Adrenaline (Epinephrine)

Cardiac dysrhythmias

Ventricular dysrhythmias have been reported in a case of adrenaline overdose [ ].

• A 5-year-old boy was given subcutaneous adrenaline 1:1000 after a severe allergic reaction to a bee sting. Inadvertently, 10 times the correct dose was given. He developed extra beats and two brief runs of ventricular tachycardia, but recovered fully after about 20 minutes. Creatine kinase activity, both total and the MB fraction, was slightly raised in this patient (total 603 IU/l, MB fraction 161 IU/l; upper limits of the local reference range 243 and 15 IU/l), suggesting cardiac damage.

Life-threatening torsade de pointes has been observed when an epidural anesthetic was given using 20 ml of bupivacaine containing only 1:200 000 adrenaline [ ].

Injection of adrenaline into the penile skin can cause genital ischemia (see also Reproductive system below) [ ].

Adrenaline is occasionally used as a hemostatic agent, with rare complications. However, they do occur, as noted in a report from Lyon [ ].

• A 64-year-old man with diabetes and hypertension bled from a site in the lower rectum. A local injection of adrenaline 0.2 mg successfully stopped the hemorrhage, but very soon after he became hypotensive, with rapid atrial fibrillation (ventricular rate not given), the first time he had experienced this. He reverted spontaneously to sinus rhythm within 24 hours.

The authors suggested that if this type of procedure is contemplated in elderly patients with cardiovascular disease an anesthetist should be present to monitor cardiovascular status; it may in any case be wiser to avoid adrenaline altogether in favor of other means of hemostasis.

Hypotension

Local administration of adrenaline can cause serious problems. For instance, a solution containing lidocaine + adrenaline is widely used for scalp infiltration before craniotomy. A group in China have compared the hemodynamic effects of scalp infiltration of 1% lidocaine (16 ml) combined with adrenaline 40, 80, or 160 micrograms, or no adrenaline at all (n = 40 in each group) [ ]. In each of the adrenaline-treated groups there was a similar and significant fall in mean arterial pressure of 17–19 mmHg at 1.5 minutes after administration, with full recovery by 3 minutes. Heart rate increased by about 12/minute over the same time. It is important that clinicians are aware that this is likely to happen and do not attempt to treat a self-limiting response, although in some patients even this brief period of hypotension can be hazardous.

In a double-blind, randomized, controlled study 84 adults undergoing endoscopic sinus surgery under general anesthesia were randomly allocated to local nasal 1% lidocaine 4 ml with different doses of adrenaline, 0, 20, or 40 micrograms [ ]. Adrenaline significantly reduced mean arterial pressure and systemic vascular resistance index and increased heart rate, cardiac index, and acceleration index.

An unusual site of adrenaline injection has been described in a Canadian report [ ].

• A 79-year-old woman developed pituitary apoplexy in an adenomatous gland and was being prepared for trans-sphenoidal hypophysectomy. Topical adrenaline (1:1000) was applied to both nostrils and then 1.5 ml of 1% lidocaine containing 1:100 000 adrenaline was injected into the nasal mucosa. The blood pressure immediately rose from 100/50 to 230/148 mmHg and the pulse rate from 48 to 140/minute. Although she was treated immediately with esmolol and intravenous glyceryl trinitrate, resulting in normalization of her blood pressure, subsequent investigations showed that she had had a painless myocardial infarction. She made a full recovery after pituitary surgery.

The authors suggested that if adrenaline is to be used in such cases, even lower concentrations might be advisable. This is reasonable, although one also wonders in this case whether her blood pressure may have been lowered too rapidly.

Cardiomyopathy

Stress cardiomyopathy (takotsubo cardiomyopathy, “broken heart syndrome”, or “gebrochenes Herz Syndrom”), was first described in Japan in the early 1990s [ ] and has been reviewed [ ]. “Tako tsubo” means “octopus trap” in Japanese. The EIDOS and DoTS descriptions are shown in Figure 1 .

Mechanism : In various observational studies of this type of cardiomyopathy there was an association with raised catecholamine concentrations [ ]. There have also been several reports following severe emotional stress [ , ], in patients with pheochromocytomas, both adrenal [ ] and extra-adrenal [ ], and in patients who have been given catecholamines [ ]. In five consecutive patients with takotsubo-like left ventricular dysfunction there was local release of noradrenaline from the heart as measured in blood taken from the aortic root and coronary sinus [ ].

Indirect effects of drugs on catecholamines have also resulted in takotsubo syndrome. In one case there was transient typical ballooning of the left ventricular apex during systole following the use of cocaine, thought to have been due to inhibition of catecholamine reuptake [ ]. A 43-year-old woman who took an overdose of venlafaxine, an inhibitor of serotonin and noradrenaline reuptake, developed a takotsubo cardiomyopathy and there was an increase in urinary normetadrenaline (normetanephrine) concentration [ ].

Irukandji syndrome, which follows a sting from the jellyfish called Carukia barnesi , found in Far North Queensland, Australia, presents with sympathetic overdrive, with direct pressor effects and tachycardia secondary to sudden release of endogenous noradrenaline and adrenaline; it can include stress cardiomyopathy [ ].

Cases of takotsubo cardiomyopathy reported after anaphylaxis [ ] may in fact have been, at least in part, due to catecholamines given as part of treatment [ ].

