND STUDYQUALITY

Data extracted on : study methods, ventilationstrategy details, study outcomes

Study methods Included : methods ofrandomisation, allocation concealment,

withdrawals, losses to follow up etc Risk of bias summarised using COCHRANE

COLLABORATION RISK OF BIASINSTRUMENT

Study quality assesed quality of evidence forclinical outcomes (mortality, treatment failure,adverse events)

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No of

patientsMean age

(years) SettingDays of ventilation

before study Details of lung injury Overall risk of bias*Arnold et al,48 1994 70 (weight

35 kg)2.8 5 US paediatric

ICUs4.5 ARDS (86%) or

pulmonary barotrauma

requiring chest tube

(14%)

Unclear (>10% (30/58)

crossovers; outcome data for

12/70 patients not available after

author contact)

Derdak et al,51 2002 148 49 ICUs in 13 UShospitals

1.9 ARDS; PEEP >10 cmH2O

LowShah et al,552004 28 49 1 ICU in Cardiff 10% (11/61)

crossovers; ICU but not 30 day

mortality available for 3/61

patients after author contact; trialterminated early because of slow

recruitment)

Papazian et al,53 2005 26 51 1 ICU in Marseille,France

15 for

4 h

Low

Demory et al,50 2007 28 49 1 ICU in Marseille,France

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High frequency oscillation Conventional ventilationFreq

uenc

y

(Hz)

Mean Paw

(cm H2O

above

CMV)P (cm H2O)

titration parameter

or goal

Recruitme

nt

manoeuvre

protocolCriteria for transition to

CMV Mode Tidal volumeAdjustment of

PEEP (cm

H2O)

Recru

itmen

t

mano

euvre

Arnold et

al,48 19945-10 4-8 Achieve chest wall

vibration oraccording to transcut

PCO2 sensor

No Mean Paw 18 cm H2O,tolerating suctioning

Pressure

limitedNR Clinician

discretionNo

Derdak et

al,51 20025 5 Achieve vibration

from chest wall to

mid-thighNo FiO2

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High frequency

oscillationConventional mechanical

ventilationSedation and

paralysis applied

equally to both

groups

Protocols for

ventilator

weaning and

extubation

Funding*

(industry

support)

Arnold et al,[48] 1994 NR NR No NR Yes

Derdak et al,[51] 2002Nitric oxide, 4/75;

prone position, 2/75,

high dose steroids,

1/75

Nitric oxide, 8/73; prone

position, 3/73; high dose

steroids, 4/73No No Yes

Shah et al,[55]2004 None None Yes NR NoBollen et al,[49] 2005 NR NR NR No Yes

Papazian et al,[53] 2005 All patients ventilatedin prone position

All patients ventilated in prone

position Yes No NoSamransamruajkit et al,[54]

2005 Nitric oxide, 1/7 Nitric oxide, 0/9 Yes No No

Demory et al,[50] 2007Prone position for 12

h before HFO in

supine positionProne position for 12 h prior to

CMV in supine position Yes No No

Mentzelopoulos et al,[52]

2007All patients received

tracheal gas

insufflation. Steroids

for ARDS, 20/27Steroids for ARDS, 21/27

No (27/27 HFO v

17/27 CMV patients

paralysed)Yes No

ADDITIONALINTERVENETIONS

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OUTCOMES

CLINICAL OUTCOMES : hospital or30 day mortality, 6 months mortality,duration of mechanical ventilation,

quality of life, treatment failure PHYSIOLOGICAL OUTCOMES :

24, 48 & 72 hrs after randomisation

oxygenation (PaO2/FiO2),oxygenation index, ventilation(PaCO2)and mean airway pressure

No of patients

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No of trialsNo of patients

with events/Total

No of patientsEvidence assessment* RR or WMD (95% CI), P

valueClinical outcomes

Hospital (or 30 day)

mortality 6 160/365Moderate quality: randomised trials with some

methodological limitations, no inconsistency (I2=0%),

direct, some imprecision, no publication bias0.77 (0.61 to 0.98),P=0.03

Treatment failure 5 73/337Moderate quality: randomised trials with some

methodological limitations, no inconsistency (I2=0%),

direct, some imprecision0.67 (0.46 to 0.99), P=0.04

Ventilator days 4 276Low quality: randomised trials with some

methodological limitations, no inconsistency (I2=0%),

direct, considerable imprecision0.8 days (5.4 to 3.9),

P=0.75Ventilator free days to

day 28 1 54 Low quality: direct, considerable imprecision2.0 days (0.7 to 4.7),

P=0.15Adverse events

Barotrauma 6 41/365Low quality: randomised trials with some

methodological limitations, no inconsistency (I2=0%),

direct, considerable imprecision0.68 (0.37 to 1.22), P=0.20

Hypotension 3 11/267Low quality: randomised trials with some

methodological limitations, no inconsistency (I2=0%),

direct, considerable imprecision1.54 (0.34 to 7.02), P=0.58

Endotracheal tube

obstruction 4 7/246 Low quality: randomised trials with somemethodological limitations, direct, considerableim recision

