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American Journal of Critical Care. 2008;17: 593-596
Copyright © 2008 by the American Association of Critical-Care Nurses.
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Cases of Note features peer-reviewed case reports and case series that document clinically relevant findings from critical and high acuity care environments. Cases that illuminate a clinical diagnosis or a management issue in the treatment of critically and acutely ill patients and include discussion of the patient’s experience with the illness or intervention are encouraged. Proposals for future Cases of Note articles may be e-mailed to ajcc{at}aacn.org.

Mimicking of Cerebral Herniation Through {gamma}-Hydroxybutyric Acid Therapy

By M. Klein, MD, J. Remi, MD, H.W. Pfister, MD, A. Straube, MD, T.A. Rupprecht, MD, S. Weckbach, MD and T. Pfefferkorn, MD. M. Klein, J. Remi and T. A. Rupprecht are residents, H. W. Pfister and A. Straube are professors, and T. Pfefferkorn is a fellow in the Department of Neurology, Klinikum Großhadern, Ludwig-Maximilian University, Munich, Germany. S. Weckbach is a resident in the Department of Radiology, Klinikum Großhadern, Ludwig-Maximilian University.

Corresponding author: Matthias Klein, MD, Department of Neurology, Neurologic Intensive Care Unit, Ludwig-Maximilian University, Marchioninistr. 15, 81377 Munich, Germany (e-mail: matthias.klein{at}med.uni-muenchen.de)


   Abstract
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 Abstract
Patient 1
 Patient 2
 Discussion
 References
 
Besides being a treatment option for narcolepsy, {gamma}-hydroxybutyrate is used as an adjuvant during anesthesia in Europe. In addition, it is illegally used as a recreational drug. Fixed and dilated, asymmetric pupils developed in 2 patients during continuous therapy with intravenous {gamma}-hydroxybutyrate, which was added to the long-term anesthetics fentanyl and midazolam. Cerebral herniation as an alternative cause for the pupillary changes was ruled out by using continuous intracranial pressure monitoring and computed tomography. In both patients, the pupillary abnormalities resolved after discontinuation of {gamma}-hydroxybutyrate. Thus, fixed and dilated pupils that are asymmetric seem to be an important side effect of {gamma}-hydroxybutyrate therapy that may mimic cerebral herniation in deeply anesthetized patients.

Intravenous {gamma}-hydroxybutyrate (GHB) produces hypnosis, sedation, and anxiolysis and can be used as an adjuvant to general anaesthesia.1,2 Oral GHB reduces the number of cataplectic attacks and improves sleep fragmentation in patients with narcolepsy3,4 and can be useful in the management of opioid and alcohol withdrawal.5 However, GHB is also abused as a recreational drug, and thus patients with GHB intoxication are treated in emergency departments.6–8 Because of the cases of abuse and the addictive potential of GHB, sale of the drug was banned by the Food and Drug Administration in the United States in 1990. Although GHB is still available as an adjunct for anesthesia in Europe, it was approved solely for treatment of narcolepsy in the United States in 2000. A variety of illicit forms of GHB are available under names such as G, liquid ecstasy, grievous bodily harm, Georgia home boy, liquid X, soap, easy lay, salty water, scoop, cherry meth, and nitro.6

GHB is an endogenous molecule that is thought to act as a neuromodulator or neurotransmitter in the mammalian brain. Two receptors, the {gamma}-aminobutyric acidB (GABAB) receptor and a GHB receptor, have been detected in the brain. GHB exerts its effects either directly or indirectly through GABAB after direct conversion or triggering of GABAB release.6,9 High levels of GHB that occur after exogenous administration lead to sedation, hypnosis, and anesthesia.10 Both its euphorigenic and its relaxant properties are reasons for the recreational use of GHB for pleasure enhancement, as a sleep aid, and as a date rape drug.11 For anesthesia, GHB is usually used as a reserve sedative, and adjunctive GHB therapy can be considered when treatment with other sedative drugs is contraindicated (as in the reported cases) or in cases of alcohol withdrawal.

Only a few adverse events associated with the use of intravenous GHB have been published. In what follows, we describe 2 patients who had fixed and dilated, asymmetric pupils after treatment with GHB.


