Evidence in Intensive Care - Host Defence

Systematic reviews and meta-analyses in blue
Other high impact trials in red


VAP – mortality prediction
SHOCK vol 33 no.6

Risk factors for mortality:
Inappropriate initial treatment
Gram –ve worse than gram +ve

NB Can use breakpoint of 1,000 cfus for PSB. Needs to be higher with BAL and tracheal aspirates (probably >10to6th for latter and 10 to the 3 for former – check this).

Subglottic secretion drainage and VAP
AJRCCM 2010;182:910-917

Reduces the incidence microbiologically confirmed VAP - early and late.
Non microbiolgically confirmed VAP no difference (many were probably not VAP).
No difference in ventilation duration or LOS or mortality or antibiotic use.
Consistent with other evidence that measures to reduce VAP (eg SDD) have no mortality benefit which is odd as VAP associated with mortality.
Is it worth it?

Hydrocortisone therapy for patients with multiple trauma: the randomized controlled HYPOLYTE study.
Roquilly et al. JAMA 2011;305:1201–1209.

Stress dose hydrocortisone (50 QDS) reduces the incidence of VAP in those with TBI and adrenal insufficiency.
No mortality difference.

Prevention of ventilator- associated pneumonia with oral antiseptics: a systematic review and meta-analysis.
Labeau et al. Lancet Infect Dis 27 July 2011.

VAP reduced with oral antiseptics. 2% chlorhexidine best.

Fluid leakage across tracheal tube cuff, effect of different cuff material, shape, and positive expiratory pressure: a bench- top study.
Zanella A et al. (2011) Intensive Care Med 37:343–347

Fluid leak past cuff decreases with increasing PEEP (zero at 15)

Ventilator bundle reduces rate of VAP
Bird et al Arch Surg 2010;145:465-470

Head of bed elevation, daily sedation hold, DVT proph, ulcer prophylaxis, daily assessment of extubation.

Rapid and reproducible surveillance for ventilator associated pneumonia.

Klompas et al. Clin Infect Dis 2012;54:370–377.

The criteria published by the CDC are used by hospital infection control services and epidemiologists to define VAP.
These criteria have two major limitations:
Many of the diagnostic criteria are very subjective and the definition correlates poorly with histological pneumonia.
There is significant inter-and intra-observer variability making it imprecise to compare rates between different ICUs and hospitals or even the same ICU over time.
This “streamlined definition of VAP” is faster and more objective and predicted outcomes as effectively as the conventional CDC definition of VAP.

Probiotics (lactobacillus sp.) reduce incidence of VAP.
Meta-analysis and randomised controlled trial
AJRCCM 2010;182:1058-1064 (RCT)
Crit Care Med 2010;38:954-62 (MA)

No mortality benefit.
Overall safety benefit of probiotics too uncertain to recommend their use.
They increase mortality in pancreatitis (may be due to post-pyloric admin).


Procalcitonin is a 116 amino-acid precursor of calcitonin. Produced in liver and cleaved in thyroid, lung and pancreas.
Most potent inducer is lipopolysaccharide of cell walls of gram –ve bacteria.
Not increased by viral infection, surgery or chronic inflam.
After bacterial stimulus, levels of PCT increase in 3h with peak levels at 6h.
Half life is 25h. Degraded by specific proteases.

Procalcitonin to guide duration of antimicrobial therapy in intensive care units: a systematic review.
Agarwal et al. Clin Infect Dis 2011;53:379–387.

Procalcitonin algorithms for antibiotic therapy decisions. A systematic review of randomized controlled trials and recommendations for clinical algorithms.
Schuetz et al. Arch Intern Med 2011;171:1322–1331.

Both reviews above show procalcitonin can be used to limit ABX course duration. Unfortunately we use shorter courses than were used in the trials included so whether it helps with 5 - 7 day courses has yet to be shown.

Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis.
Wacker et al. Lancet Infect Dis 2013; 13: 426–435.
Cut off of between 1 and 2 ng/ml most helpful.
Diagnostic sensitivity 0.77; specificity 0.79 AUROC curve 0.85. Diagnostic accuracy better than any other diagnostic test or clinical sign.
Not a definitive test but a useful marker.

Procalcitonin to guide ABX
Crit Care Med 2010;38:2229-2241
PCT resulted in less antibiotic exposure with no difference in mortality, LOS or adverse events.
Excluded patients on vasopressors/inotropes so not real world.
Most patients had peritonitis.
NB standard of care in Europe for VAP is 8 days ABX.

