ISSN - 0972-0847

Columban J. Life Sci.

Vol. 13 No. 1 & 2

1-4

2012

THIOPENTAL COMA AND PATIENTS OUTCOME

Nissar Shaikh, M. Ataur Rahman, Abdel Nasser Al-Yaafi, Sujeeth and Ghanem Al-Sulaiti Hamad Medical Corporation, Doha- Qatar. E-mail: smaheboob@hmc.org.qa Received 08 October 2012, Accepted 16 November 2012 ABSTRACT
Secondary brain injury causing refractory intracranial hypertension is usually fatal. Thiopental barbiturate coma is recommended therapy in this desperate clinical condition. It remained a second line of therapy due to its adverse effects. Aim of our study was to know the efficacy of thiopental coma, prevalence of adverse effects, risk factors for the mortality and patients outcome. Patients and methods: All patients requiring thiopental coma to control the refractory intracranial hypertension in our tertiary care hospital intensive care unit (ICU), over 4 years were prospectively enrolled in the study. Patients with hepatic, renal impairment were excluded from the study. Results: A total 58 patients were enrolled in the study, majority of these patients had traumatic brain injury (86.5%) and were males. There was significant reduction in the raised intracranial hypertension (P<0.001). Mean admission GCS was 5.63, duration of thiopental coma was 3.03 days, ICU stay was 20.68 days and ICU transfer GCS was 10.6; all patients required vasopressors, 43.1% had pneumonia, 95% had dyskalemia,50% had renal impairment. Hypokalemia, hypernatremia and renal impairment were significantly associated with risk of mortality (P<0.005). 49% of these patients had liver impairment, 23% had septic shock, and 9% had enteral feed intolerance. Eleven percent of thiopental coma patient has full functional recovery 5.2% had mild to moderate functional disabilities. Conclusion: Thiopental coma significantly reduces raised ICP; age and decompressive craniectomy in combination with thiopental coma did not showed any survival benefits. More than one vasopressor use, hypokalemia, hypernatremia, renal impairment were the risk factors for mortality in thiopental coma patients.

Key words: thiopental coma, refractory intracranial hypertension, vasopressor, hypokalemia, hypernatremia, renal impairment, decompressive craniectomy INTRODUCTION Thiopental sodium is a lipid soluble ultra-short acting barbiturate known to have intracranial pressure lowering effect since 1930. Secondary brain injury is accompanied by increased intracranial pressure, which results in cerebral ischemia and transtentorial Herniation. Up to 25% of the severe traumatic brain injury patients will have raised intracranial pressure which will not be controlled by the usual therapies; it is termed as refractory intracranial hypertension. Refractory intracranial pressure will be fatal if not treated.1 Barbiturate coma is recommended therapy for refractory intracranial hypertension (Brain trauma foundation, 2007). In majority of patients refractory intracranial hypertension will be controlled with barbiturate coma but due to the higher incidence of adverse effects it is a second line therapy for the
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management of intracranial hypertension. Patients on barbiturate coma need intensive monitoring and critical supportive care. Although with barbiturate the high intracranial pressure (ICP) is effectively reduced but its effect on patients outcome and risk for higher mortality remains unclear. According to the brain trauma foundation guidelines thiopental sodium is commonly used and more effective barbiturate in controlling the refractory intracranial hypertension (Brain trauma foundation, 2007). There is scanty literature about thiopental sodium effect on other organs of the body and recent literature is limited to the abstract and case reports only. Aim of our study was to know adverse effects of thiopental coma, risk factors associated with mortality and patients outcome.

