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Critical Care Medicine: 2009 update

Kathleen D. Liu, MD, PhD, [email protected]

ASN 2009

Nothing to disclose

OutlineOutline

• Update on glycemic targets: NICE‐SUGARUpdate on glycemic targets: NICE SUGAR

• Who should receive stress dose steroids in the ICU?ICU?

• Coming soon: PROWESS‐SHOCK, PROCESS

• Prevention of central line infections

• H1N1 updatep

Glycemic control in the ICUGlycemic control in the ICU

Glycemic control: Leuven‐1Glycemic control: Leuven 1

• Primarily surgical population (62% post‐Primarily surgical population (62% postcardiac surgery)

• Randomized to 80 110 mg/dL (intensive)• Randomized to 80‐110 mg/dL (intensive) versus 180‐200 mg/dL (conventional)

All i i d IV l i di l• All patients received IV glucose immediately upon arrival to the ICU and total

l/ l i i h denteral/parenteral nutrition the next day

• Study personnel ran protocol, not ICU RN caring for patient


• Similar study design to Leuven‐1 but inSimilar study design to Leuven 1, but in medical ICU population

• Inclusion criteria: MICU patients who were• Inclusion criteria: MICU patients who were “assumed to require care for at least 3 days”

P i h bl i l• Patients who were able to receive oral nutrition were excluded

• 1200 subjects enrolled (primary analyses based on this group); 767 stayed more than 3 days

Van de Berghe et al, NEJM 354(2006):449-61


N=767

Glycemic control: Impact on AKIGlycemic control: Impact on AKI

• Pooled analysis of 2707 patients from LeuvenPooled analysis of 2707 patients from Leuven studies

• “Baseline” Cr = Cr at study entry• Baseline Cr = Cr at study entry

• Ascertained and compared outcomes of AKI in i l d di l l i isurgical and medical populations using

modified RIFLE criteria

• 149 (53%) of oliguric patients and 147 (51%) of patients who required RRT did not meet RIFLE criteria

Schetz et al, J Am Soc Nephrol 19(2008): 571–8

Glycemic control: Impact on AKIGlycemic control: Impact on AKI

Glycemic control: Subsequent studies failed to show a benefit

• Efficacy of Volume Substitution and InsulinEfficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP): NEJM 358 (2008):125‐39; stopped early for safety(2008):125 39; stopped early for safety

• Glucontrol: Intensive Care Med, Epub 2009; stopped early for protocol violationsstopped early for protocol violations

• Rates of hypoglycemia were significantly hi h i b h di 17 0 4 1 % i VISEPhigher in both studies: 17.0 vs 4.1 % in VISEP, 8.7 vs 2.7% in Glucontrol, p < 0.0001 in both cases

Glycemic control: NICE‐SUGARGlycemic control: NICE SUGAR

• 6104 patients6104 patients

• Intensive glucose control: target blood glucose range 81 108 mg/dLrange 81‐108 mg/dL

• Conventional glucose control: target blood l 180 /dLglucose < 180 mg/dL

• Primary endpoint: 90 day all cause mortality

NICE-SUGAR Study Investigators, N Engl J Med 360(2009):1283-97


• Treatment managed by clinical staff caring forTreatment managed by clinical staff caring for patient with web‐based algorithm

• Incidence of severe hypoglycemia higher with• Incidence of severe hypoglycemia higher with intensive control: 6.8 vs 0.5%, p<0.0001

Glycemic control: Putting it all together

Inzucchi and Siegel, NEJM 360(2009): 1346-9

OutlineOutline



d• H1N1 update

Catheter related blood stream infections

• 15 million CVC days occur per year in ICU15 million CVC days occur per year in ICU patients in the United States

• Associated with an estimated 80 000 catheter• Associated with an estimated 80,000 catheter related blood stream infections (CRBSI)

M j f f i ff ff• Major focus for preventative efforts: staff education, maximum barrier precautions, hl h idi f ki hi f ichlorhexidine for skin prep, chioc of site, removal of unnecessary catheters

Can we reduce catheter related infections further?

