Venue: University Hospital Southampton
Summary: Dr Phil McGlone
Trevor Smith Cons Gastro UHS.
- Gastric residual volume less than 200mls not evidenced based
- Only one study suggests that less than 500m is safe
- All PN vs EN trails are of high versus low volume feeding.
- The meta analysis from the early 2000’s are based on old, outdated trials and probably have little if any relevance to care in the ITU today.
Practical aspects of prescribing nutrition Mark Tomlin Cons Pharmacist
Malnutrition Universal Screening Tool (MUST)
1 - Score for low BMI (20, 18.5-20, <18.5)
2 - Score for recent weight loss (5%, 5-10%, >10%)
3 - Score for poor nutrition for last 5 days, or likely to be poor for over 5 days.
1+2+3 Score > 2 Identifies high risk patients
40% of hospital patients are malnourished and this is linked to slow recovery and poor wound healing. ICU patients may loose 10% of their muscle mass each week.
Is it evolutionary that we don’t eat when acutely unwell?
MUST score quantifies detection of malnourished patients for dietetic support (>2 implies refer)
Patients who are not eating oral foods normally get referred to dieticians
If still not eating orally, consider enteral tube feeding (NG, NJ, PEG).
Document length of enteral tube at nostril
Note position check. pH <5 aspirates (H2A,PPI) and X-ray
Use of a size 8fr will aid aspiration. Use a fine bore tube unless continuously high gastric aspirates and patient is at risk of aspiration
30 degree elevation to avoid reflux and aide diaphragm movement
Macronutrients - Normal
- 25-35kcal/kg/day total energy ave. 70kg = 1750-2450
- 1kcal per kg/hr (actual body weight)
- 6.2G protein = 1G Nitrogen
- (0.13-0.24G nitrogen) per Kg/dayave. 70kg = 9.1-16.8G N/day
- 30-35ml/kg/day fluid ave 70kg = 2.1-2.5L/day =>85-100ml/hr
- Fibre as appropriate
Macronutrients – Acutely unwell
- Energy total – 1500-2000 kcal/day, ideally 1:1 CHO to fat ratio
- Protein – 7-12 G N/day
- Fluid – 1-2.5L/ day, 40-100ml/hr
- However always first bag over 48hrs
- Not on same day of operation due to SIRS
- What can a sick or under-perfused liver utilise, before jaundice or ALP rise
- Bariatric patients still need feeding. Stress of ITU is not the time to diet. ABW for 1kcal/Kg/hr? (Obese IBW +25%)
- Increase rate of enteral feed in increments of 30ml/hr if gastric residuals remain <250ml at 4hrly aspirates
- Continuous feeding or physiological breaks?
- Achieving targets
- Phenytoin, doxy, cipro. Other IV/oral conversions
- TPN vs PN/EN do you believe in a trickle?
- Start at 30ml/hr standard feed
- Aspirate after 4 hours, if less than 200ml replace and increase by 30ml/hr until full rate (70-90ml/hr).
- If more than 200ml aspirate replace 200ml, discard remainder and decrease rate by 30ml/hr to minimum 10ml/hr
- At 10ml/hr, continue for 24 hours then add metoclopramide
- If still not absorbing after 48 hours, reduce opioid if possible to Morphine < 5mg/hr or Fentanyl < 2ml/hr
- add Erythromycin 500mg BD IV/NG
- After 48 hours (OR day 5) consider TPN
- Last resort, not an emergency
- Unstable mixtures, incompatible with other drugs, dedicated line
- Risk of line insertion
- Audit of line placement and X-ray check
- Plan for more than 5 days, or persevere with Enteral
- EN 10ml/hr to avoid gut atrophy and translocation
- Phased introduction of PN over 48 hours
- Phased re-introduction of enteral
- Reliable EN for 24 hours before stop PN
- Poor nutrition previous week –obvious and oesophagectomy, post op. actual calories
- Previous nutrition status (BMI<18.5kg/m2)
- Recent wt loss > 10% in 6 months
- Alcoholics, drug abuse, IDDM, laxatives, antacids, diuretics, cytotoxics
- Start with 10kcal/kg/day (70kg=700kcal)
- Slow increases
- Thiamine 200-300 (Pabrinex 250) per day
Vitamins & Minerals
Vitamin B compound Strong (2TDS RFS)
Vitamin C 500-1000mg/day (Pabrinex 500)
Selenium ACE 1 daily
Solvazinc 1 TDS
Sanatogen A-Z 1 daily
Folic Acid 5-10mg
Vitamin B12 – Hydroxocobalamin 1mg IM/IV
Don’t fiddle with the food to manage the fluid
Central preferred – but PICC, or peripheral
Maintenance - High flow
Minimal interruption – discuss
Not usually haemofiltration Lines
Expected other drugs, compatibility reshuffle
New Line – last option due to risks of insertion
Monitoring central lines
Parenteral nutrition is not a preferred option, it is undertaken when enteral is not possible.
