2020 expert consensus statement on neuro-protection after cardiac arrest in China

Introduction

Cardiac arrest (CA) is one of the leading causes of human death and disability worldwide. Out-of-hospital CA (OHCA) occurs annually in 420,000 patients in USA, 350,000 in Europe and 544,000 in China (1,2). The incidence rate of OHCA in China is 41.84 per 100,000 (3) and higher when in-hospital CAs are recruited. Although new guidelines have greatly improved the administration of cardiopulmonary resuscitation (CPR), the outcomes of CA have not changed accordingly (1,4). The discharge rate of CA patients is 9% in Europe and 6% in North America, but only 2% in Asia (P<0.001) (5) and the situation in China is even worse. Research data shows that approximately 70% of patients with return of spontaneous circulation (ROSC) die from brain damage (6) because the brain is sensitive to ischaemia and hypoxia. After ROSC, any brain injury may lead to residual neurological complications, vegetative conditions, and death.

Clinical studies of CA patients face the difficulties of recruitment and prognosis prediction. This has resulted in a lack of standardized data on brain protection after CPR which is problem for medical practitioners and researchers worldwide. Furthermore, the research needed to produce such data involves comprehensive and complex collaborative treatment and evaluation processes involving multiple scientific and clinical disciplines and requires the participation of a full multidisciplinary team. There is both poor awareness and low implementation of neuro-protection after successful CPR in China and there are currently no guidelines for neuro-protection in CA patients in China or abroad. The Brain and Vascular Branch and the First Aid and Resuscitation Branch of the Chinese Society of Cardiothoracic and Vascular Anaesthesiology invite experts from neurology, neurosurgery, first aid, intensive care, anaesthesiology, cardiovascular science, and pharmacy to establish consensus on neuro-protection after CA.

Target users include pre-hospital emergency medical systems, emergency departments, intensive care units (ICU) and related parties. Recruited patients include those who are in the stage between successful CPR and the mid-stage of post-CA syndrome (PCAS). We present the following article in accordance with the RIGHT reporting checklist (available at http://dx.doi.org/10.21037/atm-20-7853).

Methods

A literature search included studies published from 1960 to March 2018 in the PubMed, Embase, ScienceDirect, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. The evidence was then graded, and the opinions and suggestions of experts sought. All recommendations were agreed to by expert vote.

Evidence was graded on the following basis:

• clinically relevant results from meta-analyses of large-sample double-blind randomised controlled trials (RCTs) or medium-sample RCTs;
• small-sample RCTs, RCTs without blind method, or RCTs employing effective surrogate markers;
• non-randomised controlled studies, observational (cohort) studies, case-control studies, or cross-sectional studies;
• comments of expert committees or relevant authorities.

The recommendation levels were as follows:

Grade A: data from multiple clinical randomised trials or meta-analyses;

Grade B: data from a single randomised trial or a single non-randomised study;

Grade C: data from expert consensus, case studies or medical standards;

Grade U: data lacking evidence or having insufficient evidence.

Brain injury mechanism after CA

Although the brain accounts for only 2% of total body weight, it has an extremely high metabolic rate. The ratio of cerebral blood flow to cardiac output lies between 15% and 20% and brain oxygen consumption accounts for 20–25% of body intake. The oxygen reserve of the brain is low, 65% of body glucose consumption occurs in the brain (7), and its tolerance to ischaemia and hypoxia is poor. The primary mechanism of brain injury is closely related to the time window of ischaemia and hypoxia caused by the interruption of blood flow after CA and irreversible damage occurs when cerebral blood flow is completely interrupted for more than 5 minutes. Severe brain blood barrier disruption is also strongly associated with poor neurological outcomes(8). After ROSC, the brain experiences reperfusion injury causing secondary injury. Understanding the patho-physiology of brain injury in CA and proactively performing brain protection to alleviate brain damage will improve the survival rate and neurological prognosis.

Hypoxic-ischaemic brain injury (HIBI)

Current studies suggest that the main factor affecting the prognosis of CA after CPR is HIBI (9). Studies show that HIBI results in 68% of in-hospital and 23% of OHCA deaths (10).