THIOPENTAL COMA AND PATIENTS OUTCOME

PATIENTS AND METHODS All patients received thiopental coma in surgical and trauma intensive care unit of tertiary care center, from January 2004 to December 2008 were prospectively enrolled in the study. All patients with the refractory intracranial hypertension were included in the study. Patients with the refractory intracranial hypertension and hemodynamically instability, liver, renal impairment, having pneumonia or severe sepsis were excluded from the study. Patients demographic data, diagnosis, post resuscitation Glasgow coma score (GCS), any neurosurgical intervention, ICP before and after starting thiopental coma, duration of thiopental coma, use of vasopressors, occurrence of pneumonia, hepatic, renal impairment, septic shock, ICU stay and Glasgow outcome (GOS) score were recorded. All patients received thiopental sodium 20mg/kg/hour for one hour, 10mgs/kg/hour for next 3 hours than continued 3mg/kg/hour. Hypotension was defined as systolic blood pressure of less than 90 mm of Hg and pneumonia was diagnosed by using center for disease control and prevention criteria. Septic shock was diagnosed and managed as per the Surviving Sepsis Campaign guidelines. During the thiopental coma continuous bispectral index (BIS) monitoring was applied. Permission from the institutional research committee was obtained for the study. RESULTS A total 58 patients were enrolled in the study. Majority of patients were male (Figure1). Forty one (71%) had severe traumatic brain injury (TBI) following the road traffic accident, 9 (15.5%) had TBI due to fall from height, 4 (6.9%) patients had spontaneous intracerebral hemorrhage, and 4(6.9%) patients had massive brain infraction leading to the refractory intracranial hypertension (Table 1). Twenty four (41.8%) patients had and decompressive craniectomy and postoperatively started on thiopental coma (Table 1). ICP prior to thiopental coma was 5217.8 mm of Hg, post coma ICP was 32.816.9 mm of Hg. There was significant reduction in ICP following thiopental coma (p<0.01). Survived patients had significantly higher polytrauma (Table 1). Mean age our patients was 32.31 years. GCS at admission was 5.633.06. Mean duration of thiopental coma was 3.03 days. Duration of intensive care unit stay was 20.6822.2 days, and GCS at transfer from ICU was 10.63.06 (Table 2).
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All patients on thiopental coma required vasopressors, none survivors needed more than one vasopressor to keep stable hemodynamics (Table 3). Pneumonia occurred in 43.1% patients. Ninety five percent of patients had dyskalemia; hypokalemia occurred in 62.1% of patients and non survivors had significantly higher incidence of hypokalemia (P<0.05); hyperkalemia occurred in 32.8% of the patients, more common in non survivors but not reaching statistical significance (Table 3). Fifty percent of patient had renal impairment and it was more common in non survivors (P<0.05); liver impairment occurred in 49% patients. Total 9% of thiopental patients had enteral feed intolerance and feed intolerance was high in non survivors (Table 3). Twenty three percent of patients had septic shock; it was higher in non survivors (P<0.05). Younger patients on thiopental coma had better survival, but the difference was not significant. Surprisingly the duration of coma was significantly higher in survived patients (P<0.03) {Table 4}. Fifty eight percent of patients on thiopental coma died, 10.3% had full recovery and 5.2% had mild to moderate disability (Figure 2).
Figure 1.
Gender o f Thiopentol Coma Patients

10.30%
Mal e Female

89.70%

Table : 1 Variables n (%) Survived n (%) 9 (15.5) 2 (7.7) 41 (70.7) 21 (80.8) 4 (6.9) 1 (3.8) 2 (7.7) Died n (%) p value 7 (21.9) 20 (62.5) 3 (9.4) 2 (6.3) 0.138 0.128 0.409 0.829

FFH RTA Spontane ous ICH Massive 4 (6.9) brain infarction Polytrauma 19 (32.8) Decompressive 24 (41.8) craniectomy ICP prior to 47 (81) Thiopenthol ICP post to 47(81) Thiopenthol

13 (50) 6 (18.8) 12 (46.2) 12 (37.5) 47 12 56 21

0.012* 0.506 0.103 0.26

18.53.4 202

*FFH (fall from height), RTA (Road traffic accident), ICH (Intracerebral hemorrhage)

COLUMBAN J. LIFE SCI. VOL. 13 (1&2), 2012

Table : 2 Variables Age (years) Duration of ICU stay GCS on admission ICP prior to Thiopenthol coma Duration of Thiopenthol (days) GCS at hospital discharge ICP reduction Mean 32.31 20.68 5.63 52.21 3.03 10.6 32.2 SD 13.86 22.2 2.5 17.88 1.5 3.06 16.9