Many of the problems of PN are due to gut atrophy, i.e. a lack of EN. Thus wherever possible give 10ml/hr EN to maintain gut integrity. PN for feeding the patient, EN for feeding the gut thus TPN is no longer appropriate
PN increases the infection risk but not mortality
PN is a planned event when EN has failed for 5 days. It is an inherently unstable mixture, takes 3 hours to make and costs about £100/day
Indirect Calirometry, Glutamine, & Selenium - Richard Lowe ST4 ICM
TEE - total energy expenditure
BEE – Basal energy expenditure
REE – Resting energy expenditure
DIT – Diet induced thermogenesis
AEE – Activity energy expenditure
TEE = (BEE + DIT + AEE)
RQ – respiratory quotient
CO2 produced (VCO2) / O2 used (VO2)
Normal range 0.7 – 1.2
Dependent on fuel source
Carbohydrate - 1
Protein - 0.8
Fat - 0.7
Production of chemical energy proportional to gas exchange
Weir equation used to calculate energy expenditure
Energy expenditure = (3.9VO2 – 1.1VCO2) – 2.17(urinary N2)
Abbreviated weir equation used
REE = (3.94 x VO2) + (1.1 x VCO2)
BEE may be significantly altered in critical illness
Obligatory feeding – PN
PN often results in overfeeding
Liver function abnormalities
EN often associated with feeding intolerance
BMR increased up to 40% in critical illness
Burns and trauma patients known to be heavily catabolic
Indirect calirometry (metabolic cart)
Substitute for calirometry (cumbersome / expensive)
Measures inspired & expired gas flows / volumes and concentrations (CO2 /O2)
Non invasive and accurate
Intensive Care Medicine Feb 2011
Randomized but unblinded
Mechanically ventilated for at least 3 days
Patients over 18
Expected to be ventilated > 3 days
Enteral nutrition with an energy target determined by INDIRECT CALIROMETRY
25 kcal/kg/day of enteral nutrition
PN used to supplement EN when needed
Primary outcome – 30 day survival
Length of mechanical ventilation
New pressure sores
Unplanned surgery / surgical complications
Assigned within 48 hours
REE calculated by IC
Deltatrac 2 monitor used
Fed enterally as per protocol
PN used to make up shortfall
Weight from patient / relative
IC measurements taken also
PN to make up shortfall from EN
Study group received more calories than measured to need
Control received less calories than calculated to need
Mean calorie intake significantly higher in study group
Study group patients had higher mean energy and protein intake
Significantly more in study group had PN in days 1 – 3
Trend towards lower mortality in study group with “intention to treat” p = 0.058
Significantly lower mortality for study group when “per protocol”
Hospital (28.5% v 48.2% p = 0.023)
60 day (57.9 +/- 9.9% v 48.1 +/- 7.6% p = 0.023
Similar ICU mortality
Increased length of ICU stay
Increased ventilation days
More total infections
Trend towards higher VAP
Dietician led care
Relatively small numbers
Could it be related to type of feeding
Was it just that they were fed more
Calculated energy requirements looked quite good
Feed (EN or PN) enriched with pharmaconutrients to
IMPROVE IMMUNE RESPONSE
MODULATE INFLAMATORY RESPONSE
Critical illness response
Oxidative stress and SIRS – free radicals, inflamatory cascade
Mitochondrial damage – contributing to MODS
Vitamins and trace elements taken into organs for protein and immune cell production
Relative deficiency of antioxidants
Non essential amino acid
Participates in many metabolic processes
Increased utilisation in critical illness
Plasma levels decrease
Low glutamine shown to have worse outcomes in some studies
Oudemans-Van Straaten 2001 Int Care Med (n = 25)
Favourable outcomes in burns patients – reduced bacteraemia, mortalilty and LOS
Garrel 2003 Crit Care Med
Canadian clinical practice guidelines suggest enteral glutamine should be considered in trauma and burns patients
When Parenteral nutrition prescribed to critical care patients glutamine supplementation “should be considered”
AVOID in patients with SHOCK and MOF - REDOXS
NEJM – April 2013
1223 patients – ventilated with 2+ organ failure
40 ICU’s: US, Canada and Europe
4 way randomisation
Glutamine give IV and oral
Dipeptiven 0.35 g/kg / day IV
42.5 g alanyl-glutamine / glycine-glutamine dipeptides enteral
IV selenium 500mcg
Selenium 300mcg enterally
Zinc - 20mg
Beta Carotene - 10mg
Vitamin E - 500mg
Vitamin C -1500mg
Trend towards increased mortality at 28 days in patients receiving glutamine
32.4% v 27.2% (p = 0.05)
No significant difference attributed to antioxidants
30.8% v 28.8% (p = 0.48)
In hospital mortality
6 month mortality
Median time to discharge alive
ALL SIGNIFICANTLY HIGHER WITH GLUTAMINE
No significant effect on secondary outcomes with antioxidants
Big study population
Relevant to our practice
High dose of glutamine
Low glutamine levels not consistently found in their patients
Funding – Fresenius / Biosyn
P = 0.044
Many patients excluded
Not all prescribed supplements given
Cocktail of antioxidants
Canadian clinical practice guidelines (2013) - Arginine
4 level 1 studies, 22 level 2 studies
No clear evidence of benefit (Mortality / infection)
3 studies showing possible harm (Bower / Ross / Bertolini)
NOT RECOMMENDED FOR CRITICAL CARE PATIENTS
Important precursor to glutathione peroxidase
Important plasma antioxidant
RDA 40 – 80 mcg/day
Selenium levels inversely proportional to APACHE 2
Angstwerm 1999 – replacing selenium increases glutathione
Number of studies
Cocktail of antioxidants – never alone
SIGNET study probably best study
502 ICU / HDU patients with GI failure needing PN
No clear evidence of benefit
Significant reduction in infections in selenium group who received PN for > 5 days
Recent Trials in nutrition Phil Mcglone ST5 ICM/Anesthetics
What does the recent literature tell us about how much and when to start nutrition in critical care?
