Neurocritical care management of poor-grade subarachnoid hemorrhage: Unjustified nihilism to reasonable optimism

Abstract

Background and purpose

Historically, overall outcomes for patients with high-grade subarachnoid hemorrhage (SAH) have been poor. Generally, between physicians, either reluctance to treat, or selectivity in treating such patients has been the paradigm. Recent studies have shown that early and aggressive care leads to significant improvement in survival rates and favorable outcomes of grade V SAH patients. With advancements in both neurocritical care and end-of-life care, non-treatment or selective treatment of grade V SAH patients is rarely justified. Current paradigm shifts towards early and aggressive care in such cases may lead to improved outcomes for many more patients.

Materials and methods

We performed a detailed review of the current literature regarding neurointensive management strategies in high-grade SAH, discussing multiple aspects. We discussed the neurointensive care management protocols for grade V SAH patients.

Results

Acutely, intracranial pressure control is of utmost importance with external ventricular drain placement, sedation, optimization of cerebral perfusion pressure, osmotherapy and hyperventilation, as well as cardiopulmonary support through management of hypotension and hypertension.

Conclusions

Advancements of care in SAH patients make it unethical to deny treatment to poor Hunt and Hess grade patients. Early and aggressive treatment results in a significant improvement in survival rate and favorable outcome in such patients.

Introduction

Outcomes for patients with high-grade subarachnoid hemorrhage (SAH) have historically been poor, with poor rates of morbidity and mortality. Historically, neurosurgeons have been either reluctant to treat or selective in treating such patients. Recent studies have shown that early and aggressive care leads to significant improvement in survival rates and favorable outcomes of grade V SAH patients, as the majority of complications arise within 24–72 h of onset. ¹ In this paper, we review the neurointensive care management protocols for grade V SAH patients. Acutely, intracranial pressure (ICP) control is of utmost importance with external ventricular drain (EVD) placement, sedation, optimization of cerebral perfusion pressure (CPP), osmotherapy, and hyperventilation, as well as cardiopulmonary support through management of hypotension and hypertension. Emergent therapies include antifibrinolytics to avoid rebleeding, seizure prophylaxis, and medical and surgical management of vasospasm. The focus of postoperative care is recovery optimization and secondary complication prevention, and should be centered on multimodality neuromonitoring involving continuous electroencephalogram (EEG) monitoring, measurement of brain tissue oxygenation (P_btO₂), cerebral blood flow (CBF) monitoring and cerebral microdialysis. With advancements in both neurocritical care and end-of-life care, non-treatment or selective treatment of grade V SAH patients is rarely justified. Current paradigm shifts towards early and aggressive care of such cases may lead to improved outcomes for many more patients.

Pathophysiology of hyperacute and acute brain injury after SAH

Early brain injury in acute SAH

Early brain injury (EBI) develops within 72 h of onset of SAH and is the primary cause of mortality in SAH. ² Acute aneurysmal bleeding into the subarachnoid space causes an increase in ICP and a decrease in CBF. ² The severity of SAH correlates with early infarction, as up to 84% of Hunt and Hess grade IV patients may present with infarct lesions on magnetic resonance imaging. Additionally, infarcts are the presenting symptom in 17% of all SAH patients. ³ , ⁴ The presence of a large infarct at onset is associated with poor long-term outcomes. ³ , ⁴

The extent and location of EBI is correlated with slow depolarization in corresponding areas of the brain, which serves as a biomarker of brain injury. ⁵ EBI is also associated with loss of consciousness (LOC) at onset. A longer duration of LOC is associated with worse outcomes and poorer-grade SAH. LOC is believed to be caused by decreased CPP with increased ICP. ⁶ EBI is thus as important as delayed cerebral ischemia (DCI) as a diagnostic tool to prognosticate outcome. ⁷

Ultra-early vasospasm after SAH

Ultra-early angiographic vasospasm (UEAV) is defined as cerebral arterial narrowing within the first 48 h of aneurysmal SAH. ⁸ Multiple theories have been proposed to explain the etiology of UEAV. Some authors have postulated that the occurrence of UEAV is due to direct manipulation of cerebral vasculature during aneurysm surgery and/or during angiography following vessel perforation or a rerupture of the culprit cerebral aneurysm.^9–12 Additional theories suggest that mechanical pressure on vessels surrounding intracerebral or subarachnoid hematomas, raised ICP, or the distended ruptured aneurysms may contribute to vessel narrowing on diagnostic imaging. UEAV has also been described following rupture of arteriovenous malformations and eclampsia.^13–15