After CA, systemic blood flow stops. Ten to fifteen seconds after cerebral blood flow is interrupted, the oxygen storage of brain cells is exhausted and the production of adenosine triphosphate (ATP) ceases, which affects energy-dependent particle pathways, causing intracellular Na+ accumulation and cell oedema. After 4 to 5 minutes, ATP is depleted, brain cells begin anaerobic metabolism, and lactic acid accumulation in the brain causes brain cell acidosis.

When cerebral blood flow is interrupted, the depolarisation of brain cell membranes causes an influx of Ca²⁺ which mainly accumulates in the mitochondria. This further inhibits mitochondrial oxidative phosphorylation causing mitochondrial dysfunction, the rapid consumption of ATP in brain cells, the release of excitatory neurotransmitters, the activation of lipases and proteases, and eventually brain cell apoptosis (11). Fundamental studies have confirmed that the release of large amounts of excitatory amino acids during cerebral ischaemia has toxic effects on neural cells, among which glutamate has the highest content, the widest distribution, and the strongest influence. The ischaemic time frame and glutamate concentration are proportional to the resulting level of neural cell damage (12).

After onset of ischemia, inflammatory processes start immediately and evolve through several phases as well (13). Some studies found inhibited inflammation may decrease pathological damage to brain tissue after cardiac arrest (14,15). To date, our understanding of inflammation after global brain ischemia is partly derived from the expanding knowledge on inflammation after focal brain ischemia although differences exist (16).

Ischaemia-reperfusion brain injury

During CPR, partial cerebral blood flow is restored. Increased blood perfusion results in an increase in reactive oxygen species, inflammatory mediators, cytokines, and neutrophils, which can lead to secondary brain cell damage. After ROSC, brain auto-regulation dysfunction can lead to regional differences in cerebral perfusion. This means continuous hypoperfusion occurs in some brain regions and relative hyperperfusion occurs in others. While hypoperfusion can lead to persistent ischaemic neuronal damage, hyperperfusion can exacerbate brain oedema and brain damage.

Ischaemia-reperfusion injury is primarily caused by oxygen free radical-induced damage cascades, lipid peroxidation, and deoxyribonucleic acid/ribonucleic acid cleavage. This further exacerbates the extent of damage because of changes to blood-brain barrier permeability, complement activation, and the aggregation and adhesion of coagulation factors, platelets, activated microglia, and infiltrated lymphocytes (17). Histological evidence of these damage mechanisms can appear as neuronal necrosis and apoptosis in the hippocampus, cortex, cerebellum, striatum, and thalamus and can be seen hours to days after resuscitation.

Neuro-protection

Brain protection refers to procedures to reduce brain cell damage and restore neurological dysfunction after brain ischaemia or hypoxia. Current intervention procedures include mild hypothermia therapy, mitochondrial protection, scavenging free radicals, improving cerebral haemodynamics, anti-inflammation and anti-oxidation treatments, and comprehensive medical treatments.

Mild hypothermia therapy

Mild hypothermia therapy refers specifically to intravascular mild hypothermia, or blood cooling, which is cooling through extracorporeal circulation, intravascular heat exchange, or intravenous infusion. A 1958 study was the first to evaluate its effects in patients following CA and reported the rescue rate of patients treated with low temperature of 33 °C was 50% in comparison to 14% in those treated with normal temperatures (18). In 2002, the N Engl J Med published the results of Australian and European prospective clinical studies which confirmed that mild hypothermia therapy can significantly improve the neurological function and survival rate of OHCA (19,20). Its role in brain resuscitation has quickly remained hot research topic and the recommendation that a body temperature of 32–36 °C be maintained in patients who are comatose after resuscitation has been made by the International Liaison committee on Resuscitation (ILCOR) and included in CPR guidelines (21). The “Practice Guideline: Reducing Brain Injury After Cardiopulmonary Resuscitation”, publication of the American Academy of Neurology in 2017, makes a class A recommendation for mild hypothermia treatment (target temperature of 32–34 °C, maintained for 24 hours) (22).