Catecholamines do not improve function in the apical ballooning syndrome and may make it worse. In 11 patients an infusion of low-dose dobutamine did not improve the akinetic wall motion, despite the hypercontractile basal left ventricular wall, and despite the fact that the syndrome is reversible [ ]. In other cases, takotsubo syndrome was worsened by infusion of catecholamines (in one case adrenaline, dobutamine, and noradrenaline and in another dopamine) and improved when the catecholamines were withdrawn [ , ]; beta-blockade was beneficial.

The mechanism is presumed to be mediated by adrenoceptors, since in animals the reaction is significantly attenuated by pretreatment with alpha- and beta-adrenoceptor antagonists. It has been hypothesized that high concentrations of circulating adrenaline, by an action on beta ₂ -adrenoceptors, trigger a switch in intracellular signal trafficking in ventricular cardiomyocytes, from G(s) protein to G(i) protein signalling [ ]. Although G(i) protein signalling protects against the apoptotic effects of intense activation of beta ₁ -adrenoceptors, it is also negatively inotropic. This effect is greatest in the apical myocardium, in which the beta-adrenoceptor density is greatest. It is not known what role vasospasm plays. Most cases occur in postmenopausal women, for reasons that are not understood. However, there have also been reports in younger patients [ , ], particularly after catecholamine overdose [ ].

Diagnosis : The diagnosis depends on four criteria [ ]:

• 1.

  ST segment changes or T wave inversion.

• 2.

  Transient wall motion abnormalities that are often inconsistent with coronary anatomy.

• 3.

  Absence of obstructive coronary artery disease or evidence of acute plaque rupture.

• 4.

  Absence of significant head trauma, intracranial hemorrhage, pheochromocytoma, or other causes of myocardial dysfunction.

Myocardial edema with consequent regional wall thickening has been seen using magnetic resonance imaging [ ].

Varieties : There are three main types: left ventricular apical ballooning (classical takotsubo cardiomyopathy), an inverted or reverse variant (basal akinesis with a hyperdynamic apex, also called “the artichoke heart”), and a midventricular variant.

Reports : Stress cardiomyopathy has been described in six patients after infusion of adrenaline and in three patients after infusion of dobutamine [ ]. No obstructive coronary artery disease was demonstrated in any patient and follow-up was uneventful, with return to normal hemodynamics and echocardiography. A 27-year-old man also developed transient left ventricular dysfunction resembling takotsubo syndrome after self-injection of adrenaline [ ] and a 41-year-old woman developed takotsubo syndrome after receiving two doses of intravenous adrenaline 500 micrograms for an anaphylactic reaction to a bee sting [ ]. Takotsubo cardiomyopathy was also reported in a 62-year-old man with non-topic severe persistent asthma and chronic obstructive disease, who received repeated subcutaneous injections of adrenaline (300 micrograms 8 times in 4 hours) for severe asthma [ ].

Reverse takotsubo cardiomyopathy has also been attributed to adrenaline in a 24-year-old woman with no previous history of cardiac disease [ ].

Reversible severe left ventricular systolic dysfunction with apical ballooning has also been reported during dobutamine stress echocardiography [ ] and also in one case after recovery from stress echocardiography [ ]. In one case it occurred in a patient with previous orthotopic heart transplantation [ ]. In another case it occurred in a patient who had had a subarachnoid haemorrhage [ ], in which sympathetic nervous system activity is increased and in which acute myocardial infarction can also occur.

Almost all cases after exposure to catecholamines have occurred acutely. However, in one case a dilated cardiomyopathy was attributed to chronic overexposure to inhaled adrenaline [ ].

• A 44 year old man, who had had asthma since childhood, and who was taking Franol (ephedrine hydrochloride 11 mg + phenobarbital 8 mg + theophylline 120 mg) tds and using a Brovon inhalant spray (0.5% adrenaline + 0.14% atropine methonitrate + 0.88% papaverine hydrochloride) as required, developed a dilated cardiomyopathy. He had been using the inhaler up to 40 times a day and had done so for 20 years. The inhaler and tablets were withdrawn and he improved with conventional management of asthma and heart failure.

Digital ischemia

Vasospasm has also been reported after accidental digital injection of adrenaline, reversible by the non-selective alpha-adrenoceptor antagonist phentolamine [ ]. Other cases have been reported.

• A 41-year-old woman accidentally injected adrenaline 0.3 mg into her own thumb while trying to inject into her son [ ]. She experienced severe pain and observed progressive pallor and coldness extending proximally from the end of her thumb to the wrist and forearm over the next 30 minutes. Two rounds of glyceryl trinitrate paste were applied to the area over the next hour, but without improvement, after which hot packs proved beneficial. She did not recovered full circulation until the next morning.

• A 37-year-old woman, trying to wrestle an Epipen from her 3-year-old son, was accidentally stuck in the palmar aspect of the distal right index finger, presumably injecting all or most of the dose (0.15 mg) [ ]. Within a few minutes, she developed pain and pallor throughout the finger, but the symptoms resolved within 2 hours without intervention.

• A 5-year-old boy accidentally injected adrenaline 0.15 mg into a finger [ ]. He was treated with subcutaneous phentolamine 0.15 mg in 0.5 ml isotonic saline at the site of accidental injection and finger circulation was restored within 20 minutes. He had a headache, nausea, and vomiting after 30 minutes, probably due to the phentolamine. No other complications occurred.

In a review of 26 reports of unintentional injection of adrenaline from an autoinjector in 69 people, 63 sustained injury to a finger or thumb [ ]. More than 65% of the 69 individuals were evaluated in an emergency department. Nine were not; in 17 the injured part was warmed; six were treated with glyceryl trinitrate paste and 15 with local injections of phentolamine and/or lidocaine. No permanent sequelae were reported.