Central anticholinergic syndrome (CAS) was first described in 1966 as an absolute or relative reduction in cholinergic activity in the central nervous system (CNS) produced by anticholinergic or other neuro-modulating drugs.1 The syndrome is caused by blockade of muscarinic acetylcholine receptors.2 Because acetylcholine is a ubiquitous neurotransmitter, with facilitatory and inhibitory actions in many parts of the brain, the blockade of cholinergic neurotransmission may result in alterations in the level of arousal and the response to external stimuli.1 More specific, the symptoms can be categorized as central or peripheral. Central symptoms range from an agitated state (e.g., delirium, restlessness, hallucinations, and/or convulsions) to somnolence, respiratory depression, or coma, whereas peripheral symptoms of CAS entail hypertension, tachycardia and cardiac dysrhythmia, urinary retention, decreased peristalsis, flushed skin, and dry mouth.3 Almost all drugs used in the perioperative setting, as well as in the intensive care unit (ICU), except neuromuscular relaxants, have been reported to cause CAS.4
The reported event occurred in 2008 and we have not succeeded in reaching the patient’s next of kin. Our local IRB has determined that review and written approval for publication are unnecessary as defined by the Danish Act on Research Ethics Review of Health Research Projects.
A 5-year-old boy with a history of cerebral palsy, congenital encephalopathy, microcephaly, and visual and hearing impairment was admitted to the ICU with hypovolemic shock as a result of hematemesis. He was tracheally intubated, his lungs were mechanically ventilated, and he was sedated with hypnotic and analgesic agents (propofol and later midazolam/fentanyl). Concurrently, he was treated with broad-spectrum antibiotics (initially cefuroxime 500 mg × 3 IV, subsequently meropenem 300 mg × 2 IV, ciprofloxacin 150 mg × 3 IV, and metronidazole 300 mg × 1 IV) for aspiration pneumonia. He also received furosemide, clonidine, prednisolone, glucose (50%), and parenteral nutrition during the admission.
On the 10th day of ICU admission, his vital signs were stable with a spontaneous respiratory rate of 33 breaths/min and an arterial oxygen saturation of 95% (mechanically ventilated; pressure support modus; fraction of inspired O2 0.40), arterial blood pressure 95/55 mm Hg, and heart rate 115 beats/min. Based on his body weight (16.8 kg), he was given 0.1 mg glycopyrrolate to treat excessive saliva production and immediately became agitated and subsequently developed apnea and loss of consciousness, as evaluated bedside by the attending consultant. His arterial oxygen saturation decreased to the range of 88% to 92% despite manual ventilation and 100% inspired oxygen, and there was a significant increase in blood pressure and heart rate (170/150 mm Hg and 155 beats/min, respectively), together with complete absence of urine production for 1 hour (evaluated via a preexisting urinary catheter). In the 24 hours preceding this event, his FIO2 varied between 0.28 and 0.50 (being approximately 0.30 most of the time), and his arterial oxygen saturation was in the range of 88% to 98%, hence it was not common for him to experience severe desaturations despite a diagnosis of aspiration pneumonia. The case was not initially recognized as CAS and thus he was given 1 mg midazolam, which sedated him. The symptoms were subsequently interpreted as CAS, and glycopyrrolate was discontinued immediately, whereafter the symptoms subsided. He did not develop further symptoms of CAS during the admission, but his clinical condition deteriorated and he died 2 days later due to acute respiratory distress syndrome after aspiration.
CAS is a rare syndrome caused by a variety of chemical compounds that cross the blood-brain barrier (BBB) and elicit anticholinergic actions. Acetylcholine is an omnipresent transmitter in the CNS and works by activating 2 types of receptors: nicotinic and muscarinic receptors, the latter being associated with CAS. Drugs with anticholinergic properties may act directly as competitive muscarinic antagonists or indirectly by decreasing the synthesis or release of acetylcholine or may modulate other neurotransmitters that reduce cholinergic activity in the postganglionic neurons of the autonomous nervous system.3 The autonomous nervous system, in particular, is abundant with muscarinic receptors, being the preganglionic receptors of the sympathetic nerve system, as well as both the preganglionic and postganglionic receptors of the parasympathetic nerve system. Therefore, many of the symptoms seen in CAS are symptoms of reduced vagal tone.