1.30 (0.30 to 5.60), P=0.73

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STATISTICAL ANALYSIS

Meta-analysis using RANDOM EFFECTMODELS which provides widerconfidence intervals where heterogeneityis present

Outcomes reported using weighted meandifference or ratio of means for measureof absolute change & binary outcomes as

risk ratios

Publication bias assessed using Beggs

rank correlation test and a modified

macaskills regression test

SUB GROUP ANALYSIS

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SUB GROUP ANALYSIS

HOSPITAL OR 30 DAY MORTALITY

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HOSPITAL OR 30 DAY MORTALITY

PaO2/FiO2

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PaO2/FiO2

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ADVERSE EVENTS : barotrauma,hypotension, obstruction to ETT,technical complications and

equipment failure includingunintensional system air leaks &problems with oscillatory diaphragms,

humidifier and alarm systems in HFOgroup

ADVERSE EVENTS

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ADVERSE EVENTS

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DISCUSSION

High frequency oscillation reducedhospital and 30 day mortality

Decreased risk of treatment failure

No efffect on duration of mechanicalventilation

Improved oxygenation probably by

increasing transpulmonary pressureand recruiting collapsed alveoli

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DISCUSSION CONTD

No effect on oxygenation index due tohigher mean airway pressure duringHFO

No effect on PaCO2 Not associated with increase in

adverse effects

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STRENGTH & LIMITATIONS

Minimised bias by comprehensiveliterature search

Predefined protocol to outline

hypothesis Methodological assessment of primary

studies

Planned statistical analysis

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STRENGTH & LIMITATIONS

Blinding not feasible among patients,families or clinicians

Risk of bias unclear in 2 trials

One trial terminated early due to lowrecruitment

Cross over treatment

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FUTURE RESEARCH

HFO reduces mortality in ARDScompared to conventional ventilationand unlikely to cause harm

Completion of ongoing multicentreRCTs will provide more definitive dataon mortality and safety for this

intervenetion

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FINAL WORD

WHAT IS ALREADY KNOWN Some centres routinely use HFO as a

rescue measure to treat ARDS with noevidence of mortality benefit

WHAT THIS STUDY ADDS

An updated review of 8 RCTs pooledresults suggest that HFO

Improves oxygenation

Reduces risk of treatment failure

Reduces hospital/ 30 day mortality

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TARGETING MICROCIRCULATIONAS TREATMENT OF SHOCK &

SESPIS

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LEVOSIMENDAN

Improves microcirculation andimproves mortality

PDE III inhibitor & calciumsensitizer

Inodialator

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ThankYou

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THREE MONTHS OF

RIFAPENTINE AND INH FORLATENT TUBERCULOSIS

INFECTIONN Engl J Med 2011; 365:2155-2166December 8,2011

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Background

Treatment of Latent MycobacteriumTuberculosis infection is an essentialcomponent for control and elimination.

The current standard regime ofisoniazid for 9 months is efficaciousbut is limited by

Toxicity Low rates of treatment completion

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Aim of the presentation

To prevent tuberculosis and highertreatment completion rate

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METHODS

Randomized control trial, comprisingof

3 months of directly observed therapy

with Combination therapy group

Rifapentine (900mg)+Isoniazid (900mg)

Isoniazid group Isoniazid (300mg ) for 9 months

In subjects of high risk tuberculosis

Subjects were enrolled followed for 33months

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RESULTS

Combination therapy Isoniazid therapy

Subjects 3986 3745

Tuberculosis 7 15

Rate of treatmentcompletion

82.1% 69.0%

Rate of permanentdrug completion

4.9% 3.7%

Drug relatedhepatotoxicity

0.4% 2.7%

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CONCLUSION

The use of Rifapentine plus Isoniazidfor 3 months was as effective as 9

months of Isoniazid alone inpreventing tuberculosis and had ahigher completion rate.