Initial trophic versus Full enteral feeding 6 days
Trophic feeding – increase VFD
<48hrs of ALI onset
6hrs to extubation, death or 6 days
Protocol 25ml/hr to target 25-30Kcal/kg/day
90% achieved this
Protocol 10mls/hr (20kcal/hr)
VFDs to 28 days
Secondary end points
60 day mortality
Daily % of goal feeding
Organ failure free days
No significance difference
14.9 VFDs vs 15
Except GI intolerance
Regurg .4 vs .7 %
Vomiting 1.7 vs 2.2%
Elevated GRVs 2.2% vs 4.9% (>400mls
Modest differences in calorie provision for well-nourished patients during the first week of ALI/ARDS does not appear to affect patient outcome in the ICU.
Reduced-calorie feedings may reduce perceived GI intolerance and decrease administration of prokinetic and anti-diarrheal medications.
What doesn’t it tell us
BMI 30, these patients were well nurished
AGE 50 these pts were young
Severe malnutrition were excluded
½ extubated within 6/7 so quite early!
GI difference no clinical ramifications in the study….
Enteral nutrition fewer complications
Miss Targets however
? Combining Parenteral and Enteral
Liver dysfunction, infection and death
controversy regarding PN
underfeeding with EN alone for up to 7-10 days (American guidelines)21
supplemental PN (European) within 24-48 hours in patients who are expected to be intolerant to EN within 72 hours of admission.
Canadians conclude there are insufficient therefore maximize the benefits of EN (small bowel feeding tubes and motility agents) are used prior to starting PN.
Proponents of the use of early supplemental PN have focused on data demonstrating that the cumulative energy deficit or caloric debt is associated with adverse clinical outcomes in critically ill patients.24
Opponents cite the literature demonstrating increased adverse events in patients who receive PN during their ICU stay.
Data from existing randomized trials are inconclusive
PN to prevent caloric deficit
Supplement EN early in disease
Lead to reduced complications
Withholding PN for 1/52
MC 7 ICU’s
2328 patients delayed PN until day 8
2312 patients received PN within 48hrs
Admission to a participating ICU, a nutritional risk screening (NRS) score of 3 or more (on a scale of 1 to 7, with a score ≥3 indicating that the patient was nutritionally at risk) and did not meet any of the exclusion criteria.
The primary end points
ICU days (for survivors and nonsurvivors)
time to discharge from the ICU.
new infections, infection site, duration of antibiotic therapy, inflammation (C-reactive protein), time to vent wean, need for tracheostomy, acute kidney injury, need for and duration of pharmacologic or mechanical hemodynamic support, liver dysfunction, duration of the hospital stay and time to discharge from the hospital, functional status according to the distance walked in 6 minutes and the proportion of patients who were independent in all activities of daily living, and the total incremental health care costs from randomization to hospital discharge!!!!!
The early PN group
D20 at 45 mL/hr on the day of admission
day 2 the difference between calculated goals and the amount of EN was provided as PN.
When EN provided at least 80% of nutrition needs PN was held.
The late PN group
D5 to meet whatever hydration was not provided by EN
only received PN if enteral feedings were not providing at least 80% of calculated needs by day 8.
corrected ideal body weight
with 24 kcals/kg for females > 60 years
30 kcals/kg for females < 60 years
30 kcals/kg for males > 60 years
36 kcals/kg for males < 60 years.
The primary outcome
median stay in the ICU was 1 day shorter in the late-initiation group than in the early-initiation group.
There was a statistically significant increase in the likelihood of earlier discharge alive from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P=0.04).
There were no significant differences in ICU, hospital or 90-day mortality between the groups.
The median duration of hospitalization was 2 days shorter in the late-initiation group
There were significantly fewer patients that developed new infections in the late-initiation initiation group,
Duration of mechanical ventilation and the course of renal-replacement therapy were significantly shorter in the late-initiation group.
“Early initiation of PN to supplement insufficient EN during the first week after ICU admission in severely ill patients at risk for malnutrition appears to be inferior to the strategy of withholding PN until day 8 while providing vitamins, trace elements, and minerals. Late parenteral PN was associated with fewer infections, enhanced recovery, and lower health care costs.”
How Do These Results Apply?
Can these result be generalized to all Critical care
early PN group received a large parenteral glucose load (1200 kcal) over the first 48 hours
Van den Berghe study.10 This concept of tight glucose control has subsequently been shown to be ineffective and potentially harmful.
How Do These Results Apply?
ninety percent surgery patients (mostly cardiac),
(58.5%) appeared to be admitted electively.
70% of subjects averaging only a 3-4 day length of stay.