Procalcitonin to guide duration of ABX – surgical ICU patients
Critical Care 2009;13:R83
Shorter duration of ABX and LOS in procalcitonin group
Agrees with other studies in medical and gen ICU patients that safely allows earlier discontinuation of ABX

PRORATA trial.
Bouadma. Lancet 2010
PCT group had significantly less antibiotic use without worsening of patient outcomes
Problem with the study was that ABX use in both groups was very long courses (around 14 days). There are many other ways to reduce ABX use.
If source control achieved, ABX rarely needed for more than 5 days. Staph bacteraemia, pseudomonas and neutropenic sepsis require longer course of ABX. Lipman Crit Care Resus 200;11:276-281.


Cochrane review 2009.
Topical and systemic ABX reduce RTI (NNT 4) and mortality (NNT 18).
Topical alone reduce RTI (NNT 7) but not mortality.
For some reason did not include a large Dutch study by Bonten et al in NEJM which showed a significant mortality reduction.
A comparison with oral chlorhexidine is now warranted.

SDD and SOD and antibiotic resistance
Lancet Infect Dis 2011;11:372-380
SOD - abx in oropharynx
SDD - abx in oropharynx, stomach and 4 days IV cefotaxime.
SOD - no difference in bacteraemia with resistant orgs but reduced rate RT colonisation.
SDD - reduced bacteraemia and RT colonisation by resistant organisms
Prior knowledge
The Bonten trial showed small mortality reduction.
Further publication of same study showed increased levels of ceftazidime resistance in SOD and SDD.
There are very low resistance rates in the Netherlands where benefit has been shown - long term effects not known.

SOD and SDD in surgical vs non surgical patients
Melsen et al BJS 2011 (Dutch study)
Some benefits demonstrated in mortality (non surgical SOD) and LOS (SDD surgical) and reduced bacteraemia (all).
Not good enough to change practice - need RRT with low NNT and no increased resistance.


Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo- controlled trial.

et al. Lancet 2011;377:2023–2030.
5mg IV dex OD in CAP (not ICU patients).
Reduced LOS in dex group but no mortality difference. Combining this data with a previous meta-analysis shows reduced LOS.
Available evidence too weak to support use of steroids in CAP.

Steroids for sepsis
JAMA 2009;301(22):2362-2375

Mortality for severe sepsis around 25% and 50% for septic shock.
Normal response in sepsis is for increased cortisol production.
Cytokines can suppress this adrenal response. Tissues may also become resistant by downregulation.
Low dose steroids are thought to enhance rather than inhibit immunity.
No difference in mortality.
Prolonged course (at least 5 days), low dose (<300mg hydrocortisone/day) reduced mortality significantly.
CORTICUS study showed no difference.
Annane’s study which showed benefit was in a sicker group of patients.
Different meta-analyses have come to different conclusions.
General consensus is that low dose prolonged steroids do
not improve mortality, do reverse shock and do not cause major adverse events.
Reasonable to use them in vasopressor dependent shock (especially the more severe).

Hydrocortisone therapy for patients with multiple trauma: the randomized controlled HYPOLYTE study.
Roquilly et al. JAMA 2011;305:1201–1209.

Stress dose hydrocortisone (50 QDS) reduces the incidence of VAP in those with TBI and adrenal insufficiency.
No mortality difference.


Septic shock attributed to Candida infection: importance of empiric therapy and source control.
Kollef et al. Clin Infect Dis 2012;54:1739–1746.

In patients with septic shock with
Candida bacteraemia, initial inappropriate antifungal therapy and inadequate source control are independent risk factors for hospital mortality.

Predicting those patients who have candidaemia before being culture positive is very difficult. Using the candida score - multifocal candida, surgery on ICU admission, severe sepsis, TPN - candidiasis only present in 24% of those with the maximum score ie it is rubbish.

Most trials show a benefit in removing CVCs if candidaemia present (see ICM 20 no.1)
Evidence is for candida caused by line rather than another source but difficult to know which came 1
st so always remove CVC.

IV devices

Peripheral venous catheters.
Cochrane review 2010

Background - Bacteraemia incidence 0.8%
No adverse events if catheters are replaced as clinically indicated instead of routinely every 72h.
New CDC recommendations say only need to be replaced based on time if asepsis at insertion not ensured.

