Literature Reviews

Papers of April

Here’s a look at some of the papers that caught our eye this month. We cover the best way to diagnose heart failure, the risks associated with hyperopia and the utility of ETCO2.  Take the time to have a look at the papers yourself and leave any feed back or comments at the bottom of the page.

The Papers

Diagnosing Acute Heart Failure in the Emergency Department: A Systematic Review and Meta-analysis. Martindale JL. Acad Emerg Med. 2015 Dec 21. doi: 10.1111/acem.12878. [Epub ahead of print]

Effect of supplemental oxygen exposure on myocardial injury in ST-elevation myocardial infarction.Nehme Z. Heart. 2016 Mar;102(6):444-51. doi: 10.1136/heartjnl-2015-308636. Epub 2016 Jan 6

Prognostication of out-of-hospital cardiac arrest patients by 3-min end-tidal capnometry level in emergency department. Poon KM. Resuscitation. 2016 Mar 3;102:80-84. doi: 10.1016/j.resuscitation.2016.02.021. [Epub ahead of print]

Within the podcast we talk about the fantastic ultrasound resource that is 5min sono developed by Jacob Avila, make sure you got over to the site and have a look at the superb ultrasound resources on offer. Specific to this podcast is the episode on b lines, Jacob kindly provided the images below from his video.

What’s required to identify significant B-lines on chest ultrasound; summary of Jacobs point

  • Use the phased array probe ideally, curved linear probe is possible but technically more difficult
  • Patient position; choose any that allows access to the chest
  • Probe marker towards patients head
  • Scan 4 zones to each side of the chest, superior medial, superior lateral, inferior medial, inferior lateral

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  • To diagnose b lines you need to see vertical artefact, moving with respiration that extends the full depth of the screen (as shown below)

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  • A positive zone is when you identify 3 b-lines in a zone
  • Pulmonary oedema diagnosed with 2 positive zones on each side of the chest

Related Resources


PHEMCAST Hyperoxia 





RSI checklists

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Lets be honest, Emergency Medicine clinicians don’t like checklists. They’re slow, organised and deliberate tools that get in the way of our fast, impulsive and dynamic resuscitation and they’re just not cool!

But what’s the background to checklists, is there much uptake and what have we got to gain by using them?


In England and wales nearly 130,000 surgery related events in 2007 were reported. The WHO checklist was subsequently established and has been implemented in theatres to ensure that all staff are aware of plans and the major steps that are planned and anticipated. The institution of these checklists lead to a 47% reduced rate of death and a 36% reduction of inpatient complications.

NAP4 commented on the higher complication rates of intubations that happen in ICU and ED when compared to anaesthsisa and a need to focus on ways to minimize this risk, with a major complication rate of 0.06%.

What’s been the uptake of checklists so far?

Introducing checklist for sedation and intubation into the Emergency Department; a challenge worth rising to? R I Galloway,1 F Swann2. 1Emergency Medicine, Brighton and Sussex University Hospital NHS Trust, East Sussex, United Kingdom; 2Brighton and Sussex Medical School, Brighton, United Kingdom. 10.1136/emermed-2013-203113.13

Galloway published some work in 2013 looking at this, he found (via telephone surveys) that in England 49% of EDs use a RSI checklist and 58% using a sedation checklist. He then went on to review a single centre and showed 21.5% compliance with RSI checklist and 57.8% with sedation checklists

Interviews showed barriers including problems of implementing the changes across multiple specialties and staff’s pre-concieved attitudes towards checklists.

So this demonstrates a pretty poor application of checklists throughout the country, is this justified or are we failing to use a really powerful and effective tool?

What evidence exists on ED checklists?

Impact of checklists on peri-intubation care in ED trauma patients; American Journal of Emergency Medicine. Conroy (effectively a retrospective data trawl of intubated patients)

A retrospective review of trauma patients at a level 1 centre in the US over a 2 year period getting endotracheal intubation which included 187 patients. A checklist was instituted in November 2011 and they used patients prior to this as a pre-checklist cohort vs the patients after as the checklist cohort. Data was collected for a load of information including demographics, vital signs, LOS and mortality, they also collected a number of characteristics. Compliance with the checklist in the second group was 93%. They found no difference in the number of ETI attempts, haemodynamic parameters, number of intubation attempts etc and also no differences in the length of ED stay, length of ITU stay or in mortality. The positive effect they did see was an improved post intubation analgesia from 14.4 to 27.8% (statistically insignificant)

This obviously doesn’t show the most powerful results but is a relatively small study with low level evidence. What else exists out there in a setting similar to ED?

