Hot Topics in Critical Care Medicine

Academic Department of Critical Care
Queen Alexandra Hospital Portsmouth
Hot Topics in ICM
@stevemathieu75
Consultant in Intensive Care Medicine
Queen Alexandra Hospital, Portsmouth
10th
March 2017

2015-2017

• Multicenter RCT
• 3 ICUs in France
• 220 patients post abdo surgery
• HFNC (50-60L) vs. standard oxygen therapy (nasal prongs or FM). Target Spo2 > 95%
– Treatment stopped on 1st
post op day
• Primary outcomes:
– The proportion of patients who developed hypoxaemia (P:F <300) 1 hour after extubation: 24% usual care (27/112) vs 21% HFNC (23/108)
P=0.62
– The proportion of patients who developed hypoxaemia (P:F <300) after discontinuation of the study treatment: 30% usual care (34/112) vs 27%
HFNC (29/108) P=0.57
• Secondary outcomes: (usual care vs HFNC). No differences
– Need for additional O2 at treatment end (82% vs 73%)
– Pulmonary complications by day 7 (61% vs 54%)
– Hypoxaemia: SpO2 < 92% on >10L/min, PaO2 <60mmHg on room air or PaO2<80mmHg on supplemental O2 (27% vs 28%)
– Need for intubation or NIV (13% vs 19%)
– Unexpected ICU admission (14% vs 15%)
– ICU LOS days (5 vs 6)
– Hospital LOS days (11 vs 12); In hospital mortality (3% vs 2%)
In patients who have undergone major abdominal surgery does the application of high flow nasal
cannulae compared with standard oxygen therapy, decrease the incidence of hypoxemia at one hour
after extubation?
Effect of early post extubation
HFNC vs conventional oxygen
therapy in hypoxaemia post
abdominal surgery. Jaber ICM

• Multicenter RCT
• 4 ICUs in Australia
• 140 patients randomised
• All comers with Hb < 100g/dl
– 35% cardiothoracic; 32% trauma
• IV iron vs. placebo
• Outcomes:
• No SS difference in median no of PRBC’s
• Median Hb was significantly higher in the IV group at
discharge from hospital
– 107g/l vs 100g/l
In critically ill patients who are anaemic, does early administration of intravenous iron compared to
placebo reduce the requirement for blood transfusion?
Intravenous Iron Transfusion in
Anaemic Critically Ill Patients
Litton. ICM 2016

• RCT
• 2 tertiary hospitals in China
• Elective post op
• Dexmedetomidine vs. placebo
• Outcomes:
• Incidence of delirium in 1st
7 days
– 9% vs 23% P<0.0001 NNT 8 Fragility Index 8
• Decreased time to extubation, LOS and pain scores
In elderly patients following non-cardiac surgery, does a low dose dexmedetomidine infusion, when
compared with placebo, decrease the incidence of delirium?
Dexmedetomidine for prevention
of delirium in elderly patients
after non-cardiac surgery
Xian Su. Lancet 2016

• International, multicenter RCT
• 52 centres (mostly UK)
• Decompressive craniectomy vs. Medical
management (barbiturates) if ICP >
25mmHg
• Outcomes: death and GOS-E at 6 & 12 m
• Fewer deaths in surgical group 30% v 52%
(at 12m)
• Estimated that for every 100 patients
treated with surgery: 22 more survivors. Of
these 22
– 27% VS; 36% LSD; 36% USD or better
In patients with a traumatic brain injury (TBI) and refractory intracranial hypertension, does
decompressive craniectomy, result in more favourable mortality and neurological outcomes at 6
months, compared with barbiturate coma and continued medical management?
Trial of Trial of Decompressive
Craniectomy for Traumatic
Intracranial Hypertension
Hutchinson. NEJM 2016

• RCT 47 centres, 18 countries
• 387 patients
• Therapeutic hypothermia (32-35C) for at least 48 hours and
continued until ICP controlled + standard care vs. standard care
if ICP > 20mmHg > 5mins after stage 1 treatment
• Good outcome (GOS-E)
– 25.7% in hypothermia group vs standard care group 36.5%
In patients with TBI, does hypothermia (32-35C) and standard care compared to standard care alone reduce death
and major disability at 6 months after injury?
Trial of Trial of Decompressive
Craniectomy for Traumatic
Intracranial Hypertension
Hutchinson. NEJM 2016

• In moderate or severe TBI does EPO improve neurological outcome?
• Neuroprotective effects ? Reduce apoptosis
• RCT, 29 countries; 606 patients
• 40000 IU of EPO x 3 vs. placebo
• Neurological disability at 6/12 or mortality
– GOS-E 1-4: 44% vs 45%
– 6/12 mortality 11% vs 16%
– DVT 16% vs 18%
In patients with moderate or severe traumatic brain injury does the administration of erythropoietin compared
with placebo improve neurological outcome at 6 months after injury?
Erythropoietin in traumatic brain
injury: a double-blind randomised
controlled trial

• RCT; 11 French ICUs
• 270 patients with status epilepticus
– 5 mins or more of continuous clinical seizure activity or > 2 seizures without a return to baseline in the
interval
• Target control temperature 32-34C vs no target temperature management
– Propofol sedation; continuous EEG
• Primary outcome: GOS score of 5 (indicating survival with no or minimal neurological deficit)
– No significant difference: 49% in intervention vs 43% in control (CI 0.75 – 1.99, p=0.43)
• Secondary outcomes: comparing intervention vs. control group
– No significant difference in:
• ICU mortality: 9% vs 12%, odds ratio 0.83 (CI 0.38 – 1.82, p=0.64)
• Hospital mortality: 12% vs 15%, odds ratio 0.81 (CI 0.40 – 1.64, p=0.55)
• Mortality at 90 days post discharge: 13% vs 15%, odds ratio 0.86 (CI 0.43 – 1.72, p=0.67)
• Total seizure duration: Median 75min vs 90min, p=0.26)
• Refractory status epilepticus on day 1: 31% vs 50%, odds ratio 0.68 (CI 0.40 – 1.15, p=0.15)
• Super-refractory status epilepticus, defined as ongoing or recurrent status epilepticus between 24 and 48 hours after the
initiation of anaesthetic treatment: 17% vs 23%, odds ratio 0.64 (CI 0.34 – 1.159, p=0.16)
• Length of stay in ICU: Median 8 days vs 7 days, p=0.44
• Length of stay in hospital: Median 21 days vs 19 days, p=0.89
• Incidents of 1 or more adverse events: 85% vs 77%
In patients with convulsive status epilepticus, does the addition of therapeutic hypothermia to standard care
improve neurological outcomes?
Hypothermia for Neuroprotection
in Convulsive Status Epilepticus
Legriel NEJM 2016

