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Off it! Part 4: Synthetic Cannabinoids

Synthetic Cannabinoids

Mental Model – [  ‘UP ‘ – A bad trip ]

There are over 150 different molecules in circulation under this class.  They are sprayed onto plant matter and smoked in a similar way to cannabis, thats pretty much where the similarities end.  They can also be dissolved and injected in their powdered form, snorted, inhaled, or cooked into food.

Synthetic cannabinoids were first produced to investigate the pharmacological potential of the endogenous cannabinoid receptor. They were first found in recreational products in 2008.   They are all analogues of 9-tertrahydrocannabinol (9-THC) the active ingredient in ‘normal’ cannabis, which is a partial CB1 and CB2 agonist.  Newer agonists have much greater affinities for the THC receptors, (being complete rather than partial agonists).  They also seem to last longer than normal cannabis.  CB1 and CB2 receptors are EVERYWHERE in your CNS, and as each molecule in circulation has a different affinity for different receptors, in different locations the toxidrome can be highly variable.

‘Spice’ is the second most popular drug in the US (after cannabis), and it is estimated that the spice industry is worth something like $5 billion.  Its popularity grew initially because of a perception that it is ‘legal’, ‘safe’ and ‘undetectable’.

Patients who come in intoxicated from a synthetic cannabinoid (K2, spice, Kronic etc) are agitated, confused, and paranoid.  There are no generally agreed signs to look for, some case series talk about dilated pupils, conjunctival injection, and hyper-reflexia, but these probably depend on dose, and type taken.  Patients normally seem  tachycardic and diaphoretic.   They may often be brought in by ambulance following ‘seizure-like’ activity, or by the police for erratic behaviour.

16 Cases of AKI reported in the US associated with synthetic cannabis use.  Convulsions have been reported but not proved to be related to synthetic cannabinoids.

Management

Again, this is supportive.  Use titrated IV benzopdiazepines to calm agitation.  IV fluids for dehydration.  Check a CK and a U and E if they are unwell.   If you can get close an ECG is useful for completeness, though no arrhythmia have been reported (but hypokalaemia HAS).

Withdrawl

I witnessed synthetic cannabinoid withdrawal first hand whilst working in ED in New Zealand over the weekend that a nationwide ban came into force.  Patients attend with psychosis, sweating, paranoia and delusions.  Patients were treated with benzodiazepines.

 

Harris, Carson R., and Ashley Brown. “Synthetic cannabinoid intoxication: a case series and review.” The Journal of emergency medicine 44.2 (2013): 360-366.

Spaderna, Max, Peter H. Addy, and Deepak Cyril D’Souza. “Spicing things up: synthetic cannabinoids.” Psychopharmacology 228.4 (2013): 525-540.

Off it! Part 3: GHB

GammaHydroxybutyric Acidghb

[ – Mental model: – Benzos,  ‘DOWN’]

Legal Status:  Class C

Think of GHB as a possibility in patients who are often male, body building and appear ‘drunk’.  GHB patients get VERY flat, very quickly if they get the dose wrong, and alcohol potentiates this.

Other signs of acute toxicity – LOW RR, GCS, BP and Hypersalivation

They are really hard to wake up (no matter what ‘trick’ you use).

GHB binds to GABA and inhibits the release of action potentials from the synapse.  In high enough concentrations GHB gets converted to GABA.  You may hear that someone has taken GBL (or gamma butyrolactone) that’s the precursor and has a delayed affect, especially when take with alcohol.

It seems to be used in social circles of gym fanatics.  There is a belief that it increases human growth hormone release, and improves muscle repair, AND is a calorie free way of getting the buzz people want from alcohol.  It’s also been used as a date rape drug.

Management

Supportive.

These patients sometimes require airway protection.  They will wake up on ICU the next day, thank no one, and leave.   Deaths occur when patients lose their airway control outside of hospital.

Withdrawl

Some people take GHB a lot, if they get their recreational dosing correct can re-dose, and re-dose night after night (or regularly for work outs), when their supply runs out, or changes they can get a rebound effect which is like an alcohol withdrawl, symptoms start 6 hours after the last dose.  It can last much longer (weeks), and is more resistant to benozodiazepines.