An intervention to decrease complications related to endotracheal intubation
in the intensive care unit: a prospective, multiple-center study. Jaber S. Intensive Care Med (2010) 36:248–255

This was a Prospective multicenter study in French in ICUs. Data from all ICU intubations excluding tohse in cardiac arrest were analysed over a 6 month period prior to the implementation of any protocol being used. There was then a 4 week period in which all staff received formal education and clinical training on the use of a ten point bundle of management;

1. Presence of two operators

2. Fluid loading (isotonic saline 500 ml or starch 250 ml) in absence of cardiogenic pulmonary edema

3. Preparation of long-term sedation

4. Preoxygenation for 3 min with NIPPV in case of acute respiratory failure (FiO2 100%, pressure support ventilation level between 5 and 15 cmH2O to obtain an expiratory tidal volume between 6 and 8 ml/kg and PEEP of 5 cmH2O)

5. Rapid sequence induction: etomidate 0.2–0.3 mg/kg or ketamine 1.5–3 mg/kg combined with succinylcholine 1–1.5 mg/kg in absence of allergy, hyperkaliemia, severe acidosis, acute or chronic neuromuscular disease, burn patient for more than 48 h and medullar trauma

6. Sellick maneuver

7. Immediate confirmation of tube placement by capnography

8. Norepinephrine if diastolic blood pressure remains \35 mmHg

9. Initiate long-term sedation

10. Initial ‘‘protective ventilation’’: tidal volume 6–8 ml/kg of ideal body weight, PEEP \5 cmH2O and respiratory rate between 10 and 20 cycles/min, FiO2 100% for a plateau pressure \30 cmH2O

They then collected data during a 6 month intervention phase and then recorded complications cataegorised as life threatening or mild or moderate complications for such things as cardiac arrest, cardiovascular collapse, difficult intubation etc. They has 121 patients in the control and 123 in the intervention arm with similar groups at baseline.

They found a the complication rates dropped significantly following institution of the checklist with

  • Life threatening 21 vs 34% (p= 0.03)
  • Mild to moderate 9 vs 21% (p=0.01)

Severe hypoxaemia and cardiovascular collapse were the main lifethreatening complications after intubation.

So what does it mean for us?

Well we don’t seem to like it but checklists have been well implemented in a number of areas with some extremely significant benefit. Whilst they may not be really proven in the ED in the specific case of RSI they do make sense and why should we be resistant to something so simple that could make such a huge difference to a number of our patients. One thing is for sure they are staying on our airway trolley…apart from when we pick them up to fill them in, everytime!


Editorials Surgical safety checklists. BMJ 2009; 338 doi: (Published 21 January 2009)

Introducing checklist for sedation and intubation into the Emergency Department; a challenge worth rising to? R I Galloway,1 F Swann2. 1Emergency Medicine, Brighton and Sussex University Hospital NHS Trust, East Sussex, United Kingdom; 2Brighton and Sussex Medical School, Brighton, United Kingdom. 10.1136/emermed-2013-203113.13

An intervention to decrease complications related to endotracheal intubation
in the intensive care unit: a prospective, multiple-center study. Intensive Care Med (2010) 36:248–255

NAP4 recommendations


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10 Ways To Improve Your Resus Care; EBM Style

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It’s been 2 years since starting HEFTEMCAST and it’s been a fantastic way for us to share some of the superb stuff going on at HEFT.

This podcast is taken from the recent EMCEF Conference in Birmingham run by Alon Duby.

In the podcast we’ll run through 10 papers that have made a difference to my resus care in the last few years but don’t just take my word for it have a look through the paper yourself and draw your own conclusions. Each paper has the pubmed hyperlink under the conclusion. Enjoy!



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Fever, friend or foe?

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So what’s the problem?

We give paracetamol in the ED to lower temperature, this will be happening hundreds of times every day in the UK….. in fact I think you’re sometimes more likely to get it for fever than you are if you’re in pain. This is bad. It just doesn’t make any sense to have this “knee-jerk” reaction everytime we see someone with a fever. You need to look at your patient and as with everything we do we need to think about why we are doing it….

Just because paracetamol is cheap and has a good safety profile doesn’t mean we should be thinking about it any less than any other drug we administer. If we were talking about giving TPA to lower fever, then we’d be really be considering the evidence as its expensive and has huge effects we wouldn’t want.

Now FOAM is a great medium to discuss these ideas and get people to consider different viewpoints and think about their practice.

What are we talking about?