• International RCT
• 1000 patients randomised if SBP > 180mmHg
• Intervention:
– Target systolic BP 110 to 139 mmHg throughout the 24 hours after randomisation vs.
– Target systolic BP 140 to 179 mmHg throughout the 24 hours after randomisation
– Nicardipine and labetalol in both groups
• Primary outcome: Proportion of patients who had modified Rankin scores 4 to 6 at 3
months (significant disability or death)
– No difference between groups (38.7% in intervention, 37.7% in control)
• Secondary outcome:
– No difference in death, haematoma volume at one week
– Intensive group 5% more likely to develop AKI
• NB trial halted at 1000 patients because of futility
http://pulmccm.org/main/2016/n-engl-j-med-review/blood-pressure-goals-intracerebral-hemorrhage-atach-ii/
In patients with acute intracerebral haemorrhage and who are hypertensive, does rapid lowering of systolic blood
pressure compared to standard therapy improve patient outcomes ?
Intensive Blood-Pressure
Lowering in Patients with Acute
Cerebral Hemorrhage

• 18 UK ICUs’
• 2 x 2 factorial design
• Intervention:
– Study Drug 1: Vasopressin (titrated up to 0.06 U/min) or Norepinephrine (titrated up to 12 μg/min)
– Study Drug 2: Hydrocortisone (50mg 6 hourly and then weaned) or Placebo
– If the patient was still hypotensive after the first dose of study drug 2 then additional open-label
catecholamine vasopressors could be administered
• Open labelled vasopressor was permitted for up to 6 hours before enrolment to this
study. Once study drug one was commenced, the open labelled vasopressor was
weaned off as quickly as possible
• Primary outcome: the number of days alive and free of kidney failure at 28/7
– Around 55-60% for all groups
• Fewer patients required RRT in the VA group compared with the NADR group. These
patients were mostly the non-survivors
Does early vasopressin use reduce the risk of kidney failure in patients with septic shock compared with
norepinephrine?
Effect of Early Vasopressin vs
Norepinephrine on Kidney Failure
in Patients With Septic Shock

• RCT 15 ICUs Australia
• Is Dexmedetomidine effective in reducing the incidence of agitated delirium and
days on a ventilator?
• Adult ICU patients who needed to remain mechanically ventilated because their
degree of agitation was considered so severe as to make lessening their sedation
and extubation unsafe
• Primary outcome: Statistically significant increase in median ventilator free hours at
7 days in the dexmedetomidine group 144.8 vs. 127.5 hours, P=0.01
• Patients in the placebo group received significantly more antipsychotics meds (65.6%
vs 36.8%, 95% CI -51.3,-6.3%, p=0.02), more opioid, and a significantly higher dose of
propofol for the 7-days after randomisation.
Is Dexmedetomidine effective in reducing the incidence of agitated delirium and days on a ventilator?
Effect of Dexmedetomidine
Added to Standard Care on
Ventilator-Free Time in Patients
with Agitated Delirium

• RCT. 31 ICUs in France
• 620 patients
• Initiation of RRT within 6 hours vs
later following confirmation of
KDIGO stage 3
• Primary outcome: mortality at 60
days – no significant difference
– 48.5% in early vs. 49.7% in delayed,
P=0.79
In critically ill patients with acute kidney injury does delayed compared with early initiation of renal replacement
therapy (RRT) reduce mortality at 60 days?
Initiation Strategies for RRT in the
Intensive Care Unit

• RCT. Single centred
• 230 patients
• 5 inclusion criteria including KDIGO
stage 2
• Initiation of RRT within 8 hours vs 24
hours of confirmation of KDIGO
stage 2
In critically unwell patients with acute kidney injury, does early initiation of renal replacement therapy (RRT)
compared to delayed initiation reduce all cause mortality at 90 days?
Effect of Early vs Delayed
Initiation of RRT on Mortality in
Critically Ill Patients With Acute
Kidney Injury

• French multicentre RCT
• 380 patients
• Acetazolamide vs placebo for up to 28d to patients with COPD and a metabolic
alkalosis (primary or mixed), receiving invasive mechanical ventilation
• Primary outcome: No statistical difference in the median duration of invasive
ventilation between groups
– 136.5 hours (IQR 68.7 – 234.7 hours) in the acetazolamide group vs. 163.0 hours (IQR 86.2 – 242.9
hours) in the placebo group; P=0.17
• Daily median serum bicarbonate change (mEq/L)
– Reduction in bicarbonate in acetazolamide group: -0.3 vs. 0.3; P=<0.001
• Median number of days with a metabolic alkalosis was fewer in acetazolamide group
– 2 vs 4 days; P=<0.001
Does acetazolamide reduce the duration of mechanical ventilation in critically ill patients with chronic obstructive
pulmonary disease (COPD) and metabolic alkalosis?
Effect of Acetazolamide vs
Placebo on Duration of Invasive
Mechanical Ventilation Among
Patients with Chronic Obstructive
Pulmonary Disease