The autonomic features are present, but slightly reduced, however the syndrome can last longer (up to two weeks).  Control it with benzodiazepines and baclofen (GABA agonists), and titrate down slowly like with alcohol withdrawl.

Early features – insomnia, tremor, confusion, nausea and vomiting

Late features – tachycardia, hypertension, agitation, seizures and/or myoclonic jerks and hallucinations

Off it! Part 2: Synthetic Cathinones

MCAT/Mephedrone/Bath Salts

[- mental model – amphetamines , ‘UP’]

Legal status: Class B

You will not have spent long in the ED before coming across someone who is off their face on MCAT.  This drug isn’t well described in the literature as it’s only been in the UK since 2008(1).

khatIt is a synthetic derivative of Khat (Catha edulis).  Which is a leafy green plant which in it’s natural form acts as a mild stimulant.  If the leaves are chewed, or put into tea it delivers a feeling somewhere between a big coffee and a small dose of speed.

MCAT comes as a powder, or is sprayed onto dead plant matter.  It can be eaten, smoked, snorted, or injected.  With onset times and length of action fluctuating depending on the method.  Dosage depends on delivery, but most people ‘bomb’ (MCAT wrapped in a rizla)  up to a gram.  They may take more than one bomb a night.

Information on the toxidrome for MCAT is limited because nearly all of the published material is from patients reporting what they think they may have taken.   When someone says they have taken MCAT, they may have taken MCAT, or a derivative (there are over 30 described in recent review articles(2).

synthetic cathinones

 

The derivatives have different attributes, mostly in their ability to cross the BBB, but their affinity to certain parts of the brain seems to be different too.  Most commercially available preparations that people seem to buy contain a mixture of lots of different molecules.  So when someone says they’ve taken MCAT what they’ve actually taken is a mixture of random cathinone derivatives.

Cathinone derivatives are thought to work by increasing the concentration of dopamine, serotonin, and noradrenaline in the synaptic cleft(1,3).  They do this by upregulating secretion, and blocking MAO (which breaks them down).  It is therefore theoretically possible I suppose that people on SSRIs and TCAs might get more than they bargained for.

Clinical Features

Patients attend the ED with paranoia, anxiety, agitation, aggression, they can hallucinate.   Look for tachydysrhythmias, diaphoresis and tremor.   Patients on MCAT have HUGE pupils.   One of the metabolites is thought to be an ephedrine derivative, and causes vasoconstriction so in theory you could get all of the sequelae associated with vasospasm (ACS, Dissection, ICH).

Rhabdomyolysis has been reported with mephedrone toxicity so a CK is probably worth sending if you think they are bad enough to require bloods.

A malignant hyperthermia like affect has also been reported probably due to it’s serotonergic effect.  I’ve found a handful of confirmed deaths, some due to renal failure, some due to arrhythmia.  However we are very much in case series territory.

Treatment (consensus)

Agitation – Benzodiazepines (3)

Tachycardia – Beta blockade (3)

Renal Impairment – Fluids and dialysis

Withdrawl

Not been studied well,  most information comes from research on Khat.  People who have become habituated to it, can get anhedonia, paranoia, and psychosis, but little is known about withdrawl from synthetic cathinones.

 

  1. Zaitsu, Kei, et al. “Recently abused synthetic cathinones, α-pyrrolidinophenone derivatives: a review of their pharmacology, acute toxicity, and metabolism.”Forensic Toxicology 32.1 (2014): 1-8.
  2. Valente, Maria João, et al. “Khat and synthetic cathinones: a review.” Archives of toxicology 88.1 (2014): 15-45.
  3. Richards, John R., et al. “Treatment of toxicity from amphetamines, related derivatives, and analogues: A systematic clinical review.” Drug and alcohol dependence 150 (2015): 1-13.

