Clinical Implications of Bilirubin-Associated Neuroprotection and Neurotoxicity

Bilirubin is a primary product of heme catabolism and exhibits both neuroprotective and neurotoxic effects. When present at physiologic concentrations, bilirubin is a potent antioxidant and serves to protect brain tissue from oxidative stress insults. The use of the anesthetic propofol attenuates ischemic injury in rats by exploiting these neuroprotective properties. At pathologic levels, bilirubin has been implicated as a neurotoxic agent, demonstrating the ability to aggregate and adhere to cellular membranes, thereby disrupting normal cellular function. Bilirubin-associated toxicities are amplified by administering drugs such as anesthetics that compete with bilirubin for albumin binding sites, resulting in increased plasma bilirubin concentrations. As such, it is crucial that bilirubin is considered in the critical care management of patients with hemorrhagic stroke, cerebral ischemic damage, and critically ill newborns. Central Mendez et al. (2013) Email: [email protected] Int J Clin Anesthesiol 1(2): 1013 (2013) 2/3 after middle cerebral artery occlusion was shown to attenuate ischemic injury in part by upregulating HO-1 [7]. Furthermore, experimental evidence in a mouse model of cerebral ischemia demonstrated greater neuronal damage in HO2-/knockout mice compared to their wild type counterparts, providing additional support for bilirubin’s neuroprotective role in the brain [8]. Due to bilirubin’s antioxidant capabilities, many have proposed that physiologic neonatal unconjugated hyperbilirubinemia evolutionarily developed as a protective mechanism [3]. BILIRUBIN-ASSOCIATED NEUROTOXICITY In addition to serving a protective role, bilirubin has also been implicated in the progression of neurological dysfunction in many pathological states. Many of these conditions increase bilirubin concentrations above physiologic levels, where the toxic effects of bilirubin start to exceed the protective antioxidant benefits, resulting in damage to the nervous system [9]. Bilirubin is neurotoxic when it reaches micromolar concentrations, and this is the same level at which it was found to aggregate and adhere to cellular membranes, disrupting normal cellular function [10]. In the critical care setting, it is important that attention is given when selecting drugs that compete with bilirubin for albumin-binding sites since they effectively increase plasma bilirubin levels. For example, the fatty acid components of propofol displace bilirubin from albumin, amplifying bilirubin-associated neurotoxicity in susceptible patients [11]. CLINICAL IMPLICATIONS OF BILIRUBIN ACTIVITY Neurotoxicity following hemorrhagic stroke Hemorrhagic stroke occurs when a weakened blood vessel ruptures, resulting in bleeding into the brain and subsequent neuronal injury. Patients with hemorrhagic stroke can have additional complications that lead to secondary damage days after the initial insult, such as vasospasm and cerebral ischemia [12]. The presence of blood in the brain locally induces HO-1 causing an increase in production of unconjugated bilirubin [2]. Preclinical data has suggested that the environment immediately surrounding the hematoma is highly conducive to oxidative reactions, facilitating the conversion of bilirubin into bilirubin oxidation products (BOXes) [12]. BOXes in cerebrospinal fluid follow a similar time course as the onset of cerebral vasospasm, and have proven to be vasoactive in both in vivo and in vitro studies [2]. These results collectively suggest that BOXes either cause or contribute to cerebral vasospasm and the resulting delayed neurologic deterioration following hemorrhagic stroke. Bilirubin as a negative prognostic biomarker in ischemic stroke Ischemic stroke takes place when a blood vessel supplying the brain is obstructed, which produces downstream hypoxicischemic conditions and increased oxidative stress [13]. With these conditions, bilirubin formation is amplified significantly due to HO-1 induction. It has been proposed that the serum bilirubin level is a biomarker of the degree of ischemic damage following stroke [14]. Clinical studies have found that high serum bilirubin levels measured at the time of clinical presentation positively correlate with stroke severity and degree of disability three months post-ictus [13]. These data provide compelling evidence for the use of bilirubin as an early clinical indicator in the management of patients following ischemic stroke. Manifestations of bilirubin activity in the neonate Newborns commonly develop a transient increase in unconjugated bilirubin levels, commonly referred to as “physiologic jaundice,” which often resolves without any consequences [15]. By virtue of the intrinsic antioxidant effects of bilirubin, physiologic jaundice confers protection to neonatal tissue that otherwise would be more susceptible to damage by oxidative stress [10]. Additionally, breastfed neonates have higher unconjugated bilirubin levels than formula fed infants, suggesting that physiologic jaundice is well tolerated and maybe confers an evolutionary advantage [16]. However, additional sources of hemolysis may increase the production of unconjugated bilirubin concentrations above this physiologic range [3]. These conditions include hemolysis due to ABO or Rh blood incompatibilities between the mother and fetus, G6PD deficiency, and trauma during birth [17]. Pathological levels of bilirubin can be neurotoxic leading to kernicterus or neonatal bilirubin encephalopathy [9]. In the brain, high bilirubin concentrations can inhibit mitochondrial enzymes, disrupt DNA synthesis, and attenuate protein production [3]. Acute bilirubin encephalopathy results in injury to the basal ganglia and various brain stem nuclei [18]. Universal neonatal hyperbilirubinemia screening programs have been implemented to detect and treat pathologic jaundice and prevent kernicterus [18]. There is a paucity of publications about common anesthetic medications used in neonates (such as propofol used during neonatal surgery) and their interactions with bilirubin levels. Research in neurotoxicity and neonatal anesthesia should consider the interplay between anesthetics and levels of unconjugated bilirubin.