• Chlorhexidine‐impregnated sponges and lessChlorhexidine impregnated sponges and less frequent dressing changes for prevention of catheter‐related infections in critically illcatheter related infections in critically ill adults. Timsit et al, JAMA 301(2009): 1231‐41

Chlorhexidine sponge Standard dressing

Change q3days 412 416

Change q7days 413 412

Chlorhexidine impregnated sponges d h l d fand catheter related infections

• Multicenter study in 7 French ICUsMulticenter study in 7 French ICUs

• Protocols for catheter insertion and care

ibi i d h d• Antibiotic coated catheters were not used

• Dressings changed at study intervals or if soiled

• Follow up to 48 hours after ICU dischargep g

• Investigators/staff unblinded, but microbiology personnel and those reviewingmicrobiology personnel and those reviewing infections were blinded

Chlorhexidine impregnated sponges d h l d fand catheter related infections

• 3 key outcomes:3 key outcomes:– Catheter colonization: quantitative catheter tip culture with > 1000 CFUs/mLculture with > 1000 CFUs/mL

– Catheter related clinical sepsis without bloodstream infection: Fever or hypothermia withbloodstream infection: Fever or hypothermia with + cath tip culture, purulent drainage at insertion site or resolution of sx after catheter removal

– Catheter related blood stream infection

– Major catheter related infection: Clinical sepsis without blood stream infection OR CRBSI

Chlorhexidine‐impregnated sponges decrease the risk of CRI

Timing of dressing changes does not impact the rate of CRI

Timing of dressing changes does not impact the rate of CRI

• However median # of dressing changes was 3However, median # of dressing changes was 3 and 2 in the 3 day and 7 day groups, respectively with a median duration ofrespectively, with a median duration of catheter insertion of 6 days (25‐75% IQR 4‐10 days) in both groupsdays) in both groups

• Unplanned dressing changes occurred more often in the 7 day group (40% unplanned inoften in the 7 day group (40% unplanned in the 3 day group, 50% unplanned in the 7 day group p < 0 001)group, p < 0.001)

CRI and chlorhexidine sponges: Limitations

• BlindingBlinding

• Major CRI without bacteremia – difficult to diagnose?diagnose?

• 6.5% of cultures were not cultured – similar to h diother studies

• Povidone iodine, not chlorhexidine, used for skin antisepsis due to availability of chlorhexidine in France

• Includes both arterial and venous catheters

CRI and chlorhexidine spongesCRI and chlorhexidine sponges

• Number needed to treat: 117Number needed to treat: 117

• Estimated cost of preventing one major CRI: $2106$2106

• Estimated cost of one major CRI: $8000‐28000

• Major risk: severe contact dermatitis (observed rate 5.3/1000 catheter days)

OutlineOutline



d• H1N1 update

H1N1: Current StateH1N1: Current State

H1N1: DetectionH1N1: Detection

• Novel strain of influenza ANovel strain of influenza A

• First reports of human infection in April 2009

d i d l d i f 2009• Pandemic declared in summer of 2009

• Initially many samples sent to CDC for confirmation, this is no longer standard

• Several different assays available: rapid y pantigen assays, direct immunofluorescence assays, viral cultures and PCRy ,


• Ginocchio et al J Clin Virol 2009Ginocchio et al, J Clin Virol 2009– NYC/Long Island experience

6090 patients 14114 viral diagnostic studies– 6090 patients, 14114 viral diagnostic studies

– Gold standard: Luminex Respiratory Viral Panel, which detects seasonal H1 and H3 influenzawhich detects seasonal H1 and H3 influenza viruses; all unsubtypeable influenza A viruses considered H1N1


• Ginocchio et al J Clin Virol 2009Ginocchio et al, J Clin Virol 2009

• 1831 samples, 164 + for influenza A: 123 novel H1N1, 1 seasonal H1N1, 40 seasonal H3N2, ,



• 288 samples, 175 + for influenza A: 132 novel H1N1, 1 seasonal H1N1, 42 seasonal H3N2, ,



• Kapelusznik et al, J Clin Virol 2009

h di hi hli h h f h• These studies highlight the fact that many with severe disease may have negative rapid

i di i flantigen or direct immunofluorescence assays

• PCR based tests are much more sensitive


• Consider diagnostic testing in:Consider diagnostic testing in:– Hospitalized patients with suspected influenza