Brain metabolism can be reduced by 6–10% for every 1 °C decrease in body temperature. Mild hypothermia reduces the rate of free radical production, the influx of calcium ions, the degree of mitochondrial damage (23), and the production and release of excitatory amino acids such as glutamate, and inhibits the endogenous and exogenous apoptotic pathway to reduce cell death. It can also limit secondary cell damage by reducing brain oedema, repairing the blood-brain barrier, and inhibiting inflammatory responses (24). The mortality rate may increase by as much as 20% for each one-hour delay of mild hypothermia therapy (25). Studies showed targeted temperature management can improve long-term neurological outcome, such as memory function (26).

At present, most hospitals in China do not have equipment for direct intravascular blood cooling and instead use other cooling procedures including body cavity, body surface and drug cooling. Body cavity cooling involves the use of cooled sterile saline to lavage and cool the chest or abdominal cavity. However, this may entail operational difficulties such as ice water directly contacting the heart causing ventricular fibrillation or other heart rhythm disorders. Body surface cooling is performed using an ice cap or ice bag placed on the head and the superficial parts of large blood vessels. The procedure is simple, but the cooling speed is slow and the target body temperature is difficult to maintain. Artificial hibernation can also be achieved by administering chlorpromazine, promethazine, or Dilantin.

Although therapeutic hypothermia treatment is currently the only clinically proven brain resuscitation method, more evidence-based studies are required as there are many unresolved issues surrounding its use in clinical practice. Consensus on its treatment length, time course, cooling method, and rewarming speed is lacking and its influence on basal heart rate and neural function remains unclear. Controversy regarding its efficacy and safety in patients with in-hospital PCAS and the complications of its use also exist.

Recommendation 1: commence mild hypothermia therapy as soon as possible within 12 hours of the cardiopulmonary resuscitation of CA patients (target body temperature of 32–34 °C for 12–24 hours). (I, A).

Recommendation 2: intravascular cooling is preferred. If the conditions cannot be satisfied, other cooling methods may be considered. (IV, C).

Drug treatment

There is presently little direct evidence from clinical studies in the field of drug treatment, due to the urgent condition of CA patients, unpredictability of emergent events, and because many procedures during the rescue process cannot be interrupted. However, some drugs have been clinically shown to protect the brain by safeguarding mitochondria, guaranteeing perfusion, enhancing microcirculation, and improving energy metabolism.

The ROSC in CA patients enables the body to develop rapidly from “the ischaemia and hypoxia state of systemic blood flow disruption” to the “pathophysiological state of systemic ischaemia-reperfusion injury”. The process of ischaemia-reperfusion injury at this stage was defined as PCAS by the International Liaison Commission on Resuscitation (ILCOR), the American Heart Association’s Emergency Cardiovascular Care Committee (AHA-ECCC), and the Council on Cardiovascular Surgery and Anaesthesia (CVSA). This process can be divided into four main stages (27).

The first stage is within 20 minutes after CPR has reached ROSC and is defined as the ultra-early stage of PCAS. Here, the oxygen and glucose reserves of brain cells are gradually depleted, mitochondrial functions are damaged, and Ca²⁺ overload causes brain cell damage. This stage is the key time window for brain protection and mitochondrial protective drugs should be used as soon as possible.

The second stage is from 20 minutes after ROSC to 6–12 hours after resuscitation and is defined as the early stage of PCAS. The restoration of blood flow now results in secondary injury by inflammatory mediators, cytokines, and oxygen free radicals. Protection of mitochondria should continue and treatments providing anti-inflammation, anti-oxidation, and the elimination of inflammatory factors and oxygen free radicals should be proactively performed.

The third stage from 6–12 to 72 hours after resuscitation is defined as the mid-stage of PCAS and is the main stage of comprehensive treatments to correct metabolic disorders.

The fourth stage commences 3 days after resuscitation and is defined as the recovery stage of PCAS. This stage is the time in which to evaluate brain and neural functions to obtain an accurate prognosis.