Although the incidence of UEAV may be as low as 4–5% of patients with aneurysmal SAH, it is associated with a 2-fold increase in the risk of DCI and cerebral infarctions. Sentinel headaches are associated with an increased risk of developing UEAV, but do not appear to confound or mediate the observed effect of UEAV on DCI and cerebral infarctions. Clinicians should aggressively monitor patients with UEAV for signs of DCI early in their course, and recognize that these patients are at high risk to be refractory to cerebral vasospasm treatment.

Ictal infarctions

Ictal infarctions are associated with mild, sustained cerebral depolarization. ¹² Longer-lasting spreads of depolarization are associated with larger infarcts and worsened edema. ¹⁶ An estimated 3–21% of patients have SAH with seizures at onset.^17–19 Seizures at onset are typical of a younger patient population and are predictive of eventual hydrocephalus and rebleeding. However, they are not associated with epilepsy later in life. ¹⁷ Overall, patients with early-onset seizures have better long-term outcomes, despite worse initial grade. ¹⁸ Despite all this, true tonic-clonic activity at onset is shown to be associated with poor outcomes, in-hospital seizures, higher risk of pneumonia, and higher systemic inflammatory response syndrome (SIRS) burden. ¹⁹

Global cerebral edema

Global cerebral edema (GCE) is associated with increased risk of cerebral metabolic crisis. Patients with GCE are shown to have higher levels of lactate and pyruvate, indicating metabolic distress. Comparatively, patients with GCE on admission and those who eventually develop GCE were not found to have a significant difference in CPP or brain oxygen tension. However, patients with higher CPP had normal lactate/pyruvate ratios and better outcomes than those who had lower CPP. Episodes of metabolic distress are correlated with worse outcomes. ²⁰ , ²¹

GCE is thought to be caused by altered cerebral hemodynamics, as well as being caused by several factors at a molecular level such as aquaporin-4, MMP9, and vascular endothelial growth factor (VEGF), among others. It is also believed to be caused by loss of autoregulation, neuroinflammation, and toxic blood products. GCE is much more likely to develop in patients who have global perfusion deficits after SAH. ²² , ²³ LOC at onset is also associated with later GCE. ⁶

DCI

DCI is defined as focal neurological impairment, a decrease of Glasgow Coma Scale score, and/or radiological signs of ischemia or infarction. DCI develops later in the progression of SAH, typically more than 72 h after onset, and is believed to be due to a combination of vasospasm, endothelial dysfunction, failure of cerebral autoregulation, and microvascular thrombosis. DCI is also noted to be a response to decreased regional CBF. DCI is associated with elevated lactate, lactate/pyruvate ratios, and glutamate early in management. ²⁴ DCI is also associated with a spreading depolarization, similar to EBI. ¹⁶ Current understanding of DCI shows an unclear relationship of DCI with an initial LOC. ⁶ , ²⁵ Ictal seizures are a predictor of DCI. ¹³ The presence of DCI is a very strong indicator of poor long-term outcomes. ¹⁰

ICP control

Intracranial hypertension is frequently associated with an SAH. Patients are generally treated for intracranial hypertension at a threshold of 20 mmHg. Approximately 95% of patients have transient increases of ICP above this threshold, yet only 7% maintain an ICP above 20 mmHg for the first week post injury. ²⁶ Most patients are treated with placement of an EVD to remove excess cerebral spinal fluid or via decompressive craniectomy. Other possible treatment modalities include sedation, optimization of CPP, osmotherapy, and hyperventilation. ²⁷