   Patient 1
Top
 Abstract
 Patient 1
Patient 2
 Discussion
 References
 
A 50-year-old, 85-kg man had epileptic seizures and decreased vigilance due to acute subarachnoid bleeding (Hunt-Hess grade IV, Fischer grade III) from an aneurysm of the left anterior cerebral artery. The aneurysm was clipped the day the patient was admitted to the intensive care unit (ICU), and an external ventricular drain was placed because hydrocephalus developed. Because the patient had aspiration pneumonia, he remained intubated (treatment with ceftriaxone 2 g/d).

On day 3, generalized cerebral vasospasm developed and was treated with intravenous nimodipine 2 mg/h and triple H therapy consisting of induced hypertension, hypervolemia, and hemodilution (hematocrit <30%). On day 7, ventriculitis was diagnosed (treatment with meropenem 2 g 3 times per day and vancomycin 1 g/d). Because of the severe complications, deep anesthesia was continued by using a combination of fentanyl (0.4 mg/h), midazolam (30 mg/h), and propofol (600 mg/h). Possible reasons for the required high amounts of anesthetics were the duration of the sedation and the patient’s history of alcohol abuse. On day 8, increases occurred in the serum levels of creatine kinase (948 U/L; reference, <180 U/L), amylase (244 U/L; reference, <100 U/L), and lipase (224 U/L; reference, <50 U/l). (To convert units per liter of creatine kinase, amylase, and lipase to microkatals per liter, multiply by 0.017.) Because propofol infusion syndrome12 was considered a likely cause of the increases, the infusion of propofol was discontinued and administration of intravenous GHB (2 g/h) was started.


GHB is a neuromodulator used as an anesthesia adjuvant, to treat narcolepsy, and as a recreational drug.

 

Three hours later, the patient had maximally dilated asymmetric pupils that were unreactive to light. Intracranial pressure (ICP), which was monitored continuously, was 14 mm Hg, similar to values on the days before. Additional medications at that time included nimodipine (2 mg/h), noradrenaline (1.1 mg/h), meropenem (2 g twice daily), vancomycin (1 g/d), phenytoin (250 mg 3 times per day), and heparin (to achieve a partial thromboplastin time of 50–60 seconds). Computed tomography showed no evidence of increased ICP or brain stem compression (see Figure), and transcranial Doppler imaging of the basilar artery revealed an orthograde blood flow (ie, in the usual direction) without any indications of stenosis or occlusion. Treatment with GHB was discontinued, and administration of ketamine was started.


Two patients developed asymmetric pupils, pupillary dilatation, and areflexia with intravenous GHB therapy.

 

Eight hours after discontinuation of GHB, the patient’s pupils were equally round and reactive to light. The patient’s tracheostoma was removed on day 37, and the patient was sent to rehabilitation on day 47. At discharge, he had no clinical indications of brain stem damage. One year later, the patient was living with his family and had no focal neurological sequelae.


   Patient 2
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 Abstract
 Patient 1
 Patient 2
Discussion
 References
 
A 39-year-old, 63-kg patient who had received a kidney transplant, had hypertension, and was taking ticlopidine experienced an acute onset of left-sided hemiparesis and progressively decreasing vigilance that required intubation. Computed tomography showed a space-occupying right-sided temporoparietal intracerebral hemorrhage with a midline shift of 1 cm and blood in the lateral ventricles. No signs of brain stem compression were evident. An external ventricular drain was placed. The patient was anesthetized and sedated with fentanyl (0.4 mg/h), midazolam (40 mg/h), and propofol (500 mg/h). Because ICP values remained consistently high (22–28 mm Hg), 20% mannitol (125 mL 3 times per day) was administered, and GHB (0.8 mg/h) was added to deepen the anesthesia.


GHB intoxication should be suspected in patients who present with fixed and dilated pupils.

