Management of Acute Ischemic Hypoxic Encephalopathy in Newborns with Hyperbaric Oxygen: A Review

Review Article

Austin J Cerebrovasc Dis & Stroke. 2016; 3(2): 1049.

Management of Acute Ischemic Hypoxic Encephalopathy in Newborns with Hyperbaric Oxygen: A Review

Sánchez EC*

Department of Hyperbaric Medicine, Universidad Nacional Autónoma de México, Mexico

*Corresponding author: E. Cuauhtémoc Sánchez, Department of Hyperbaric Medicine, Hospital Agustín O´Horan and Centro de Especialidades Médicas del Sureste, Universidad Nacional Autónoma de México, Calle 38 # 101c x 27 y 29 Col. Buenavista, Mérida97127, Yucatán, Mexico

Received: September 20, 2016; Accepted: November 21, 2016; Published: November 23, 2016

Abstract

Objectives: Describe the use of HBO2 in the management of acute ischemic hypoxic encephalopathy.

Materials and Methods: The therapeutic mechanisms of hyperbaric oxygen in acute ischemic hypoxic encephalopathy are outlined, based on information obtained from peer-reviewed medical literature.

Results: HBO2 promotes survival of marginal tissue (penumbra), reduces edema, improves microcirculation, breaks the edema-hypoxia-edema vicious cycle, enhances healing, promotes growth factors up-regulation and improves neovascularization. At cellular level, it maintains the levels of ATP, restores mitochondrial dysfunction, reduces oxidative stress and apoptosis, and promotes anti-oxidant effects. HBO2 did not show significant differences in fatality rates at six months (RR0.97, 95%CI 0.34 to 2.75, p=0.96). It showed improvement in the disability and functional performance scales. Trouillas Disability Scale was lower with HBO2 (MD 2.2 point reduction with 95%CI 0.15 to 4.3, p=0.04), and the mean Orgogozo Scale was higher (MD 27.9 points, 95%CI 4.0 to 51.8, p=0.02).

Conclusion: When used promptly, HBO2 can modify cerebral inflammation, ischemia, hypoxia, and ischemia-reperfusion injury. It helps preserve marginal tissue and recover the ischemic and metabolic penumbra. A prospective, randomized, and controlled study within the window of opportunity (< 5h) in a stroke center is needed, to determine the real use of HBO2 in these cases.

Keywords: Acute ischemic hypoxic encephalopathy, Hyperbaric oxygenation, Ischemia-reperfusion-injury, Mitochondrial dysfunction

Introduction

Acute ischemic-hypoxic encephalopathy (stroke) is the most important preventable cause of disability for Americans and the second cause of death worldwide. Every year, more than 795,000 people in the US have a stroke and about 610,000 of these, are first or new strokes. About 25% of strokes (185,000) happen in people who had a previous stroke. The prevalence of stroke (2009-2012) for people aged 20-39, was 0.2 for men and 0.7 for women; for ages 40-59, 1.9 for men and 2.2 for women; for ages 60-79, 6.1 for men and 5.2 for women; and for ages 80+, 15.8 for men and 14.0 for women. About 87% of all strokes are ischemic strokes [1-3].

The risk of having a stroke varies with race and ethnicity. The risk of having a first stroke is nearly twice as high for African Americans compared to whites, and African Americans are more likely to die following a stroke than are whites. Hispanics’ risk of stroke falls between that of whites and African Americans. American Indians, Alaska Natives, and African Americans are more likely to have had a stroke than all other groups [1-3].

The incidence of mortality and morbidity due to neonatal acute ischemic-hypoxic encephalopathy (AIHE) has not changed substantially in the last 40 years. It is estimated that close to 25% of the neonatal deaths and 8% of all deaths at 5 years of age throughout the world, annually, are associated with signs of asphyxia at birth [4,5]. Death or moderate to severe disability can occur in 50-60% of infants diagnosed as having moderate to severe AIHE [6,7].

The average length of stay in non-federal short-stay hospitals was 4.8 days, although in some hospitals; it extended to up to 10.9 days [3]. The annual cost of stroke in the US is estimated in $34 billion. It includes the cost of health care services, medications and workdays lost [1-3]. Stroke has high direct costs and very high indirect costs. It is estimated that indirect costs account for 80% of the total cost. According to the World Health Organization (WHO) stroke will become the fourth cause of the Global Burden of Disease (GBD) in 2030 [8,9].