Sedation

In instances when drainage inadequately lowers ICP below threshold, sedation may be used. The induction of a barbiturate coma is a classical method of decreasing high ICP in poor-grade SAH patients. Thiopental and pentobarbital were first noted to reduce ICP in 1974. ²⁸ However, there is no benefit in using barbiturates in traumatic brain injury patients, as decreases in ICP are matched by decreases in mean arterial pressure (MAP) and an unchanged CPP. ²⁹ Propofol is the currently recommended sedative and can be used in doses of 1.5–2.5 mg/kg/h. Due to its short-lasting nature, propofol allows the patient to be woken frequently and on short notice for neurological examination. ³⁰ Ketamine can also be used to increase CBF and decrease the probability of infarct in patients that are sedated and intubated but may cause an increase in ICP. ¹⁵ Patients that are on ketamine should be carefully monitored and arterial partial pressure of carbon dioxide (P_CO2) should be adjusted to control changes in ICP. Inhaled sevoflurane causes a decrease in both MAP and CPP, as well as increased ICP in 33% of patients, ³¹ therefore it is not recommended for sedation in cases of increased ICP. Inhaled isoflurane shows similar effects on MAP and CPP, but no statistically significant increase in ICP. ³²

CPP optimization

CPP can be optimized when high ICP cannot be relieved through sedation. Real-time CPP can be compared with optimal CPP by using invasive ICP monitors and arterial blood pressure monitors. Positive outcomes are correlated with a CPP threshold of 60 or 70 mmHg. ³⁰ Further, the risk of metabolic crisis is kept below 10% when CPP is between 70 and 110 mmHg. As CPP decreases below 70 mmHg, the risk of DCI increases. ³¹

Osmotherapy

Hypertonic saline is effective in decreasing ICP, as well as increasing CBF and P_btO₂ in patients with poor-grade SAH. Patients can be infused with 23.5% hypertonic saline at 2 mL/kg over 10–30 min and display statistically significant improvements in these parameters for 4–5 h before returning to baseline. Hypertonic saline infusion also increases arterial blood pressure for an hour following infusion. ³³ Additionally, mannitol can be used at doses of 0.25–1 g/kg body weight to decrease ICP, but may contribute to arterial hypotension. Arterial pressures should be carefully monitored so that they do not fall below 90 mmHg. ³⁴ SAH patients treated with mannitol for high ICP also show a statistically significant increase in risk of early-onset ventilator-acquired pneumonia. ³⁵

Hyperventilation

Hyperventilation therapy causes vasoconstriction which leads to decreased CBF and cerebral blood volume, which in turn diminishes, ICP. ³⁶ There is no evidence that prolonged hyperventilation improves outcomes, as the decreased CBF may put patients at increased risk of ischemia. ³⁷ The current Brain Trauma Foundation recommendations for use of hyperventilative therapies state that there is not enough evidence for a formal recommendation. Furthermore, hyperventilation therapies should not be conducted within 24 h post injury. ³⁴ , ³⁸

Acute cardiopulmonary support

Neurogenic cardiopulmonary complications are common immediately following SAH. These complications can negatively and critically affect a patient’s brain perfusion and oxygenation.

Neurogenic myocardial stunning

Neurogenic myocardial stunning is characterized by left ventricular dysfunction and is a common result of SAH, occurring in up to 30% of patients. ³⁹ Neurogenic myocardial stunning in patients with SAH, especially those with poor grade, is diagnosed with the use of echocardiography and electrocardiography (ECG); however, there are no formal criteria at the moment. QT elongation on ECG is commonly associated with SAH, reported in 42–67% of SAH patients. ⁴⁰ , ⁴¹ A poor Hunt and Hess grade (grades IV and V) is a strong predictor for ventricular wall abnormalities, as well as ST changes and T wave inversions. Wall motion abnormalities have been associated with mortality in SAH patients and seem to correlate strongly with ECG changes. Therefore, using ECG changes to assess the risk in SAH patients may be recommended. ECG changes often occur within the first 72 h following onset. ⁴² However, in more severe cases of SAH (Hunt and Hess grades IV and V), examination of ECG data within 24 h may be warranted due to this critical period for many complications.