Butylphthalide

Butylphthalide improves cerebral ischaemia, enhances the activity of mitochondrial ATP enzyme and mitochondrial complex IV, protects the integrity of membrane structure and the functions of mitochondria, and improves energy metabolism (28,29). After CA, the endurance effect of ATP promoted by butylphthalide can effectively increase the level and utilization rate of ATP in brain cells and reduce brain damage. In animal study, butylphthalide reduces neurovascular inflammation and ischemic brain injury (30). It can significantly improve the prognosis of the early or recovery stage of cerebral ischaemia through improving microcirculation in the ischaemic area, increasing cerebral blood flow and cerebral blood vessel density, opening collateral circulation, and promoting the recovery of cerebral blood flow (31-34). During the stage of ischaemia-reperfusion injury, the anti-radical action of butylphthalide can enhance the activity of superoxide dismutase (SOD) in serum and reduce malondialdehyde (MDA) content to promote the recovery of neurological function. The anti-inflammatory and anti-apoptosis effect of butylphthalide may also play an important role in brain protection after CA (35-39). Moreover, butylphthalide can upregulate the expression of 5-hydroxytryptamine (5-HT) in the ischaemic hippocampal penumbra and play a protective role in hippocampal neurons. By reducing the expression of matrix metalloproteinase-9 (MMP-9), butylphthalide also alleviates the degree of blood-brain barrier injury (40,41). Although this research evidence is mainly derived from animal studies of butylphthalide injection in the treatment of ischaemic stroke and phase III multi-centre RCTs (42,43), the mechanisms are sufficiently understood to recommend the use of butylphthalide injection in CA patients after CPR.

Recommendation 3: after establishing effective circulation in pre-hospital first aid CPR, CA patients should immediately receive intravenous butylphthalide infusion. This should be repeated 6 hours later, after which butylphthalide should be administered twice per day, at 25 mg (100 mL) per dose, for 14 days. (I, B).

Free radical scavengers

Edaravone is a small-molecule free radical scavenger that effectively passes through the blood-brain barrier, inhibits the activities of xanthine oxidase and hypoxanthine oxidase, stimulates the production of prostacyclin, reduces the production of leukotriene, and directly reduce the concentration of hydroxyl radicals generated after cerebral ischaemia. In this way, it can alleviate the damage caused by free radicals to macromolecules such as lipids, proteins, and nucleic acids and preserve the integrity of the membrane structure of important organelles, such as the cell membrane, mitochondria, and endoplasmic reticulum. The scavenging of free radicals also inhibits the release of inflammatory mediators, and the mitigation of inflammatory responses reduces the delayed death of neural cells, which contributes to the recovery of neural function after cerebral resuscitation (44,45). Fundamental studies have proven that edaravone can significantly improve neural function injuries in mice with brain oedema and in mice treated with CPR to improve survival rates (46).

Recommendation 4: CA patients should commence 30 mg of edaravone twice per day within 12 hours of CPR and this should continue for 14 days. (II, B).

Calcium channel antagonists

Calcium channel antagonists can reduce Ca²⁺ overload in brain cells, relax vascular smooth muscle, resist oxidation, and limit the damage caused by oxygen free radicals to the endothelium. Common calcium channel antagonists include nimodipine and lidoflazine. Although in theory, reducing Ca²⁺ influx can alleviate brain tissue damage, there is insufficient evidence in current studies demonstrating calcium channel antagonists have brain protection effects and the safety of these antagonists after CPR in CA patients remains to be confirmed.

Excitatory amino acid receptor antagonists

When cerebral ischaemia occurs, large amounts of glutamate are released, the reuptake of glutamate by neurons is inhibited, and extracellular glutamate accumulates directly causing toxicity and damage to neurons (47). While excitatory amino acid receptor antagonists may be beneficial for brain protection, their use cannot be supported as there is insufficient evidence of their clinical benefit.

Other medicines

The Practice Guideline: Reducing Brain Injury After Cardiopulmonary Resuscitation released by the American Academy of Neurology in 2017 made a class C recommendation for the use of co-enzyme Q10 to improve the survival rate of out-of-hospital PCAS patients on the basis of mild hypothermia therapy. However, there is insufficient evidence to support or deny the use of steroids to improve survival rates or neurological prognoses (24).

Recommendation 5: evidence for the efficacy and safety of calcium channel antagonists, excitatory amino acid receptor antagonists and steroids, is lacking. (IV, U).