 Fever is a preserved physiological response to a wide variety of infectious and non-infectious triggers, which induce, by different methods, upregulation of the thermostatic setpoint in the preoptic area of the hypothalamus, finally resulting in fever. We’re talking about these patients presenting to the ED with a fever, in whom we suspect an infective cause.

We’re not talking about patients with hyperthermia due to environmental factors, use of recreational drugs or malignant hyperthermia, as these involve different pathophysiology, requiring rapid cooling, for which paracetamol doesn’t work.

 Whats going on?

Thermoregulation is a fundamental homeostatic mechanism that maintains body temperature within a tightly regulated range. The ability to internally regulate body temperature is known as endothermy and is a characteristic of all mammals and birds.

In humans, the central processing center controlling the thermoregulatory set-point is the hypothalamus.

The core body temperature is tightly regulated around a set point by homeostatic mechanisms under normal physiological conditions.

How are we defining fever?

A threshold value of ≥38.3°C has been recommended by several societies for the diagnosis of fever. – WHO

There is a female hormonal-induced variation and a diurnal variation. So, Mackowiak and colleagues found that the mean temperature was 36.8°C, with a range of 35.6 to 38.2°C, the temperature being lower in the morning than in the evening. Mackowiak PA, Wasserman SS, Levine MM: A critical appraisal of 98.6°F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA 1992, 268:1578-1580.

How are we recording fever?

The core temperature is important as a core to peripheral temperature gradient is common in critically ill patients, especially in those who are hypovolaemic, have a low cardiac output or are peripherally vasoconstricted.

We want a core temp…. this would be pulmonary artery catheter ideally, but more commonly in the ED we use either tympanic or oral.

So what are the potential benefits of fever?

Effects on infectious agents – Human pathogens grow under optimal temperatures of 35-37C. Above that, in vitro studies have shown reduced growth of pathogens. Prescott LM: Microbiology. Boston, MA: WCB/McGraw-Hill; 1999.

They have also found a progressive rise in the activity of antimicrobial agents dependent on temperature – i.e. the hotter the patient, the better they work. Mackowiak PA, Marling-Cason M, Cohen RL: Effects of temperature on antimicrobial susceptibility of bacteria. J Infect Dis 1982, 145:550-553.

Effects of fever on heat shock response (critical for cellular protection and reducing organ damage) – animal studies (sheep and rats) with abdo + lung sepsis induced show longer survival time with higher temperatures.

For the common cold…… the use of paracetamol was associated with a longer duration of virus shedding and delayed antibody response……. They were symptomatic for longer. Stanley ED, Jackson GG, Panusarn C, Rubenis M, Dirda V: Increased virus shedding with aspirin treatment of rhinovirus infection. JAMA 1975, 231:1248–1251.

Graham NM, Burrell CJ, Douglas RM, Debelle P, Davies L: Adverse effects of aspirin, acetaminophen, and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis 1990, 162:1277–1282.

For children undergoing vaccination programmes…….. giving paracetamol at the time of vaccination induced a delayed and crucially a lower antibody response to several antigens. Prymula R, Siegrist C, Chlibek R, Zemlickova H, Vackova M, Smetana J, Lommel P, Kaliskova E, Borys D, Schuerman L: Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet 2009, 374:1339-1350.

Some history

Julius Wagner-Jauregg (Nobel prize winner 1927) – went on to become a nazi sympathiser…… so his work doesn’t get talked about that much.

Wagner-Jauregg J: The treatment of dementia paralytica by malaria innoculation. In Nobel Lectures: Physiology or Medicine 1922–1941. Elsevier, New York, 1927: 159–169

Essentially – gave malaria to patients paralysed with neuroshyphilis to make them spike a temperature. This temperature caused resolution of symptoms in 33% of cases i.e. no longer paralysed – the patient was then treated with quinine which cured their malaria.

“he tried in 1917 the inoculation of malaria parasites, which proved to be very successful in the case of dementia paralytica (also called general paresis of the insane), caused by neurosyphilis, at that time a terminal disease.It had been observed that some who develop high fevers could be cured of syphilis.”

In real patients…..

Higher survival in patients who developed fever on the day of bacteraemia.

Reduced mortality in spontaneous bacterial peritonitis with fever >38C. Weinstein MP, Iannini PB, Stratton CW, Eickhoff TC: Spontaneous bacterial peritonitis. A review of 28 cases with emphasis on improved survival and factors influencing prognosis. Am J Med 1978, 64:592–598.