Patients for whom a diagnosis of influenza will– Patients for whom a diagnosis of influenza will inform decisions regarding clinical care, infection control, or management of close contactscontrol, or management of close contacts

– Patients who died of an acute illness in which influenza was suspectedp

• Do not delay treatment waiting for diagnostic testing!testing!

http://www.cdc.gov/h1n1flu/guidance/diagnostic_tests.htm

Diagnostic Tests: SummaryDiagnostic Tests: Summary



• May not need subtyping data (novel H1N1May not need subtyping data (novel H1N1 versus seasonal H1N1 or H3N2) since antiviral susceptibilities are (currently) similarsusceptibilities are (currently) similar


H1N1: MexicoH1N1: Mexico

Chowell, NEJM 361 (2009):674-9


Dominguez-Cherit, JAMA 2009


• Observational study at 6 hospitals N =58Observational study at 6 hospitals, N =58

• These patients were strikingly young:


H1N1: CanadaH1N1: Canada

Kumar, JAMA 2009

H1N1: Australia/New ZealandH1N1: Australia/New Zealand

ANZIC Influenza Investigators, NEJM 2009

H1N1: Australia/New Zealand

• 722 patients 602 adults

H1N1: Australia/New Zealand

722 patients, 602 adults

• 456/706 required mechanical ventilationM di d ti 8 d 25 75% IQR 4 16 d– Median duration 8 days, 25‐75% IQR 4‐16 das

– 53 went on to ECMO

• Of discharged patients (N=608), 103 (16.9% had died)– Risk factors for death: mechanical ventilation at ICU admission, any co‐existing condition, and ldolder age

ANZIC Influenza Investigators, NEJM 2009

H1N1 is associated with severe ARDS

ANZIC ECMO Influenza Investigators, JAMA 2009

H1N1: At‐risk populationsH1N1: At risk populations

• Intensive‐Care Patients With Severe NovelIntensive Care Patients With Severe Novel Influenza A (H1N1) Virus Infection ‐Michigan, June 2009; MMWR July 2009June 2009; MMWR July 2009– Case series of 10 patients admitted to University of Michiganof Michigan

– All confirmed to have H1N1 by RT‐PCR; DFA negative in all 10 casesega e a 0 cases

– Referred to the ICU for refractory hypoxemia and consideration of ECMO


• Intensive‐Care Patients With Severe NovelIntensive Care Patients With Severe Novel Influenza A (H1N1) Virus Infection ‐Michigan, June 2009; MMWR July 2009June 2009; MMWR July 2009– 3/10 had underlying lung disease; overall patients had relatively few comorbiditieshad relatively few comorbidities

– All but 1 required HFOV or ECMO

– 9/10 had BMI ≥ 30; 7/10 had BMI ≥ 40– 9/10 had BMI ≥ 30; 7/10 had BMI ≥ 40

– 3/10 patients died

5/10 had pulmonary emboli (by chest CT)– 5/10 had pulmonary emboli (by chest CT)


• Pregnant women: Jamieson et al Lancet 2009Pregnant women: Jamieson et al Lancet, 2009– Based on reporting from April‐May 2009 to the CDCCDC

– 34 confirmed/probable cases in pregnant women, of whom 11 were admitted to the hospitalof whom 11 were admitted to the hospital

• 0.32 admissions/100K pregnant women (95% CI 0.13–0.52)

• 0.076 admissions/100K at risk (95% CI 0∙07–0∙09)

– 6 fatalities reported to CDC between April 15 and J 16 2009 ll d l d ARDS d i dJune 16, 2009 – all developed ARDS and required mechanical ventilation


• Other at risk populations:Other at risk populations:– Those less than 2 years of age

Those less than 19 years of age on chronic aspirin– Those less than 19 years of age on chronic aspirin therapy

– Immunosuppressed adults (including meds and– Immunosuppressed adults (including meds and HIV)

– Those with chronic medical conditionsThose with chronic medical conditions

– Those > 65 years of age?