Long term safety monitoring will beimportant

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2010 AHA Guidelines- TheABCs of CPR Rearranged

to CAB

2010 American Heart Association

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2010 American Heart AssociationGuidelines for CPR and emergency

cardiovascular care

The AHA has rearranged the A-B-C ofCPR to C-A-B

Chest compressions are therefore the

first step for lay and professionalrescuers to survive an individual formsudden cardiac arrest

Speed of rate of chest compression at

least 100 times a minute Between each compression, rescuers

should avoid leaning on the chest so that

it can return to the starting position

C i h ld b d d l i t

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Compression should be made deeply intothe chest to a depth of at least 2 inches inadults

To confirm intubation and monitor CPRquality professional rescuers should usewaveform capnography to measure tomonitor cardiac output

Therapuetic hypothermia should beincorporated into overall interdisciplinarysystem of care after resuscitation fromcardiac arrest

For management and treatment of Pulselesselectrical activity (asystole) atropine is nolonger recommended for use

For intial diagonosis and treatment ofstable, undifferenciated regular,monomorphic wide complex tachycardia

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ThankYou

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Decreasing Sleep-Time Blood Pressure

Determined by Ambulatory MonitoringReduces Cardiovascular Risk

Journal of the American College of Cardiology Vol. 58, No. 11,2011

2011 by the American College of Cardiology Foundation ISSN0735-1097

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Objectives

Whether reduced cardiovascular riskis more related to the progressivedecrease of asleep or awake blood

pressure.

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Background

Independent studies have concludedthat elevated sleep-time bloodpressure is a better predictor of

cardiovascular risk than awake or 24hrblood pressure means.

However, the impact on

cardiovascular risk of changes inthese ambulatory blood pressurecharacteristics has not been properlyinvestigated previously.

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Methods

3,344 subjects(1,718 men &1,626women), 52.614.5yrs of age, during amedian follow-up of 5.6yrs wereprospectively studied.

Those with hypertension at baselinewere randomized to ingest all theirprescribed hypertension medicationsupon awakening or 1 of them atbedtime.

Blood pressure was measured for 48hrat baseline and again annually or more

frequently (quarterly) if treatment

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Results

With data collected at baseline, whenasleep blood pressure was adjusted byawake mean, only the former was asignificant predictor of outcome in a Cox

proportional hazards model alsoadjusted for sex, age, and diabetes. Analyses of changes in ambulatory blood

pressure during follow-up revealed a17% reduction in cardiovascular risk foreach5-mm Hg decrease in asleep systolicblood pressure mean (p

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Conclusions

The sleep-time blood pressure mean is themost significant prognostic marker ofcardiovascular morbidity and mortality.

Most importantly, the progressive decrease in

asleep blood pressure, a novel therapeutictarget that requires proper patient evaluationby ambulatory monitoring, was the mostsignificant predictor of event-free survival.(Prognostic Value of Ambulatory BloodPressure Monitoring in the Prediction ofCardiovascular Events and Effects ofChronotherapy in Relation to Risk [theMAPEC Study]http://www.clinicaltrials.gov/ct2/show/NCT00295542

as a unct on o t e ange n s eep ean ur ngFollow Up:

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Follow-Up:Hazard ratio (HR) was adjusted by age, sex, diabetes, baselineblood pressure and number of hypertension medications used fortreatment. Studied population was divided into quintiles. Negative

change indicates a BP reduction during follow-up.

HR as a Function of the Change in Clinic SBP During Follow-Up

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HR as a Function of the Change in Clinic SBP During Follow UpThe Hazard ratio (HR) was adjusted by age, sex, diabetes,baseline BP, and number of hypertension medications used fortreatment. Studied population was divided into quintiles.Negative change indicates a BP reduction during follow-up.

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Conclusion

ABPM for proper CVD riskassessment and patient evaluation.

Decreased CVD risk associated with

progressively reducing the asleep BP. ABPM for the routine evaluation of

treatment efficacy and BP control.

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Laptop Exposure

Associated WithNonthermal Effect on

Sperm Quality

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Method

The effect of laptop computersreceiving wireless Internet signals onhuman spermatozoa.

Researchers evaluated semensamples from 15 men.

The samples were separated into 2

incubation groups: one that wasexposed to a laptop computerreceiving a WiFi signal for 4 hours,and another that was not.

Prior to incubation the sperm was

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Prior to incubation, the sperm wasassessed for parameters such as

concentration, motility, morphology,and vitality.

Evaluation after incubation showeddecreased sperm motility in thelaptop-exposed group(73.5 8.2 vs63.6 7.3; P < 0.05), increasedsperm immotility (18.8 6.9 vs 28.3

7.3; P < 0.05), and an increase insperm DNA fragmentation (6.3 8.1vs 13.1 9.2; P < 0.05), compared

with the nonexposed group.

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Despite the fact that the 2 groupswere kept at a controlled temperature(25 C) to rule out thermal effects, the

results showed significant DNAdamage and decreased sperm motilityin the laptop-exposed group.

