|Year : 2015 | Volume
| Issue : 2 | Page : 140-145
The use of barbiturate-induced coma during cerebrovascular neurosurgery procedures: A review of the literature
Nathaniel R Ellens, Bryan E Figueroa, Justin C Clark
Great Lakes Neurosurgical Associates, Grand Rapids, Michigan, USA
|Date of Submission||31-Aug-2015|
|Date of Acceptance||17-Nov-2015|
|Date of Web Publication||31-Dec-2015|
Justin C Clark
Great Lakes Neurosurgical Associates, 414 Plymouth NE, Grand Rapids - 49505, Michigan
Source of Support: None, Conflict of Interest: None
Barbiturates are indicated for use during vascular neurosurgery procedures such as carotid surgery, arteriovenous malformation (AVM) surgery, cerebral aneurysm surgery, extracranial-intracranial bypass, and following significant bleeding due to AVMs or subarachnoid hemorrhage (SAH). These drugs are commonly used for their neuroprotective effects during focal cerebral ischemia and for their ability to treat intractable intracranial hypertension. Currently, thiopental and pentobarbital are the most frequently used barbiturates for these purposes, although methohexital and phenobarbital have been studied as well. Depending on the drug used and the desired effect, the dose administered may vary. Additionally, barbiturates are known to cause significant, severe side effects including depression of cardiac output, increased liver enzymes, increased risk of cardiac arrhythmia, lowered immune threshold, adversely affected brain temperature, systemic hypotension, and dyskalemia. For these reasons, these drugs should be monitored carefully and only used in circumstances of clear benefit. Finally, in order to evaluate barbiturates use during these procedures, information was gathered via an extensive PubMed literature review in addition to reviewing the resources of previous reviews on this topic or similar, relevant topics.
Keywords: Cerebroprotection, focal ischemia, intractable intracranial hypertension, neuroprotection, pentobarbital, thiopental
|How to cite this article:|
Ellens NR, Figueroa BE, Clark JC. The use of barbiturate-induced coma during cerebrovascular neurosurgery procedures: A review of the literature. Brain Circ 2015;1:140-5
|How to cite this URL:|
Ellens NR, Figueroa BE, Clark JC. The use of barbiturate-induced coma during cerebrovascular neurosurgery procedures: A review of the literature. Brain Circ [serial online] 2015 [cited 2018 Dec 17];1:140-5. Available from: http://www.braincirculation.org/text.asp?2015/1/2/140/172887
| Introduction|| |
The first barbiturate was synthesized in 1864 by Adolph von Baeyer.  Nearly 40 years later, in 1903, barbiturates with hypnotic activity were synthesized, followed by barbiturates with anticonvulsant properties (e.g., phenobarbitone) in 1912.  Phenobarbitone was initially popularized for its use in treating patients with epilepsy. However, due to its long, undesirable half-life, this drug was not preferred for anesthetic purposes.  This prompted the research and discovery of thiopentone and pentobarbitone in the early 1930s. 
Today, barbiturates are known to have neuroprotective properties in cases of ischemia, subarachnoid hemorrhage (SAH), carotid surgery, arteriovenous malformation (AVM) surgery, and cerebral aneurysm surgery. ,,,, These effects are believed to be due to barbiturates' four main actions on the central nervous system: Anticonvulsant effects, hypnotic activity, depression of cerebral metabolic rate (CMR), and reduction of cerebral blood flow (CBF). ,,, Additionally, it is believed that the neuroprotective functions of barbiturates may also result from antioxidant activity; γ-aminobutyric acid (GABA)ergic activity; facilitation of protein synthesis; removal of free radicals; and possibly the role of adenosine neuromodulation in the depression of excitatory synaptic neurotransmission. ,, In this article, we will review the use of barbiturates during cerebrovascular neurosurgery. Specifically this will include a review of the indications, types of effective barbiturates, dosing, and side effects. Information was gathered via an extensive PubMed literature review in addition to reviewing the resources of previous reviews on this topic or similar, relevant topics.