More than 600 pharmacologic substances have anticholinergic properties (available at: http://www.uptodate.com/contents/anticholinergic-poisoning; accessed February 20, 2015), of which the most common are shown in Table 1, and almost all drugs used in the perioperative setting have been reported to induce CAS.4 These include not only the tertiary amines atropine and scopolamine, which are most commonly associated with anesthesia-related CAS, but also fentanyl, midazolam, ketamine, etomidate, propofol, and halogenated inhaled anesthetics.5,6 CAS as a consequence of glycopyrrolate, however, is extremely rare and has only been reported once in 1991.6 Glycopyrrolate is a quaternary ammonium compound and is characterized by a very limited ability to penetrate the BBB and is therefore considered devoid of CNS effects.6 However, studies have shown that although penetration of glycopyrrolate across the BBB is poor, it is not completely absent.7 Furthermore, in patients with sepsis, where the integrity of the BBB may be disturbed,8 drugs that do not readily cross the BBB could be able to do so.
The incidence of CAS has been reported to be 10% and 4% after general and regional anesthesia, respectively.9 A prospective study including 962 patients reported an incidence of 1.9% after routine general anesthesia.4 The incidence in the ICU setting, however, has never been investigated, but it has been proposed that it may exceed the incidence in both general and regional anesthesia because of the frequent use of multiple anticholinergic drugs.10
Central and peripheral symptoms associated with CAS are summarized in Table 2. It has been reported that CNS depression predominates in adults, whereas agitation is the dominant feature in children.11 In the present case, both central (i.e., agitation, apnea, and loss of consciousness) and peripheral symptoms (i.e., hypertension, tachycardia, and anuria) were present simultaneously.
Diagnosis is usually based on clinical symptoms of reduced vagal tone followed by complete resolution of symptoms on administration of a cholinesterase inhibitor (i.e., physostigmine).3 Unfortunately, a cholinesterase inhibitor was not administered in the present case because the patient’s symptoms quickly subsided after discontinuation of glycopyrrolate, and although suggestive of CAS, the present event could have been the result of a more common (“man-made”) mistake, that is, the wrong medication or wrong dose was administered. Accordingly, the rate of medication errors may be as high as 20%, as suggested by a systematic review including 91 studies12 and therefore needs to be considered a possibility.
Relevant differential diagnoses for CAS entail other reasons for altered mental state, such as neurological events, pain, deep sedation, hypoxia, hypercapnia, electrolyte or acid-base imbalances, hypoglycemia, embolism, and hemorrhage. However, none of these were suspected or evident in this patient to an extent that could have explained his sudden development of symptoms.
Symptoms of CAS can easily be interpreted as prolonged action of anesthetics4; therefore, CAS may often be overlooked, and it has been called the “forgotten diagnosis.”3 The reasons for this are probably the diverse, nonspecific signs and doctors’ lack of awareness of the syndrome.5 Although the present case describes a rare cause of CAS, it nevertheless serves as an important reminder of an iatrogenic condition that may be encountered after administration of several drugs used on an everyday basis in the operating theater or in the ICU. When CAS is suspected, physostigmine may be administered to reverse the symptoms and thereby confirm the diagnosis.
1. Longo VG. Behavioral and electroencephalographic effects of atropine and related compounds. Pharmacol Rev. 1966;18:965–96
2. Schneck HJ, Rupreht J. Central anticholinergic syndrome (CAS) in anesthesia and intensive care. Acta Anaesthesiol Belg. 1989;40:219–28
3. Moos DD. Central anticholinergic syndrome: a case report. J Perianesth Nurs. 2007;22:309–21
4. Link J, Papadopoulos G, Dopjans D, Guggenmoos-Holzmann I, Eyrich K. Distinct central anticholinergic syndrome following general anaesthesia. Eur J Anaesthesiol. 1997;14:15–23
5. Katsanoulas K, Papaioannou A, Fraidakis O, Michaloudis D. Undiagnosed central anticholinergic syndrome may lead to dangerous complications. Eur J Anaesthesiol. 1999;16:803–9
6. Grum DF, Osborne LR. Central anticholinergic syndrome following glycopyrrolate. Anesthesiology. 1991;74:191–3
7. Proakis AG, Harris GB. Comparative penetration of glycopyrrolate and atropine across the blood–brain and placental barriers in anesthetized dogs. Anesthesiology. 1978;48:339–44
8. Davies DC. Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat. 2002;200:639–46
9. Rupreht J, Dworacek B. Central anticholinergic syndrome in anesthetic practice. Acta Anaesthesiol Belg. 1976;27:45–60
10. De Keulenaer BL, Philpot S, Wilkinson M, Stephens DP, DeBacker A. Central anticholinergic syndrome in the intensive care unit. Eur J Anaesthesiol. 2004;21:499–501
11. Richmond M, Seger D. Central anticholinergic syndrome in a child: a case report. J Emerg Med. 1985;3:453–6
12. Keers RN, Williams SD, Cooke J, Ashcroft DM. Prevalence and nature of medication administration errors in health care settings: a systematic review of direct observational evidence. Ann Pharmacother. 2013;47:237–56