Epinephrine is a catecholamine produced by the adrenal glands and has actions on nearly all cell types in its role as a hormone and neurotransmitter. Epinephrine acts upon p1 and p2 adrenergic receptors. It produces the ‘fight or flight’ response; namely, increased cardiac output and bronchodilation (Bylund et al, 1994).
In lower doses, the p receptors are stimulated preferentially resulting in smooth muscle relaxation, peripheral vasodilatation and hypotension. Higher doses result in stimulation of peripheral alpha-receptors resulting in an increase in peripheral vascular resistance and elevation of blood pressure (Davis et al, 2008).
It was first artificially synthesized in 1904 by Friedrich Stolz (original paper reviewed by Brucke, 1954) and since that time has become a key tool in managing critically unwell patients. Its role in a diverse range of conditions is well documented, from respiratory problems such as croup (Bjornson et al, 2011) and anaphylaxis (Simons and Simons, 2010) to cardiac arrest victims (Morley, 2011).
The routes of administration of the drug are varied. It can be given as a nebulizer; down an endotracheal tube; subcutaneously; intramuscularly or intravenously. It cannot be given orally as it is degraded by gut enzymes and then metabolized in the liver to inactive metabolites. Subcutaneous or intramuscular injection may result in delayed absorption due to local vasoconstriction. Massage of the designated area can speed up its rate of onset (Simons and Simons, 2010).
In this article, we will review the evidence-base behind the use of epinephrine in acute asthma and discuss when it may be appropriate to administer it prehospital.
Case study
A 41-year-old Caucasian female was admitted to the emergency department, via blue-light ambulance, following an episode of acute dyspnoea associated with wheeze. She had no recent history of cough, sputum production, fevers or rigors. No steroids or antibiotics had been prescribed by the general practioner preadmission.
The paramedic team made a diagnosis of life-threatening asthma. She was given 15 litres of oxygen via non-rebreathe face mask, salbutamol and ipratropium bromide nebulizers. In line with UK Resuscitation Council and Joint Royal Colleges Ambulance Liaison Committee (JRCALC) guidelines (2006), she was also given 0.5 mg intramuscular epinephrine. On arrival to the hospital, she had improved—she was not dyspnoeic, was afebrile and normotensive. Oxygen saturations were 98% while breathing room air. Chest auscultation revealed good air entry bilaterally and no wheeze. There were no specific signs of infection or anaphylaxis.
The initial blood tests demonstrated an elevation in her inflammatory cells with a total white cell count of 35.5. The differential count revealed neutrophils of 27 and lymphocytes of 5.8. Her C-reactive protein (CRP) was <5 and her chest X-ray did not reveal any focal consolidation or pneumothorax. The abnormal differential white cell count was confirmed by a haematologist, but she otherwise had a normal blood film. This raised the question of whether her raised white cell count reflected an infective exacerbation of asthma or had another origin. In the absence of infective symptoms such as fever or cough productive of sputum, she was not given any antibiotics.
Further observation over the next twenty-four hours was unremarkable and subsequent blood tests the next day revealed that her white cell count had normalized. She rapidly recovered from her asthma exacerbation and was discharged after twenty-four hours. On discussion with the haematologist, it was decided that her initial leukocytosis was a direct result of epinephrine administration. This is a rare but recognized complication, as will be discussed further in this article.
Discussion
Acute severe asthma
Asthma remains a condition associated with a significant mortality rate and affects individuals who are otherwise fit and well. Approximately 2000 people die per year in the UK (JRCALC, 2006). The risk of a fatal outcome can be reduced by effective early treatment (Delbridge et al, 2003).
Confidential enquiries into asthma mortality have shown that the majority of deaths occur prehospital (Mohan et al, 1996). This is likely due to the fact that patients who are seen in the emergency department will have already been stabilized by initial treatment from the paramedic.
Adverse outcomes are associated with the failure of assessing clinicians to respond appropriately to worsening asthma symptoms. It is therefore vital for paramedics to recognize which individuals are at risk of a fatal outcome to allow early and effective treatment. The severity of an attack can be assessed using the clinical parameters summarized in Table 1. It is also important to recognize that asthma is a dynamic illness and patients have the potential to deteriorate rapidly even if initial symptoms did not appear severe.