In elderly patients with CAP, afebrile patients had a 29% mortality risk, this dropped to 4% in those who developed a febrile response. Ahkee S, Srinath L, Ramirez J: Community-acquired pneumonia in the elderly: association of mortality with lack of fever and leukocytosis. South Med J 1997, 90:296–298.


If you give patients paracetamol you take away your ability to see if they develop a fever (+ removes a SIRS criteria – they might not get the sepsis 6 etc..)… and its crucial for determining the management plans of patients in the ED where you have a not forgetting we have a limited time window to do this.

Fever can lower your a NEWS score by 1 which removing it can reduce there response obtained and the frequency of observations. Paracetamol does nothing to treat the underlying cause, and may only delay diagnosis…….


What are the problems of having a fever?

Fever is believed to be harmful, especially in patients with life-threatening illnesses, because febrile responses are known to increase the metabolic rate, minute ventilation, and oxygen consumption.

Response – The conservation of a metabolically costly response across a broad range of animal species suggests that the response probably has an evolutionary advantage.

Bottom Line

Paracetamol in fever may not be the simple answer that we are all looking for in patients with an infection. Blindly administering it to patients who are systemically well may infer mild harm to patients, of course if the patient is feeling unwell as a result of the fever then it may infer a significant amount of benefit.

The HEAT study just out in the NEJM didn’t show any benefit to routine administration to ITU patients with a fever secondary to an infection with the length of ITU stay or in mortality. What we need is a prospective trial of ED patients looking at the administration in our ED cohort with patient centered outcomes, hopefully we’ll find out soon…..



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Fluids in Trauma

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Lets have a think about fluids in trauma.

Wildly different guidelines exist out there on the topic and we thought it might be wise to have a look back through some of the literature specifically on the fluid management in Haemorrhagic Shock (HS).  We are talking about purely HS so these findings won’t fit all the other conditions we can have together with HS (e.g. Head Trauma and haemorrhage/ Spinal shock and Heamorrhage).

Now, in a perfect world, a patient presenting to the ED would have a clear picture of haemorrhagic shock without any other complicating factors but we know that in real life things are a little more tricky…..but lets say u=you’ve made it to that conclusion!

In your sick trauma patient in suspected haemorrhagic shock;

What are your priorities?

Will you give crystalloids aiming for a normal MAP, are you giving RBC/FFP/Platelets and your target MAP is definitely lower than a normal one?

Will you tailor your treatment to individual patients or will you follow a standard approach?

Let’s have a look to the literature and to help inform our approach to these critical patients

I reckon it is pivotal to start with the founding father of the major trauma management: ATLS, this breaks down the EBL in four distinct categories: the more the patient bleeds, the worse his/her physiology will be.

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The classifications show a stepwise progression in physiology the greater the volume of blood lost. The treatment recommended by ATLS is 1-2 litres if i.v. warmed crystalloid based on the physiological response to the infusion in classes 1-2, class 3 should get crystalloids and blood and class 4 blood alone.

Recently, there have been some doubts about the accuracy of these shock classes and thanks to the Military research and experience in the battlefield, we already know that too many crystalloids do more harm than good to this category of patients.

Military benchmark: (2,3,4)

The military population is very different from the civilian one: young and fit adults who suffer from blast or blunt injuries (mainly IED or GSW). The leading but often treatable cause of death is caused by HS secondary to the devastating effects of their wounds. Due to their exposure, the military developed a deep knowledge and a broad experience in the treatment of major haemorrhages.

In the meantime, the concept of Damage Control Resuscitation (DCR) was born and while rapidly controlling the source of the bleeding was a focal point, they realised RBC/FFP and Platelets were the fluids of choice while crystalloids had to be limited during resuscitation.

DCR is a new concept but even in the WWI some surgeons highlighted that a limitation of fluids was beneficial unless the source of the bleeding had been already controlled by a trauma surgeon.

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But DCR , which is composed by permissive hypotension+ early haemostatic resuscitation plus Damage control surgery, and subsequent restoration of organ perfusion & oxygen delivery with definitive resuscitation.

NB We have to be more cautious with Damage Control Resuscitation principles (DCR) when our patient has got a head injury. In that case, we have to be less strict and allow a MAP >90 or a SBP > 110 just to avoid any other secondary brain injury caused by hypotension.

Furthermore, also if our patient has got a suspected spinal cord injury we need to maintain a higher SBP/MAP to avoid any further spinal cord ischaemia. (10-11)

So how should we approach the early resuscitation in DCR with regards to fluids?