| Review of the Indications|| |
In vascular neurosurgical procedures, barbiturates can be used for a variety of different purposes. They are used to manage intractable intracranial pressure (ICP) elevations following vascular procedures such as AVM resection, extracranial-intracranial bypass, aneurysmorrhaphy, and acutely after significant bleeding due to AVMs or ruptured aneurysms. ,, In addition, one of the most important uses of barbiturates in vascular neurosurgery is as neuroprotective agents during episodes of temporary or permanent focal ischemia. ,,,,,,,,,,,,
Intractable intracranial hypertension
In patients with sustained ICP, standard modes of therapy including drainage of cerebrospinal fluid (CSF), elevation of patients' head-of-bed, hyperventilation, and osmotic and loop diuretics should be instituted as first-line therapies. Avoidance of hyperthermia is also an important consideration in these situations. Barbiturates are only used if ICPs remain persistently above 20 cm H 2 O despite the institutions of the therapies mentioned above. In a study conducted by Awad et al., the investigators instituted barbiturate therapy in 9 out of 32 patients with cerebral AVMs. Barbiturate therapy with the infusion of pentobarbital was instituted in these 9 patients as a result of elevations in ICPs that were not responsive to the standard, conventional measures listed previously.  Pentobarbital therapy was initiated if patients had intractable ICPs of greater than 30 mmHg, despite treatment with conventional therapy. Their protocol for barbiturate therapy was a loading dose of 10 mg/kg of pentobarbital administered over 30 min, followed by 5 mg/kg per hour for the next 3 h. Barbiturate therapy was maintained using a pentobarbital drip at a dose of 1-2 mg/kg per hour when needed. The dose of the maintenence drip was adjusted to achieve electroencephalogram (EEG) burst suppression and ICPs in the normal range. Pentobarbital-induced coma was required on the first postoperative day in 7 of the 9 patients with intractable ICP elevation, and on the second postoperative day in the remaining 2 patients.  Pentobarbital was able to successfully maintain ICPs below 30 mmHg in all 9 cases.
In this study, 50% (5 out of 10) of patients with AVMs defined as distal or border-zone in location had intractable ICP elevation. Additionally, AVMs with basal or sylvian major vessel feeders had intractable ICP elevation 44% (4 out of 9) of the time. Together, these accounted for every case of intractable ICP elevation, suggesting that location along with size of the AVM are contributing factors to patients experiencing intractable ICP elevation.  However, 50% (6 out of 12) of patients with an AVM greater than 6 cm had intractable ICP elevation, as opposed to 17% (1 out of 6) and 18% (2 out of 11) of patients with AVMs less than 3 cm and 3-6 cm, respectively. Therefore, size and location of the AVM likely correlate with intractable intracranial hypertension and the need for barbiturate therapy.  Another study conducted at Royal North Shore Hospital in Wales treated 10 patients with thiopental therapy.  These 10 patients had AVM resections that were complicated by intracranial hemorrhages. After 1 month, only 1 patient had died, suggesting that barbiturates may be clinically useful in patients with complicated AVMs and should be studied further. ,
Another study evaluated the use of barbiturates in treating intractable ICP elevation caused by hypertensive and SAHs.  This study defined intractable ICP elevation as greater than 15 mmHg and barbiturate therapy was delivered 15-30 min following the elevation of ICP and the failure of conventional therapy. Despite the prompt delivery of barbiturates and extensive monitoring, only 5 of these 15 patients had sustained ICP reductions.  However, although this study is too small to determine whether barbiturates were truly effective, it appears that, given the current outcomes of patients with elevated, intractable ICP, barbiturate therapy may have contributed to these patients' survival.  A more recent study conducted by Finfer, Ferch, and Morgan evaluated the use of thiopentone coma in 27 patients. They considered thiopentone to be indicated when a patient had greater than 50% narrowing due to vasospasm of a major cerebral artery following SAH or when a patient had intractable intracranial hypertension. , Of these 27 patients, thiopentone was used in 15 patients due to vasospasm and 12 patients due to intractable ICP elevation, and the mortality rate at 1 month was 11% or 3 patients. 
Thus, barbiturate therapy can be an effective option for treating patients with intractable intracranial hypertension and should be considered when traditional methods such as osmotic loop diuretics and hyperventilation are insufficient.