Comprehensive medical treatments

Complications including cerebral oedema and acidosis are seen in CA patients following CPR. Comprehensive medical treatment should be targeted to the specific complication and may include dehydration, anticonvulsant and acid-reducing treatment, glucocorticoid application, oxygen therapy, and blood sugar management (Table 1).

Table 1 Recommendations for brain protection after cardiopulmonary resuscitation in cardiac arrest patients
Full table

Neurological assessment

Procedures to monitor, assess, and predict neurological outcomes are important and the accurate estimation of prognosis can guide follow-up treatment. Neurological assessments should be carried out throughout the entire therapeutic process. In particular, the diagnosis of brain death should be made with extreme caution and must be carried out in accordance with current national standards and technical specifications.

After ROSC in hospital, 80% of patients experience coma and 40% enter a persistent vegetative state (48). Timely and continuous neurological assessment and effective prediction of the prognosis of brain function is required. The definition of a poor prognosis of brain function after CPR includes death, unconsciousness 1 month after CPR, severe disability 6 months after CPR, and the inability of a patient to care for themselves (49). Accurate and reliable indexes must be employed to assess the prognosis and the accuracy and reliability of a poor prognosis are mainly assessed by the false-positive rate (FPR) which should ideally be 0% (50). A detailed medical history can help predicting the prognosis and should include general conditions and comorbidities (age >70 years, history of stroke, renal failure or congestive heart failure before admission), the time and speed of CA onset, and CPR-related conditions (hypoxia time, CPR duration, arrhythmia type). However, these factors are not completely sufficient and reliable and the accuracy of most current clinical research evidence on the neurological prognoses after CA is unsatisfactory due to diagnostic bias. The FPR of prognosis assessment using any single method is high (50) and at present, there is no single examination that can 100% accurately predict the recovery of neurological function after CA. On this basis, the use of multiple models to evaluate the neurological prognosis of brain resuscitation is recommended. A detailed clinical physical examination remains essential for assessing the prognosis of coma patients after CA. In guidelines for the neurological examination of critically ill patients, the European Society of Intensive Care Medicine proposed that the pupillary light reflex, corneal reflex, and motor responses should be performed in coma patients following CA (51). Somatosensory evoked potential (SSEP) and electroencephalogram (EEG), which have high specificity, can improve the accuracy of the assessment (Table 2).

Table 2 Recommended neurological assessments after cardiopulmonary resuscitation in CA patients
Full table

The Glasgow Coma Scale (GCS)

The GCS is commonly used for assessing the neurological status of patients. The maximum of 15 points indicates clear consciousness, a score of 8 or less indicates coma status, and the minimum is 3 points. A lower score indicates a more serious disturbance of consciousness. Although the GCS is suitable for the evaluation of neurological function after CPR in CA patients, it contains three aspects; blinking, language, and motor reactions, that are susceptible to factors such as tracheal intubation/incision, facial oedema, sedative muscle relaxation and mild hypothermia treatment. The European Resuscitation Council Guidelines for Resuscitation 2014 recommends the use of the Glasgow Coma Scale-Motor Component (GCS-M) score, which uses the motor responses of the GCS to assess brain function prognosis. Although a GCS-M score of 2 or less suggests a poor neurological function prognosis (50), it is important to be aware that analgesic drugs and muscle relaxants may influence this. The GCS and GCS-M are not specific for CA patients after CPR and do not include pupil size, light response, eye movement and other brainstem responses or the observation of vital signs, which are critical for evaluating neural system function. It is necessary to develop corresponding scales to fill this gap.

Biomarkers

The advantages of biomarker evaluation are its non-invasiveness and potential for early implementation. Compared with electrophysiology and clinical physical examinations, biomarker evaluation can be quantitative and independent of sedative effects. However, it is difficult to define uniform thresholds for biomarkers and the concentrations of biochemical indicators are constantly changing, limiting their clinical applications.