Only moderately severely ill, with an 8% ICU mortality (and 11% hospital mortality).
Almost 75% of study patients had a normal or slightly high BMI between 20 and 30.
Most practitioners would not consider there to be a role for early PN in low mortality risk patients with short ICU stays and a normal BMI
Finally, it is hard to attribute the adverse events seen in this study to early PN, when the majority of study patients received very little exposure to early PN.
(58%) of the patients in the early PN group were exposed only to 1 to 2 days of PN.
Only 25 % late PN patients ever received PN.
It is plausible that the increase in adverse events seen in this study in the early PN group were due to the delivery of a large glucose load in the first 48 hours in the ICU. This may be related to increased insulin resistance in the early phase of acute illness.
While early PN in low risk patients is clearly harmful, it is not clear whether supplemental PN added to insufficient EN early in the course of high risk patients would also be harmful
EPaNIC results targeted wide spectrum of patients
Systematic reviews show benefits PN when EN Contraindicated mortality and infection however these were based on Small Trials
Uncertainty surrounding infection implications
This is reflected in the guidelines Reflected in guidelines within 24-48hrs (European) vs 7-10days (US)
RCT, single blinded
Assess effects of PN within 24hrs of ICU admission
With short term relative contraindications to enteral nutrition.
Within 24hrs admission
Expected to stay remain on ITU calendar day after enrolment
Considered to be ineligible for EN as decided by attending
Were not expected to get EN day of or after enrolment
Not expected to survive 24hours
Known long term contraindication to EN
Height < 140cm
Malnutrition as primary reason for admission
Received PN on day 1 and reached goal calories by day 3
Reevaluated day 3 for EN
60 day mortality
Quality of life and physical function measures
Tertiary end points
Fat loss, muscle loss etc
No difference in 60 day mortality
Statistically difference in quality outcome measures but not enough to meet the pre established definition that would be clinically meaningful
No difference infection rate
1.07 days fewer ventilation early PN
0.43 fewer coagulation failure days early PN
Less Fat and muscle wasting early PN
Early PN reduced mechanical ventilation days
Did not shorten hospital stay of ICU stay
No harm in early PN
Subjective opinion that patient could not have EN
Bias as investigators knew which group ? Earlier extubation
25% PN <48hrs in >1/3 standard care got PN
? Too similar to detect difference in infection rate
?? Measures of Fat and Muscle loss, skin fold and upper arm measures shown to be poor
I would have liked to have seen europe vs US debate answered.
Allowing larger tx differences
More likely to see outcome differences
Indeed subgroup analysis of 40% standard grp whom remained unfed maybe useful
EN – GI intolerance
PN – Infectious problems ? Reducing
Formulations and central access improvements
The primary objectives:
To estimate the effect of early (defined as within 36 hrs of the time/date of original admission to the ICU) PN compared with early EN on mortality at 30 days.
To estimate the incremental cost effectiveness of early PN compared with early EN at one year
Secondary objectives: to compare the following:
Duration of specific & overall organ support in the ICU between PN & EN
Infectious & non-infectious complications in the ICU between PN & EN
Duration of ICU & acute hospital length of stay between PN & EN
Mortality at discharge from the ICU & from hospital between PN & EN
Mortality at 90 days & at one year between PN & EN
Nutritional & health-related quality of life at 90 days & at one year between EN & PN
Resource use & costs at 90 days & at one year between PN & EN
Estimated lifetime incremental cost-effectiveness between PN & EN
Patients who either on, or soon after admission within 36 hours that are:
Adult (18 years or over)
An unplanned admission (including planned admissions becoming unplanned e.g. unexpected postoperative complications)
Expected to receive artificial nutrition for two or more days in the ICU
Not planned to be discharged within three days from the ICU
Results to follow !!!