 

Two hours after GHB therapy was begun, the patient’s pupils became fixed, dilated, and asymmetric. ICP was 26 mm Hg. Additional medication at that time included noradrenaline (0.8 mg/h), dopamine (20 mg/h), fentanyl (0.4 mg/h), midazolam (40 mg/h), propofol (500 mg/h), and low-dose heparin (200 IU/h). Computed tomography revealed progression of the perifocal edema with narrowing of the basal cisternas, but did not show any signs of brain stem herniation. However, after GHB was discontinued, pupillary asymmetry resolved within 5 hours and the dilatation decreased. The patient partly recovered and was discharged to rehabilitation after 32 days of treatment in our ICU, conscious and able to follow commands. His left arm and leg remained paralyzed. Unfortunately, the patient died of acute cholangitis and sepsis 3 months later.


   Discussion
Top
 Abstract
 Patient 1
 Patient 2
 Discussion
References
 
Asymmetric, dilated, unreactive pupils developed in 2 patients who were treated with intravenous GHB. The pupillary changes developed 2 and 3 hours after continuous GHB administration was started. Both patients had continuous ICP monitoring via external ventricular drainage devices, which did not indicate a coinciding further elevation in ICP. In addition, computed tomography showed no indications of brain stem herniation at the time the pupils were fixed and dilated. Most important, the pupillary changes resolved 5 and 8 hours after GHB treatment was terminated, and both patients recovered without clinical indications of brain stem damage. Therefore, causes other than administration of GHB probably do not account for the observed pupillary changes.

The spectrum of clinical signs and symptoms of GHB overdose is wide and mainly based on observations after the uncontrolled ingestion and overdosing of GHB for recreational purposes. The mental status of such patients with GHB intoxication ranges from confused agitation to unconsciousness and complete coma.13,14 Although blood pressure levels remain normal in most instances, hypoventilation and apnea requiring intubation have been reported.15 Lack of pupillary reflexes in patients with GHB intoxication have also been reported.14 In addition, various degrees of dilatation but not asymmetric pupils have been noted.7,15,16

Both of our patients received additional narcotics. Combining anesthetics is a necessary clinical practice to gain maximal anesthesia and minimize possible toxic side effects of high doses of each drug, especially in patients who require long-term anesthesia. GHB likely plays a role in the GABAB, dopamine, and opioid pathways. A recent case report17 suggested a possible interaction of GHB with benzodiazepines, and interactions of GHB with the opioid system have been noted.18 Thus, we cannot tell whether the development of asymmetric pupils in our patients was due solely to GHB or was due to the combination of GHB with other drugs such as midazolam or ketamine.

Size, shape, and reactivity of pupils are often the only clinical parameters for monitoring the neurological state of sedated patients in ICUs. The development of pupillary abnormalities such as dilatation, asymmetry, or anisocoria often indicates damage to the brain stem, such as ischemia or increased ICP and transtentorial cerebral herniation. Thus, pupillary changes require instant diagnosis. Furthermore, fixed and dilated pupils are important prognostic markers and are often the basis for further therapeutic steps.19 Our 2 cases show that dilated and fixed pupils in patients anesthetized with GHB may also occur in the absence of brain stem damage. In order to avoid diagnostic pitfalls, GHB should not be considered a first-choice anesthetic in patients at risk for brain stem herniation or ischemia.

Our 2 cases of pupillary changes during GHB therapy occurred in ICUs. However, such pupillary changes might also occur in patients with GHB intoxication due to recreational use of the drug. This possibility is particularly important because routine drug screening usually does not include analysis for GHB. After other life-threatening causes are ruled out, GHB intoxication should be considered in the differential diagnosis for patients who come to the emergency department with fixed and dilated pupils.

In conclusion, fixed and dilated, asymmetric pupils are possible side effects of anesthesia with GHB. This observation is important because these GHB-induced changes can mimic brain stem damage, such as that caused by ischemia, hemorrhage, or cerebral herniation due to increased ICP.


Figure 1
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  		Figure A-C, Cerebral computed tomography scans of patient 1 taken 30 minutes after development of fixed, dilated, asymmetric pupils show severe subarachnoid hemorrhage. No brain stem herniation is evident (A). The basilary cisternas are still circumscribable. An external ventricular drain is apparent in the right lateral ventricle (C).

 
FINANCIAL DISCLOSURES
None reported.

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   REFERENCES
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 Abstract
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 Patient 2
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