• RCT 23 ICU’s in Oz/Nz. 700 patients
• 1g paracetamol 6 hourly vs placebo up to 28 days
• ?immunomodulatory
• Median ICU-free days to day 28: no significant difference
– 23 (IQR 13-25) in the paracetamol group vs 22 in the placebo group (IQR 12-25) CI 0-1; P=0.07
• all cause mortality at 28 days
– no significant difference13.9% vs 13.7%
• all cause mortality at 90 days
– no significant difference15.9% vs 16.9%
• Liver dysfunction necessitating stopping study drug
– lower in paracetamol group8.1% vs 9.9%
Does the regular administration of paracetamol to critically ill patients with fever and known or suspected
infection, affect the number of ICU-free days?
Acetaminophen for Fever in
Critically Ill Patients with
Suspected Infection

In critically ill patients, does the use of a balanced crystalloid solution compared to normal saline effect the
incidence of acute kidney injury?
Effect of a buffered crystalloid
solution vs saline on acute kidney
injury among patients in the
intensive care unit: the SPLIT
randomised clinical trial
• RCT 4 ICU’s in Oz/Nz. 2278 patients
• 0.9% NaCL vs Plasmalyte (median 2000mls each)
• Primary outcome: proportion of patients with AKI based
on RIFLE criteria (‘injury’ or greater and based solely on
creatinine component) within 90 days of enrolment: no
statistical difference
- 9.6% in intervention group vs 9.2% in control group; P=0.77
• Secondary outcome: Plasma-Lyte 148 vs. 0.9% sodium
chloride – no statistical difference in any of the
following:
- RRT requirement; mechanical ventilation; LOS; all cause mortality

NEW DEFINITION SEPSIS life-threatening organ dysfunction caused by a dysregulated host response to infection
Septic Shock: Sepsis with persisting hypotension requiring vasopressors to maintain MAP ≥65mmHg and having a
serum lactate level >2mmol/L (18mg/dL) despite adequate volume resuscitation.
Sepsis 3
Organ dysfunction = acute change in total SOFA
score ≥2 points due to the infection (The baseline
SOFA score can be assumed to be zero in patients
not known to have preexisting organ dysfunction)
A SOFA score ≥2 = mortality risk of approximately
10%; Septic shock = mortality > 40%
Screening Patients ? Sepsis: Patients with
suspected infection that are likely to have a
prolonged ICU stay or to die in the hospital can be
promptly identified at bedside with qSOFA. Less
robust but no lab tests
Thanks to REBEL EM for images http://rebelem.com/sepsis-3-0/

Does cognitive function in TTM cardiac arrest survivors differ between the 33 and 36 degree groups and also
compared with a cohort of patients who sustained STEMI but no cardiac arrest
•652 cardiac arrest survivors from TTM
•Survival until 6/12 52%
- invited to follow up
- about half had psychometric testing
- compared with a control group (STEMI & PCI but no cardiac arrest)
•About 50% had cognitive impairment
•33 vs. 36 vs. control group
- cognitive outcome no different between temperature groups
- attention & mental speed more affected in cardiac arrest patients-
- memory & executive functioning similar in all groups
Cognitive Function in Survivors of
Out-of-Hospital Cardiac Arrest
After TTM at 33ºC Versus 36ºC

In organ donors, following diagnosis of BSD, does TH decrease delayed graft function in kidney recipients?
•2 organ procurement centres in US
•RCT 394 donors
•Mild hypothermia (Target 34 – 35C) vs Normothermia (Target 36.5 – 37.5C)
•Delayed graft function
- the recipient’s requirement for dialysis during the 1st week post-transplantation
- 28.2% vs 39.2%, P=0.008
Cognitive Function in Survivors of
Out-of-Hospital Cardiac Arrest
After TTM at 33ºC Versus 36ºC

In paediatric patients with septic shock, does adrenaline compared with dopamine reduce 28 day mortality?
•RCT; single centre Brazil
•120 patients
•Adrenaline vs dopamine after 20mls/kg bolus
•Once 60mls/kg fluid given, if still shocked, clinician choice of vasoactive drug
•28 day mortality
- Adrenaline group vs Dopamine group 0.7% vs 20.6%
Double-Blind Prospective
Randomized Controlled Trial of
Dopamine vs Epinephrine as
First-Line Vasoactive Drugs in
Pediatric Septic Shock

CALORIES
• Open, multicentre, RCT
• 2400 patients in 33 ICUs in UK
• PN vs. EN within 36 hours for 5/7
• Primary outcome:
– All cause mortality 33.1% (PN) vs. 34% (EN)
• Secondary outcome:
– Vomiting more in EN
– No difference on other 16 outcomes including ‘serious’ hypoglycaemia
– NB daily calorific targets achieved in <40% in both groups

In adult patients with alcoholic hepatitis, does prednisolone and / or pentoxifylline compared to placebo reduce
mortality?
•RCT 65 UK hospitals
•Pentoxyfylline + placebo vs. Prednisilone + placebo vs. both vs placebo x 2
•ICUs in Canada and France; 2510 patients
•28d mortality no statistical difference
STOPAH: Prednisolone or
Pentoxifylline for Alcoholic
Hepatitis

• In ICU patients who require a CVC, does the choice of insertion site affect the
complication rates?
• 10 ICUs in France (4 university hospitals and 5 general hospitals)
• SC, IJ or femoral (>1000 lines in each group)
• Composite measure of CRBSI and DVT
• SC = lower infection; higher PTX
PERMIT

• Is “fresh” blood (stored for 8 days or less) better than old (stored 2-42 days)?
• RCT 64 ICUs in Canada and France; 2430 patients
• RBCS: 6 days vs 22 days
• 90 day mortality (37% vs. 35%)
• Transfusion triggers and processes for safe administration of blood are probably
more important
PERMIT

TRISS
• RCT 32 general ICUs in Scandinavia
• 998 patients with septic shock & Hb <9
• Transfusion threshold <7 vs. <9
• Excluded patients with ACS
• Mortality at 90 days (43% vs 45%)
• Secondary outcomes
• Vasoactive drugs
• Ventilation
• RRT
• % of days alive & out of hospital
• Ischaemic events