Civilian literature: (5,6,7,8,9)

Here it comes the pivotal article by Dutton (Haemostatic Resuscitation). In this article, the author breaks down and explains what happens to the human physiology when a major insult strikes and the pathophysiology of haemorrhagic shock is explained and discussed:

Fluid administration means increased venous return to the heart-> increased cardiac output-> reduces the reflex vasoconstriction of HS-> more bleeding allowed.

Increased output means increased blood pressure-> wash away of clots already formed + haemodiluition which leads to decreased blood viscosity and dilution of clotting factors/platelets and RBCs.

So, this is primarily an article about the pathophysiology of HS but I strongly suggest to have a look at it!

In the review by Harris, Rhys Thomas and Brohi (Early fluid resuscitation in severe trauma) other evidence is collated and the authors state “DCR approach has seen a fall in the volume of crystalloid delivered in the ED and an associated fall in mortality”.

In the retrospective analysis by Duke (Jan 2007 to May 2011) at a Level I Trauma Centre in the US, the authors suggest that a restricted fluid resuscitation (RFR) in combination with DCR conveys a survival benefit in patients with severe haemorrhage. 307 patients were included, all patients with penetrating torso injuries and Systolic BP <= 90mm Hg. They analysed 2 groups where the patients were either classifies as Standard fluid resuscitation (SFR 43% of total patients) where more than 150mL of crystalloids were given prior to DCR, or as Restricted fluid resuscitation (RFR 57% of total patients) where less than 150 mL were given before DCR. They found RFR held a statistically significant reduced mortality compared with SFR. The demographics and clinical characteristics were similar in both groups.

In a 2-year retrospective review by Duchesne, the authors compared patients treated in the post-DCR institution  with patients treated in the conventional way pre-DRC at the same centre, a historical cohort. They included 1866 patients with both blunt and penetrating injuries. Again they found a significant mortality reduction in those undergoing DCR

Similar results can be seen in the retrospective study by Ley where data collected from a Level I Trauma Centre between January 2000 and December 2008 were analysed. They demonstrated the more crystalloids administered to trauma victims the higher the associated mortality, this was not proof of causation but certainly one of association.

Last but not least in  August 2015 NICE released the new guidelines “Major Trauma: assessment and initial management”(draft).

The key points relating to this part of the story;

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So it’s fair to say that the literature base isn’t perfect, there’s no big multi centre RCT that will be generalisable to your patients showing crystalloids to have an adverse effect on morbidity and mortality. But there is a good scientific basis for why they may be harmful, there is softer evidence to align with this and NICE’s new draft guideline on Major Trauma certainly helps to unify the anti-crystalloid approach to haemorrhagic shock.

And what do we do if we find ourselves stuck without the blood products available? Well Harris, Thomas and Brohi suggested very small boluses (250mL) in the absence of central pulses (as per prehospital management) until blood products can be obtained is probably the most pragmatic approach.

And most importantly gain definitive control of that bleeding!



(1)  ATLS

(2) WB Cannon, J. Fraser, Cowell EM. The preventive treatment of wound shock. JAMA.1918; 70:618-621

(3) R. Dawes, G.O.R.Thomas. Battlefield reuscitation. Curr. Op. Crit. Care 200915:527-535

(4) BA Cotton, JS Guys, Morris JA et al. The cellular, metabolic and systemic consequences of aggressive fluid resuscitation strategies. Shock 2006;26:115-121.

(5) R.P. Dutton. Haemostatic Resuscitation. BJA 2012;10(1):39-46

(6) T.Harris, GO Rhys Thomas, K.Brohi. Early fluid resuscitation in severe trauma. BMJ 2012;e345

(7) MD Duke, C. Guidry, J Guice, L Stuke et al. Restrictive Fluid Resuscitation in combination with damage control resuscitation: Time for adaptation. J Trauma Acute Care Surg 2012,73;(3)674-678.

(8) J.C. Duchense, J.M. Barbeau, T.M. Islam et al. Damage control resuscitation: from Emergency Department to the Operating Room. The American Surgeon 2011;77(2):201-206.

(9) EJ Ley, MA Clond, MK Srour et al. Emergency Department Crystalloid Resuscitation of 1.5 L or more is associated with Increased mortality in elderly and non elderly trauma patients. J Trauma 2011;70:398-400.

(10) European Trauma Course- The Team Approach Ed 3.1

(11) D.M. Stein, V. Roddy, J.Marx. Emergency Neurological Life Support: Traumatic Spine Injury. Neurocrit Care (2012);17:S102-S111


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Acute Heart Failure

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Acute heart failure is extremely common amongst patients presenting to our ED’s. No doubt you’ll have several patients each day presenting who need assessment and treatment for this condition. Understanding some of the underlying physiology and evidence base surrounding the condition can greatly improve the treatment you can give to your patients.