70% intraluminal ethanol for 2 hours reduces CRBSIs in haematology patients
J Antimicrob Chemo 2008;62:809-815

The risk of catheter-related bloodstream infection with femoral venous catheters as compared to subclavian and internal jugular venous catheters: a systematic review of the literature and meta- analysis.
Marik PE et al. Crit Care Med 2012;40:2479–2485.
No difference in CRBSI among the 3 sites. Possibility of bias in studies (mostly non randomised). No good evidence assoc with increased infection but no good evidence not.

Routine versus clinically indicated replacement of peripheral intravenous catheters: a randomised controlled equivalence trial.
Rickard et al. Lancet 2012;380:1066-1074.
Catheter replacement when indicated rather than routine replacement just as safe but cheaper.
Agrees with systematic review by same author.

CRBSIs and coag –ve staph (CoNS)
Raad et al Clin Inf Dis 2009;49:1187-1194

Removal of catheters reduces the risk of recurrence
CoNS are the most common cause of CRBSIs but can often be a contaminant if aseptic technique. Do peripheral cultures along with a culture from each line. Record time to positivity of each culture. This is reduced in the central sample (<2h) if catheter infected.
Antibiotic locks (catheters filled with ABX and left for hours or days) allow line salvage in 80% (where lines are precious eg tunnelled) – Mermel et al Clin Inf Dis 2001;32:1249-1272.


Hand washing worse at night.
Am J Infect Control 2010.

Intervention to reduce transmission of resistant bacteria
NEJM 2011;364:1407-1418
Screening for MRSA and VRE and full barrier precautions compared to hand washing alone showed no reduction in transmission of resistant organisms (despite high background rate).
More adverse events in barrier group.

Transmission of organisms is by hands of health care workers between patients.
No evidence that clothes transmit organisms but CDC recommends full contact precautions if colonized or infected with resistant orgs.
Contact precautions have adverse consequences as workers spend less time with the patient - shown in this study and previously.
Shows screening and full barrier precautions are unnecessary and latter potentially harmful.
Health care workers should wash their hands between every patient contact.
Single bed rooms are better - see Arch Intern Med 2011;171:32-38.

Effect of daily chlorhexidine bathing on hospital-acquired infection.
Climo et al. NEJM 2013;368:533-542

Daily bathing with chlorhexidine impregnated wash cloths significantly reduced the risks of acquisition of MDROs and development of HABSIs.
Reduced gram +ve, -ve and fungal infections.
Simple and economical.
Chlorhex susceptibility of organisms not altered over course of study.

Supported by study in critically ill children
(Lancet 2013;381:1099–1106) showing bacteramia reduced by 36% by bathing with chlorhex cloths.

An evaluation of environmental decontamination with hydrogen peroxide vapor for reducing the risk of patient acquisition of multidrug-resistant organisms.
Passaretti et al. Clin Infect Dis 2013;56:27–35.

Reduced environmental contamination and subsequent patient contamination.

Chlorhex 2%/alcohol vs povidone- iodine for surgery.
Darouiche. NEJM 2010; 362: 18-26

Chlorhex better at preventing surgical site infection. NNT 17


Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study.
Egi et al. Crit Care 2012; 16: R33.

Multicentre, prospective, observational study

High fever not associated with increased mortality in septic patients.
Mild fever associated with reduced mortality.
Antipyretic agents (paracetamol and NSAIDs) in sepsis associated with increased mortality.
Antipyretic agents without sepsis did not increase mortality.
High fever in patients without sepsis associated with increased mortality.

Fever is an important HD mechanism.
Do not treat fever in sepsis.
Do treat fever if no infection.

Severe hypothermia increases the risk for intensive care unit acquired infection.
Laupland et al. Clin Infect Dis 2012; 54:1064–1070.

Hypothermia (<36) is common in ICU patients (16%).
Severe hypothermia (<32) much less common (1%).
Only severe hypothermia increases the risk of infection.
It is likely that hypothermia results from MODS causing CNS (hypothalamus) dysfunction. If it is because of deranged thermoregulation it is not clear whether external (or internal) warming measures would improve the clinical course.


Excess deaths with tigecycline
Clin Inf Dis 2012;54:1699-1709

Significant increase in mortality and non-cure rates with tigecycline compared to comparator ABX.
This is probably because of under dosing.
ICU patients have a larger than normal Vd, have low protein levels which mean highly protein bound drugs will have greater free drug concentration and be eliminated quicker, drug elimination may be impaired by renal or hepatic dysfunction and drug elimination may be increased (augmented clearance from fluid administration if no AKI).