TITRe2
• In adults undergoing cardiac surgery, does a
restrictive transfusion strategy vs liberal one lead
to fewer infections and ischaemic events within 3
months?
• RCT 17 cardiac ICUs in UK
• Trigger Hb 75 vs 90g/dl
• Composite outcome of serious infections or
ischaemic events within 3/12
– 35% vs 33%
TRICC, TRISS, Villanueva

PROPPR
• RCT in 12 N. American Level 1
trauma centres
• 680 patients
• 1:1:1 vs. 1:1:2 FFP / plt / PRBCs
• 24 hour and 30d mortality no
different
• Time of haemostasis; Any of 23 pre-
defined complications; Hospital,
ventilator & ICU free days
• Post- hoc analysis:
- Death by exasanguination in 1st
24 hrs
much less in 1:1:1 group

Guidelines

Standards - quality
• Staffing
– Consultant presence
• 24/7 & within 30 minutes
– Consultant: patient 1:8 – 1:15; ICU resident/patient
1:8
– Designated CD
– Ward rounds x2 daily
– Training / FICM / Board Tutors
– Nursing 1:1 (level 3); 1:2 (level 2)
– MDT e.g. physio, pharmacy, dieticians
• Operational
– Large ICUs divided into pods of 8-15 patients
– Admit within 4 hrs of decision to admit
– Avoid non-clinical transfers
– Transfer to ward – clear and formalised
– Out of hours transfers
– Readmission within 48 hours bad
– Assessment of rehab for each patient
• Equipment
– Training
• Data Collection
– ICNARC
– Risk register
Quality Indicators
SMR
Scoring Systems

•Definitions: CPIS, CDC, HELICS
•Pathogens:
- Early: strep pneumonia; H.influenzae; MSSA; Klebsiella, E.Coli
- Late: MRSA, acinetobacter, pseudomona
•Elevation of head of bed (30-45 degrees)
•Daily sedation interruption and assessment of readiness to extubate
•Use of subglottic secretion drainage
•Avoidance of scheduled ventilator circuit changes
•? Stress ulcer prophylaxis
•? Avoid oral chlorhexidine
• Reduces nosocomial pneumonia in cardiac surgery
• Meta-analyses showing benefit heavily influenced by cardiac patients
• No benefit for VAP in general ICU’s
•ICUs in Canada and France; 2510 patients
•28d mortality no statistical difference
https://ccforum.biomedcentral.com/articles/10.1186/cc13775
ICS Recommended bundle of interventions for the prevention
of ventilator associated pneumonia

NAP 4 - 2011
• All NHS hospitals for 1 year ’08-’09
• 184 reports
133 anaesthesia
36 ICU
15 ED
• Inclusion criteria
death, brain damage
emergency surgical airway
unanticipated ICU admission
Prolongation ICU stay

Summary of NAP 4
25% of major airway events in a hospital occur in ICU or the ED
46% of ICU events and 53% of ED events occurred out of hours
50% of ICU events were due to tracheostomy related events
50% events in ICU and 27% events in ED resulted in death
61% events in ICU resulted in death or severe neurological harm

Recommendations
Capnography
Airway equipment
Back up planning
Staffing
Patient transfers
Education/training
Tracheostomy tube
design
Team working

Tracheostomy standards
• Indications for tracheostomy
• Cautions and contraindications
• Consent
• Equipment
• Ultrasound
• Anaesthesia
• Staffing
• Types of tracheostomy tubes
• Inner cannulae
• Complication
– Early
– Late
– Airway emergencies
T R A C H E O S T O M Y C A R E
I N T E N S I V E C A R E S O C I E T Y S T A N D A R D S © 2 0 1 4

Antibiotic Stewardship
https://www.ficm.ac.uk/sites/default/files/FICM-Start_Smart_Then_Focus_FINAL.pdf

Community Acquired Pneumonia
https://www.nice.org.uk/guidance/cg191/chapter/1-Recommendations#community-acquired-pneumonia-2

Brain Trauma Foundation Guidelines 22nd
Sept 2016
https://braintrauma.org/guidelines/guidelines-for-the-management-of-severe-tbi-4th-ed#/:guideline

http://www.britishinfection.org/files/5614/5674/2938/McGill_meningitis_guidelines_Final_published_proof.pdf

Guidelines for managing delirium

Designing a new Intensive Care Unit

Fire on the ICU
1. Protect patients and staff
2. Manage fire hazard
3. Identify cause and prevention
Management of Fire Hazard – RACER
RESCUE
ALERT
CONTAIN
EXTINGUISH
RELOCATE

Care of the dying patients (2015)
https://www.nice.org.uk/guidance/ng31
Rehabilitation after Critical Illness (2015)
https://www.nice.org.uk/guidance/cg83
AKI: Prevention, Detection and Management (2013)
AF Management (2014)

Useful resources

Neuro
http://www.neuroicu.org.uk/
The SAH section
definitely worth a
read for the exam
The SAH section
definitely worth a
read for the exam

2014 &
earlier

ALBIOS
• RCT, 100 ICUs in Italy
• 1795 patients with severe sepsis
• 300mls 20% HAS daily + CSL vs. CSL
• Target serum albumin 30g/dl
• 287 mortality: no different
– HAS + CSL: 31.8%
– CSL: 32%
• Secondary outcomes: 90 d mortality
– No difference

ARISE
• Randomised, controlled, multicentre,
• 51 hospitals 1,600 patients with septic shock
• EGDT vs. Usual Care
• No difference in:
– All cause mortality at 90d (18%)
– ICU & Hospital LOS

ProCESS
• RCT 31 ICUs in US
• 03/2008 – 05/2013
• 1351 patients with septic shock
• 3 groups
– EGDT
– Protocol based standard therapy
– Usual care
– No difference in 60 d mortality between groups