In this podcast we’ll run through just that. Below are a list of some of the references and resources we’ll cover.

We’d love to hear any comments or feedback you have for us.

Rob Fenwick

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Relevant FOAMed resources

St Emlyns (blog post)

EMCRIT (podcast)


National Institute for Health and Care Excellence. (2014) Acute heart failure: diagnosing and managing acute heart failure in adults. (Clinical Guideline CG187).Available from:

European Society of Cardiology; Nieminem, M. S., Bohm, M., Cowie, M. R., Drexler, H., Filippatos, G. S., Jondeau, G., Hasin, Y., Lopez-Sendon, J., Mebazaa, A., Metra, M., Rhodes, A & Swedberg, K. (2005) Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: The task force on acute heart failure of the European Society of Cardiology. European Heart Journal. Vol 26, pp384-416.

Cochrane systematic reviews; Salvador, D. K., Punzalan, F. E & Ramos, G. C. (2005) Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database of Systematic Reviews. Issue 3. Article number: CD003178.

Wakai, A., McCabe, A., Kidney, R., Brooks, S. C., Seupaul, R. A., Diercks, D. B., Salter, N., Fermann, G. J & Pospisil, C. (2012) Nitrates for acute heart failure syndromes. Cochrane Database of Systematic Reviews. Issue 8. Article number: CD005151.

Vital, F. M. R., Ladeira, M. T & Atallah, A. N. (2013) Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic oedema. Cochrane Database of Systematic Reviews. Issue 5. Article Number CD005351.

Referenced articles


Hasselblad, V., Gattis-Stough, W., Shah, M. R., Lokhnygina, Y., O’Connor, C. M., Califf, R. M & Adams, K. F. (2007) Relationship between dose of loop diuretics and outcomes in a heart failure population: Results of the ESCAPE trial. European Journal of Heart Failure. Vol 9, number 10, pp1064-1069.

Faris, R., Flather M., Purcell, H., Henein, M., Poole-Wilson, P & Coats, A. (2002) Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials. International Journal of Cardiology. Vol 82, number 2, pp149-158.


Publication committee for the VMAC (Vasodilation in the Management of Acute CHF) investigators. (2002) Intravenous nesiritide vs. nitroglycerin for treatment of decompensated congestive heart failure: a randomised controlled trial. JAMA. Vol 287, number 12, pp1531-1540.

Sharon, A., Shpirer, I., Kaluski, E., Moshkovitz, Y., Milovanov, O., Polak, R., Blatt, A., Simovitz, A., Shaham, O., Faigenberg, Z., Metzger, M., Stav, D., Yogev, R., Golik, A., Krakover, R., Vered, Z & Cotter, G. (2000) High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema. Journal of the American College of Cardiology. Vol 36, pp832-837.

Cotter, G., Metzkor, E., Kaluski, E., Faigenberg, Z., Miller, R., Simovitz, A., Shaham, O., Marghitay, D., Koren, M., Blatt, A., Moshkovitz, R., Zaidenstein, R & Golik, A. (1998) Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. The Lancet. Vol 351, pp389-393.

Levy, P., Compton, S., Welch, R., Delgado, G., Jennett, A., Penugonda, N., Dunne, R & Zalenski, R. (2007) Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis. Annals of Emergency Medicine. Vol 50, number 2, pp144-152.


Vital, F. M. R., Ladeira, M. T & Atallah, A. N. (2013) Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic oedema. Cochrane Database of Systematic Reviews. Issue 5. Article Number CD005351.

Gray, A., Goodacre, S., Newby, D. E., Masson, M., Sampson, F & Nicholl, J., for the 3CPO Trialists. (2008) Noninvasive ventilation in acute pulmonary edema. New England Journal of Medicine. Vol 359, pp142-151.

Plaisance, P., Pirracchio, R., Berton, C., Vicaut, E & Payen, D. (2007) A randomised study of out-of-hospital continuous positive airway pressure for acute cardiogenic pulmonary oedema: physiological and clinical effects. European Heart Journal. Vol 28, pp2895-2901.


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NIV in asthma

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Asthma is common. It affects our patients, our family and our friends. Thankfully, severe and poorly controlled asthma is less common however, it is this asthma that we often see in the Emergency Department in the form of acute exacerbations.

It goes without saying that we need to be mindful that all patients with acute asthma can deteriorate quickly but how do we spot the individuals with greater risk of a near-fatal or fatal outcome? Risk factors outlined by the British Thoracic Society include non-adherence, previous hospital admission or ED attendance, and failure to measure pulmonary function.