Barbiturates can also be used as neuroprotective agents in procedures involving focal ischemia, but not global ischemia. , This includes procedures involving temporary clip placement such as extracranial-intracranial bypass procedures, carotid endarterectomies, and aneurysm clipping.  Barbiturates have been shown to be effective in these cases by decreasing the CMR up to 50-60% and increasing blood flow to the ischemic areas of the cortex. ,, Barbiturates have also been shown to reduce the oxygen requirement of the brain and reduce the size of cerebral infarction in animal models. ,,,,, A study conducted by Selman et al. found barbiturates to provide neuroprotection after a middle cerebral artery (MCA) occlusion for up to 6 h. Additionally, it is clear that barbiturates are most effective when given prior to ischemia.
In a study of 36 patients treated with thiopental as a means of neuroprotection for their craniotomy and aneurysm clipping, 27 patients (75%) made a good recovery, as defined by the Glasgow Outcome Scale. Specifically, 21 out of 29 (72%) patients who presented with a SAH and 6 out of 7 (86%) patients who presented with unruptured aneurysms made a good recovery.  Additionally, as discussed in the previous section, barbiturate therapy can be beneficial in treating patients with vasospasm following SAH. ,
Barbiturates can also be used as a form of neuroprotection in carotid endarterectomies. These procedures have a risk of ischemic insult due to cross-clamping and plaque migration. In a study regarding barbiturate use in carotid endarterectomies, Gross et al. administered barbiturate therapy in patients with significant EEG changes refractory to hypertension therapy. Every patient who received barbiturate therapy had a good outcome with no instances of ischemic deficiency. 
Another study conducted by Spetzler et al. evaluated routine barbiturate therapy in 200 carotid endarterectomies.  This study resulted in two strokes (1% of patients) and one death (0.5% of patients) due to a massive hypertensive hemorrhage the day prior to discharge. There were no complications specifically related to or caused by the use of barbiturates. 
Frawley et al. also indicated in a study of 37 carotid endarterectomies that barbiturate-induced cerebral protection may prevent ischemic stroke due to intraoperative cross-clamping and plaque migration, and may also be preferred to intraluminal shunting due to the inherent risks involved in shunting. 
There has been significantly less research studying the effects of barbiturates on cranial bypass procedures than there has been on its effects on cerebral aneurysm clippings and carotid endarterectomies; however, the available studies indicate that barbiturates have the same beneficial effects. A study by Lawner et al. evaluated superficial temporal artery-middle cerebral artery (STA-MCA) bypass and barbiturate therapy both together and individually.  It found that when barbiturate therapy was combined with STA-MCA bypass in 93 mongrel dogs with intracranial carotid and MCA occlusions, there was decreased neurological deficit and hemispheric infarction, with no mortality.  Additionally, Lawner et al. have reported a case of barbiturate therapy alongside STA-MCA bypass procedures as an additional form of neuroprotection. 
| Barbiturate Types and Dosing Regimens|| |
There are several types of barbiturates currently used in vascular neurosurgery and the dose and timing of administration each play an important role in patients' outcomes. Barbiturates given prior to the onset of ischemic events or elevated intracranial pressures are significantly more effective than barbiturates given after the onset of these pathologic conditions. , However, even if therapy cannot be given prior to occlusion, it should be given as soon as possible afterwards, due to its ability to minimize the negative ischemic effects even up to 96 h later. ,
Information is given in the following paragraphs describing the common dosing regimens for barbiturate-induced coma. Because a wide array of dosing regimens have been used with varying success, only the most common regimens will be outlined in this paper. It is important to note that EEG-confirmed burst suppression is widely accepted as the most appropriate end-point for cerebral neuroprotection following barbiturate therapy, and dosing regimens should be administered with this end goal in mind. ,,, Despite this wide acceptance, there have been studies demonstrating that burst suppression was not necessary for maximum neuroprotection in rats, but to our knowledge there have been no studies indicating this in humans to date. , Therefore, EEG-confirmed burst suppression remains the standard when treating patients with high-dose barbiturate therapy.