PEITHO
• RCT; 13 countries; 1006 patients
• Tenecteplase vs placebo
• Death or haemodynamic decompensation
within 7 days – Significantly lower in
thrombolysis group
– 2.6% vs. 5.6% in placebo group (NNT 34)
• Mortality at 7 days and 30 days
– 7 days: 1.2% vs. 1.8%; 30 days: 2.4% vs. 3.2%
• Major extracranial bleeding - higher in
thrombolysis group
– 6.3% vs. 1.2% (NNH 19)
• Haemorrhagic stroke – higher in
thrombolysis group
– 2% vs 0.2% (NNH 55)

HARP 2
• 540 patients ARDS; 40 UK ICUs
• ARDSnet +/- statin for 28 days
(80mg od simvastatin)
• Primary outcome
– No difference in ventilator free days
at 28d
• Secondary outcome
– No difference in SOFA, oxygenation
– Elevated CK or ALT/AST > in statin
group

CATIS
• 4,071 patients
• Within 48 hrs ischaemic stroke
• nonthrombolysed and ↑BP
• Hypertension therapy vs no BP Rx
• BP control effective
• No difference
– death and major disability
• 14 days / hospital discharge
• 3 months

CRISTAL Study
• Stratified open label RCT
• Recruitment over 9 years
• Any colloid vs any CSL
• 2857 patients with hypovolaemic shock
• 28 day mortality
• Colloids favoured:
– 90 day mortality (30% vs 34%)
– More days alive without MV
– More days alive without vasopressors
– Less RRT
-

Themes

TracMan - 2013
•Early tracheostomy (by d 4)
or late (>10/7)
– 455 patients
– Mortality the same 31%
– LOS the same 13 d
– Complications slightly higher
in late group 6% vs. 5%
Young et al. JAMA 2013 May 22;309(20):2121-9

ARDS - Incidence
• 1 yr prospective
observational study; 255
patients
• Incidence
7.2/100,000/year (? US
75/100,000)
• Despite use of lung
protective ventilation
overall ICU mortality
>40%

OSCAR
• 795 patients with moderate - severe
ARDS (<26.7kPa / 200mmHg)
• CMV vs. HFOV (MV <7 days)
• No difference in
– 30/7 mortality (41%)
– Duration antimicrobial agents (2/3
chest sepsis)
– Vasoactive support duration
– ICU LOS
– Hospital LOS

OSCILLATE
• 548 patients with moderate - severe
ARDS
• HFOV vs low Vt/High PEEP CV (MV < 3d)
• Trial stopped early as harm with HFOV
• HFOV
– Hospital mortality 47% vs 35%
– More sedation
– More NMBA’s
– More vasopressors

PROSEVA
• 466 patients with severe ARDS
• Prone position vs supine position
• Prone position was associated
with
– Improved mortality
• 28 day: 16% vs 33%
• 90 day: 24% vs 41%
– Less cardiac arrests
– No difference in complications

PROSEVA

Statins in ARDS
• Multicentre, RCT
• Rosuvastatin vs. placebo in ARDS
• Statin may modulate inflammatory response
• 745 patients (trial stopped early because of
futility)
• 60d mortality: 28.5% vs. 24.9% (statin vs. placebo)
• Ventilator free days: 15.1 vs. 15.1

Statin & VAP
• 300 patients with suspected VAP (CPIS
≥ 5)
• Simvastatin 60mg vs placebo
– 28d survival
– ICU or hospital mortality
– Duration MV
– Delta SOFA
• Increased mortality in statin naieve

BALTI - 2012
• 162 patients; 46 UK ICU’s
• ARDS & MV
- salbutamol 15mcg/kg/hr or placebo
- Treatment for up to 7 d
• Mortality greater in those given
salbutamol 34% vs 23% at 28d

Steroids in ARDS
• 9 studies (4 RCT’s & 5 cohort)
• 648 patients
• Trend to reduced mortality but
only ss when result pooled
• Trials vary ++
1. Dose
2. Initiation of treatment
3. Course length
4. Not all studies report adverse events

Functional disability 5 years after ARDS
109 survivors from ’98 - ’01
Interview, PFT’s, 6 min walk
test, resting & exercise
oximetry, chest imaging, QOL
survey
PFT’s normalish
BUT 6 min walk test 76%
predicted,
physical/psychological
problems

Nitric oxide – just say No
• Potent pulmonary vasodilator which when inhaled =
selective vasodilation in well ventilated lung units
• Improved V/Q mismatch and PVR & PAP
• Also anti-inflammatory effects
• Systematic review of 12 trials with 1200 patients =
improved oxygenation d1, no improvement in
mortality
• AKI and methaemaglobinaemia
intracranial bleeding in children
Afshari Cochrane review 2007 - adults
Barrington Cochrane review 2010 – children
Afshari – systematic review 2011

Magnesium in asthma
• 1200 patients 2008-2012
• Neb vs. IV Mg vs. placebo
• No role for neb Mg
• Limited role at best for IV
Mg
• Not life threatening asthma
Intravenous or nebulised
magnesium sulphate
versus standard therapy
for severe acute asthma
(3Mg trial): a double-
blind, randomised
controlled trial
Goodacre et al Lancet 2013 Vol 1 (4) 293-300

• In ICU patients undergoing intubation does apnoeic oxygenation during
laryngoscopy increase the lowest arterial oxygen saturation experienced by
patients
• Single centre
• HFNC + other NRBM/BiPAP/BVM/standard nasal vs. NRBM/BiPAP/standard
nasal cannulae
• Median lowest SpO2
PERMIT

• 12 French ICU’s; 310 patients
• ‘ALI’
• NRB vs HFNC vs NIV
• Proportion of patients who required endotracheal intubation within 28 days
after randomisation:
• High-Flow oxygen: 40 patients (38%)
• Non-invasive ventilation: 55 patients (50%)
• Standard oxygen: 44 patients (47%)
• p = 0.18
PERMIT

NCEPOD 2014: Tracheostomy
• Documentation & consent
– Indications, type, inner tube, reasons for
failed extubation/why no trial of
extubation
• Different types of tubes
• Rapidly available difficult airway trolley
• Training programmes in blocked/displaced
tubes
• Capnography
• Discharge of patients with tracheostomy
• MDT – physio & SALT

