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Reducing the Burden of Severe Sepsis and Infections
in Indian ICUs
J.V. Divatia
Professor & Head Department of Anaesthesia, Critical Care & Pain
Tata Memorial Hospital Mumbai
India
Infections in the ICU • Sepsis and multiple organ failure is the
commonest cause of death in ICU’s • ICU patients are 5-10 times more prone
to infection • Increased nosocomial infections • Infections with resistant strains
ICU
Community Hospital
• Widespread use of oral QN and Ceph
• Free availability of OTC antibiotics
• Self-medication by patients
• Availability of cheap generics of variable potency and quality
• Spread by crowding and poor sanitary conditions.
• Lack of hospital-wide infection control or antibiotic policies
• Extensive empirical use of cephalosporins in hospitals and ICUs
• Prolonged use of antimicrobial prophylaxis in surgical patients
• Failure to restrict privileges to prescribe major antibiotics
Absence of national agency to survey and report on nosocomial inffections Absence of effective national or statewide antimicrobial policy
• Predominance of open ICUs • Failure to implement or adhere to
infection control protocols • Prolonged use of broad-spectrum
antibiotics • Inadequate staffing, especially
nurses
800
1,000
1,200
1,400
1,600
1,800
2001 2025 2050
Year
300
400
500
600
Seps
is C
ases
(x10
3 )
Tota
l US
Popu
latio
n (m
illion
)
Angus DC, et al. JAMA 2000;284:2762-70. Angus DC, et al. Crit Care Med 2001;29:1303-10.
Severe Sepsis is Increasing in Incidence
Severe Sepsis Cases US Population
Title: This is the footer Date: 13th September 2012 Slide no: 5
Sepsis is a Medical Emergency
0
50
100
150
200
250
300
Severe Sepsis Stroke Breast Cancer Lung Cancer
IncidenceMortality
* Calculated data based on information compiled from the American Heart Association, American Cancer Society, National Center for Health Statistics and the US Census Bureau (1995-1999) † Severe sepsis mortality rates range from 28%-50% (79/100,000 to 141/100,000 population).
Severe Sepsis Incidence and Mortality
Rat
e pe
r 10
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opul
atio
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†
Title: This is the footer Date: 13th September 2012 Slide no: 7
Sepsis : A neglected but common entity
Title: This is the footer Date: 13th September 2012 Slide no: 8
Reducing the Global Burden of Sepsis
EPIC-II INDIA
Total Patients 13796 533
Total ICUs 1265 39
EPIC II India
• 39 ICUs, 533 patients from India • Infected 213 (40%) • ICU Mortality 13.4% • Hospital Mortality 17.2% • Central and South America had the highest
infection rate (60%) • Africa had the lowest (46%)
Microorganisms Microorganisms (%) EPIC-II India
Positive isolates 69.8 63.4
Gram-positive 46.8 23
Gram-negative 62.2 77.8
Anaerobes 4.5 0.7
Fungi 19.0 8.1
Viral/Parasitic 0.7 5.1
Other bacteria 1.5 3
Other organisms 3.9 2.2
Types of organisms Microorganisms % EPIC-II All India Gram-positive
Staphylococcus aureus 20.5 10.4 MRSA 10.2 3.7 S. epidermidis 10.8 0.7 S. pneumoniae 4.1 1.5 Enterococcus 11.0 5.9 Others 6.4 5.9
Gram-negative E. coli 16.0 21.5 Enterobacter 7.0 1.5 Klebsiella spp 12.7 23.7 Pseudomonas spp 19.0 33.3 Acinetobacter spp 8.8 16.3
*P < 0.05 vs Western India
Types of organisms
Microorganisms % EPIC-II All India Others 17.0 6.7
Anaerobes 4.5 0.7 Other bacteria 1.5 3 Fungi