 

Off it! A practical guide to people who are off their face in the ED

 

What medical school, the foundation programme, and by and large the ACCS curriculum does not prepare you for is how to manage the patient who is mashed (I think it should be a major presentation).  These people who attend at a time when the department is at it’s busiest, and when we are at our weakest. These patients are clinically complex with an added legal dimension in terms of consent,  and mental capacity, which sucks up a lot of ED resource.

drugsIn the coming few weeks I’m going to take you through a basic approach to patients who are intoxicated, and talk about some of the less well known/understood intoxicants.  Much of the teaching and learning on the subject is based around the particular drug the patient has taken.  This makes it difficult to apply at 3 am when ‘Harry’ has backed into the corner of one of your cubicles because he is convinced the Dynamap is going to devour him.  He does not know what he has taken.  He is not sure of his own name.

In the ED there are 2 syndromes that you can slide people into, this will give you an idea of what to expect, what to watch out for, and for how long.  The key is often to be relaxed, have an easy friendly manner, and de-escalate as much as you can.  Use the ‘up/down’ as a mental model, gain control/safety, and then go searching for causes.  Know that time is normally on your side, most patients will finish their trip, and some will even apologise for wasting your time.

Rules:

  • ‘Just’ drunk / high / tripping is a diagnosis of exclusion.
  • People do stupid things when drunk/high/tripping too, and may have injuries.  Look for them.

Excited delirium (up)

These are the patients that can come in being held down by 2-3 police officers and couple of paramedics.  The history is normally non-existent or vociferously denied by the individual who just wants to go.  You can’t assume they have capacity, which is frustrating for them, and for you.

Approach

  • ABCs, de-escalate.
  • Glucose and a 12 lead is a good idea, but may be impractical.  A temperature is also useful.
  • D look at the pupils (BIG: amphetamines, MCAT, anticholinergics, serotinergic, neuroleptics. SMALL: opiates, alcohol)
  • If de-escalation, bargaining, and brute force aren’t working consider something to make the situation a little calmer – midazolam, diazepam, or propofol all work well when used in experienced hands.  This lets you work out if there is anything wrong, and also keeps you and your colleagues safe.

People who are screaming and shouting and fighting off police officers and nurses may have serious pathology (I have found a frontal lobe tumour in a guy fighting off police officers).  Rapidly expanding space occupying lesions can make some people get very fighty.  Don’t assume they are just being annoying.

If someone can’t calm down enough for you to have a conversation with them, they probably don’t have capacity.

Hypoactive delirium (down)

These patients are brought in cold often being ‘found’ by some unlucky member of the general public.  Sometimes the police bring them in, sometimes ‘friends’.

  • ABCs
  • Glucose, 12 lead, temp.
  • GCS – A GCS of <8 only counts if it’s done by an ED sister or ED spr.  We are brutal.  We will teach you our tricks if you ask nicely, or give us cake.
  • Pupils: BIG: amphetamines, MCAT, anticholinergics, serotinergic, neuroleptics. SMALL: opiates, alcohol

Be more concerned with patients with big pupils and hypoactive delirium, this means they’ve taken A LOT, and are closer to the final common pathway of all toxicology which is SEIZURE->COMA->DEATH.

 

Next week MCAT!

Can we electrically cardiovert stable AF in the ED?

True Story:

A 56 year old anaesthetist presents to your department, he states he started having palpitations while cycling up a large hill.  He took his pulse which felt irregular and so he cycled to the ED.  His HR 107, BP 130/75 RR 18 Sats 98% ORA Apyrexial.  His ECG shows AF, with no ST changes.  He ‘demands’ electrical cardioversion.

For the basics the brilliant RCEM learning website, has a great article on ED management of Atrial Fibrillation.   It doesn’t go into much detail about the nuts and bolts of electrical cardioversion in the ED.

Lets try and go into a bit more detail.

Now what does NICE say?  The relevant verse is here:

1.7.2 In people with atrial fibrillation presenting acutely without life-threatening haemodynamic instability, offer rate or rhythm control if the onset of the arrhythmia is less than 48 hours, and start rate control if it is more than 48 hours or is uncertain. [new 2014]  

1.7.3 Consider either pharmacological or electrical cardioversion depending on clinical circumstances and resources in people with new-onset atrial fibrillation who will be treated with a rhythm control strategy. [new 2014]

 

http://www.nice.org.uk/guidance/cg180/resources/guidance-atrial-fibrillation-the-management-of-atrial-fibrillation-pdf  [page 23]

 

We can consider EC or PC depending on the clinical circumstances and resources.  The implication here is that EC is more resource heavy.  I would argue that it might be in the ED, but that across the organisation as a whole it is less resource intensive to sort in our department than to clog up an acute ward. This is backed up by studies in Ottawa8, Rochester6 and Pennsylvania which show that length of stay (the biggest determinate of health care cost) is less if we just get on and do it9.