MCA & DoLS
DoLS
• 3 cases in 2014

INTERACT 2
• 2,839 pts with early spontaneous
intracerebral haemorrhage & ↑SBP
• Compared SBP <140 mmHg vs <180
• Aggressive BP control associated
with
– Trend for less adverse events
(p=0.06)
– Lower modified Rankin scores
• No difference in mortality

Magnesium for aneurysmal SAH (MASH-2): a
randomised placebo-controlled trial
Mees S et al. 2012 The Lancet. Vol 380 9834:44-49
• 8 ICU’s in Europe and S America
• 1204 patients
• The question: does Mg reduce poor
outcome by reducing vasospasm and
delayed cerebral ischaemia (DCI)
• Magnesium 64mmol/day for 20/7 or
placebo
• Primary outcome of poor outcomes
as defined by score 4-5 on modified
Rankin Scale at 3/12, or death
• NO DIFFERENCE

Delirium
HOPE ICU
• 142 patients with delirium
• CAM-ICU assessment
• Double blinded
• Haloperidol vs. placebo
• No change in duration of delirium
in critically ill patients
• Haloperidol should be reserved
for short term management on
acute agitation
Effect of intravenous
haloperidol on the duration of
delirium and coma in critically
ill patients (Hope-ICU): a
randomised, double-blind,
placebo-controlled trial
Valeirie Page. The Lancet Respiratory Medicine,
Volume 1, Issue 7, Pages 515 - 523, September 2013

Treating Delirium
101 MV patients RCT
haloperidol vs. ziprasidone vs placebo
21/7 study period
No difference in any of the groups!

The beginning; Kress NEJM 2000 Reduction in
LOS
Girard Lancet 2008
Decreased ICU stay, time on ventilator and
mortality
Strom Lancet 2010
Reduction in LOS and ventilator days
No sedation group - boluses of morphine, well established in
institution, more agitated delerium in no sedation group
Jacob JAMA 2012 PRODEX/MIDEX
No better than midaz or propofol at maintaining
light to mod sedation and more adverse effects.
Increased patient interactions. Less vent days than
midazolam
Ryker JAMA 2009
Reduction in ventilator days and delirium
Mehta 2013
For MV patients managed with protocolised
sedation, the additon of daily sedation interruption
did not reduce duration MV or ICU LOS

Don’t forget the simple things….
• Small RCT 136 patients
• Used NEECHAM score
• Delirium (20%) similar but
less mild confusion with
ear plugs and good night
sleep <50% vs. 25%

Neuro-ICU
ICP Monitoring
• Multicentre RCT of 324
patients Bolivia and
Ecuador
• Intraparenchymal ICP
monitoring vs. clinical &
imaging
• No difference in mortality
or neuropsycholoigcal
status at 6/12
A Trial of Intracranial-Pressure
Monitoring in Traumatic Brain Injury
Randall M. Chesnut et al
N Engl J Med 2012; 367:2471-2481

Neuro
http://www.wessexics.com/WICS_Guidelines/
The SAH section
definitely worth a
read for the exam
The SAH section
definitely worth a
read for the exam

VAP
What is VAP?
What are the common organisms (early vs.
late?
Scoring systems e.g. CPIS, HELICS
What antibiotics would you use?
How can you reduce incidence

TTM
• 950 unconscious adults; 36 ICU’s
• 33°C (n=473) with 36°C (n=466)
– All cause mortality
33°C (50%) with 36°C (48%)
– poor neurological function at
180 days
33°C (54%) with 36°C (52%)

Pre-hospital hypothermia
• Prehospital cooling vs. standard care
• 2L of cold normal saline once ROSC
• 1,359 OOHCA patients
• Cooling effective (reduced temp)
• No difference
– Survival to hospital discharge
• VF 63% vs 64%
• nonVF 19% vs 16%
– Good neurological recovery
• VF 57% vs 62%
• nonVF 14% vs 13%

CO Monitoring – COMET-UK
• Survey to all UK ICUs
• Respondents
– Majority used CO monitoring
• Oesophageal doppler 57%
• LiDCO 43%
• PiCCO 42%
How does doppler work?
Thermodilution?Pulse contour analysis ?
How does doppler work?
Thermodilution?Pulse contour analysis ?

OPTIMISE
• RCT, multicentre, 17 UK ICUs
• 734 patients
• > 50y undergoing GI surgery with one or more ‘high risk’ risk factors
• Algorithm-directed care dictating colloid and dopexamine administration
using vs. clinician directed care without use of CO monitoring
• Primary outcome: composite of 30d mortality and mod/major
complications
– Intervention: 36.6%
– Control arm: 43.4%
• No SS difference in secondary outcomes
– POMS, infectious complications, critical care free days at 30d, mortality at 30d
and 180d, hospital LOS

IVOIRE Study
• Randomised, open study
• 18 ICU’s in France, Belgium and
Netherlands 2005-2010
• 140 pts with septic shock & AKI
• HVHF 70mls/kg/hr v 35mls/kg/hr
• Slow recruitment
• No difference in mortality = 40%
28/7
• HVHF not recommended

IABP – SHOCK II
• 600 patients with cardiogenic shock
secondary to AMI
• IABP vs no IABP
• All received early revascularisation
and best medical therapy
• No difference
– 30/7 mortality (40%)
– ICU LOS, catecholamine, bleeding
• Lancet 2013 Sept – 12/12 results = no
difference in mortality or reinfarction
rate

VSE in cardiac arrest
• 268 patients in hospital cardiac arrest
• Vasopressin(20IU/CPR cycle) +
epinephrine (1mg/CPR cycle) +
methylprednisilone (40mg) vs
placebo + epinephrine (1mg/CPR
cycle)
• VSE group
– ROSC at 20 mins higher 84% vs 66%
– Improved survival to hospital discharge
with CPC 1 or 2
– Improved haemodynamics & cvSpO2
– Less organ dysfunction
• andAcademic Department of Critical Care

