For the resuscitation out-of-hospital one of the mainstays besides compression and defibrillation ist the application of adrenalin and amiodarone. According to the new ACLS guidelines 2015 these are the only drugs remaining in the treatment for shockable rhythms.
While adrenaline is given for maximum vasoconstriction in order to promote coronary perfusion pressure CPP, amiodarone and sometimes lidocaine are used to promote successful defibrillation of shock-refractory ventricular fibrillation VF or pulseless ventricular tachycardia VT. While the usage of these drugs is undoubtedly very effective in patients with existing circulation the effectiveness during resuscitation remains a matter of debate.
The Effect of Adrenaline
As a matter of fact it has never been proven that adrenalin actually improves long-term outcome. In 2014 Steve Lin and colleagues published a systemativ review on the efficacy of adrenaline in adult out-of-hospital cardiac arrest (OHCA). They were able to show that according to current evidence standard dose adrenaline (1mg) improved rates of survival to hospital admission and return of spontaneous circulation (ROSC) but had no benefit in means of survival to discharge or neurologic outcomes.
What about Amiodarone and Lidocaine?
Kudenchuck et al. now made the effort to look into the efficacy of amiodarone and lidocaine in the setting of OHCA. Used according to the ACLS guidelines 2016 amidarone is given after the third shock applied when treating a shockable rhythm. Two rather small controlled trials have shown so far that using amidarone actually does increase the likelihood of ROSC and the chance to arrive at a hospital alive. It's impact on survival to hospital discharge and neurologic outcome though remains uncertain.
In this randomized, double-blind trial, the investigators compared parenteral amiodarone, lidocaine and saline placebo in adult, non-traumatic, OHCA. They ended up with 3026 patients meeting inclusion criteria and which were randomly assigned to receive amiodarone, lidocaine or saline placebo for treatment. They finally found that neither amiodarone nor lidocaine improved rate of survival to discharge or neurologic outcome significantly. There were also no differences in these outcomes between amiodarone and lidocaine. Across these trial groups also in-hospital care like frequency of coronary catheterisation, therapeutic hypothermia and withdrawal of life-sustaining treatments did not really differ, making a bias due to treatments after admission unlikely.
- This study was not able to show any benefit of amiodarone or lidocaine in the the setting of OHCA in terms of survival to hospital discharge and neurologic outcome
- Amiodarone seems to improve the likelihood of ROSC and survival to hospital admission (similar to adrenaline)
- As there are no other options, I believe amiodarone should remain part of the standard treatment for shockable rhythms in OHCA
- Lidocaine can be safely removed from CPR sets as there is no benefit of over amiodarone
N Engl J Med 2016;374:1711-22
Resuscitation, June 2014, Vol 85, Issue 6, p 732-740
New ACLS Guidelines 2015, The Changes
As posted on BIJC before, Asad et al. had performed a systematic review on the usage of ketamine as a continuous infusion (>24h) in intensive care patients. The same authors have now published a narrative review providing a more depth discussion about the pharmacological and pharmacokinetic properties of ketamine. Also they present recommendations for dosing and monitoring in an ICU setting.
The Goodies of Ket
Current evidence shows that Ketamine...
- Has no adverse effects on the gastrointestinal tract (bleeding) and does not cause acute kidney injury (compared to nonsteroidal anti-inflammatory drungs, NSAID's)
- Does not negatively influence bowel motility (in contrast to opioids)
- Preserves laryngeal protective reflexes
- Lowers airway resistance
- Increases lung compliance
- Is less likely to cause respiratory depression
- Is sympathomimetic, facilitates adrenergic transmission and inhibits synaptic catecholamine reuptake, therefore increasing heart rate and blood pressure
The Concerns of Ket
- Might increase pulmonary airway pressure and therefore aggravate pulmonary hypertension
- Might cause well known psychotomimetic effects which are of concern in the critically ill patient as this might predispose to delirium
- Interacts with benzodiazepines via the P450 pathway which could result in drug accumulation and prolonged recovery
Concerns Proven Wrong
- Ketamine need not to be avoided in patients at risk for seizures, particularly when used for analgosedation for short periods in the ICU setting
- Current evidence shows no increased intracranial pressure or associated adverse neurologic outcomes associated with ketamine administration in critically ill patients
The use of ketamine for analgosedation in the ICU continues to lack high-level evidence.However, it is effectively used around the globe and remains an attractive alternative agent for appropriately selected patients. Taking current knowledge and evidence into account this is especially true for patients with severe pain unresponsive to conventional therapies.
Taking precautions and contraindications into account ketamine is considerably safe and even avoids potentially adverse side effects of other agents used.
Erstad BL, J Crit Care, Oct 2016, Vol 35, p 145-149
Continuous Etomidate Suppresses the Adrenal Gland in a Dose-Dependent Manner - A Potentially Life-Saving Intervention
An endogenous Cushing's syndrome, mostly caused by an adenoma of the pituitary gland, is associated with significant morbidity and mortality when left untreated. The condition is closely associated to life-threatening infections, diabetes mellitus, hypertension and increased risk associated with surgery.