Candida 17.0 6.7 Aspergillus 1.4 2.2 Others 1.0 0.7
Parasites 0.7 1.5 Other organisms 3.9 5.9
International Nosocomial Infection Control Consortium
• Non Profit Organization • Collects and analyses infection related data from the developing countries and prepares a report which is sent to the ICU • Publishes data in high quality journals
MISSION: An International scientific community that works interactively through a network aiming at reducing healthcare-associated infections in developing countries
HCAIs – Indian Data • 12 ICUs of 7 Indian cities • Prospective surveillance from July 2004 to
March 2007 • 10 835 patients hospitalized for 52 518 days • 476 HCAIs, 4.4% or 9.06 HCAIs/1000 ICU-days • CVC-BSI rate 7.92/ 1000 catheter-days
– Excess mortality 4% • VAP rate10.46 / 1000 ventilator-days
– Excess mortality 19% • CAUTI rate 1.41 /1000 catheter-days
– Excess mortality 11.6%
Antibiotic Resistance • Overall 87.5% of all Staphylococcus
aureus HCAIs were caused by MRSA Enterobacteriaceae resistance • 71.4% resistant to ceftriaxone • 26.1% to piperacillin-tazobactam Pseudomonas aeruginosa resistance • 28.6% resistant to ciprofloxacin • 64.9% to ceftazidime • 42.0% to imipenem
Antimicrobial Resistance at TMH Pseudomonas sp
Antimicrobial Resistance at TMH E. Coli & Klebsiella sp
Indian Intensive Care Case Mix and Practice Patterns Study
July 14, 2010; October 13, 2010; January 12, 2011, April 13, 2011
INDICAPS Study Design
• Multicenter, All-India observational, one-day prevalence study, performed on four separate days
• Inclusion criteria • All patients present in the ICU on the second
Wednesdays of July and October 2010, January and April 2011 – July 14, 2010 – October 13, 2010 – January 12, 2011 – April 13, 2011
• Data of all patients in the ICU for the 24 hours starting 0800 am to 0800 am next day.
Severe Sepsis or Septic Shock
Characteristic Patients Age APACHE II SOFA ICU Mortality
Severe Sepsis / Septic Shock
1144 (28.3%)
53.8 ± 17.7
20.0 ± 8.4 **
5.9 ± 4.3**
42.1% **
No severe Sepsis
2894 (71.7%)
54.2 ± 17.7
16.9 ± 7.9
2.6 ± 2.9
17.6%
• Severe Sepsis / Septic Shock was diagnosed in 1144 patients (28.3%) – Males 725 (63.4%), Females 419 (36.6%)
• Infection developed in ICU in 235 patients (20.5%)
** : p=0.000
Patients with Tropical Infections vs. Others with Severe Sepsis / Septic Shock
Tropical Infection N = 231 (20.2%)
No Tropical Infection N=913 (79.8%)
Age 46.2 ± 17.9 55.7 ±17.2**
APACHE II 16.4 ± 7.5 20.9 ± 8.3 **
Acute Physiology Score
14.0 ± 7.0 16.1 ± 7.2**
SOFA 6.3 ± 4.3 5.8 ± 4.3
ICU Mortality 71 (30.7%) 411 (45.0%)**
** : p=0.000
Microorganisms Identified
Gm Neg 69%
Gm Pos 17 %
Fungi 8 %
Virus 1 %
Mycobact 2 %
Micro-organisms • Cultures sent in 909 patients (79.5%)
• Positive in 368 / 909 patients (40.5%)
• 576 organisms identified
• Polymicrobial cultures in 140 / 368 positive cultures (38%)
Major Microorganisms (n=576)
Gram Negatives N =400 (69.4%)
Pseudomonas aeruginosa
92 (23%)
Pseudomonas spp 13 (3.2%)
Acinetobacter spp 89 (22.3%)
Klebsiella spp 84 (21%)
E. Coli 76 (19%)
Gram Positives N = 98 (17%)
MRSA 22 (22.4%)
MSSA 17 (17.3%)
Enterococcus (Vancomycin sensitive)
14 (14.3%)
MR-CNS 13 (13.3%)
MS-CNS 9 (9.2%)
Strep. pneumoniae
7 (7.1%) Fungi n=44 Candida albicans 27 (61.4%) Candida non-albicans 15 (34.1%)
MR: Methicillin resistant; MS: methicillin sensitive SA: staph. aureus; CNS: coagulase negative staph.