CHEER
• Refractory cardiac arrest treated with
mechanical CPR, hypothermia, ECMO
and early reperfusion
• 26 patients (11 OHCA; 15 IHCA)
• Primary outcome
– Survival with good neurological recovery (CPC 1-2) 14/26
(54%)
• Secondary outcomes
– ROSC achieved in 25/26 (92%) of patients
– Survival to hospital discharge 14/26 (54%)

The oxygenator in veno-venous ECMO

ECMO
Study
type
Year
pub
N
(ECM
O)
N
(non
ECMO)
%
H1N1
ECMO
mortalit
y
Non-
ECMO
mortality
p
RCT 200
9
90 90 0 37% 50% 0.07
RCT 199
4
21 19 0 67% 58% 0.8
RCT 197
9
48 42 0 90% 92% 0.84
Cohort 200
6
32 118 0 47% 29% 0.06
Cohort 200
0
62 183 0 45% 39% NS
Cohort 199
7
49 73 0 45% 11% <0.001
Case
series
200
9
68 133 100% 23% 13% 0.06
Case
series
201
1
69 11 100% 27.5% ?52% ***

ECMO for H1N1
• 2009-2010
• 80 patients referred for ECMO
• 69 received ECMO
• 22 of these died (27.5%)
• Matching cohort = 52%
• For patients with H1N1
related ARDS, mortality
reduced with ECMO

• Meta-analysis
• 16 trials inc PEITHO, MAPPETT,
MOPETT, TOPCOT
• Thrombolysis + anticoagulation
vs. anticoagulation alone
• All cause mortality less in
thrombolysis group but major
bleeding & ICH higher

SEPSIS

Ferrer: Empiric antibiotics in sepsis
• Retrospective observational cohort study
• 165 ICUs – Europe, US & S America
• Jan 2005- Feb 2010
• 18,000 patients with septic shock
• Delay in antibiotics administration over first 6 hours after
identification of SS or septic shock -> increased mortality
• < 1 hr 24.6%; 1-2h 25.9% > 6h 33%

SEPSISPAM
• RCT, multicentre, 29 French ICUs
• March 2010 – Dec 2011
• Septic shock
• Target MAP 80-85 vs. 65-70
– 28 day mortality (high MAP 36.6% vs. 34%)
• New AF 6.7% in higher MAP group vs. 2.8% P=0.02
• In chronic hypertension group, worsening creatinine and need for RRT
was lower in higher MAP group

PROWESS SHOCK
• Randomised, controlled, multicentre,
parallel group study
• 1,697 patients with septic shock
– 28 day mortality (APC 26.4% vs
24.2%)
– 90 day mortality (34.1% vs 32.7%)
• No subgroup effect seen in protein C
deficient group
• Serious bleeding n = 10 APC vs 8
placebo

B blockers in septic shock
• Open label, single unit
• Septic shock + HR ≥ 95 + NADR
• 77 patients – esmolol infusion (HR 80-
94) vs 77 patients standard treatment
• Esmolol group
– 28d Mortality 50% vs 81% in placebo
– Improved SV index, LVSWI, lactate
– Less NADR requirement
– Less fluid requirement

Esmolol in refractory VF
• Single centre, non randomised
• 25 patients with refractory (>3 defib
attempts) VF or pulseless VT
• Esmolol vs. placebo
• Primary outcome
– Survival with good neurological recovery
– 50% esmolol vs 11% control group
– No difference in rates of ROSC or survival
to hospital discharge

Steroids in Sepsis

ADRENAL

The evidence…..let’s give it
8 trials published before ’89
- No mortality benefit (some worse)
- Decreased time for shock resolution
- More secondary infections
- Higher doses and for shorter periods
19 ICU’s 300 patients
- 50mg hydrocortisone + fludrocorisone vs. placebo by 8hrs of onset of
septic shock.
- ‘Non responders’ (adrenal suppression) better ICU (53% vs. 63%)
and hospital mortality (61% vs. 72%).
- Increase secondary bacterial infections
- NNT = 7
(Annane JAMA 2002)

The evidence…..perhaps don’t give
CORTICUS
- 52 ICU’s, 499 patients
- 50mg hydrocortisone QDS vs. placebo 6/7
- 28/7 mortality no different between groups and subset of non-
responders
Quicker shock resolution, catecholamine sparing, more secondary infections
Sprung et al. NEJM 2008: 358; 111-24
- Etomidate used in 1/5th
of patients
- Only 35% power to detect a 20% mortality reduction
- High variability between laboratories in cortisol assays

VASST
- RCT 778 pts with septic shock
- Noradrenaline vs. Norad & Vaso (0.03 units/min)
- No mortality benefit
- Higher doses associated with ischaemia
“Possible use if other vasopressors failed”
Less severe shock associated with reduced mortality when vasopressin used
Russell et al. NEJM 2008: 358: 877-87

ABLE Multicentre UK RBC transfusion (7d vs. 15-25d)
Transfusion triggers – TRICC, TRISS & Villaneuva, TITRe2
PROPPR: Plasma, Platelets & PRBC’s 1:1:1 vs. 1:1:2
Guidelines on the management of anemia and RBC transfusion in
adult critically ill patients (BCSH Guidelines 2012)
Serious Hazards of Transfusion (SHOT) – JICS July 2013

Acute UGI Bleed
• Randomised, parallel group study
• 921 pts with severe upper GI bleeding
• Compared restrictive (Hb <7g/dL) vs liberal
transfusion strategy (Hb<9g/dL)
• Restrictive strategy associated with
– Reduced number of pts receiving
transfusion (15% vs 51%)
– Increased probability survival (HR 0.55)
– Less rebleeding (10% vs 16%)
– Less adverse events (40% vs 48%)

TXA
CRASH - 2 Lancet 2010
• tranexamic acid in reducing transfusion requirements and
death from significant haemorrhage following injury
• 20,000 patients
• Risk of haemorrhage reduced by 0.8%
• No reduction in transfusion usage
• Only 50% received blood and average only 3 (? ‘significant
haemorrhage’)
CRASH - 2 subanalysis Lancet 2011
• Mortality directly related to haemorrhage
Tranexamic acid only effective if within first 3 hours. Beyond
this time mortality increases