H1N1: TreatmentH1N1: Treatment

• Antivirals can reduce the severity/duration ofAntivirals can reduce the severity/duration of influenza and severe complications, including deathdeath

• Not everyone needs treatment or prophylaxis

T i i d f i h• Treatment is required for anyone with suspected influenza requiring hospitalization

• Treatment, if indicated, should be started early (greatest benefit when started within 48h)

http://www.cdc.gov/h1n1flu/recommendations.htm


• Consider early empiric treatment in:Consider early empiric treatment in:– Children less than 2

Adults older than 65– Adults older than 65

– Pregnant women and up to 2 weeks post‐partum

P l f ith t i h i di l– People of any age with certain chronic medical conditions

Children less than 19 on chronic aspirin therapy– Children less than 19 on chronic aspirin therapy[Children from 2‐4 are more likely than older kids/adults to have severe disease, but many have mild disease only], y y]


H1N1: Chronic medical conditionsH1N1: Chronic medical conditions

• Chronic pulmonary (including asthma), cardiovascular (except p y ( g ), ( phypertension), renal, hepatic, hematological (including sickle cell disease), or metabolic disorders (including diabetes mellitus)mellitus)

• Disorders that that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders)

• Immunosuppression including that caused by medications or• Immunosuppression, including that caused by medications or by HIV

• Evaluate those who are obese closely for these conditions!



• Current H1N1 viruses are oseltamivir (Tamiflu)Current H1N1 viruses are oseltamivir (Tamiflu) and zanamivir (Relenza) sensitive, amantidine and rimantidine resistantand rimantidine resistant

• This may change, so stay tuned for new recommendationsrecommendations

• Adult and pediatric treatment algorithms il bl PDFavailable as PDFs at

http://www.cdc.gov/h1n1flu/clinicians/


• Limited dosing on oseltamivir with renalLimited dosing on oseltamivir with renal dysfunction, but levels are higher with reduced GFRreduced GFR

http://www.tamiflu.com/hcp/dosing/default.aspxRobson Nephrol Dial Transplant 21(2006): 2556-62


• Oseltamivir (Tamiflu)Oseltamivir (Tamiflu)– Nausea, vomiting

Transient neuropsychiatric effects reported in– Transient neuropsychiatric effects reported in Japan; retrospective analyses conducted by Roche, have not found evidence for an increasedRoche, have not found evidence for an increased risk of neuropsychiatric events BUT FDA recommends monitoring for abnormal behavior

– Allergic reactions


• Zanamivir (Relenza)Zanamivir (Relenza)– Only licensed for those without underlying respiratory or cardiac diseaserespiratory or cardiac disease

– Can cause bronchospasm

– Should not be nebulized– Should not be nebulized

– Allergic reactions


• Peramivir: Intravenous neuraminidasePeramivir: Intravenous neuraminidase inhibitor that is not FDA approved – October 23 2009: Emergency Use Authorization– October 23, 2009: Emergency Use Authorization granted by the FDA to the CDC

– Can be released quickly (within 6 hours)Can be released quickly (within 6 hours)

http://emergency.cdc.gov/h1n1antivirals/

H1N1: PeramivirH1N1: Peramivir

• Can be prescribed for treatment of suspectedCan be prescribed for treatment of suspected or lab‐confirmed 2009 H1N1 infection if– Patient is not responding to either oral or inhaled– Patient is not responding to either oral or inhaled antiviral therapy

– Drug delivery by a route other than IV is notDrug delivery by a route other than IV is not expected to be dependable or is not feasible

– The clinician judges IV therapy is appropriate dueThe clinician judges IV therapy is appropriate due to other circumstances (adults only)


• Must document in the patient’s medicalMust document in the patient s medical record that the patient/caregiver has been: – Given the Fact Sheet about the drug– Given the Fact Sheet about the drug

– Informed of alternatives to receiving Peramivir

Informed that Peramivir is an unapproved drug– Informed that Peramivir is an unapproved drug that is authorized for use under Emergency Use AuthorizationAuthorization

• Renally dosed

C t i di t d ith ll i ti• Contraindicated with severe allergic reactions to other neuraminidase inhibitors