So NICE asks us to consider the clinical circumstances of people with new-onset AF.  So what clinical circumstances do we need to consider?

Cause of AF

AF caused by electrolyte abnormalities, ACS, Sepsis, Structural heart disease, or Thyrotoxicosis is unlikely to resolve with a single shock.  After all you will need to treat the underlying cause first.  It is only really appropriate to offer ED EC to patients with idiopathic AF.  It is also important to note that up to 60% of patients with idiopathic AF revert spontaneously with no treatment at all.

Suitability for Procedural sedationbeaker

This depends on the skills present in your department, as well as the patient’s history.  It is unlikely that it is going to be appropriate to perform EC on a patient who has an ASA grade 3 or more.  Similarly you aren’t going to want to sedate someone whose airway looks like Beaker from the muppets.

Choice of sedation technique and agents depends on your skills and preferences.

Risk of thromboembolic complications (before and after EC)

Most guidance, and most studies seem to have a 48 hr cut off mark.  If the AF has been going for less than that time the received wisdom is that you aren’t going to shoot off a thrombus.  There is some opinion out there that EC might stun the right atrial appendage and a thrombus forms AFTER cardioversion.  This remains to be proven.

If the AF has no definitive time of onset, then the safest thing to do is anticoagulation first (depending on centres this can be clexane + warfarin and a clinic, or an admission and IV heparin), and an elective cardioversion later (usually 4 weeks).

What is the incidence of Thromboembolic events (TE) after EC?  I did find a meta-analysis3 from 1998 (Berger et al) which looked at 32 studies, giving 4621 participants.  92 patients had a thromboembolic episode (2%).  The duration of the AF was less than 2 days in the TE group in only 3 patients (0.06%).

Duration of AF Number of patients with TE episode/4621
<2 days 3 (0.06%)
3 days – 1 month 21 (0.45%)
>1 month 42 (0.9%)
Unknown 26 (0.5%)

 

The paper doesn’t tell us how many patients were in each group, so the data has little meaning when broken down as above, so we can only really take from this the overall percentage of 2% for thromboembolic events.

Berger et al was more interested in the timing of thromboembolic event after the cardioversion, this peaks in the first few days following the cardioversion no matter the duration of the AF.  I also found a study looking at NOACs (novel oral anticoagulants eg dabigatran) vs warfarin for anticoagulating patients prior to cardioversion but they got a 30 day thromboembolic rate of 0.8% with warfarin10.

A retrospective study from Denmark of 16 274 DC cardioversions7 without and with anticoagulation was published this year.  Unfortunately they didn’t look at the timing of the AF, but conclude quite reasonably that the risk of TE’s is higher in non-anticoagulated people with AF than people who are.

360/16274 Anticoagulation        n=11 190 No Anticoagulation n=5084 NNT
0-30 days0-360 days 32 [0.28%]144 [1.28%] 54  [1%]216 [4.24%] 12934

Weigner et al looked specifically at incidence of thromboembolic events (TE’s) after cardioverting recent onset AF (<48 hours). They conducted a prospective observational study which was published in 19972.  They identified 375 adults with recent onset AF, 66.7% reverted spontaneously, the rest had some form of active management (electrical or pharmacological or both).  Three patients out of the 375 had a TE event, none of them received electrical cardioversion, all were managed with anticoagulation, and various drug combinations.  All 3 of these patients had essentially benign echoes during that admission, suggesting that the ‘safe’ (drugs and anticoagulation) approach isn’t actually that safe.  All 3 patients were elderly people that had multiple co-morbidities that even the most EC fanatical ED doctor would baulk at doing a cardioversion on.