TXA
CRASH – 2 Does TXA reduce the risk of intracranial
bleeding in patients with TBI? BMJ 2011
• 250 of the 20,000 patients eligible.
• Brain haemorrhage growth 5mm vs. 8mm (TXA vs. placebo)
• Not SS
• No mention of extent of extracranial injuries in either group
making mortality comparisons difficult
• Not well matched as there were more pts with SAH (61% vs
43%)
• No increase is focal cerebral ischaemia
• Conclusion “it is probable that benefits of tranexamic acid
outweigh risks’

Trauma Haemorrhage
1. Coagulation monitoring and measures to
support coagulation should be implemented
early
2. Damage control surgery
3. Physiological targets, suggested use & dosing
of fluids, blood products and TXA
4. Patients on antiplatelet agents and/or oral
anticoagulants require special attention
5. Mutlidisciplinary approach & evidence based
protocols adapted to local circumstances need
to be developed and implemented

Fluids
• Don’t give too much
• Don’t give too little
• Make sure you give the right
amount
• Starches bad…very bad
Association of HES administration with mortality and AKI in
critically ill patients requiring volume resuscitation. Meta-
analysis. JAMA 2013 vol 309 (7)
• Albumin back in?
SAFE subgroup analysis 1200 pts with severe sepsis - 28/7
mortality lower in albumin group (30% vs. 35% OR 0.87)
Finfer S et al 2011 Intensive Care Med 37:86–96
Delayney metaanalysis. Role of albumin as a resuscitation
fluid for patients with sepsis. 17 studies, 1977 patients. Crit
Care Med 2011
Albios Study – Gattinoni (video ion ESICM website)
“lets talk about fluid responsiveness”
NO!

ESICM statement on colloids
1. Recommend not to use HES with mw ≥
200kDa in patients with severe sepsis or risk of
AKI
2. Suggest avoid 6% HES or gelatin in these
groups
3. Recommend not to use colloids in patients
with head injury and not to administer gelatins
and HES in orhan donors
4. Suggest avoid hyperoncotic solutions for fluid
resuscitation

6S Study
• 804 ICU pts with severe sepsis
• Compared fluid resuscitation
– 130/0.4 hydroxyethyl starch
(tetraspan) vs Ringer's acetate
• HES associated with
– Increased 90 day mortality
51% vs 43%
– Increased RRT requirement
22% vs 16%
– Trend for increased bleeding
10% vs 6%

CHEST Study
• 7000 ICU pts
• Fluid resuscitation with 6% HES
130/0.4 (Voluven) or 0.9% saline
• No differences in
– Mortality (HES 18% vs 17%)
– LOS – ICU / Hospital
• HES associated with increased
– RRT (7% vs 5.8%; RR 1.21)
– Pruritus / Rash / Hepatic failure
-Academic Department of Critical Care

• In patients with severe pancreatitis, does early enteral feeding compared with
on-demand feeding reduce death or major infection?
• RCT; Netherlands; 208 patients
• Early NJ within 24 hours vs IV fluids + ‘on demand’
• Composite outcome of death or major infection within 6 months

• In critically ill adults, does restriction of non-protein calories (permissive
underfeeding) compared to standard feeding reduce mortality at 90 days?
• RCT; Saudi Arabia and Canada; 894 patients
• Permissive enteral underfeeding (40-60%) vs standard (70-100%) for up to 14
days
• ? Moderate survival benefit from permissive underfeeding with moderate
caloric intake (around 50% of target calories) and maintenance of full protein
requirement (1.2-1.5g per kg per day)
PERMIT

Need a nice summary?

The SuDDICU study
SDD
12 meta-analyses of 28 RCT’s. 10
show reduced pneumonia rate; 6
show morality benefit
• Why have clinicians avoided
implementing it in UK?
• What are the barriers?
• What further evidence is required
before full scale clinical
implementation

VITdAL-ICU
• RCT, Single Centre with 5 ICUs in
Austria, 475 patients
• Vit D or placebo
– Hospital LOS no different
• Secondary outcome. No difference:
– ICU LOS
– ICU-, 28d- , hospital- & 6 month- mortality
• Subgroup analysis
– If severe vit D def and given Vit D3 -> improvement in
28d- hospital- and 6 month- mortality

Systematic review: CCM 2010
In those patients receiving
enteral nutrition, stress
ulcer prophylaxis may not
be required and may
actually increase VAP

H2R antagonists vs PPI
• Cohort Study of 35,000 pts
• MV > 24 hours and either
H2R antagonist or PPI
• H2R antagonist group had
– Less GI haemorrhage 2.1 vs
5.9%
– Pneumonia 27% vs 39%
– C.Diff 2.2% vs 3.8%

Hepatology
• ALD
Alcohol related illness costs NHS £1.7
billion/year
Systematic review of 21 articles
Overall ICU mortality 40-50%
Mackle study only one to provide data
on GI haemorrhage - mortality 48%,
62%, 67%,68% for unit, hospital, 6/12
and one yr - if get out of hospital most
will survive
Organ support - 3 papers (ventilation,
vasoactive drugs, RRT)
Mackle -
- if MV and vasoactive drugs hospital mortality 86%
- If MV, vasoactive drugs and RRT > 90%
- If just MV 31%
Saliba RRT 90%
Rye 100% mortality if require RRT

Intraabdominal pressures
http://www.wsacs.orghttp://www.wsacs.org//

Microbiology
• 96 ICU’s
• Data from 60,000 admissions
’09-’11
• Invasive fungal disease defined as
BC or sample from normally
sterile site showing yeast/mould
cells in a microbiological or
histopathological report
• 383 (0.6%) were admitted with or
developed IFD
• Conclusion:
Incidence of IFD in non-
neutropenic, critically ill patients
is low

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