Initial resuscitation always involves using an ABC approach to the patient and early use of P2 agonist therapy; such as nebulized salbutamol. The goal is to rapidly reverse airflow obstruction and ensure adequate oxygenation. Intravenous access and cardiac monitoring should be instituted in acute severe asthma.
There are several published treatment algorithms on the treatment of acute asthma (JRCALC, 2006; UK Resuscitation Council, 2010; British Thoracic Society (BTS), 2011). In this article, we look at the drug treatments common to these major treatment pathways. In particular, we are focusing on the role of epinephrine in acute severe or life-threatening asthma.
Drug treatments
Oxygen
The guidelines for the use of oxygen in the treatment of acute asthma produced by the BTS (O'Driscoll et al, 2008) emphasize the importance of oxygen therapy. Oxygen must be given to all patients with asthma who are hypoxaemic, aiming to maintain oxygen saturations between 94 and 98%. Lack of pulse oximetry should not preclude the use of oxygen.
Where possible, nebulizer therapy should be oxygen-driven, but if it were not available (for example, in a GP surgery) then lack of availability should not prevent nebulizer use.
Beta-2 agonists
Paramedics will be familiar with β-2 agonists such as salbutamol. Most commonly, this is administered in inhaled or nebulized form, but it can also be administered intravenously in the treatment of life-threatening asthma (Travers et al, 2002). Beta-adrenergic agonists are the most important step in the treatment of the bronchospasm associated with acute asthma. They exert their effects by binding to beta-adrenergic receptors on the cell membrane with a subsequent rise in intracellular cyclic adenosine monophosphate (cAMP). This has the result of decreasing the myoplasmic calcium concentration that then causes bronchial smooth-muscle relaxation allowing the bronchial airways to open (Levitzki, 1988).
Nebulizer therapy is widely used in the prehospital environment and the emergency department. This is despite the fact that numerous studies show that a metered dose inhaler (MDI) combined with a spacer chamber is therapeutically equivalent (Turner et al, 1988; Rodrigo and Rodrigo, 1998; Newman et al, 2002). The combination of an MDI with spacer is less expensive, easier to administer, and provides an opportunity to assess whether the patient is using the device correctly.
However, if the patient is acutely dyspnoeic, they may find nebulized therapy easier to tolerate and it provides the additional benefit of allowing concomitant oxygen delivery.
The evidence regarding the utility of intravenous β-agonists is limited. A recent meta-analysis examining the effectiveness of intravenous β-2 therapy in the emergency department found no additional benefit over nebulized therapy and may produce increased adverse effects such as tachyarrythmias (Travers et al, 2002). Parenteral β-2 agonists may be preferable to nebulized in ventilated patients in extremis, but there is little evidence to support this. The routine use of intravenous β-2 agonists is not recommended in prehospital practice.
Ipratropium bromide
Ipratropium bromide is an anticholinergic agent which acts by antagonizing the action of acetylcholine at the postganglionic parasympathetic receptor. This results in a reduction of vagus nerve mediated bronchospasm in the larger airways (Pakes et al, 1980).
The use of ipratropium nebulizers in chronic obstructive pulmonary disease (COPD) is well recognized (Soto and Varkey, 2003). Its role in acute severe asthma has become more widely accepted in recent years. Current JRCALC guidelines (2006) and the newly updated BTS guidelines (2011) encourage its use.
A meta-analysis of 32 randomized control trials (Rodrigo and Castro-Rodriguez, 2005) evaluated the role of inhaled ipratropium in patients with moderate to severe asthma exacerbations in the emergency department. The authors found there was a reduction in hospital admission rate and also improvement in the spirometric parameters 1–2 hours post-administration in patients treated with inhaled anticholinergics. Anticholinergic bronchodilation peaks within 1–2 hours—therefore simultaneous treatment with β-adrenergic agents and anticholinergics may produce an additive effect.