Several different barbiturates have been used in vascular neurosurgery, but the most common drugs used today are pentobarbital and thiopental. Although these two drugs are very similar in structure, pentobarbital has an oxygen group at the C2 position rather than a sulfur group, allowing for a considerably slower onset of action and half-life termination.  Pentobarbital has a half life of approximately 30 h and is often administered in in a loading dose of 3-10 mg/kg at 1 mg/kg/min followed by an intravenous (IV) infusion of 1-2 mg/kg/h to obtain burst suppression. , Additionally, blood levels should be monitored and maintained at 25-40 mg/mL in order to minimize the recovery time following a barbiturate coma. , It is important to note again that although multiple dosing mechanisms have been utilized, the amount of barbiturate indicated should be the lowest amount necessary to obtain EEG-confirmed burst suppression. ,,, Barbiturate levels significantly beyond burst suppression have not been shown to provide any additional benefit and have increased the therapeutic toxicity. ,
Thiopental, on the other hand, has a considerably faster onset of action and a half-life of 3-8 h, making it the barbiturate of choice when effects are desired immediately. , When giving thiopental, usually a dose of 3-5 mg/kg is given IV in order to obtain blood levels of 10-30 mg/mL and up to 10 min of burst suppression.  Sreedhar and Gadhinglajkar have also outlined more specific dosing models for thiopental, depending on therapeutic use, for a low dose, a low dose followed by IV infusion, and a high dose followed by infusion, described below.
When given at a low dose for immediate, short-term protection, a dose of 4 mg/kg over 3 min is sufficient to produce 6 min of burst suppression. , This may be useful to deliver a drug to an ischemic area prior to cross-clamping. It is believed that the ischemia induced upon clamping would prevent the drug from being washed out, therefore extending its effects beyond the point of EEG-confirmed burst suppression. ,
Another common use of thiopental involves giving a low initial dose of 1-3 mg/kg followed by an IV infusion of 0.06-0.2 mg/kg/min. , This is the common administration used for controlling intractable intracranial hypertension. , Additionally, periodic doses of thiopental can be given during neurosurgical operations to decrease intracranial pressure. ,
When given in a high dose, thiopental is most effective in treating situations of focal ischemia. , The suggested initial loading dose is 25-50 mg/kg followed by a constant infusion of 2-10 mg/kg/h in order to obtain a concentration of 10-50 mg/L in the plasma. ,, However, other sources indicate that an even greater serum concentration (>50 mg/L) must be obtained to achieve burst suppression and maximal neuroprotection.  Because of the high dose of barbiturate therapy received by these patients, it is often impossible to assess the neurological condition via physical exam for several days. As a result, this regimen is reserved for high-risk cases, and therapy should be administered prior to induced ischemia when feasible. ,
It should be noted that despite its effectiveness in vascular neurosurgery procedures, thiopental is no longer available for use in the United States. However, thiopental does remain a widely used drug throughout Europe.
Another barbiturate that has been used previously in vascular neurosurgery is methohexital. In comparison to other barbiturates, methohexital is classified as ultrashort-acting oxybarbitone and has a neuroprotective efficacy similar to that of thiopental.  It is also rapidly metabolized and approximately twice as potent as thiopental, due in part to its very low fat solubility.  This drug has been shown to depress mean arterial blood pressure (MABP) more than thiopental during administration, but also to increase cardiac index and stroke volume more quickly following its use.  Additionally, methohexital decreases CBF, although unlike thiopental and pentobarbital, this decrease is not effective in reducing intracranial pressure for unknown reasons. , As described by Boarini et al., the decrease in MABP may be beneficial when treating aneurysms or AVMs, but it may have a negative effect on the treatment of procedures already involving low pressures, such as carotid endarterectomy and bypass procedures.  Despite the proposed advantages of methohexital, it is used less frequently than pentobarbital and thiopentone due to the severe side affects addressed later in this paper.
Phenobarbital is commonly seen for its use in treating alcohol withdrawal and seizure prevention. It has also demonstrated neuroprotective effects. , However, due to the extensive half life of 80-120 h, phenobarbital is not often used as a neuroprotective agent during cerebrovascular procedures. ,
| Side Effects|| |
Although barbiturates have been shown to be effective in vascular neurosurgical procedures, they have substantial side effects. Therefore they should be monitored carefully and used only in circumstances of clear benefit.