Dr Adrian Wong - ST7 ICM & Anaesthesia, Wessex
Dr Matt Williams - Consultant in ICM & CLOD, QA Hospital, Portsmouth
South Central Collaborative - Tuesday 13th May 2014
Royal College of Anaesthetists
09.30 - Coffee and Registration
10.00 - Welcome - Susan Richards. Regional Manager
10:05 - Feedback from CLOD/Chair Survey Monkey & End of year Donation Data - Dr Malcolm Watters, Regional CLOD
10.15 - Transplantation Liver - Mr Hector Vilca-Melendez, Consultant Transplant Surgeon, Kings College Hospital
10.45 - Renal, Pancreas & Bowel Transplantation, Mr James Gilbert, Consultant Transplant Surgeon, Oxford University Hospital
11.15 - Coffee
11.30 - Cardiothoracic Transplantation - Dr Bart ZychLead, Transplant Fellow, Harefield Hospital
12.00 - Panel Discussion
12.15 - Performance Management to 2020 - Andrew Jackson, Performance & Business Manager NHSBT
12.45 - Lunch
13.45 - 2020 Strategy – A local hospital level, Andrew Jackson
14.15 - Consent Research - Feedback, Neil Phillips – Head of Strategic Marketing NHSBT
15.00 - Coffee
15.15 -16.00 - Public engagement
Cheltenham’s Experience, Ian Mean – Chair of Cheltenham & Gloucester Hospitals
Northampton Experience, Peter Martin – Chair of Northampton General Hospital ODC
16.00 - Close and Future meetings
End of year Donation Outcome Data – Dr Malcolm Watters, Regional CLOD
Donation after Brain Death (DBD)
• Increased numbers nationally (n=780) but decreased in South Central (SC) Region (n=60)
• Mean number of organs after DBD – 4.2
• Significant rise in heart & heart lung donors (n=203)
• DBD testing rate in SC region – 74% (target 80% nationally)
• Numbers across individual trusts fairly consistent across region
• SNOD involvement high
• Consent rate after brain death – 71%
Donation after Cardiac Death (DCD)
• Considerable variation in rates nationally and within region reflective of uncertainty surrounding DCD
• Referral rates in SC for DCD – 62% (amongst lowest nationally. Lowest in England)
• Consent rate after cardiac death – 56% (just above national average)
• If No SNOD involved, the consent rate drops to 10%
Liver Transplantation – Mr Hector Vilca-Melendez, Consultant Transplant Surgeon, King’s College Hospital
7 liver transplant units in UK (3 paediatrics)
Kings College Hospital (KCH) – 494 active waiting list in 2013
12% of patients on waiting list will die waiting for a transplant
King’s acceptance rate about 1/3 only ½ will be retrieved only 40% of these will be transplanted
20% of offers will be transplanted
King’s acceptance rate 56% 100% will be retrieved 86% will be transplanted
49% of offers will be transplanted
Overall outcome in King’s in 2012-13 (better than other centres, also shown over a 10y period)
• 90 day mortality – 0%
• 90 day graft loss – 0.8%
In super urgent transplants
• 90 day mortality – 0%
• 90 day graft loss – 0%
Cardiothoracic Transplantation – Mr Bart Zych, Lead Transplant Fellow, Harefield Hospital
Heart transplant numbers have plateaued but waiting list numbers have increased
Lung transplant numbers and waiting list numbers both slowly increasing. DCD = DBD lungs outcomes at 1y, perhaps better at 4y outcome (but small numbers).
UK Donor Scout Project (pilot)
• Aggressive donor assessment and management
• Invasive monitoring
• Performed by dedicated team of cardiothoracic transplant team
After brain death, sympathetic storm leads to permanent myocardial damage in 25% of patients.
Transmedic organ care system
Continuous perfusion of retrieved organ at 34 degrees
Organs can be kept at this state for 8 hours compared to 4 hours when kept on ice
Harefield have used to aid 30 heart transplants in 2012-13.
Management of the heartbeating brain-dead organ donor. McKeown et al. BJA 2012;108(1):i96-i107
Renal, Pancreas and Bowel Transplantation – Mr James Gilbert, Consultant Transplant Surgeon, Oxford University Hospital
• Over 6300 people waiting for kidney transplant
• Transplantation improves quality and quantity of life; doubles life expectancy.
• 1 year of HD = 1 tranplant (cost)
• Over 100 altruistic kidney donors last year
• Longer spent on dialysis, the poorer the outcome post transplant
Definitive treatment for type 1 DM
230 transplants last year in UK, Oxford performed 79
Pancreas donor score index – there is an app for that (https://itunes.apple.com/gb/app/pancreas-transplant-donor/id396068767?mt=8)
• Simultaneous pancreas kidney transplant (pancreas exocrine secretions plumbed to duodenum; kidney function marker of both kidney and pancreas graft function.
• Pancreas after kidney
• Pancreas only transplant
Graft function normally monitored by measuring urinary amylase in pancreas-only transplants
Indication – intestinal failure: short gut (<40cm) or non-functioning bowel e.g. ischaemia
Technically, may be difficult to close the abdomen – multiple laparotomies, fistulas, etc. Some now require abdominal wall transplantation (retrieved from deceased donors). Transplanted skin acts as a marker of graft rejection. Possible role of sentinel skin graft (radial forearm).
There is no national coordination for the activities of the various transplant teams. The limited resources may be better utilised by a more central body. This possibility is being reviewed.
Feedback from CLOD/Chair survey monkey – Dr Malcolm Watters, Regional CLOD
Majority of Organ Donation Chairs are from clinical background despite previous recommendations that they are not. Majority of CLODs are Intensivists.
Majority of CLODs and Chairs want further training for their roles and a significant proportion did not attend the 2010 PDP programme.
Case Presentation – Dr Dale Gardiner, Consultant ICM, Deputy National CLOD
2 cases discussed
Redflag discussed – Brainstem testing in context of patients with underlying neuromuscular condition.
Some slight alterations to ICS guidance for brainstem death testing (written originally by Dr Gardiner) have been submitted by Dr Gardiner.
Keep open and transparent communications with families.
Consent Research – Neil Phillips, Head of Strategic Marketing NHSBT
Research around consent for organ donation
• Attitudes towards consent
• Organ donor cards
1) Organ donation not a topic that people are exposed to
a) 50% ever spoken to others about organ donation
b) Women more likely to have chat
2) Theoretical support for organ donation doesn’t translate to personal support
3) Number of strong motivation to discuss donation
a) Improve/save other lives
b) Organ do not go to waste
c) Feel good
d) I would accept and therefore I will donate
a) Worry that staff won’t do all to help save their lives
b) Do not want to think about death
c) Worry over family if organs donated
5) Support less likely with ethnic minority (despite National Faith leaders saying otherwise and agreeing statements).
