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

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600

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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

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50

100

150

200

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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

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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

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China Hong Kong India Malaysia Singapore South Korea

Others

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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