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Conclusion

Exposure to laptop computers(radiofrequency electromagnetic waves fromits WiFi) might adversely affect male

fertility by inducing DNA fragmentationand decreasing progressive motility.

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ThankYou

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EFFECTS OF BETA-ADRENERGICANTAGONISTS IN PATIENTS WITH

CHRONIC KIDNEY DISEASE

A SYSTEMATIC REVIEW & META- ANALYSIS

JACC 2011 Vol.58,No.11 2011

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BACKGROUND

Excess burden of cardiovascular disease& death in patients with CKD.

Observational studies in CKD patientsdemonstrated better survival &cardiovascular outcomes in those treatedwith blockers.

Despite their potential benefits,the effectsof blockers in patients on dialysis are

uncertain.

AIM OF SYSTEMATIC

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AIM OF SYSTEMATICREVIEW

To determine the effects of blockers

on clinical end points in patients with

CKD stages 3 to 5 including those ondialysis.

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PROTOCOL

Search strategies Study selection

Bias assessment

Data extraction

Outcome assessment

Statistical analysis

Effects of intervention

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Search strategies

Relevant studies were identified throughelectronic searches of Medline,Embase,CENTRAL.

In addition relevant review articles,treatment guidelines,textbook

chapters,conference proceedings & onlinetrial registeries were searched.

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ELIGIBLE STUDIES

Randomized controlled trials Participants with CKD stages 3 to 5

(eGFR,< 60ml/min/1.73m2),including

those on dialysis therapy. Patient follow up for atleast 3 months

post-randomization.

Reported mortality outcomes.

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DATA EXTRACTION

Patient demographic details

Study design & conduct

Rates of outcome events

Adverse events

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Bias assessment

Quality of each individual study wasassessed by cochrane bias methodsgroup.

Random sequence generation

Allocation concealment

Blinding

Incomplete outcome data

Selective outcome reporting

Any other bias

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OUTCOMES ASSESSED : All cause mortality

Cardiovascular mortality

Sudden death

All cause hospitalisation

Hospitalisation for worsening of heart

failure

Adverse events

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STATISTICAL ANALYSIS

For dichotomous outcomes,the resultswere expressed as risk ratios (RR)with95% confidence intervals.(CIs)

Summary estimates were obtained byrandom effect models.

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RESULTS :

Eight trials met criteria for review

HEART FAILURE STUDIES

6 placebo controlled trials involving5,972 participants with chronic systolicheart failure.

Only 1 of 6 heart failure studiesincluded patients on hemodialysis.

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NON- HEART FAILURE STUDIES: 2 ACE inhibitor comparator trials

involving 977 participants without

heart failure. None of the 2 trials included dialysis

patients.

EFFECTS OF

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EFFECTS OFINTERVENTION In CKD patients with heart failure

compared with placebo, blocker

treatment reduced the risk of all

cause and cardiovascular mortality.(RR:0.66,95%CI:0.49to 0.89)

Risk of sudden death was alsoreduced by beta-blockers.

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Quantitative meta analysis was notperformed for non- heart failurestudies due to substantial clinical

diversity or lack of informative data.

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ADVERSE EFFECTS

Compared with placebo,there was anincreased risk of bradycardia &hypotension with blocker therapy in

patients with heart failure.

Risk of hyperkalemia was similar in the

two groups.

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STUDY LIMITATIONS

Relatively small number of eligiblestudies.

Post hoc nature of analysis of the

largest studies. Difficulties in defining symptomatic

heart failure in patients with CKD.

Lack of systematic data on adverseeffects.

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Findings of this systematic reviewapply to patients with CKD & heartfailure with LVEF but not to patients

with heart failure & preserved LVEF.

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CONCLUSION

blockers decreased all cause &

cardiovascular mortality in patients

with CKD who have heart failure &low LVEF.

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NSAIDS Which ones hurt theheart ? which dont ?

Individual NSAIDS have different degrees

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Individual NSAIDS have different degreesof cardiovascular safety.

Ibuprofen - 29% greater risk for fatal ornon-fatal stroke.

Rofecoxib - 66% risk for cardiovascular

death. Diclofenac - 91% risk for cardiovascular

death.

Celecoxib - findings inconclusive Naproxen - NOT associated with

cardiac risk

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NAPROXEN IS THE SAFESTCHOICE FOR YOUR HEART

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ThankYou

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Ruxolitinib First ever drug

for myelofibrosis

MYELOFIBROSIS

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MYELOFIBROSIS

RARE DISEASE OF BONEMARROW.