In some clinical studies, the 5-year survival rate is 50%. Specialized stroke units have reduced morbidity and mortality (OR 2.2, 95%CI 1.6-2.8, p<0.001), but less than 20% of all stroke cases arrive at the units within the window of treatment (3 to 5 hours) [10]. The phrase “time is brain”, emphasizes that human tissue is rapidly lost as stroke progresses and emergent evaluation and therapy are required [11].

AIHE is such a devastating pathology that any gain, no matter how small, can make a big difference in these children’s and their families’ quality of life (QoL). Prompt treatment should restore adequate perfusion and correct metabolic or cellular alterations. Maintaining adequate perfusion and the cellular metabolic needs may be the cornerstone to reduce CNS damage and promote early neuro protection [3,12,13]. The extent of the damage depends on the duration, extension, localization, comorbidities and metabolic changes of the lesion [3,14].

Pathophysiology of AHIE (Ischemia- Reperfusion Injury)

When there is an interruption of the cerebral blood flow or oxygen supply to the Central Nervous System (CNS), several changes occur depending on the degree of hypoxia; these could be reversible or irreversible [15]. Reversibility depends on the mitochondrial ability to maintain ATP production. Once it stops, there is a dysfunction of the ion pumps (Na-K and K-Ca) that eventually will create cytotoxic edema. When the mitochondrial dysfunction is severe, calcium is released into the cytoplasm and becomes the first inflammatory mediator [16,17].

The main player in the pathophysiology of acute ischemichypoxic encephalopathy (AIHE) is the ischemia-reperfusion injury (IRI) to the Central Nervous System (CNS). The injury is the result of a series of ischemic and metabolic events that present shortly after the interruption of flow, oxygen, and nutrients to the affected regions of the brain [3].

The center of the lesion is the area of necrosis surrounded by the area of ischemia, hypoxia, and edema, i.e. the recoverable area of the brain (penumbra). The area of penumbra constitutes close to 80% of the damaged brain in IRI. If the ischemic and metabolic penumbras are not resolved in a timely and effective fashion, the damage will extend and deepen due to IRI and apoptosis [3].

Mitochondria in AIHE: There are seven stages of cellular shock in (AIHE). The first four stages are reversible. The reversibility depends on cells’ capability to maintain adenosine tri-phosphate (ATP) production by the mitochondria [8]. Once ATP is reduced beyond a critical level (< 1 mol/kg), there is an energy crisis within the cell [9]. During the CNS energy crisis, hypoxia upsets the passage of protons (H+) across the mitochondrial complexes, reducing production of ATP at the ATPase-synthase level. This produces oxidative stress and the increase of reactive oxygen species (ROS)and its production inside the mitochondria; also, the promotion of neural (nNOS) and inducible nitric oxide synthase (iNOS) production [18,19]. If the oxidative stress is not controlled early, it will progress to oxidative damage. This generates an increase of the intrinsic apoptotic pathway. The energy crisis also promotes glutamate production, the most important excitatory transmitter in the brain [20-22].

With mitochondrial dysfunction, there is a loss of calciumpotassium and sodium-potassium cellular pumps, which creates ionic misbalance and cytotoxic edema. The release of cytochrome C occurs immediately before total mitochondrial dysfunction, due to the rise of nitric oxide. The opening of the mitochondrial transition pore follows. Once the pore is open, it releases its calcium content into the cytosol, increasing cellular edema and affecting cellular homeostasis [3,23-26].

Inflammation in AIHE: Calcium is the first modulator of inflammatory cascades [27,28]. It stimulates the activation of calcium protease, which enhances xanthine dehydrogenase conversion to xanthine oxidase, promoting the production of reactive oxygen species (ROS) [29]. It also stimulates the arachidonic acid cascade with the subsequent elevation in the levels of cyclooxygenase (COX), lipoxygenase, leukotriene, thromboxane and prostaglandins [30]. It also promotes the expression of the most important transcription factor for inflammation, nuclear transition factor kappa b (NFκb) and enhances the production of endothelins and cytokines (IL-1, IL- 6, IL-8, TNF-α) [31-34]. There is also an elevation of interferon-Υ, glutamate, Caspases (3,8, and 9), hypoxia induced factor-1α (HIF- 1α), and nitric oxide from inducible nitric oxide synthase (iNOS) [35-38].