A 2013 Finnish observational study of acute cardioversion5 (EC within 48 hours of AF onset) pegs the rate of thromboembolic events at less than 1%.  There were 38 thromboembolic events within 30 days in a total of 5116 cardioversions, in 2497 patients, this gives us an incidence rate of 1.5% per patient (or 0.7% per cardioversion).  The study goes on to suggest that using either the CHADS2 score or CHA2DS2-VASC score to risk stratify allows us to reduce that risk further if we only attempt to cardiovert low scoring individuals without anticoagulating them first (it remains to be shown if anticoagulating the high risk group actually reduces thromboembolic events).

afdecThey produce this brilliant decision tree, which I think I might use when discussing the options with patients.  The risk of thromboembolism with delayed elective cardioversion and anticoagulation is also about 1% (confirmed by our study into NOACs10 and the big Danish study7).

I can see myself talking patients through this decision tree to help them make an informed choice about their options.

The question about whether we should be offering this cardioverted group anticoagulation is difficult.  On the one hand the Finnish research suggests that CHADS2VASC scores or similar can help us estimate the risk, but the large study from Denmark seems to suggest blanket prescription (but neglected to sub categorise the time of onset of AF).

This may again come down to giving your patient the choice between nothing, something for 4 weeks and something for longer, depending on their CHADS2VASC score.  So the risk of TE’s following ED EC seems to be about 1%, which is similar to the risk of doing an in-hospital EC with anticoagulation.  So if the risk is the same, is one approach better than another?

Is electrical cardioversion more effective than chemical cardioversion for acute onset AF?

Strangely there is not much to go on here.  Most trials use combination therapy if they study EC at all.  I could only find 3 trials that were in any way useful, and only one compared EC to PC directly.

The first trial I found was a single centre randomised controlled trial that compared electricity alone to pharmacological cardioversion from Italy in 20111.  Patients were excluded if their CHADS2 score was >2, if they were unstable, or if it was felt that the AF was secondary to another process (eg Hyperthyroidism, Sepsis, ACS etc).  All patients had an ED transthoracic ECHO, looking for significant valvular disease.  However the authors neglect to say how many patients they excluded because of their ECHO findings.

Results
N= 247 EC 121 PC 126
Success 108 [89.3%] 93 [73.8%] HR 0.34(CI 0.17-0.68 p= 0.02
Adverse Events 1 6 HR 2(0.22-18.29) p=0.29
Recurrence of AF @2/12 26.3% 

31 lost to follow up

28.3% 

52 lost to follow up

HR 0.9 CI 0.45-1.8 p = 0.86]

 

Patients in the EC arm were more likely to be successfully cardioverted than in the PC arm.  There were more adverse events (flutter, bradycardia and ischeamia) in the PC arm (but this was not significant).  The recurrence rates were broadly similar, but there were a lot more PC patients lost to follow up than EC, so this may have skewed the results in the favour of EC.

The other trial evidence is not as impressive.  Jacoby’s chart review9 compared 30 ED electrical cardioversions with ‘eligible’ controls.  This study also included people with known paroxysmal AF that were managed with a rhythm control strategy (so a few of them got shocked on more than one occasion).  The ED cardioversions were successful 97% of the time.  Follow up was only to 3 weeks, but found no thromboembolic events, however one patient did end up having a mitral valve replacement.  This study was primarily looking at length of stay, and cost per admission.  EC was found to have shorter lengths of stay (23 h vs 56 h), the median cost of admission was also significantly less in the EC group [$1,598 vs $4,274].  This was effectively a small observational study of relatively poor quality, but the conclusions agree with the Italian study.

stiellThis brings me on to my third study – Stiells Ottawa Aggressive protocol for AF6,4.  This was a consecutive cohort study looking at the safety and efficacy of using procainamide and then using electrical cardioversion if cardioversion had not been achieved.

This study included 628 patients with AF. Procainamide successfully cardioverted in 376 (60%) of patients. In the 252 patients where procainamide had failed, EC was attempted in 223 patients of which there was a 92% success rate (203 success, 20 fail). Cardioversion was not attempted in the remainder of the patients (29 patients).

No one was anticoagulated in this study if the onset time was less than 48 hours.  No one in the study had a stroke, no one died, and only 8.6% of patients relapsed, but the follow up was only 7 days.