For Cushing's disease the first line therapy is surgical removal of the pituitary tumor. Sometimes though urgent medical therapy is needed first. It has been shown, that surgical risk may be significantly reduced if cortisol concentrations are normalised preoperatively. Conditions requiring urgent cortisol-lowering measures are severe biochemical disturbances (e.g. hypokalaemia), immunosuppression or mental instability.
Medical Treatment Options
Ketokonazole (yes, the antifungal agent) and metyrapone are used to suppress adrenal steroidogenesis at enzymatic sites. Both agents carry the risk of postential side effects. Mifepristone, a glucocorticoid receptor antagonist, and pasireotide, a new targeted pituitary therapy, are alternative agents. However, they also have their limits and side effects.
Now that's where etomidate joins the game. Interestingly, etomidate and ketokonazole are chemically closely related... they are both members of the imidazole family. Etomidate is used as an anaesthetic agent since 1972 and became popular for hemodynamic stability and the lack if histamine release. In 1983 a Lancet article noted an increased mortality when etomidate was used in critically unwell patients. In 1984 an article in Anaesthesia first showed a link to low serum cortisol levels caused by etomidate. Until now the discussion continues, whether a single induction dose actually negatively influences patient outcome. A meta-analysis in 2010 was unable confirm this apprehension and the debate continues.
Etomidate suppresses the production of cortisol by inhibiting the mitochondrial cytochrome p450-dependent adrenal enzyme 11-beta-hydroxylase and therefore lower serum cortisol levels within 12 hours. In higher doses it also blocks side chain cleavage enzymes and also aldosterone synthase. It might even have anti-proliferative effects on adrenal cortical cells.
On this basis the idea arose, that etomidate might be a useful therapy for severe hypercortisolaemia.
Continuous Etomidate - What's the Evidence
A review article by Preda et al. in 2012 identified 18 publications about the primary therapeutic usage of etomidate in Cushing's syndrome, most of which were case reports. Review of current literature reveals that etomidate indeed suppresses hypercortisolaemia safely and efficiently in patients requiring parenteral therapy. Moreover, etomidate shows a dose-dependent suppression and allows adjustment of the medication to target cortisol levels. At recommended dosages etomidate is considered safe with almost no serious side effects.
The authors conclude, that etomidate is a useful therapeutic option in a hospital setting when oral therapy is not tolerated or inappropriate.
- Continuous etomidate (in non-hypnotic doses) reduces cortisol concentrations in a dose-dependent manner in both hyper- and eucortisolaemic subjects
- The application of continuous etomidate in Cushing's disease is safe and efficient
- After termination of infusion adrenocortical suppression persists for about 3 hours
- The suspicion, that a single dose of etomidate for rapid sequence inductions might negatively influence patient outcome in the critically ill remains a matter of debate
J Clin Endocrinol Metab. 1990 May;70(5):1426-30.
Preda et al. European Journal of Endocrinology (2012) 167 137-143 OPEN ACCESS
Soh et al. Letter to the Editor, European Journal of Endocrinology (2012) 167 727–728
Ge et al. Critical Care201317:R20 OPEN ACCESS
Fluids are one of the cornerstones in the treatment of patients with shock. But with any drug applied, also fluids can harm if given inappropriately! While inadequate fluid resuscitation might result in tissue hypoperfusion and worsening of end-organ function, to much fluid might lead to problems like pulmonary oedema and finally increased mortality. Many measures are used in clinical practice, but most of them lack specificity and are not very representative as a sole marker. One of the better methods to evaluate fluid requirements is the use of dynamic measures that estimate the change in cardiac output (CO) in response to a fluid bolus.
In this regard the use of point-of-care ultrasound (POCUS) has become increasingly attractive in order to use basic critical care ultrasound to asses the need of fluids in a specific clinical setting. Lee at al. have now looked at the sonographic assessment of the inferior vena cava and lung ultrasound in order to quite fluid therapy in intensive care. By taking into account current evidence they have produced an algorithm using these measures to help guiding fluid therapy.
As with any measurement in critically ill patients the pathophysiologic cause of shock must be taken into account. The algorithm presented here seems to work best in patients in hypovolemic shock. To fully understand the following algorithm and its limitations we recommend to read the open access article (see link below).
The algorithm provided is a helpful tool to help assess the need of fluids in a simple and quick manner.
Lee C et al. J of Crit Care 31 (2016) 96-100 OPEN ACCESS
Sepsis certainly keeps us going... either when treating patients on ICU or when it comes to the discussion on what actually sepsis is and how to define it. So far the SIRS (Systemic Inflammatory Response Syndrome) criteria have provided some degree of handle to cope with this syndrome but of course we weren't all quite happy with this. In fact every person with any sort of infectious disease will respond with 2 or more SIRS criteria... but doesn't necessarily have to be septic. As a matter of fact a SIRS is nothing else but a physiologic response to any sort of inflammation.