Antibiotic use
No. of antibiotics given
• 1032 (90.2%) patients were receiving antibiotics on the study day
• Patients received a median of 2.0 (IQR 1,3) or mean of 1.9 ± 1.1 antibiotics
9,8
27,4
34,6
20,5
7,8
05
10152025303540
0 1 2 3 4No. of Antibiotics
% patients
Antibiotics Used Antifungal
13% Aminoglycoside
8% AntiTB
1 % Antimalarial 5%
Antiviral 3%
Aztreonam 2%
Carbapenems 30%
Cephalosporins 27%
Glycopeptide 15%
Linezolid 6%
Macrolides 5%
Other 20%
Penicillins 24%
Quinolones 14%
Tigecycline 4%
Colistin / Polymixin B
9%
Major Antibiotics used • Antifungals (154)
– Fluconazole 56%, Caspofungin13%, Amphotericin B 10% • Cephalosporins (309)
– Ceftriaxone 34%, Cefoperazone-sulbactam 28% • Penicillins (272)
– Piperacillin-tazobactam 72% • Carbapenems (346)
– Meropenem 66%, Imipenem 25% • Glycopeptides (177)
– Teicoplanin 70%, Vancomycin 30% • Levofloxacin (111 / 155), 72% of Quinolones • Colistin / Polymixin B (108)
Management of Severe Sepsis
• Antibiotics for primary infection • Percutaneous or surgical drainage • High-quality intensive care • Modulate inflammatory response • Prevent secondary infections
– Exogenous & endogenous
Antibiotic Therapy in Sepsis • Start early, after obtaining samples for C/S • Intravenous • Adequate doses • Broad-spectrum • Initially empirical • Specific therapy after C/S • De-escalate whenever possible
Consequences of Overdiagnosis of Sepsis
• Inappropriate use of antibiotics • Increases costs • Risk of adverse drug reactions • Selects for resistant microbial flora
– increase morbidity and mortality • Incorrect diagnosis can engender a false
sense of security – Distract a clinician from finding and treating
the true cause of a patient’s clinical deterioration
JAMA 2007; 297:1583-93
Broad-Spectrum Antibiotics Creating problems
• Kill harmful organisms, and several other non-pathogenic ones as well
• Negative culture reports • Overgrowth of Cl. difficile • Overgrowth of fungi • Selects out resistant organisms • Induces resistance
Antimicrobial Stewardship Strategies
• Education • Clinical guidelines • Antimicrobial restriction • Preprescription approval • Prospective audit and feedback
– Postprescription review • Computer-based decision support • Antibiotic cycling?
Optimising antimicrobial therapy
• Avoid prolonged Prophylactic Antibiotics • Combination therapy • Dose and route • PK / PD principles • De-escalation • Duration of therapy • Biomarker guided therapy : procalcitonin • Patenteral to oral conversion
AUC
Cmax (Peak)
MIC
T >MIC
Time (Hours)
Conc
entr
atio
n
Cmax / MIC
Time dependent • B-lactams • Carbapenems • Linezolid • Erythromycin • Lincosamines
Concentration dependent • Aminoglycosides • Metronidazole • Daptomycin
Conc and Time Dependent • Fluoroquinolones • Glycopeptides • Tigecycline
Barriers to De-escalation • Negative blood / other cultures.
– 40-60% of blood cultures may be negative • Positive cultures : colonization or infection?
– Contaminants – Errors in collection of samples – Quantitative instead of Non quantitative cultures
• No clinical improvement • Clincal improvement
• Why change a winning team?