At endothelial level, there is an increased expression of adhesion molecules (selectins, vascular adhesion molecule, intercellular adhesion molecule) and leukocyte (integrin beta 2).In the late phase of IRI, the adhesion molecules are the predominant mediators of damage, promoting leukocytes production of ROS, perivenular arteriolar vasoconstriction, apoptosis, and creating the no-flow state [39-42].

Few of the early neuro protectors tested have made a real difference. Stenting, angioplasty, hypothermia, and thrombolysis have shown benefits, especially when applied in the first 3 to 5 hours of the onset of AHIE. Only the Food and Drug Administration (FDA) has accepted the plasminogen activator (rtPA) [43-48]. Nevertheless, none of these have proven to resolve the metabolic penumbra. Medication has not shown the same neuroprotective effects of other therapies [49-51].

Growing evidence suggests that a spectrum of epigenetic processes play an important role in the pathophysiology of cerebral ischemia. DNA methylation, histone deacetylase, histone methylation and micro RNAs (miRNAs) regulate vascular and neuronal regeneration after cerebral ischemia. MiRNAs are supposed to be potential biomarkers for stroke and other related pathologies. Epigenetic strategies for ischemic stroke treatments may modulate neural cell regeneration and promote brain repair and functional recovery [52,53].

Hyperbaric Oxygen in Acute Hypoxic Ischemic Encephalopathies

Hyperbaric oxygen (HBO2) is a treatment option in which a patient breathes 100% oxygen while inside a treatment chamber at a pressure higher than 1.4 atmospheres absolute (atm abs). The treatment chamber could be mono- or multi place [3,54].

HBO2 is based on gas laws. Increasing the pressure inside the chamber will promote the amount of oxygen that will dissolve in all body fluids, especially in plasma. The normal treatment pressure varies from 1.5 to 3.0 atm abs and lasts from 45 to 120 minutes, except for diving accident management that could take longer. The primary effect of breathing oxygen at pressure is hyper oxygenation. Partial pressures in plasma at 2.0 atm abs are close to 1500 millimeters of mercury (mmHg) and at 3.0 atm abs are around 2200 mm Hg [3,54].

HBO2 produces several secondary effects. Hyper oxygenation increases the endovascular oxygen partial pressure. Restoring tissue oxygen tension to normal or supernormal levels, will break the edema-hypoxia-edema vicious cycle. The vasoconstriction effect of HBO2, without affecting tissue oxygenation due to the increased partial pressure of oxygen, reduces tissue edema and improves microcirculation [55,56]. HBO2 also restores damage to the blood brain barrier (BBB) [57,58] and modulates the aquaporin 1response in the choroid plexus, neurons; and astrocytes; aquaporin 4 in astrocytes; and aquaporin 9 in astrocytes and catecholaminergic neurons [59,60].

HBO2 promotes wound healing, angiogenesis, lymphogenesis, and increases growth factor production [3,12,54,55,61-67]. HBO2 has direct and indirect antimicrobial effects [12,68,69]. It promotes bone remodeling [70-72] and has rheological effects that are synergistic with pentoxifylline [73]. It also reduces hyper coagulation induced by zymosan and in multiple organ failure [74,75]. Finally HBO2 increases the mobilization of stem cells from bone marrow and has been used for traumatic brain injury and spinal cord injury [76-78].

By reducing cerebral loss of energy, hyperbaric oxygenation restores cellular ion homeostasis, reduces acidosis, and stabilizes cellular calcium. It also limits excitatory mediators, ROS toxicity, apoptosis, and ischemia reperfusion injury. This is accomplished through several mechanisms. First, it increases oxygen tension and restores oxygen content at tissue and cellular level. If it is applied in a timely fashion, it salvages the cerebral ischemic and metabolic penumbrae, and restores mitochondrial oxidative phosphorylation (Figure 1) [3,12,79,80].

Citation: Sánchez EC. Management of Acute Ischemic Hypoxic Encephalopathy in Newborns with Hyperbaric Oxygen: A Review. Austin J Cerebrovasc Dis & Stroke. 2016; 3(2): 1049. ISSN : 2381-9103