When it comes to the medical management of acute asthma we are all familiar with the guidelines and the approach is fairly straightforward due to the limited number of agents available. That approach should involve an escalating strategy in line with the patient’s disposition based on respiratory effort, PEF, vital signs, and blood gases.

What’s the next course of action when our medical strategies don’t work? Should we run for the phone to bleep the ITU reg to get the patient tubed and admitted to ITU? Is there another option that might be useful such as a non-invasive strategy of intermittent positive pressure ventilation (NIPPV) as used in COPD and acute pulmonary oedema? On that matter the BTS/SIGN guidelines are less prescriptive and there is variable practice across the UK.

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BTS Asthma Guidelines

If we are to consider using NIPPV in acute asthma we really should know how it works, in whom, and when it should be started. The nomenclature around NIPPV is, quite frankly, confusing. There are myriad terms many of which are used interchangeably and include NIV, NIPPV, NPPV, CPAP, BiPAP, ePAP, iPAP, and countless others.

In simple terms NIV is a form of ventilatory support that does not require the use of an artificial airway. Most commonly it is delivered by means of a tight-fitting face mask (or similar device, such as a hood) that allows oxygen to be delivered under pressure measured in cmH20.

In the context of type two (hypercapnic) respiratory failure that may occur in acute asthma, NIV is delivered using two different pressure support levels, often known as the inspiratory- and expiratory-positive airway pressures (iPAP and ePAP, respectively) and collectively referred to as BiPAP (bi-level positive airway pressure). Typical initial pressure levels would be 12/5 cmH20. Increases in iPAP serve to increase tidal volume and reduce CO2 levels; increases in ePAP serve to splint the airways and help to improve oxygenation. When only a single continuous positive airway pressure is used, this is known as CPAP with a typical starting pressure of 5 cmH20.

It’s pretty obvious that asthmatics have tight airways. This means when they exhale, they do so against a pressure known as intrinsic PEEP, also known as auto-PEEP. NIPPV is thought to offset this auto-PEEP and have a direct bronchodilatory effect independent of drug dispersion. As gas flow improves atelectatic lung re-expands and improves V/Q mismatch.

Put simply, NIPPV reduces the work of breathing and improves ventilation. Compared to intubation NIPPV has the advantage that it can be applied intermittently, sedation is not required, and there is reduced incidence of ventilator and nosocomial pneumonia.

With all of the above said, and clear guidelines advocating the use of NIPPV for COPD and acute pulmonary oedema, should we not simply be able to extrapolate its use to our critically unwell asthmatic?

In an overview of the topic up to 2008 Sutton and Ferguson published work in the EMJ asking ‘is NIV an effective intervention for patients with acute exacerbations of asthma?

They searched the literature including the Cochrane register, MEDLINE, EMBASE, and CINAHL to identify 282 papers or which nine were relevant and of sufficient quality and included three RCTs.

Each of the papers looked at slightly different outcomes including degree of shortness of breath, PEFR, oxygen saturations, heart and respiratory rate, blood pH, intubation rate, hospitalisation and change in FEV1 over time.

Generally, each of the papers concluded that use of NIV in asthma resulted in improvements in the primary outcomes compared to controls however, most studies including the RCTs had small sample sizes and methodological issues.

Sutton and Ferguson concluded that the published evidence up to 2008 did not support the use of NIV in acute asthma but did support further better-wrought RCTs.

The main paper we are going to discuss today comes from the Cochrane database and was published by lead author Lim in 2012.

The meta-analysis included RCTs that compared the treatment of asthma with usual medical care plus NIPPV versus usual medical care alone. Studies of adults presenting with acute severe asthma as the primary presentation to the ED were included using standard internationally defined definitions (BTS, American Thoracic Society). Studies looking at COPD or with a primary diagnosis of pneumonia were excluded.

Of 746 identified abstracts, five completed studies were included for meta-analysis whilst one study was awaiting publication. Of the five studies a detailed manuscript was unavailable for one; data extraction was based on the published abstract only. All RCTs were single centre and from different geographic regions including India, Brazil and Israel. A total of 206 patients were included across each of the five trials with a range from 21 to 63 patients in each.

In each of the RCTs patients were randomised to either intervention (NIPPV) or control group. Blinding was not undertaken due to the nature of the intervention and only one study used sham NIPPV in the control group. Four of the five studies utilised BiPAP for intervention whilst CPAP was used for intervention in one trial. Airway pressures were titrated in two studies, pre-determined in two studies, and not reported in one study. Duration of intervention ranged from nine minutes to 14 hours: two studies delivered intervention for less than one hour, two studies for more than one hour and one study intervention duration could not be determined.

