Part 1:Contemporary Neuroprotection Strategies During Cardiac Surgery: State Of The Art Review

ali.ma@wecistanche.com

Palesa Motshabi-Chakane 1, Palesa Mogane 1 , Jacob Moutlana 1, Gontse Leballo-Mothibi 1, Sithandiwe Dingezweni 1 , Dineo Mpanya 2 and Nqoba Tsabedze2,*

Department of Anaesthesiology, Faculty of Health Sciences, School of Clinical Medicine,

University of the Witwatersrand, Johannesburg 2193, South Africa; Palesa.Motshabi@wits.ac.za (P.M.-C.); moganep@gmail.com (P.M.); drhlamatsi@gmail.com (J.M.); gleballomothibi@gmail.com (G.L.-M.); sdingezweni@ymail.com (S.D.)

Department of Internal Medicine, Division of Cardiology, Faculty of Health Sciences,

School of Clinical Medicine, University of the Witwatersrand, Johannesburg 2193, South Africa;

Dineo.Mpanya@wits.ac.za

Correspondence: Nqoba.Tsabedze@wits.ac.za

Citation: Motshabi-Chakane, P.; Mogane, P.; Moutlana, J.;

Leballo-Mothibi, G.; Dingezweni, S.; Mpanya, D.; Tsabedze, N. Contemporary Neuroprotection Strategies during Cardiac Surgery: State of the Art Review. Int. J. Environ. Res. Public Health 2021, 18, 12747. https://doi.org/10.3390/ ijerph182312747

Academic Editor: Paul B. Tchounwou

Cistanche tubulosa powder has a very good neuroprotective effect

Abstract: Open-heart surgery is the leading cause of neuronal injury in the perioperative state, with some patients complicating with cerebrovascular accidents and delirium. Neurological fallout places an immense burden on the psychological well-being of the person affected, their family, and the healthcare system. Several randomized control trials (RCTs) have attempted to identify therapeutic and interventional strategies that reduce the morbidity and mortality rate in patients that experience perioperative neurological complications. However, there is still no consensus on the best strategy that yields improved patient outcomes, such that standardized neuroprotection protocols do not exist in a significant number of anesthesia departments. This review aims to discuss contemporary evidence for preventing and managing risk factors for neuronal injury, mechanisms of injury, and neuroprotection interventions that lead to improved patient outcomes. Furthermore, a summary of existing RCTs and large observational studies are examined to determine which strategies are supported by science and which lack definitive evidence. We have established that the overall evidence for pharmacological neuroprotection is weak. Most neuroprotective strategies are based on animal studies, which cannot be fully extrapolated to the human population, and there is still no consensus on the optimal neuroprotective strategies for patients undergoing cardiac surgery. Large multicenter studies using universal standardized neurological fallout definitions are still required to evaluate the beneficial effects of the existing neuroprotective techniques.

Keywords: neuroprotection; cerebrovascular; delirium; cardiac surgery; cardiac anesthesia

1. Introduction

Neuroprotection encompasses strategies that preserve neuronal structure and function. Neurological fallout must be prevented in all patients undergoing any form of surgery, particularly those referred for cardiac surgery. For example, in a study involving 10,250 patients that underwent cardiac surgery, 221 (2%) experienced a postoperative stroke, and the duration of hospitalization was significantly longer in these patients compared to those without postoperative stroke (10 vs. 16 days, p < 0.001) [1]. Numerous randomized controlled trials (RCTs) have investigated the efficacy of pharmacological and non-pharmacological interventions that reduce neurological injury during and after cardiac surgery [2–4]. However, there is still controversy on the optimal neuroprotection strategy that leads to better patient outcomes.

This review aims to discuss contemporary evidence for preventing and managing risk factors for neuronal injury, mechanisms of injury, and neuroprotection interventions that lead to improved patient outcomes.

2. Materials and Methods

Data on RCTs using various neuroprotective agents was obtained after conducting a systematic literature search in PUBMED, Scopus and Google scholar. The following search string was used: (neuroprotection strategies OR neuroprotection OR pharmacological therapy OR non-pharmacological therapy) AND (cardiac surgery OR cardiopulmonary bypass surgery) AND (postoperative cognitive dysfunction OR stroke OR delirium OR seizure) AND adult patients. We included randomised control trials, systematic reviews and meta-analyses published in the past 15 years. The focus of the literature search was on pharmacological and non-pharmacological neuroprotective strategies (Table 1). Where systematic reviews or meta-analyses of the RCTs of interventions were available, these were preferentially reported on rather than the individual RCTs.

Table 1. Summary of randomized control trials comparing interventions to standard therapy for neuroprotection in cardiac surgery.