Conclusion

So in an ED with the right skill set it’s perfectly possible to electrically cardiovert patients with acute onset AF with or without pharmacological cotherapy, in fact electricity might have a better success rate.  The risk of thromboembolic events is also similar to doing a delayed cardioversion with anticoagulation, but recent data suggests it may be worth considering prescribing anticoagulation for a short time afterwards and risk stratifying our patients based on CHADS2VASC score.  If their score is <2 I would offer them EC. If there score is >2 I think I’d try to limit their risk by admitting them for anticoagulation.

Pros and Cons

Pros to ED EC Cons to ED EC
As successful as in-hospital careSame relapse rate

Possibly slightly higher success rate

No side effects from rate control drugs

Risk of thromboembolism 1% same as in hospital care

Can go home faster

Hospital care still an option if ED EC fails

Cheaper for the hospital

Risks of procedural sedationMight not need it (up to 60% revert spontaneously)

Possibly higher risk of thromboembolism after EC if sent home with no anticoagulation

More resource intensive in the ED

 

References

  1. Bellone, Andrea, et al. “Cardioversion of acute atrial fibrillation in the emergency department: a prospective randomised trial.”Emergency Medicine Journal (2011): emj-2010.  [http://emj.bmj.com/content/29/3/188.short]
  2. Weigner MJ, Caulfield TA, Danias PG, Silverman DI, Manning WJ. Risk for Clinical Thromboembolism Associated with Conversion to Sinus Rhythm in Patients with Atrial Fibrillation Lasting Less Than 48 Hours. Ann Intern Med. 1997;126:615-620. doi:10.7326/0003-4819-126-8-199704150-00005 [http://annals.org/article.aspx?articleid=710444]
  3. Berger, Marvin, and Paul Schweitzer. “Timing of thromboembolic events after electical cardioversion of atrial fibrillation or flutter: a retrospective analysis.”The American journal of cardiology12 (1998): 1545-1547.
  4. Safety of Urgent Cardioversion for Patients With Recent-Onset Atrial Fibrillation and Flutter Stiell, Ian G. et al. Canadian Journal of Cardiology , Volume 31 , Issue 3 , 239 – 241 [http://www.onlinecjc.ca/article/S0828-282X(14)01616-X/abstract]
  5. Airaksinen, KE Juhani, et al. “Thromboembolic complications after cardioversion of acute atrial fibrillation: the FinCV (Finnish CardioVersion) study.”Journal of the American College of Cardiology 13 (2013): 1187-1192. [http://www.sciencedirect.com/science/article/pii/S0735109713025266]
  6. Stiell, Ian G., et al. “Association of the Ottawa Aggressive Protocol with rapid discharge of emergency department patients with recent-onset atrial fibrillation or flutter.”Cjem 3 (2010): 181-91.  [http://www.cjem-online.ca/v12/n3/p181]
  7. Hansen, Morten Lock, et al. “Thromboembolic risk in 16 274 atrial fibrillation patients undergoing direct current cardioversion with and without oral anticoagulant therapy.”Europace 1 (2015): 18-23.
  8. Decker, Wyatt W., et al. “A prospective, randomized trial of an emergency department observation unit for acute onset atrial fibrillation.”Annals of emergency medicine 4 (2008): 322-328.
  9. Jacoby, Jeanne L., et al. “Synchronized emergency department cardioversion of atrial dysrhythmias saves time, money and resources.”The Journal of emergency medicine 1 (2005): 27-30.
  10. Nagarakanti, Rangadham, et al. “Dabigatran Versus Warfarin in Patients With Atrial Fibrillation An Analysis of Patients Undergoing Cardioversion.”Circulation2 (2011): 131-136.

ARISE in the PROMISE of the PROCESS

Squeeze your face in, like you’ve sucked a lemon, then say the following ‘Early Goal Directed Therapy doesn’t work’  We’ve had three massive, well run RCTs published in the last 6 months which compared “usual care” to “EGDT” for severe sepsis.  They all show no difference between EGDT and “Usual Care”.