First and arguably most importantly, barbiturates are known to depress cardiac output when given at high doses. They can also increase the risk of cardiac arrhythmias. , As a result, these effects should be considered prior to administration in patients with heart conditions. ,,, If barbiturate therapy is still indicated, these patients will likely require extensive cardiac monitoring. Additionally, despite their cerebral vasoconstrictive effects, barbiturates cause systemic hypotension. , These effects can be more severe in patients with decreased blood volume as a result of hemorrhage caused by AVMs or ruptured aneurysms.  Therefore it is not uncommon for patients to receive phenylephrine in combination with barbiturates to offset the hypotensive effects and maintain an adequate cerebral perfusion pressure. ,,, This is especially common in procedures requiring cross-clamping and induction of temporary ischemia such as carotid endarterectomy, aneurysm clipping, extracranial-intracranial bypass, and AVM resection. 
In addition to the depressive effects on the myocardium, barbiturates also induce respiratory depression, necessitating the use of mechanical ventilation regardless of the neurovascular procedure. ,,
When barbiturates are given at high doses to cause barbiturate-induced coma, it can prolong postoperative drowsiness and make it difficult to monitor and evaluate neurological status. ,,,, Therefore ICP and EEG monitoring devices in addition to computed tomography (CT), magnetic resonance imaging (MRI), or angiography may be beneficial to determine adverse neurological affects promptly. , For methohexital specifically, high doses are also associated with postoperative seizures, likely due to acute habituation and withdrawal due to this drug's high potency. ,,,, These effects can also include hiccups, muscle twitching, shivering, and prolonged apnea. ,,
Barbiturates are also responsible for lowering the immune threshold, substantiating the risk for pulmonary infections. ,, In fact, one study by Stover and Stocker indicated that in 23 patients given barbiturate therapy for traumatic brain injury, leukocytes and neutrophils were significantly decreased in every case.  Additionally, pulmonary infection rates nearly doubled.  Another study by Neuwelt et al. found that barbiturates suppressed lymphocyte response, with a two- to threefold greater suppression by thiopental than pentobarbital. 
Severe dyskalemia is also a rare but life-threatening complication for patients receiving high levels of barbiturate therapy. ,,, Initially, this dyskalemia often presents as hypokalemia within two days of coma induction, and is followed by a fatal rebound hyperkalemia shorty after the cessation of barbiturate infusion. ,,, However, current studies have not shown a correlation between the dose of barbiturate therapy and the likelihood of severe dyskalemia. ,,,
Barbiturates have also been shown to both increase and decrease brain temperature. ,, The current literature, however, indicates that a reduction in brain temperature is more commonly seen, likely due to the decrease in CBF and CMR. , A study by Thorat et al. found that barbiturates lowered brain temperature in 6 out of 7 patients by an average of 2°C when administered following traumatic brain injury.  Considering its prevalence and its influence on patient outcomes, some groups recommend that brain temperature be monitored during barbiturate-induced coma, despite the invasive nature of this monitoring technique. , However, monitoring of brain temperature is not routinely done, due to its invasive nature.
Finally, although long-term effects have not been evaluated in humans yet, barbiturates may induce neurodegeneration in adult and newborn rats. ,, Therefore, further evidence and long-term studies evaluating these potential neurological effects in humans is needed. Additionally, because thiopental is metabolized almost entirely in the liver, patients with hepatic dysfunction or insufficiencies may require an alternative, personalized therapeutic approach.  Even patients with normal hepatic function at baseline will require serial hepatic enzyme monitoring, in order to determine whether liver dysfunction is being induced by the barbiturates.
| Conclusion|| |
Cerebrovascular neurosurgical operations are often high-risk. Due to the nature of the pathologies treated, there is a consistent possibility that the patient could experience excessive intraoperative bleeding, intraoperative ischemic events, and/or intra- and postoperative intracranial hypertension. Treating these patients with barbiturates is believed to provide neuroprotection through a number of biologic effects. It is imperative that the neurosurgeon treating patients with these pathologies be knowledgeable in the indications, benefits, and risks of using barbiturate therapy. The cerebrovascular neurosurgeon's work is often high-risk due to the susceptibility of patients experiencing vascular occlusive episodes as a result of treatment.
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