Abbreviations: RCT, randomised control trial; CPB, cardiopulmonary bypass; POCD, postoperative cognitive dysfunction; MM-RR, Mantel–Haenszel risk ratio; CI, confidence intervals; OR, odds ratio; TIVA, total intravenous anaesthesia; WMD, weighted mean difference; POD, postoperative delirium; CABG, coronary artery bypass grafting; MAP, mean arterial pressure; SD, standard deviation. Lidocaine* bolus of 1–1.5 mg/kg. Infusion of 2–4 mg/kg/hour: dependent on centres’ protocol. Lidocaine plasma concentrations ranged between 7 and 30 µmol/L. Magnesium* doses of at least 2 g within 24 h of cardiac arrest or cardiac surgery. Rivastigmine*, 1.5 mg dose 8 hourly, from evening preoperatively; a total of 22 doses (up to day 6 postoperatively). Deep hypothermic circulatory arrest (DHCA) with retrograde cerebral perfusion (RCP)*, cooled to nasopharyngeal temperatures of 14.1 o C to 20 o C. Remote ischaemic preconditioning (RIPC)* by the use of BP cuff in the upper limb with three alternating cycles of inflation (200 mmHg for 5 min) and deflation for 5 min (reperfusion). Cerebral oxygenation monitoring*: Cerebral deoxygenation episodes < 60% for > 60 s.

3. Incidence and Prevalence of Neurological Deficit after Cardiac Surgery

The International Code of Nomenclature recommends the term “perioperative neurocognitive disorders” to describe both postoperative delirium (POD) and postoperative cognitive dysfunction/decline (POCD), with the latter not having a Diagnostic and Sta- tistical Manual of Mental Disorders 5 (DSM5) criterion for diagnosis [14,15]. Another broad terminology used is “neurological injury post-cardiac surgery.” Perioperative stroke, delirium, and encephalopathy are some of the neurological sequelae of cardiac surgery [16]. The risk of stroke varies depending on the type of surgery performed [17]. For example, double or triple valve surgery is associated with a 10% risk of stroke, while the risk is lower in patients referred for “beating-heart”, also known as “off-pump”, coronary artery bypass graft (CABG) surgery [17].

In a meta-analysis involving 174,969 patients referred for cardiac surgery, the pooled event rate for early and delayed strokes was each less than 1% [18]. Furthermore, delirium is common in the elderly, with a higher incidence of 12% [19]. There is a paucity of studies reporting neurological complications after cardiac surgery in patients residing in low and middle-income countries (LMIC). In a retrospective chart analysis of 1218 consecutive patients referred for CABG surgery in Johannesburg, the perioperative stroke rate was 1.2% [20]. Moreover, one year after the onset of a stroke, the annual cost in British pounds per person is estimated at GBP 18,081, increasing to GBP 22,961 in patients older than 84 years [21]. These high healthcare costs necessitate an urgent need for strategies that reduce the burden of stroke post-cardiac surgery.

4. Risk Factors Associated with Neurological Decline

In addition to the type of surgery, the stroke risk is increased in patients with existing cerebrovascular disease, peripheral vascular disease, diabetes, hypertension, a history of previous cardiac surgery, preoperative infection, urgent surgery, cardio-pulmonary bypass (CPB) time of more than 2 h, the need for intraoperative hemofiltration, and high transfusion requirements [18]. Risk factors for cognitive decline post-cardiac surgery are multifactorial (Figure 1). The neurological outcomes are diverse and have previously been classified as Type I (includes fatal or non-fatal stroke, stupor, or coma at discharge) and Type II, which includes cognitive function deterioration, memory deficit, or seizures [22].

Figure 1. Risk factors for neuronal injury before, during, and after cardiac surgery.

Assessment for the cognitive function must be done preoperatively and postoperatively using a validated cognitive test assessment tool. Furthermore, the timing of testing impacts the rate of diagnosing neurological injury post-cardiac surgery [23]. Diagnostic tests done within 30 days postoperatively have confounders such as postoperative pain, and medication use may affect the assessment score [15]. Emergence delirium occurs before, during, or after awakening from anesthesia, while postoperative delirium occurs 24–72 h after, and postoperative cognitive decline occurs weeks to months postoperatively [15,24]. Most of the risk factors for POCD are related to their potential for interfering with basic principles of organ protection, such as oxygen delivery, organ perfusion, organ nutritional requirements, pre-existing organ reserves, and any toxic exposure during surgery [25]. Prevention of POCD post-cardiac surgery is directed at understanding and managing these risk factors.

5. Mechanism of Brain Injury

The mechanism of cardiac surgery-related brain injury is complex and multifactorial. The most common mechanism results from ischaemic causes leading to cerebral hypoperfusion and embolism [26,27]. In addition to ischaemic causes, the inflammatory response, cerebral hyperthermia, hyperglycemia, perioperative anemia, and atrial fibrillation have also been implicated (Figure 2) [27].

Figure 2. Mechanisms of brain injury.