*ICP (Intracranial pressure), GCS (Glasgow Coma Score) Table : 3

Variables Noradrenaline Adrenaline Vasopressin pneumonia Hypokalemia Hyperkalemia Hypernatremia Renal impairment Liver impairment Feed intolerance Septic shock Survived Died n (%) n (%) 23 (88.5) 1 (3.8) 0 10 (38.5) 13 (50) 8 (30.8) 20 (76.9) 7 (26.9) 31 (96.9) 10 (31.3) 2 (6.3) 15 (46.9) 23 (71.9) 11 (34.4) 32(100) 22 (68.8) Total 54 (93.1) 11 (19) 2 (3.4) 25 (43.1) 36 (62.1) 19 (32.8) 52 (89.7) 29 (50) P value 0.209 0.008* 0.3 0.52 0.076* 0.771 0.006* 0.002*

15 (57.7) 13 (40.6) 1 (3.8) 3 (11.5) 4 (12.5) 10 (31.3)

28 (48.3) 0.196 5 (8.9) 0.243 13 (22.4) 0.073*

*Statistically significant:
Table : 4 Survived mean SD Age 29 10 ICU Stay (days) 25 13 GCS on admission 62 Duration of Thiopentho 3.5 1.4 l (days) Variables Died mean SD 35 16 17 26 53 2.6 1.4 P Value 0.091 0.178 0.211 0.033*

*GCS(Glasgow Coma Score), ICU (Intensive Care Unit) Figure 2.

5.20% 12.10%

10.30%

Expired Severe disability

58.60%

vegetative moderate disability

13.80%

Full recovery

DISCUSSION Refractory intracranial hypertension following the brain injury is a life threatening clinical entity. In this disparate situation thiopental barbiturate coma is the remedy which lowers the intracranial pressure significantly1. Thiopental has the brain protective
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effect by various mechanisms, (i) it reduces the oxygen requirement of the brain by decreasing the metabolism, (ii) by altering the vascular tone thiopental decreases the blood supply to the brain (iii) brain scavenging effect by inhibiting the free radicals (iv) stabilization of lyosomal membrane (VI) anticonvulsant activity (Perez-Barcena et al., 2005). The significant mechanism by which thiopental reduces the intracranial pressure is the combination of decreased blood flow with decreased brain metabolism (Perez-Barcena et al., 2005). Thiopental coma is not only used in TBI but it is also documented to be useful therapy for other brain injuries (spontaneous intracerebral and massive brain infarction) leading to the refractory intracranial hypertension (An et al., 2010). In spite of beneficial effect in difficult clinical situation (refractory intracranial hypertension), it remained a second line therapy due to its adverse effects on other body organs. The main adverse effect of thiopental is on hemodynamic system. All our patients on thiopental coma required vasopressor to keep a stable mean arterial pressure (MAP). Chin et al., (2006) also reported that 96% of their patients on barbiturate coma needed vasopressors. This is one of the most worrisome side effects of thiopental as we noticed that non survivors required more than one vasopressor. Pneumonia occurred in forty three percent of our patients and their incidences were higher in non-survivals. Schalen et al (1992) reported higher incidence of respiratory complications (76%). Frenette and Bernard (2004) concluded their study with significantly higher incidence of acute respiratory distress syndrome in thiopental coma patients (Frenette and Bernard, 2004). Nadal et al (1995) reported that thiopental therapy as a risk for development of pneumonia, which was independent of mechanical ventilation (Nadal et al., 1995). Hypokalemia occurred in 62% of our thiopental coma patients whereas 33% had rebound hyperkalemia. Ng et al (2011) reported hypokalemia in 89% of thiopental coma patients and hyperkalemia in 34% of these patients (Ng et al., 2011). Various reasons are postulated for the hypokalemia in thiopental coma patients; stress response, catecholamine surge, urinary potassium loss, use of insulin and or vasopressors (Ng et al., 2011). Thiopental also inhibits voltage dependent potassium currents leading to the intracellular sequestration of potassium. It also causes increased intracellular PH and promoting intracellular potassium shift (Ng et al ., 2011). Rebound