6) Misconception surrounding process
a) Organ donor register is not well understood
7) Appetite for organ donor cards
a) Majority of people who donate are not actually on ODR
b) Should donor cards be more readily available?
8) Raising awareness that family will still be asked for consent
a) 91% think it important to discuss but only 37% have actually done it
9) Respect individual’s wishes
10) Prior discussion is the most compelling factor
a) On ODR but not discussed wishes 57% consent compared to 90% consent rate if on ODR and discussed
11) When views unknown, not agreeing is seen as the safest option
12) Common misconceptions are widespread
a) BUT 1 in 5 will change view if presented with key facts
The key is to encourage discussion. For every 1 million people more on ODR, only 5 more transplants occur.
• Cheltenham’s Experience – Ian Mean, Chair of Cheltenham and Gloucester Hospitals
• Northampton Experience – Peter Martin, Chair of Northampton General Hospital
2 talks on how the Donation Committees are engaging their local communities.
NHSBT - NHS Blood and Transplant
NHSBT - NHS Blood and Transplant Organ Donation
Supplementary: The presentations on the day are now available on the Organ Donation & Transplant website here
1. The Dean (Dr A Batchelor):
Shape of Training (SoT) occupying much time/worry. Broad based themes to the training, as perhaps more generalists vs specialists required.
Concern for FICM is that ICM training may be seen as a post-credentialing specialty…
GPICS – build on core FICM/ICS standards document (cf RCoA accreditation process).
2. FICM training & assessment committee (Dr S Badouin):
No sooner than a curriculum out than drivers are likely to lead to a revamp! (SoT, HEE, RCP’s future hospital report, Francis report, crisis in acute care)
Special skills year: academic / PICU / CTITU / neuro / education
Then made quite a “blue sky” suggestion that ICM might be best placed to help provide 24/7 hospital care….!
3. FFICM exam (Prof N Webster):
SBA in the MCQ section from July 2014
Case summaries – 2 per year for ICM CCT trainees as per spiral learning (locally assessed; % centrally validated)
SAS doctors can sit FFICM with RA support.
Considering allowing Stage 1 trainees to sit exam (rather than only in stage 2 – ie ST5/6).
4. Training (Dr C Thorpe, Lead RA):
Survey: 2 DCC PAs ICM considered essential for new consultants to retain skills. 1.5 SPA for core consultant business.
QA: standards for ICM training (FICM), GPICS, FICM standards for Tutors/RAs & recruitment.
Quality “nexus”: RA reports, RA visit reports, FFICM results, info from ARCPs, annual GMC/FICM surveys, GMC/LETB visits.
5. Recruitment (Dr T Gallacher):
National process organized by West Midlands.
Stepped entry remains for now. Upper limit proposed as ST5. 103 posts this year, 8 for Wessex.
6. e-portfolio (Dr L Plenderleith):
Using the NES platform (as used by FP, CEM, RCP, so familiar to most of us).
Curriculum broken down – each competency will turn green once “attained”.
Training days soon.
Already started soon after the meeting. All on from August 2014.
Don’t forget to look at Critical Eye for latest published information from the Faculty
Pro debate: Alteplase for Stroke Thrombolysis
Dr Tom Daubeny
Firstly the background...
Epidemiology of Stroke:
Cause of 8.5% of UK Deaths, leading cause of adult disability
Broadly people who’ve had a stroke will have:
- 26% No Disability
- 25% Mild - Moderate Disability
- 27% Severe Disability
- 22% Death
The Outcome Measures used to analyse treatments for Stroke:
Modified Rankin Score (mRS):
0 – No symptoms, 1 – No significant disability, 2 – Slight disability, 3 – Moderate disability (can walk unassisted), 4 - Moderately severe disability, 5 – Severe disability, 6 – Dead
10 Activity measures scored to give a total of 100:
Feeding, Bathing, Grooming, Dressing, Bowel Control, Bladder Control, Toilet use, Transfers, Mobility, Stair use
Glasgow Outcome Scale
1 – Death, 2- Persistent vegetative state, 3- Severe disability (permanent need for help with daily living), 4-Moderate disablility, 5- Low disability
National Institutes of Health Stroke Scale (NIHSS)
11 outcome measures to give a total score of 42
Level of consciousness, Horizontal eye movement, Visual field deficit, Facial palsy, Motor deficit upper limb, Motor deficit lower limb, Ataxia, Sensory deficit, Dysphasia, Dysarthria, Sensory inattention
And the Current UK guidelines for Thrombolysis of Stroke
- NICE Recommendations
- “Alteplase for the treatment of acute ischaemic stroke 2007” (reviewed 2010)
- “Stroke – Diagnosis and initial management of acute stroke and TIA 2008”
- Given by physician trained in neurological care and in a well organised stroke service (staff trained in thrombolysis, immediate access to imaging and re-imaging)
- Given within 3hours of symptoms, post imaging to exclude intracerebral haemorrhage (ICH)
- Age range 18-80
- 0.9mg/kg (up to 90mg) over 1 hour with 10% initial bolus
So what is the evidence supporting these guidelines of giving Alteplase within 3 hours of onset of stroke symptoms?