5.1. Altered Cerebral Perfusion

The effects of cardiac surgery and CPB on cerebral perfusion can be classified into cerebral hypoperfusion and reperfusion. Cerebral hypoperfusion resulting from reduced cerebral blood flow (CBF) during CPB is the primary cause of ischaemic brain injury. This form of injury may further be exacerbated by the impaired clearance of micro-emboli during periods of reduced CBF. Advanced age, extensive cerebrovascular disease, and a history of stroke increase the risk of cerebral hypoperfusion [26]. The early period of CPB is usually associated with episodes of a low mean arterial pressure (MAP) during cannula insertions and manipulation of the large vessels of the heart. As a result, cerebral hypoperfusion may occur, and blood flow in the watershed regions of the brain may become critically reduced. Towards the end of CPB, cerebral reperfusion occurs, resulting in the generation of free oxygen radicals [28]. During the ischaemia/reperfusion injury, various secondary mechanisms are initiated and ultimately lead to the death of neurons.

5.2. Hypoxia Related Cerebral Injury

Hypoxic conditions occurring during periods of cerebral hypoperfusion result in the upregulation of various molecules, such as hypoxia-inducible factor (HIF) and sulfonylurea receptor 2A (SUR2A) protein, which then initiate events that may lead to neuronal injury [28]. A drop in oxygen levels leads to the translocation of HIF into the neuronal cell nucleus. HIF is comprised of an α and β subunit. The α subunit is constitutively expressed. However, it rapidly degrades under normal oxygen concentrations. Furthermore, hypoxia is associated with a decline in adenosine triphosphate (ATP) levels, which results in the failure of ATP-dependent ion pumps, a rise in intracellular sodium and calcium levels, and ultimately cytoplasmic and mitochondrial swelling, which may lead to cell death [28].

5.3. Reperfusion Related Cerebral Injury

The reperfusion phase is associated with reactive oxygen species (ROS) production, predominantly in the mitochondria. The ROS react with nitric oxide (NO) to form peroxynitrite. This molecule is highly reactive and nitrosylates proteins, leading to neuronal functional impairment and cerebral injury [28].

5.4. Cerebral Macro- and Micro-Embolism

Cardiac surgery often results in the production of various embolic materials. Ac- cording to size, emboli can be differentiated into macro-emboli, which occlude flow in arteries with a diameter of 200 µm or more, and micro-emboli, which occlude smaller arteries, arterioles and capillaries. Atherosclerotic plaques arising mainly from the aorta constitute macro-emboli [26], whereas micro-emboli consist of gaseous emboli and biologic aggregates such as thrombus, platelet aggregates and fat [26,28,29]. Emboli arising from inorganic debris such as fragments of polyvinyl chloride tubing and silicone antifoam have been reported in the past [29].

Although the CPB machine has protective mechanisms, such as bubble traps [28], gaseous emboli may still be introduced into the CPB circuit through venous cannulation, administration of drugs and from the open cardiac chambers of the left heart [26]. Furthermore, manipulation of the aorta during surgery increases the risk of embolization despite the placement of arterial filters [28,30]. Cerebral micro-embolism as a mechanism for cognitive dysfunction is supported by the presence of a relationship between cerebral macro/microemboli load during CPB and cognitive dysfunction in various studies [26,31–34]. Additionally, macro/micro-emboli can also occur during aortic decannulation, particularly when the patient has not received sufficient anticoagulation therapy.

5.5. Inflammatory Response

The inflammatory processes associated with CPB further exacerbate neuronal in- jury [27]. The interaction of patient blood with the CPB components such as tubing, reservoirs, the oxygenator and connections result in the activation of the complement system, leading to the release of pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNFα) [28,35]. This systemic inflammatory response results in blood-brain barrier leakage, cerebral oedema and ultimately cerebral derangement [28].

5.6. Cerebral Hyperthermia

Hyperthermia has also been reported to cause brain damage under various clinical conditions and has been shown to exacerbate neuronal death after ischemia. The detrimental effects of hyperthermia in the brain are related to hyperthermia-induced cell swelling and necrotic death in the case of very high temperatures [36]. During cardiac surgery on CPB, cerebral hyperthermia might occur due to the proximity of the aortic cannula to the cerebral vessels or underestimating brain temperature by standard monitoring [27].

5.7. Hyperglycaemia

The stress response induced by CPB and hypothermia during cardiac surgery leads to elevated serum glucose levels even in non-diabetic patients [27]. The pathophysiology of hyperglycemia-induced cerebral injury is multifactorial. Hyperglycaemia increases reactive oxygen species production via a protein kinase C-mediated pathway and the increased production of nicotinamide adenine dinucleotide phosphate (NADPH) [37]. The reactive oxygen species can lead to neuronal death, as described earlier. There is also a well-described association between hyperglycaemia and the increased expression of nuclear factor-kappa B [38]. The metabolic effects of hyperglycemia, such as increased lactic acid production with subsequent acidosis and mitochondrial dysfunction, is another suggested mechanism of hyperglycemia-associated cerebral injury [39].