Neuron-specific enolase (NSE) is released by apoptotic neurons. A previous study (52) showed that an NSE concentration greater than 33 µg/L within 1–3 days after ROSC in CA patients suggests a poor prognosis. However, in patients receiving hypothermia therapy, the neurological prognosis assessment of CA patients using NSE may result in false positives and false negatives (53,54), suggesting the previously used NSE threshold is not a reliable indicator of neurological prognosis. The formation of a prognosis using only one threshold value is not recommended. Early-stage haemodynamics and red blood cell lysis at low temperatures may cause interference with NSE, although serial changes of NSE concentration within 72 h may be more accurate (55).

Serum S-100β protein is released by glial cells after craniocerebral injury and can also be released by extracranial tissues such as fat and muscle. Some studies suggest that S-100β can be used as a marker of brain tissue damage. However, the critical levels of S-100β at which a poor prognosis is predicted differ widely among studies, thus its clinical prognostic value awaits further clarification.

Imaging examinations

Imaging examinations are also important methods for the prognostic evaluation of brain function in CA patients. Conventional brain imaging examinations such as computed tomography (CT) and magnetic resonance imaging (MRI) are less sensitive in detecting the pathological changes of transient systemic hypoxia-ischaemia because neuron damage in this state does not involve the destruction of neuron structures. A recent study used a standardized method to detect differences between white matter and grey matter to reflect severe global brain cytotoxic oedema (56). By detecting the grey to white matter ratio (GWR) in the putamen and internal capsule, the specificity of predicting poor neurological prognosis in patients within 1–7 days after CA was 100%, and the sensitivity reached 44%. Some studies show that advanced MRI sequences such as the apparent diffusivity coefficient (ADC), diffusion tensor imaging, and resting state functional magnetic resonance imaging (fMRI) (57-61) can be used for prognostic evaluation after CA. Although the results of these clinical studies are very promising, further validation is required before they can be routinely used in the clinical setting.

Neurophysiology

EEG is non-invasive, affordable, can monitor brain electrical activity in real time, and is routinely used for evaluating coma patients. In coma patients after CA, low background activity, status epilepticus, burst suppression and low voltages of EEG indicate poor prognosis (49).

SSEP can reflect functional brain status to some extent, and changes to the primary cortical response (N20) have the greatest clinical significance. In HIBI, the N20 wave may be delayed or lost, reflecting a loss of nerve conduction from the brainstem or thalamus to the cortex. A clinical study (62) has suggested that bilateral N20 wave loss indicates poor prognosis regardless of whether mild hypothermia therapy is performed and a meta-analysis (63) showed that bilateral N20 wave loss in CA patients with cerebral resuscitation had extremely high specificity for indicating a poor prognosis after mild hypothermia therapy. The best time to evaluate the disappearance of the bilateral N20 wave is during the mild hypothermia state and after rewarming (72 hours after ROSC).

Clinical symptoms and signs

Physical examination can reveal a series of signs indicating a poor prognosis after CA including the disappearance of the pupillary light and corneal reflexes although sedatives and muscle relaxants may restrict adequate physical examination, especially in patients receiving mild hypothermia therapy. Therefore, examination should be delayed for at least 72 hours after rewarming or the withdrawal of sedatives and analgesic drugs and should be repeated multiple times. While the value of the pupillary light and corneal reflexes immediately after ROSC in prognosis prediction is limited, their absence after 72 hours indicates poor prognosis, with a FPR of 0%. It is possible to perform primary screening for coma patients after CA based on the high sensitivity of pain-stimulated motor responses for poor prognosis (49) (the specificity of the pupillary reflex is superior to the corneal reflex (64), then perform further evaluations using multiple methods. Other physical signs (including myoclonus) are unreliable in predicting poor prognosis and are not recommended for prognosis prediction (65).

Summary

Neuro-protection is one of the keys to successful CPR and good prognosis in CA patients. Patients with ROSC after CPR should receive both treatment procedures to prevent brain injury in the ultra-early stage of PCAS and effective management during the entire therapeutic process. This consensus recommends early diagnosis, pre-hospital intervention, continuous assessment, and comprehensive treatment for all CA patients after CPR to effectively improve the survival rate and the neurological prognosis of patients through standardized management. Knowledge gaps are evident in neuro-protection after cardiac arrest. To determine the efficiency and safety of treatment, more questions need to be addressed.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the RIGHT reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-7853

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-7853). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: B. Draper)