Primary outcome measures were 1) need for endotracheal intubation (ETI) and 2) mortality. Secondary outcome measures included respiratory rate, pH, lung function measurements, length of hospital stay, length of ITU stay, treatment failure defined as the combination of mortality, ETI, and intolerance to allocated treatment, symptom score, and complications.

Only two of the five studies the 5 studies (86/203 participants) assessed mortality and tracheal intubation, and neither study had evidence of an effect for these primary out- comes.

In the two studies with mortality data, there were no instances of death in either; therefore meta-analysis could not be reported. With regards the need for tracheal intubation, two studies with 45 participants in the NIPPV arm and 41 in the control arm were assessed with no evidence of an effect between groups (RR 4.48; 95% CI 0.23 to 89.13). In the location subgroup analysis, there were no statistically significant differences in risk of tracheal intubation in both the ICU (Gupta 2010) and ward (Soroksky 2003) subgroups

In general, NIPPV provided favourable outcomes with respect of the majority of secondary outcomes. In summary:

  • Number of hospital admissions (one paper, n=33 (NIPPV n=3/17; control n=10/16): statistically significant in favour of NIPPV (RR 0.28, 95%CI 0.09-0.84)
  • Length of hospital stay (two studies, n=86): Meta-anlysis not performed due to methodological issues in each study. One found in favour of intervention and one in favour of contrl (NIPPV = 4 days, control 2.5 days)
  • Length of ICU stay in ours (two studies): One study in ITU (n=53) reported a statistically significant benefit but meta-analysis could not be performed due to methodological issues. The second study (n=30) did not find a statistically significant benefit (mean difference 0.3, 95%CI -0.63 to 1.23)
  • Treatment failure (two studies, NIPPV n=45; control, n=41): Overall, no statistically significant benefit was identified for this outcome on meta-analysis (RR 0.73; 95% CI 0.21 to 2.53)
  • None of the studies formally assessed the complications of NPPV. One study with 53 participants reported that NPPV was well tol- erated by all participants without serious adverse effects; however, frequent complaints of pain in the nasal bridge area were reported

Lung function tests (PEF, FVC, FEV1, MV, IC) were reported with mixed results:

  • PEF (four studies, n=153). Three out of four reported statistically improved PEF with NIPPV however, only two studies were meta-analysed due to data availability: NPPV was found to confer an absolute PEF improvement of 19.97% predicted, which was both clinically and statistically significant (MD 19.97%; 95% CI 15.01 to 24.93
  • FVC (three studies, n=90). Mixed results. Two available for meta-analysis (n=66) on the hospital ward and finding statistically and clinically significant results in favour of NIPPV (MD 12.27; 95% CI 4.38 to 20.16)
  • FEV1 (four studies, n=140). Two available for meta-analysis (n-66, ward patients) finding a statistically and clinically significant improvement of FEV1 as a % predicted (MD 14.02; 95% CI 7.73 to 20.32)
  • ABG (one study, n=53). Overall no statistically significant differ- ences were found between control and intervention groups.
  • Respiratory rate (five studies, n=203). Three studies (n=146) available for meta-analysis and indicated that the intervention provided a statistically but not clinically significant improvement in respiratory rate (MD -1.42; 95% CI -2.77 to – 0.07)

So what’s the take home message?

Whilst each of the individual studies concluded that the addition of NIPPV to standard medical therapy may be beneficial the results of meta-analysis do not give us any further clarity. The main problem with each of the studies is sample size. Further methodological problems cloud the picture further. What we can say is that there seems to be a trend towards clinically and statistically significantly improvement in secondary outcomes in favour of NIPPV.

Should we be trialling NIPPV in the ED for our critically unwell asthmatics? Probably not based on the current evidence. The cost of resource allocation and impact to the patient should not be underestimated and until further, larger, better-wrought trials are undertaken it is unlikely we will see NIPPV added to the guidelines.


Relevant resources

Setting up NIPPV via CORE EM

How to set up NIV from Shrewsbury Hospital


  1. Sutton L, Ferguson C. BET 3. Non-invasive positive pressure ventilation for patients with acute exacerbations of asthma. Emerg Med J 2009;26:59-60
  2. Lim WJ, Akram RM, Carson KV, et al. Non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma. Cochrane Database Syst Rev. 2012 Dec 12;12:CD004360




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