THIOPENTAL COMA AND PATIENTS OUTCOME

hyperkalemia occurs once thiopental coma is stopped; this happens because of sudden redistribution of potassium into the extracellular space. The rebound hyperkalemia correlates with amount of potassium replaced and hypokalemia prior to thiopental coma (Ng et al ., 2011). Hypernatremia occurred in 90% of our thiopental coma patients. It had a significantly higher incidence in non-survived patients. Hepatic and renal impairment was also significant higher in nonsurvived patients. In the literature it is described that up to 87% on thiopental coma will have hepatic impairment and renal impairment in 47% Schalen et al., (1992). Various types of gastrointestinal complications are described in patients on thiopental coma ranging from enteral feed intolerance to the bowel ischemia (Cereda et al ., 2009) in our study only gastrointestinal complication occurred was enteral feeding intolerance and its incidences were lower than mentioned in the literature. It may be due to our policy of using prokinetic medications in patients on enteral feeding. Twenty- three percent of our patients had septic shock, it has higher incidence in non-survived patients. Barbiturate coma causes leukopenia, granulocytopenia, lymphocyte suppression and the end result of all these is immunosuppression leading to the higher incidence of infection and septic shock (Loop et al., 2002). Post decompressive craniectomy use of thiopental coma didnt improve the survival in our patients (Table 2). Schalen et al (1992) described the negative impact on survival if patients are elder or more than 40 years of age (Schalen, et al., 1992). In our study non survived thiopental coma were older but there was no stastically significant difference. As described in the literature, in our study the mortality of thiopental coma patients was 59%; 11% survived without any functional deficit whereas 5% of our patients had mild to moderate functional disabilities. Recently An et al (2010) have compared higher dose and low dose of barbiturate for induction of coma in patients with severe brain injury with refractory intracranial hypertension. They proved that the low dose of barbiturate coma has a significantly lower incidence of adverse effect and better patient outcome.

CONCLUSION Thiopental coma significantly lowers the refractory intracranial hypertension. Forty-two percent of our thiopental coma patients had survived and with a full functional recovery in 11% of patients. In our study the risk factors for mortality of thiopental coma patients were more than one vasopressor use, hypokalemia, hypernatremia, and renal impairment. According to our study age of the patient and decopmressive craniectomy did not showed any survival benefits. REFERENCES
Brain trauma foundation, American association of neurological surgeons, Congress of neurological surgeons. Guidelines for the management of severe traumatic brain injury. J Neurotrauma; 2007, 24:S1-106 Perez-Barcena J, Barcel B, Homar J, Abadal JM, Molina FJ, De la Pena et al. 2005. Comparison of the effectiveness of pentobarbital and thiopental in patients with refractory intracranial hypertension. Preliminary report of 20 patients. Neurocirugia (Astur). 16: 5-12 An HS, Cho BM, kang JH, Kim MK, Oh SM, Park SH. 2010. Efficacy of low dose barbiturate coma therapy for the patients with intractable intracranial hypertension using the Bispectral index monitoring. J Korean Neurosurg Soc. 47: 252-257 Chin KJ, Ng SY, Kwek TK. 2006. Thiopentone barbiturate coma: A review of outcome and complications. Can J Anesth. 53: S1-26098 Schalen W, Masseter K, Wordstrom CH. 1992. Complications and side effects during thiopentone therapy in patients with severe head injuries. Acta Anesthesiol Scand. 36:369377 Frenette AJ, Bernard F. 2004. Barbiturate coma use and safety in traumatic and non-traumatic brain injury. Crit Care Med. 32:A101 Nadal P, Nicolas JM, Font C, Vilella A, Nogue S. 1995. Pneumonia in ventilated head injury patients. The role of thiopental therapy. Eur J Emerg Med. 2:14-16 Ng SY, Chin KJ, Kwek TK. 2011. Dyskalemia associated with thiopentone barbiturate coma for refractory intracranial hypertension. A case series. Intensive Care Med. 37: 12851289 Cereda C, berger MM, Rossetti AO. 2009. Bowel ischemia: a rare complication of thiopental treatment for status epilepticus. Neurocrit Care. 10: 355-358 Loop T, Liu Z, Humar M, Hoetzel A, Benzing A et al. 2002. Thiopental inhibits the activation of nuclear factor kB. Anesthesiology. 96: 1202-1213.