• Role of biomarkers • Advanced molecular diagnostic
techniques
Bundles of Care • Concept of “bundles” developed by IHI
• Help health care providers more reliably deliver the best possible care for patients undergoing particular treatments with inherent risks
• Structured way of improving the processes of care and patient outcomes
• A small, straightforward set of evidence-based practices — generally three to five — that, when performed collectively and reliably, have been proven to improve patient outcomes
Sepsis Resuscitation Bundle Goals in the first 6 hours
1. Serum lactate measured 2. Blood cultures obtained prior to antibiotics 3. From the time of presentation, broad-spectrum antibiotics administered
within 1 hour In the event of hypotension and/or lactate >4 mmol/L 4. Deliver an initial minimum of 20 ml/kg of crystalloid (or colloid
equivalent*) 5. Vasopressors for hypotension not responding to initial fluid
resuscitation to maintain MAP ≥65 mm Hg 6. Achieve CVP of 8 mm Hg 7. Achieve ScvO2 of ≥ 70%
Sepsis Management Bundle Goals over 24 hours
• Low-dose steroids administered for refractory septic shock not responding to fluids and vasopressor therapy
• Glucose control maintained ≥ lower limit of normal, but < 180 mg/dl
• Inspiratory plateau pressures maintained < 30 cm H2O for mechanically ventilated patients
Management of Sepsis in Indian ICUs Indian Data from the MOSAICS Study
Management of Sepsis in Asia’s Intensive Care Units
India Co-ordinator : JV Divatia BMJ 2011;342:d3245
MOSAICS Study Prospective, observational non-interventional
study • 1285 patients recruited, 16 countries, 148 ICUs
• All consecutive patients with severe sepsis in July 2009 • Excluded patients
– < 21yrs – Transferred from another hospital or from another ICU – Previously admitted to the ICU for severe sepsis
• Primary Outcome – Compliance with the 6-hour and 24-hour bundles
• Secondary Outcome – All-cause in-hospital mortality
MOSAICS Study
Asia India No. Of ICUs 150 17
No. of Patients 1285 162
APACHE II 22.8 ± 8.7 21.9 ± 8.4
Hospital mortality 44.9% 38.3%
Overall Bundle Compliance India
0102030405060708090
100
Resus Bundle ManagementBundle
Mx Bundlewithout aPC
Both (withoutaPC)
6,8 8 13 2,5
% Compliance
Compliance with Sepsis Bundles Asia
8.5
1
6.87.5
18
11.4
2.72.6
4.9
8
4.23.1
2.4 2.1
8.5
13.713
10.8
14.8
11.810.9
0
2
4
6
8
10
12
14
16
18
20
China Hong Kong India Malaysia Singapore South Korea
Others
6-hr bundle24-hr bundle24-hr bundle less aPC
Com
plia
nce
(%)
INICC - Process Surveillence
• Hand Hygeine • Care to prevent Nosocomial Pneumonia • Vascular Catheter Care • Urinary Catheter Care
Care to Prevent Nosocomial Pneumonia
• Elevation of the Head of the Bed (30-45
degrees)
• Tubings / Water traps free of fluid and
secretions
• Absent air leak around cuff
• Smooth enteric nutrition
• Aseptic Aspiration technique
Care to prevent CLABSI
• Date of Catheter Insertion • Correct condition of dressing • Sterile Dressings for peripheral lines • Use needleless intravascular catheter
access systems avoid stopcocks. • Closed catheter access systems should be
preferred to open systems.
Process Surveillance Forms – Vascular Catheter Care
• Correct condition of dressing - well coated - clean - no fluid collection • Date of Catheter Insertion
Process Surveillance Forms – Urinary Catheter Care
• Catheter over thigh • Level of the urine bag below level of the bladder • Urine bag should not have floor contact
Effectiveness of a multidimensional approach for prevention of VAP in adult ICUs from 14 developing countries of 4
continents: INICC findings • 55,507 patients in 44 ICUs in 38 hospitals • Before and after study • Intervention:
– bundle of infection-control interventions – Education – outcome surveillance – process surveillance – feedback of VAP rates – performance feedback of infection-control practices.
Crit Care Med 2012
INICC Multidimensional aproach to prevent VAP Results
Phase 1 VAP rate • 22.0 per 1,000 mechanical ventilator days Phase 2 VAP Rate • 17.2 per 1,000 mechanical ventilator days
• 55.83% reduction in the rate of VAP after
the intervention Crit Care Med 2012
Research Opportunities Diagnosis of Sepsis
Empirical Antibiotics
Optimal Dosing
De-escalation
Differentiate non-infectious conditions: Biomarkers (procalcitonin)
• Rapid accurate diagnosis incl fungi, viruses • Rapid culture, • Molecular / PCR, microarrays, other • Identify resistant patterns
• ESBL +ve, carabapenemase, MBL, MRSA, VRE,
• New drugs!
• Therapeutic drug monitroing • Point of care tests • Rapid drug assays
• Diagnosis of absence of infection • Biomarkers
Research Opportunities • Develop effective strategies for communication,
dissemination and implementation of guidelines • Develop simple effective strategies to prevent
nosocomial infections – Bundles – INICC strategy
• Nationwide surveillance of antimicrobial therapy, AMR
• Nationwide Process surveillance – Hand hygiene
• Monitoring and feedback
Recommended