MUTATION OF JANUS ASSOCIATED

KINASE(JAK1 AND 2). BONE MARROW IS REPLACED BY

SCAR TISSUE.

RESULTING IN ANAEMIA ANDTHROMBOCYTOPENIA.

SIGNIFICANT EXTRA-MEDULLARY

HAEMATOPOIESIS.

RUXOLITINIB

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RUXOLITINIB

ORPHAN DRUG INHIBITS BOTHJAK1 AND JAK2.

FIRST APPROVED JAK INHIBITOR.

TWO PIVOTAL CLINICAL TRIALSWERE SUBMITTED FORAPPROVAL.

SIGNIFICANT REDUCTION OFENLARGED SPLEEN IN TREATEDPATIENTS.

DOSAGE:20MG PO TWICE DAILY.

RECOMMENDED STARTING

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RECOMMENDED STARTINGDOSE

PLATELET COUNT STARTING DOSE

GREATER THAN 200109/L 20mg ORALLY TWICE DAILY

100109/L TO 200109/L 15 mg ORALLY TWICEDAILY

CLINICAL STUDIES

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CLINICAL STUDIES

TWO RANDOMIZED PHASE 3STUDIES WERE CONDUCTED INPATIENTS WITH MYELOFIBROSIS.

IN BOTH STUDIES,PATIENTS HADPALPABLE SPLEENOMEGALY ANDRISK CATEGORY OFINTERMEDIATE2 OR HIGH RISK .

STARTING DOSE BASED ONPLATELET COUNT.

STUDY 1

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STUDY 1 Double blind,randomized,placebo-controlled

study in 309 patients.

Median age-68 years:61%older than 65 and54%male.

Primary Myelofibrosis:50% Post-polycythemia vera:31%

Post-essential thrombocythemia:18%

Median haemoglobin-10.5g/dl

Median platelet count-251*109/l. Median palpable spleen :16cm below the costal

margin.

Median spleen volume as measured by MRI:2595

cm3

Patients were given both

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Patients were given bothJAKAFI(RUXOLITINIB) and placebo.

Primary efficacy end point: patients withgreater than or equal to a 35%reduction

in spleen volume at 24 weeks.

Secondary end point: patients with 50%or

greater reduction in total symptom scoreat 24 weeks.

STUDY 2

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STUDY-2 Open label, randomized study in 219 patients.

Randomized as 2:1 to JAKAFI vs. best availabletherapy(hydroxy urea and glucocorticoids).

Median age-66 years:52%older than 65 yearsand 57% male.

Primary Myelofibrosis:53% Post-polycythemia vera:31%

Post-essential thrombocythemia:16%

Median haemoglobin-10.4g/dl

Median platelet count-236*109/l.

Median palpable spleen :15cm below the costalmargin.

Median spleen volume as measured by

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Primary efficacy end point: patientswith greater than or equal to a35%reduction in spleen volume at 48

weeks. Secondary end point: patients

achieving 35%or greater reduction ofspleen volume at 24 weeks.

EFFICACY RESULTS

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EFFICACY RESULTS

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LONG TERM OUTCOME OFTREATMENT WITH

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TREATMENT WITHRUXOLITINIB Article published in NEJM. Clinical trial was conducted in 51

patients at the mayo clinic for long

term outcome. Treatment has discontinued in 47

patients.

Reasons for discontinuation includedisease progression,toxicityand lack ofresponse.

To date 18 patients died and 5

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Conclusion of the article:

NO significant difference in thesurvival rate.

EFFECTIVE in alleviating constitutionalsymptoms.

MODEST activity in reducing spleensize and always durable.

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Vitamin Supplements AssociatedWith Increased Risk for Death!!!

The link between vitamin supplement

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use and total mortality rate wasevaluated using data from the IowaWomen's Health Study.

A total of 38,772 older women wereincluded in the analysis.

Women were aged between 55 to 69years, with an average of 61.6 yearsat the beginning of the study in 1986.

Self-reported data on vitaminsupplement use were collected in1986, 1997, and 2004.

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The use of multivitamins overall was

associated with 2.4% increasedabsolute risk for death (hazard ratio,1.06; 95% confidence interval, 1.02 -1.10).

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Vitamin B6, folic acid, iron,magnesium, and zinc were associatedwith about a 3% to 6% increased riskfor death, whereas copper wasassociated with an 18.0% increased

risk for total mortality. In contrast, use of calcium was

inversely related to risk for death

(hazard ratio, 0.91; 95% confidenceinterval, 0.88 - 0.94; absolute riskreduction, 3.8%).

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"Those supplements do not replace oradd to the benefits of eating fruits andvegetables and may cause unwanted

health consequences."

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ThankYou