Recommendation by J. Lipman (top dog in ICU antibiotics):
Only use tigecycline when absolutely necessary.
Use a higher dose than recommended on the packet/BNF

Continuous or extended infusions of beta-lactams
Crit Care Med 2009 vol 37 no.6
Concentration dependent ABX more efficacious by increasing ratio of Cmax to MIC. Time dependent ABX most efficacious when time above MIC is increased.
Gram –ve orgs likely to be treated better by extended infusions as beta-lactams do not have post antibiotic effects on these bugs.
Time > MIC targets (from in vitro studies) are:
Carbapenems 40%
Penicillins 55%
Cephalosporins 65%

No improvement in outcomes.
Lower daily doses in continuous group.
Large confidence intervals mean still possibility that there is a benefit – need better evidence.

Prophylactic antibiotics for pancreatic necrosis.
Cochrane review 2010

Unclear whether any antibiotic can penetrate into necrotic tissue or if high concentrations in surrounding tissue or bloodstream prevents infection.
Non significant trend to less pancreatic infections and mortality.
Small patient numbers.
No evidence to support the practice but not proved does not work.

Early vs late broad spectrum antibiotics in severe sepsis
Cochrane review 2010

No studies met inclusion criteria so no level 1 evidence. Observational studies not included.

Combination antibiotics
Crit Care Med 2010 vol 38, no.8 1651

The sickest group had a lower mortality with combination.
The least sick group had a greater mortality with combination.
Evidence not good to influence clinical practice.

De-escalation of antibiotics
Cochrane review 2010

Therefore no evidence if de-escalation is effective or safe in sepsis.
But the rationale is sound.

Linezolid vs glycopeptide antibiotics for the treatment of suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia.
A meta-analysis of randomized controlled trials.
Walkey et al. Chest 2011;139:1148–1155.

Already known that linezolid penetrates solid organs (like lung) much better than bacteriostatic vancomycin.
Some surrogate outcomes for pneumonia are better with linezolid but overall outcome has not been shown to be better.

Impact of antibiotic use on carbapenem resistance in Pseudomonas aeruginosa: is there a role for antibiotic diversity?
Plüss-Suard et al. Antimicrob Agents Chemother 2013; 57: 1709–1713.

Reducing ABX use and broad spectrum use and increasing the diversity of ABX used reduces ABX resistance.

Colistin administration in critically ill patients
Clin Inf Dis 2012;54:1720-1726

Gram -ve bacteria susceptible only to colistin are increasing.
Current dosing regimens produce subtheraputic peak concentrations and prolonged time to steady state.
Concentration dependent antibiotic.
Trial showed that high dose, extended interval IV colistin provided high rates of clinical cure without significant renal toxicity.
Loading dose of 9MU colistimethate sodium followed by maintenance dose of 4.5MU every 12h.
Dose and interval adjusted if renal impairment.

Antibiotic use and impact on outcome (BASIC study).
J Antimicrob Chemo 2010;65:1276-1285

Prospective study showing no impact on mortality with either type of antibiotic therapy (empirical or targeted) or timing in relation to a positive blood culture in ICU patients.
Suggests susceptibility data not useful.

Antibiotic use and risk of carbapenem resistance in ESBLs
J Antimicrob Chemother 2011;66:1383-1391

Risk of infection with resistant organisms rose with increasing duration and prior use of B-lactam/B-lactamase inhibitor combinations, fluroquinolones and carbapenems.

Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care unit-acquired infection: a quasi experimental, before and after observational cohort study.
et al. Lancet Infect Dis 2012; 12: 774–780.
Conservative approach (delaying ABX until positive cultures), when suspected infection without obvious site, reduced mortality (ABX were allowed for those needing vasopressors).


Granulocyte and granulocyte-macrophage colony stimulating factor.
Critical Care 2011 15:R58
Mortality in sepsis may be due to immunosuppression.
CSF enhances myeloid cell function.
No mortality difference.
Increased infection reversal with CSF.
Results support undertaking more research but not in its use outside of clinical trials.

Increased mortality associated with meticillin-resistant Staphylococcus aureus (MRSA) infection in the Intensive Care Unit: results from the EPIC II study.
Hanberger et al. Int J Antimicrob Agents 2011,

Mortality for MRSA is 50% higher than with MSSA