Headline figures

ARISE PROCESS PROMISE RIVERS 2001
n 1600

796 EGDT

804 “Usual”

1341

439 EGDT

446 Protocol Standard

456 Usual

1260

630 EGDT

630 Usual

263

130 EGDT

133 Usual

Outcome

Mortality

147/792 18.6% EGDT

150/796 18.8% Usual

 

[90 day mortality]

129/405  31.9% EGDT

128/415 30.8% Protocol

139/412 33.7 % Usual

[90 day mortality]

184/623 29.5% EGDT

181/620 29.2% Usual

 

[90 day mortality]

50/130 44.3%EGDT

70/133 56.9% Usual

 

[60 day mortality]

 

All of the recent MCT RCT’s showed no significant difference between EGDT (the River’s protocol) and “Usual” care.

Pooling Results EGDT Vs “Usual”

n 4201

1865 EGDT

1890 Usual

Outcome Mortality 90 days 460/1865 24.66% EGDT

470/1890 24.86% Usual

 

So if there is no difference between EGDT and ‘normal’ care, can we just ditch the sepsis six, buffalo, or whatever acronym reminder is used in your department to manage sepsis early?  Some trusts are creating sepsis nurses, or sepsis champions who go around helping fight sepsis on the wards.  Is all this expenditure, time, and effort (for god sakes think of the sheer number of blood cultures alone).  Not worth it?

Well you could collapse down into a nihilistic funk if you want, but if you take a slightly longer view things are looking up for sepsis mortality, and this is probably because “Usual Care” now in 2015 is different to “Usual Care” in 2001.

I found a prospective meta-analysis looking at sepsis mortality between 1958 and 1997 (n= 10 694).  This gives a headline overall mortality of 49.7% but there was a trend to improving mortality.  So if we take 49% as a historical mortality, something has happened to drop mortality between 1997 and 2015 by almost half.

Mortality from Sepsis pre 1997 49.7%, mortality from Sepsis in 2015 25%.

In fact the news has got even better (at least in Australasia), a retrospective observational study from 2000 to 2012 in 171 ICUs in Australasia showed an absolute mortality decrease from 35% to 18.4%.  This at least agrees with ARISE’s slightly better numbers than PROCESS or PROMISE.  It might be interesting to find out why outcomes in Australasia are better than in the US and UK.

There are massive caveats to this, the 3 big RCTs excluded lots of patients for logistical and clinical issues.  Do we DNAR more people now than we used to?  A lot patients got excluded from all 3 trials because the treating physician felt ‘aggressive care was unsuitable’.  That’s going to skew the results slightly.

What do we do differently now?  What’s making the difference?  Antibiotics haven’t changed, if anything our ability to treat systemic bacterial infections has got a little less impressive given the rise of resistant organisms.  The widespread implementation of early warning scores, awareness raising, and early fluid resuscitation and early antibiotics are probably the biggest difference. Certainly the main component of the EGDT that’s been adopted (at least where I have worked) is the ‘E’.  In terms of critical care the same tools are used, just as they always were, the actual targets or ‘goals’ might be different, but intensivitists are still aiming to perfuse tissues and organs, and it’s entirely probable that they are keeping similar numbers in their heads as Emanuel Rivers did 15 years ago.  What we may have here is the biggest contamination confounding variable ever.

Maybe we can tentatively conclude that sepsis treatment has improved in the US, UK and Australasia.  The surviving sepsis campaign must surely take the lion’s share of the credit here, at least for giving hospitals implementation and treatment strategies, as well as raising the awareness of systemic infection.

There is much we still don’t understand, exactly how much fluid to give remains elusive, and the pathogenesis of septic shock on biochemical level is still poorly understood.  The FEAST trial suggested that we still don’t understand fully the effects of giving simple intravenous fluid boluses to people in shock.

In conclusion ARISE, PROMISE and PROCESS probably don’t show a benefit because EGDT is now very similar to “usual care”.