Corticosteroids
Steroids play a vital role in the management of acute asthma. When corticosteroids are administered within one hour of an acute exacerbation, hospital admission and subsequent readmissions are reduced (Edmonds et al, 2001).
However, there is still ongoing debate as to whether steroids should be given prehospital in acute asthma.
The recent BTS guidelines (2011) have recommended giving steroids to all acute asthma exacerbations, although the timing for administration is not specified. The JRCALC guidelines (2006) do not put such emphasis on their use, they recommend prehospital administration only if arrival time to hospital is greater than thirty minutes.
Both sets of guidelines emphasize that early administration of corticosteroids is preferred, if they are to be given, as the therapeutic effect of corticosteroids will not peak until four to six hours post-administration.
Provided the patient can take medications via the oral route, there is no evidence that parenteral steroids are any more effective than oral tablets (Edmonds et al, 2001). In practice, however, intravenous steroids (200 mg hydrocortisone) are often given as first-line therapy, due to the patient's dyspnoea and to prevent breaks in oxygen therapy. While the exact mechanism of action of corticosteroids in asthma is unclear, one theory proposes a reduction of airway inflammation, as well as restoration of P-adrenergic responsiveness in the constricted airways. They also suppress the immune system response by decreasing the formation of chemical mediators such as prostaglandins and leukotrienes (Dimeloe et al, 2010).
‘There is still ongoing debate as to whether steroids should be given prehospital in acute asthma’
Epinephrine
Current recommendations for the use of epinephrine in life-threatening asthma are found in the JRCALC guidelines (2006). It must be emphasized that it is not a first-line agent and its use should be reserved for patients who are critically unwell and not responding to other measures (Quadrel et al, 1995).
The dosing of epinephrine is very important as its actions on alpha and beta receptors are dose dependent (Davis et al, 2008). The usual dose is 500 mcg (0.5 ml of epinephrine 1/1000) by intramuscular or subcutaneous injection. This dose may be repeated several times at 5-minute intervals according to blood pressure, pulse and respiratory function.
Nebulized epinephrine
Several small randomized controlled trials have looked at the efficacy and safety of nebulized epinephrine vs a nebulized P-2 agonist. The results from a meta-analysis of this data suggests that nebulized epinephrine is as safe and effective as nebulized P-2 agonists (Rodrigo et al, 2006).
The overall data did suggest, however, that to reach parity with P-2 agonists, nebulized epinephrine had to be given at high doses (e.g. 2 mg nebulized epinephrine). This has the potential to be associated with more severe side-effects. Given the lack of superiority of epinephrine and familiarity with their use, P-2 agonists remain the first-line recommended treatment.
Endotracheal epinephrine
Occasionally, despite effective treatment, a patient's condition becomes so severe that they are at risk of cardio-respiratory arrest and the decision is made to intubate the patient. Signs that would suggest this include: increasing drowsiness, a silent chest on auscultation, and a rising pCO2 on arterial blood gas sampling.
| The patient is suffering from life-threatening asthma |
| Ventilation is failing |
| Deterioration continues despite oxygen and continuous nebulized therapy. |
‘The dosing of epinephrine is very important as its actions on alpha and beta receptors are dose dependent’
A trial of endotracheal epinephrine administration in patients who had suffered respiratory arrest secondary to severe asthma found no benefit (Nutbeam and Fergusson, 2009). It is not currently recommended in Resuscitation Council Guidelines (2010).
Subcutaneous epinephrine
The JRCALC guidelines advocate the use of subcutaneous or intramuscular epinephrine in life-threatening asthma. This approach is not shared by the BTS 2011 guidelines which make no mention of the use of subcutaneous epinephrine in acute asthma. The discrepancy arises over concerns about its clinical safety.
Trials of subcutaneous epinephrine have shown it can be as efficacious as nebulized salbutamol (Baughman et al, 1984; Sharma and Madan, 2001) in the treatment of life-threatening asthma. The safety concerns surround the potential for cardiac dysrhythmia and myocardial ischaemia, which are discussed further below. A review of all published studies on the use of subcutaneous epinephrine in asthma (Safdar et al, 2001) found only three case reports of adverse incidents. Currently, however, the use of subcutaneous epinephrine remains reserved for life-threatening asthma in which severe bronchoconstriction is likely to render administration of nebulized medication ineffective.