The New Approach to Sepsis - The SOFA
The new international consensus definitions for sepsis and septic shock try to focus on the fact that sepsis itself defines a life-threatening organ dysfunction caused by a dysregulated host response to infection. By saying this the aim is to provide a definition that allows early detection of septic patients and allow prompt and appropriate response. As even a modest degree of organ dysfunction is associated with an increased in-hospital mortality the SOFA score (Sequential or 'Sepsis-related' Organ Failure Assessment) was found to be the best scoring system for this purpose. It's well known, simple to use and has a well-validated relationship to mortality risk.
Sepsis (related organ dysfunction) is now defined by a SOFA score increase of 2 points or more
The Quick Approach to Sepsis - The BAT
In the out-of-hospital setting, on the general wards or in the emergency department the task force recommends an altered bed side clinical score called the quickSOFA - or alternatively 'the BAT' score:
The New Approach to Septic Shock -Vasopressors and Lactate
Septic shock is now defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of death than sepsis alone. Keeping a long story short:
Septic Shock is now:
- The need for vasopressors to maintain a mean arterial pressure of at least 65mmHg
- a serum lactate level of more than 2mmol/L... after adequate fluid resuscitation
The Bottom Line:
The way it looks like we are left with Sepsis and Septic Shock
Severe Sepsis has vanished and the question remains, whether these new definitions will actually benefit the ones that need it most... our septic patients!
Singer M et al. JAMA. 2016;315(8):801-810.
Seymour CW et al. JAMA. 2016;315(8):762-774.
Shankar-Hari M et al. JAMA. 2016;315(8):775-787.
One of the most controversial manoeuvres in anaesthesia and critical care has got some new support since the Difficult Airway Society has published their new guidelines in which they basically continue to support the use of cricoid pressure (CP) for rapid sequence induction. The authors of the Obstetric Anaesthetists' Association and Difficult Airway Society Guidelines for the Management of Difficult and Failed Tracheal Intubation also continue to recommend routine CP, which is considered level 3b evidence.
Surprised on how obstinately CP persists in current guidelines I think that following statement by Priebe HJ is an important reading. It summarises nicely why there is such a disagreement with these recommendations.
He states that
- not a single controlled clinical study provided convincing evidence that the use of cricoid pressure was associated with a reduced risk of pulmon ary aspiration. At the same time, there is good evidence that nearly all aspects of airway management are adversely affected by cricoid pressure
- if cricoid pressure were considered a new airway device, it would not be considered for further evaluation because Level 3B evidence for its efﬁcacy does not exist
- when using cricoid pressure, we may well be endangering more lives by interfer ing with optimal
airway management than we are saving lives by preventing pulmonary aspiration
Priebe HJ, Anaesthesia 2016, 71, 343–351
Want to get more information on the controversy of cricoid pressure? Read here:
Cricoid Pressure for RSI in the ICU: Time to Let GO?
Time to let go? Remarkable article on RSI and Cricoid Pressure
Difficult Airway Society DAS: New Guidelines OUT! Cricoid Pressure still IN?
The discussion on the so called lactic acidosis and its causes has become increasingly interesting over the last couple of years as several biochemical explanations have been challenged. A big confusion persists on the various relationships between lactate, lactic acid and metabolic acidosis.
Most clinicians continue to refer to the classical understanding of impaired tissue oxygenation causing increased lactate production, impaired lactate clearance and therefore resultant metabolic acidosis. Just recently we had a discussion on our ward round on this topic when I was presented the most recent article of UpToDate online on the causes of lactic acidosis. The authors state that 'Lactic acidosis is the most common cause of metabolic acidosis in hospitalised patients' and that 'Lactic acidosis occurs when lactate production exceeds lactate clearance. The increase in lactate production is usually caused by impaired tissue oxygenation...'... finally suggesting that lactate is no good!
These statements support the classical understanding that:
- Hyperlactatemia is caused by tissue hypoxemia, and
- This in turn then leads to a metabolic acidosis called lactic acidosis
This biochemical understanding has persisted for decades but there are some good reasons to strongly challenge this classical aspect on the 'bad' lactate. Lactate turns out to be by far more complex in its characteristics and functions, so I decided to try and make a short but comprehensive overview on this molecule.
What is lactate?
Lactate is a small organic molecule with the chemical formula CH3CH(OH)CO2H and structurally looks like on the image to the left. It is produced in the cytoplasm of human cells largely by anaerobic glycolysis by the conversion of pyruvate to lactate by LDH. This chemical reaction normally results in a blood lactate to pyruvate ratio of about 10:1. And while lactate is produced, NAD+ also is incurred and this actually can accept protons itself, so does not result in acidosis itself.
Lactate arises from the production of energy by consuming glycogen and glucose.