• Phase II/III studies have enrolled 1891 patientsPhase II/III studies have enrolled 1891 patients– No children enrolled, but can be released for compassionate use under EUAcompassionate use under EUA

– No pregnant women

• Adult dose is 600 mg IV over 30 minutes once• Adult dose is 600 mg IV over 30 minutes once daily for 5‐10 days

T i i i f i i• To initiate a request for peramivir, go to

http://emergency.cdc.gov/h1n1antivirals/

H1N1: Peramivir Renal DosingH1N1: Peramivir Renal Dosing

• No data for CRRT or PD

H1N1: PeramavirH1N1: Peramavir

• Side effects: Nausea, vomiting, diarrhea, neutropeniaSide effects: Nausea, vomiting, diarrhea, neutropenia

• Selected adverse events must be reported to the FDA within 7 days: y– death

– neuropsychiatric events

– renal adverse events

– serious skin adverse events (e.g., Stevens‐Johnson d t i id l l i )syndrome, toxic epidermal necrolysis)

– hypersensitivity reactions adverse events

– severe IV site or IV administration adverse eventssevere IV site or IV administration adverse events

– other severe adverse events

H1N1: ChemoprophylaxisH1N1: Chemoprophylaxis

• Rationale: Most people shed virus for one day prior to p p y psymptoms and up to 7 days after symptoms start (may be longer in children and immunosuppressed individuals)

C id i P h t hi h i k f li ti• Consider in: Persons who are at higher risk for complications OR healthcare personnel, public health workers, or first responders who have had a recognized, unprotected close contact exposure to a person with confirmed, probable, or suspected 2009 H1N1 or seasonal influenza during that person’s infectious periodperson s infectious period

• Not recommended > 48 hours since last contact with sick person

• Education (early signs/symptoms is key)

http://www.cdc.gov/h1n1flu/recommendations.htm#table1

H1N1: Healthcare Prevention Strategies

• Vaccinate!Vaccinate!

• Respiratory hygeine/cough etiquette

• Establish facility access control measures and triageEstablish facility access control measures and triage procedures

• Manage visitor access and movement within theManage visitor access and movement within the facility

• Establish policies and procedures for patient p p pplacement and transport AND follow them!

• Limit the number of healthcare personnel entering p gthe isolation room

http://www.cdc.gov/h1n1flu/guidelines_infection_control.htm


• Isolation precautions*Isolation precautions– Standard precautions apply

– Respiratory precautions (fit tested, disposable N95 respirator) for those in close contact (less than 6 feet or closed patient room)

Be aware of aerosol generating procedures– Be aware of aerosol generating procedures• Bronchoscopy

• Sputum induction

d h l b d b• Endotracheal intubation and extubation

• Open suctioning of airways

• Cardiopulmonary resuscitation

• Autopsies

*7 days or 24 hours after fever/respiratory sx resolve, whichever is longer


• Isolation precautions*Isolation precautions– Standard precautions apply

– Respiratory precautions (fit tested, disposable N95 respirator) for those in close contact (less than 6 feet or closed patient room)

Be aware of aerosol generating procedures– Be aware of aerosol generating procedures• Bronchoscopy

• Sputum induction

d h l b d bLimit # of procedures,

• Endotracheal intubation and extubation

• Open suctioning of airways

• Cardiopulmonary resuscitation

personnel exposedConsider airborne infection isolation room

• Autopsies

*7 days or 24 hours after fever/respiratory sx resolve, whichever is longer

H1N1: Clinical ResearchH1N1: Clinical Research

• InFACT the International Forum for Acute CareInFACT, the International Forum for Acute Care Trialists has information on several projects– Global Registry: ANZICS ARDSNet and PALISI– Global Registry: ANZICS, ARDSNet and PALISI, Canadian Critical Care Trials Group, European Society of Intensive Care Medicine, Intensive Care y ,National Audit and Research Centre; other groups and individuals are welcome to join

– Clinical trials: Statins & steroids

http://www.infactglobal.org/initiative/

H1N1: VaccinationH1N1: Vaccination

• Coming soonComing soon…

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