1/Evidence to show significantly improved outcome if given within 3 hours
2/NO mortality difference (despite initial increased ICH rate with treatment)
3/ Large post marketing and phase 4 studies support these findings of improved outcome and no mortality difference
National Institute of Neurological Studies (NINDS) Randomised Control Trial 1995
- 2 part double blind trial of 624 patients
- Outcome at 24hours (291patients) and outcome at 3months (333patients) analysed
- Favourable outcome at 3months for all outcome measures (Barthel index, modified Rankin Scale, Glasgow outcome scale and NIHSS) with odds ratio 1.7 (1.2-3.6)
- 30% more likely to have minimal or no disability at 3 months
- Symptomatic ICH 6.4% vs. 0.6%, no difference in mortality
- NNT 3 to change improve 1 in mRS
- Data reanalysed in 2004 – odds ratio 2.1
European Cooperative Acute Stroke Study 3 (ECASS 3) 2008
- Multicentre double blind RCT in 19 European Countries
- 821 patients looking at 3-4.5 hours
- Follow up at 3 months
- Better outcome up to 4.5 hours – Modified Rankin Score 0-1 at 90 days Odds Ratio 1.34 (1.02 – 1.76)
- NNT 15
International Stroke Trial 3 (IST 3) 2012
- Multi centred randomised open trial 3035 patients from 12 countries
- Allocated 0.9mg/kg alteplase or standard of care within 6 hours
- Follow up at 18months
- No difference mortality
- Significantly increases survival free of handicap – odds ratio 1.28 (1.03-1.57)
Lancet 2012 Systematic review and meta-analysis
- 12 RCTs alteplase within 6 hours included- 7012 patients
- Final follow up between 1-6 months
- Increase favourable outcome 5.5% (3.3-7.7) on modified Rankin scale
- Increase in survival free of dependency 4.2% (1.9-6.6%)
- If given within 3hours: 9% (4.6-13.5) increase in survival free of dependency and 8.7% (4.6-12.8) increase in favourable outcome
- Symptomatic ICH – 5.8% (4.9-6.8) absolute increase, no significant mortality at final follow up
- Review commented no significant heterogeneity between trials for any of these outcomes
Safe Implementation of Thrombolysis – Stroke Monitoring Study (SITS-MOST) 2002-2006
- Prospective, open, multicentre, multinational, observational monitoring study established as a condition by the European Union for licensing
- 6483 patients 285 centres 14 European countries
- 39% with no or mild disability at 3 months vs. 29% controls
Get With the Guidelines (GWTG) 2012
- USA National Stroke Registry 2003-2012
- 58,353 patients from 1395 hospitals alteplase within 4.5 hours
- Faster Onset to treatment time associated with reduced in hospital mortality, reduced symptomatic ICH, increased independent ambulation at discharge and increased discharge home
Safe Implementation of Treaments in Stroke - International Stroke Thrombolysis Register (SITS-ISTR)
- International monitoring registry for auditing the safety and efficacy of thrombolysis across 19 countries
- 29,618 patients, 25,279 within 3 hours
- Confirms safety profile up to 3 hours and supports safety up to 4.5 hours post symptom onset
Canadian Alteplase for Stroke Effectiveness Study 2005
- 60 centres across Canada
- 2247 patients, 1135 within 3 hours
- Concludes stroke thrombolysis is a safe and effective therapy
What is the future for Alteplase?
Use of scoring to help individualise risk or select subgroups of patients most likely to benefit e.g. DRAGON Score, HAT score and iScore
Lower risk of intracerebral haemorrhage patients with posterior circulation stroke
J Neuro Sci 2013• 518 patients treated with Alteplase: 434 anterior circulation – 8.1% sICH vs 84 posterior circulation – 1.2% sICH
4 factors identified increasing ICH risk in NINDS analysis
Baseline NIHSS > 20; Age > 70; Ischemic changes present on initial CT; Glucose > 16.7 mmol/L
0 risk factor 1.8%; 1 risk factor 4.9%; >2 risk factors 21.2%
Increasing the benefit of alteplase
Concurrent use of agents that will work on older clots
Agents to protect against haemorrhage e.g. trials looking at minocycline
Directing Alteplase to site of occlusion
Alteplase has good evidence for beneficial outcome in functional status post ischaemic stroke if given within 3 hours of symptom onset.
It has been given a Level A recommendation for use by the major international institutions examining its efficacy: NICE (National Institute of Clinical Excellence), SIGN (Scottish Intecollegiate Guidelines Network), ESO (European Stroke Organisation), ACEM (Australasian college emergency medicine), AAEM (American Academy of Emergency Medicine)/ AAN (American Academy of Neurology/ American Stroke Association (ASA), Candadia Stroke Network.
There is no mortality difference with placebo in long term follow up. This is despite an early increased intracerebral haemorrhage rate and indicates that with targeted therapy a mortality benefit may also be possible.
Stroke Thrombolysis The ‘No’ Campaign
I got the chance to campaign against stroke thrombolysis. I first went through the trials that have shown a benefit for thrombolysis.