References

  • Rivers, Emanuel, et al. “Early goal-directed therapy in the treatment of severe sepsis and septic shock.”New England Journal of Medicine 19 (2001): 1368-1377.
  • Peake, Sandra L., et al. “Goal-directed resuscitation for patients with early septic shock.”The New England journal of medicine 16 (2014): 1496.
  •   Trial of Early, Goal-Directed Resuscitation for Septic Shock. (ProMISe Trial). N Engl J Med 2015;epublished March 17th
  • Friedman G, Silva E, Vincent JL (1998) Has the mortality of septic shock changed with time? Crit Care Med 26:2078–2086
  • Systemic Inflammatory Response Syndrome Criteria in Defining Severe Sepsis. N Engl J Med 2015;epublished March 17th
  • Yealy, Donald M., et al. “A randomized trial of protocol-based care for early septic shock.”The New England journal of medicine 18 (2014): 1683-1693.

The aggressive agitated elderly patient

The alarm has gone off in the CDU toilet.  Inside the toilet was an 87 year old man in only his hospital issue paper y-fronts demanding someone call the police because he is being “held against his will”.  He is refusing to leave the toilet, refusing to let you switch off the godawful crash alarm.  One nurse is hanging for dear life on the other side of the door to keep it open.  2 other patients with dementia in the same bay keep on wandering past, wanting to “help”.

What is your approach to the agitated patient?

There are 2 arms to any case such as this, first off we have to ensure the safety of the patient, other patients in the vicinity, other staff, and ourselves.  The next thing we need to establish is why has this person become agitated?

Medical causes of potential agitation are wide and varied.  Delirium in itself should be thought of as a medical emergency, as it carries a potentially high mortality (though estimates vary hugely 20%-70%).

This mnemonic may help – “SHED WIMP HELPS”

Substances, Hypoxia, Events (vascular), Dehydration, Withdrawl, Infection, Myocardial Infarction, Psychiatric, Head Injury , Endocrine, Low BM,  Pain, Seizures.

The key information here is going to be what you glean from the ambulance record, and whoever normally looks after your patient.  Is their behaviour normal for them?  Is it out of character?  If you are seeing that patient for the first time in the ED you are in the best position to assess them, as very often family members, carers, and other information will be lost prior to the RMO’s clerking them on the medical ward 6 or 7 hour later (on a good day).  If they are more confused than normal this does need investigating.

So say we’ve established that the patient has dementia, that they are in CDU for some form of social care assessment, and that to all intense and purposes there is no medical problem.

The best way to nurse someone with delirium or dementia is to keep them in a brightly lit room, with visual cues as to where they are, and what time it is.  It’s important to have consistent contact with the same individuals, such as carers from a nursing home, or the same nurse.  It’s important that the environment is calm, quiet, and free of interruptions.  Try to make sure that the patient has access to their hearing aids, and glasses, to avoid sensory disturbances.  There should be easy access to food and drink.  If you were going to design an environment to provoke a patient with dementia into confusion and agitation you’d design a place pretty much like an emergency department.

It’s noisy, there is no consistency of staff, patients are moved often, there are often absolutely no visual cues as to what time of day or night it is, if there are clocks they are always wrong.  The trolleys or wheelchairs are not comfortable, there is often no access to food or drink.

If they’ve trapped themselves in the toilet, or a running around the ward trying to escape you might feel under pressure to try some medication.  For elderly patients with dementia most of the literature tends to recommend either haloperidol or midazolam, but there is very little good quality data for elderly patients.  There is a Cochrane review of both antipsychotics and benzodiazepines in depression, they conclude that there is no difference in efficacy between atypical and typical antipsychotics, but no evidence that benzos help with non-alcohol related delirium.  So be cautious with both, haloperidol is thought to be safer because it doesn’t cause as much respiratory depression. IV doses are safer and more predictable if you can get a line in.

IF you can’t get a line in, this is what I’d put in my dart gun, either of…

Haloperidol 1-5mg IM Avoid if QTc is prolonged (risk of Torsade)Risk of dystonic reaction
Midazolam 2.5mg IM Risk of respiratory depression

 

After some time using de-escalation techniques, offers of food, drink, escape, to downright begging, we tried some IM medication.  I got punched in the face giving our gentleman 2.5mg of IM haloperidol.  About 5 minutes later his daughter arrived.  She took one look at her dad held out her hand, sighed, said “come over here Dad”, her father immediately let himself out of the toilet, and came to his daughter’s outstretched hand.

As she walked him back to his bed I heard him say “Thank god you came, I don’t know why they were keeping my trapped in that loo”

I love my job.