Intravenous epinephrine
The use of intravenous adrenaline is not recommended prehospital in patients who are not in cardiac arrest. This, again, is due to the risk of life-threatening arrhythmias or profound hypotension. In experienced hands, it can be a vital tool in preventing death from cardiorespiratory arrest, but only in controlled circumstances with full cardiac monitoring.
Anaphylaxis
Acute severe asthma can present in a similar way to anaphylaxis, making differential diagnosis difficult. This initial presentation can include respiratory wheeze and upper airway oedema. Epinephrine can be administered in either scenario since it promotes bronchodilation and inhibits mast cell degranulation, thus reducing laryngeal oedema (Rainbow and Browne, 2002). If there is any clinical suspicion that the underlying diagnosis is anaphylaxis with respiratory compromize, then administration of epinephrine should not be delayed.
Epinephrine side-effects
Routine use of epinephrine has not been recommended on the basis of potentially severe side-effects outweighing any therapeutic benefit. The potential side-effects of epinephrine administration are noted in Table 3.
| Common/benign |
| Tremor |
|
Serious/rare side-effects
|
Symptoms are usually transient and not severe, but can occur even when used responsibly and in suitable patients. The major concern with the use of parenteral epinephrine is the potential to cause life-threatening cardiac arrhythmias.
Caution is particularly required with patients with coronary artery disease or known history of arrhythmias.
Two studies have looked at the safety of intravenous epinephrine in the emergency department setting (Smith et al, 2003; Putland et al, 2006). The larger of the two studies (Putland et al, 2006) looked at over two hundred patients admitted with a diagnosis of asthma given intravenous epinephrine and found that adverse events occurred in nearly one third of patients.
However, the vast majority of these were minor and self-limiting.
No deaths occurred and major effects were noted in less than 4% of patients. These were mainly effects on the myocardium and ranged from supraventricular tachycardias (commonly) to epinephrine-induced myocardial ischaemia. This study did, however, exclude patients over the age of 55 who may be more vulnerable to cardiogenic toxicity due to a higher prevalence of coronary artery disease (Putland et al, 2006).
The second smaller study (Smith et al, 2003) found no adverse incidents with the use of intravenous epinephrine, but only twenty-seven patients were assessed and the oldest patient was fifty-eight years of age.
One study has assessed the safety of subcutaneous epinephrine in patients up to the age of 98 who presented with severe asthma (Cydulka et al, 1998). This did not find any significant difference in arrhythmic events in the over 40 age group, compared to the less than 40 age group. This was using subcutaneous epinephrine at a lower dose and the study excluded any patients suffering from known coronary artery disease or angina.
Epinephrine-induced leukocytosis
As well as these common side-effects, the case report described above highlights the importance of being aware of less common side-effects.
It is well known that epinephrine can cause an acute neutrophilia, but induction of leukocytosis is less common. It is postulated that this may occur by two different mechanisms. Under normal physiological conditions, a pool of leukocytes exists which adhere to vascular endothelium, these can be rapidly released into the circulating blood by specific stimuli such as increased epinephrine levels. Increasing blood flow to the pulmonary vasculature may also result in mechanical demargination of these intravascular non circulating leukocytes (Enberg et al, 1986)
It is important to be aware of this effect as it can falsely suggest infection and may lead to unnecessary antibiotics, prolonged hospital stay and the subsequent risks associated with this.
Conclusion
Parenteral epinephrine has a role to play in the treatment of life-threatening asthma and paramedics should be familiar with its use. However, the scientific literature does not promote its efficacy above P-2 agonists which should remain the first-line treatment along with oxygen therapy. The use of epinephrine remains reserved for life-threatening asthma in which significant bronchoconstriction is likely to be rendering effective administration of nebulized medication ineffective. When giving any medication, it is important to know the common side-effects and also be able to interpret results in the light of known, albeit rare, side-effects of a commonly given medication.