The first of these was NINDS. The first part of this trial looked at improvement at 24 hours following tPA compared with placebo, when given within 3 hours of stroke onset. When previously thrombolysing myocardial infarctions we remembered that we would see a quick improvement in ST changes, and therefore if tPA is going to make a difference in strokes, we would expect to find an improvement within 24 hours. Unfortunately there was no significant difference.
It is common teaching that a TIA lasts an average of 10 minutes and rarely greater than an hour. It was therefore of note that in the sub-group analysis of patients that had symptoms for 91-180 minutes prior to thrombolysis, or placebo, 39% and 37% respectively had resolution of their symptoms or an improvement in ≥4 points on the NIHSS score at 24 hours. Therefore the next time a stroke doctor claims benefit from tPA within 24 hours of treatment, point out that the evidence does not support that claim and that ~40% of patients will make an improvement at this stage with, or without thrombolysis.
NINDS II investigated the proportion of patients with minimal or no deficit at 3 months. They showed an absolute risk reduction of 13% following tPA compared to placebo. What they didn’t initially tell you was that there were big differences in the baseline characteristics. In the 91-180 minute subgroup, the tPA group had an extra 15% of patients with a NIHSS score of 0-5, whereas the placebo group had an extra 9.2% of patients with a NIHSS score of >20. With these huge differences in baseline characteristics it’s surprising that they only found an ARR of 13% with tPA.
The only other RCT to have shown benefit from thrombolysis is ECASS III. The time window for thrombolysis in this study was 3-4.5 hours. They found that the proportion of patients with a modified rankin score (mRS) of 0 or 1 at 90 days was 52.4% in the thrombolysis group vs. 45.2% in the placebo group. (P=0.04, OR 1.34 (1.02-1.76)). However, the placebo group had a 14.1% incidence of previous stroke vs. 7.7% in the placebo group. Some of these patients are unlikely to have had a mRS of 0/1 at the onset of the trial, which seems a little unfair! By using a cut-off of 0/1 for the mRS, this meant that death (mRS of 6) was counted the same as slight disability (mRS 2 = unable to carry out all previous activities, but able to look after own affairs without assistance) If the outcome had been the proportion of patients with a mRS of 0-2 at 90 days the results would have no longer been significant. Therefore thrombolysis was not significantly more likely than placebo to leave you independent following a stroke. And considering that 27% of patients in the tPA group had an intracerebral bleed, this study wouldn’t convince me that thrombolysis is the answer!
We then reviewed the trials that have either shown harm or no benefit from thrombolysis.
There have been 3 streptokinase trials. Two of these were stopped early due to excess mortality (MAST Europe and ASK). Whereas MAST Italy showed no change in the primary outcome of combined 6 month fatality and severe disability; but an excess 10 day mortality. Of note a recent Cochrane review found no difference in affect when comparing one thrombolytic agent with another. Although there was not a direct comparison of streptokinase vs. tPA.
Looking at the tPA/alteplase trials:
ATLANTIS A, included patients within 6 hours of stroke onset. They found an improvement in the NIHSS score in the tPA group but unfortunately had to be stopped early due to excess mortality in the tPA group (23% vs. 7%, P=0.01).
They then tried again with ATLANTIS B, which was predominately within 5 hours of stroke onset. This time they just showed a trend to excess mortality in the tPA group (10.9% vs. 6.9%, P=0.08)
ECASS I included patients up to 6 hours. They found no difference in their primary outcome of a mRS score but again an excess mortality in the tPA group.
ECASS II included patients predominately within 3-6 hours of stroke onset. They found no benefit in the primary outcome of mRS at 90 days, but at least the mortality was not significantly increased!
IST-3 was supposed to be the trial that finally put this matter to rest with the inclusion of over 3000 patients, within 6 hours of stroke onset. They found no difference between the tPA and the placebo group for the primary outcome of being alive and independent at 6 months. This was despite the trial being hugely biased in favour of the tPA group. The majority of the trial was non-blinded. We know that non-blinded trials are more likely to find a positive outcome for an intervention when compared when blinded trials. Of interest, the trial was initially blinded and for those patients there was a trend to improvement in the placebo group, where as in the non-blinded group there was a trend to improvement in the tPA group. The non-blinding meant that patients were treated differently with patients in the tPA group being much more likely than those in the placebo group to have been admitted to HDU. Therefore they are likely to have had their low oxygen saturations and hypotension picked up at an earlier stage, thereby preventing secondary brain injury. After being given this ‘wonder drug’ and having the care and attention of the HDU staff the patients may have been more likely to engage in their rehabilitation and they may have given more favourable answers to the questionnaire that was sent out to them (Which was how the primary outcome was determined for a number of patients) Therefore when a non-blinded trial of over 3000 patients, that is biased in favour of the intervention finds no improvement in the primary outcome, I am concerned that a higher quality trial may have found harm related to the intervention
In summary there have been 2 trials that have shown a benefit in the primary outcome following tPA. Both of these have methodological flaws. Whereas 3 trials have had to be stopped because of an excess mortality in the thrombolysis group. Another study showed an excess mortality but wasn’t stopped early. And 5 trials have shown no benefit in the primary outcome. Therefore it is clear that stroke thrombolysis has not been proven to be of benefit and currently