Cardiac troponin elevation

Elevated cardiac troponin levels (isoforms I and/or T) are frequently encountered in patients following SAH (20–37%) and have been associated with an increased mortality and morbidity, specifically DCI. ³⁹ , ⁴³ , ⁴⁴ Furthermore, evidence suggests an association between poor Hunt and Hess grade (grades IV and V) SAH and cardiac troponin elevation. ⁴¹ Monitoring of cardiac troponin levels in poor-grade SAH patients could thus pose an advantage in management. In poor-grade SAH patients, cardiac troponin I levels were found to be predictive of increased risk of hypotension, pulmonary edema, left ventricular systolic dysfunction on echocardiography, and DCI from vasospasm. ⁴⁵ Cardiac troponin I levels peak between 24 and 72 h following SAH, and a peak of >0.5 µg/L increases the risk of DCI by 50%. ⁴⁶

Management of hypertension

Hypertension is a common sign following SAH and is associated with an increased risk of rebleeding, therefore management of hypertension following SAH is vital. Poor-grade SAH patients are two times as likely to develop hypertension following ictus compared with lower-grade patients. ⁴⁷ The standard goal of a systolic blood pressure below 120 mmHg in low-grade patients is not comparatively ideal in high-grade SAH patients with elevated ICP. Inotropes such as milrinone or dobutamine are commonly used, which may aid with left ventricular flow. ³⁹ Calcium channel blockers such as nimodipine should be considered following endovascular management to prevent vasospasm. ⁴⁸ Other agents used to lower blood pressure include labetalol and nicardipine. ⁴⁹

Management of hypotension

Hypotension should be avoided during antihypertensive treatment to avoid secondary injury. ⁴⁸ Hypotension following SAH is associated with a larger risk of developing major medical complications and less favorable outcomes at 6 months post ictus. ⁴⁷ The three preferred agents to treat hypotension are phenylephrine, dopamine, and norepinephrine. Because phenylephrine is a pure alpha agonist, it may exacerbate other cardio-related complications. Presently, there are no official recommendations; however, some authors find norepinephrine to be more efficient at maintaining brain perfusion. ⁵⁰

Rebleeding

Rebleeding is one of the most severe complications of SAH, contributing the majority of the poor outcomes and mortality following SAH. ⁵¹ Regardless of the transition to earlier treatment of SAH (e.g. clipping, coiling), the rates of rebleeding are still high, ranging from 7% to 20%. ⁵² The majority of rebleeding events occur within the first 72 h, often occurring within the first 24 h following ictus. Many predictors of rebleeding have been investigated, such as a poor Hunt and Hess grade and hypertension. A poor Hunt and Hess grade increases the odds of rebleeding by 4.5. ⁵³ Patients who are at a high risk of rebleeding may benefit from immediate (<24 h) treatment. ⁵¹ , ⁵⁴ Desmopressin at admission in patients with a poor Hunt and Hess grade reduced the odds of rebleeding by 45%. ⁵⁵

Antifibrinolytic therapy

Antifibrinolytic agents have been and are commonly used in the prevention of rebleeding. Previously, when delayed clipping was recommended, antifibrinolytic agents were used to prevent rebleeding. However, these agents lead to an increased risk in cerebral ischemia and other complications. ⁵⁶ More recently, a short-term approach with antifibrinolytic treatment has been shown to significantly reduce the rate of rebleeding without an increase in unwanted complications, such as DCI. ⁵⁷ The American Heart Association/American Stroke Association revised their guidelines with regards to antifibrinolytic treatment in 2012, stating that treatment with tranexamic acid or aminocaproic acid is justified in reducing the risk of rebleeding in aneurysmal SAH patients. ⁵⁸

Seizure prophylaxis

Seizures occur in less than 20% of SAH patients, and frequently occur within the first 24 h of onset of SAH. In an effort to prevent recurrent bleeding in SAH patients, it is recommended that all poor-grade patients receive prophylactic antiepileptics, as recurrent seizures increase the chance of rebleeding. ⁵⁸ Phenytoin is a commonly used antiepileptic in SAH, but levetiracetam is sometimes used and can be utilized for a shorter period of time with fewer drug interactions. Levetiracetam (500 mg twice a day) has been shown to increase the rate of late seizures in comparison with patients treated with phenytoin (15–20 mg/kg) for 3 days by a significant 4.9%. ⁵⁹ Patients who are at high risk for seizures and patients who have higher grade SAH should be continuously monitored with EEG and receive appropriate antiepileptic prophylaxis for 3 days. If a seizure occurs during this time frame, phenytoin can be administered for a maximum of 14 days with a 5 mg/kg maintenance dose to avoid a high phenytoin burden. ⁶⁰ Increased duration of antiepileptic drugs is associated with worse outcomes cognitively and neurologically in poor-grade SAH patients. Increased seizure burden, or the amount of time the patient spends actively seizing, is associated with a higher likelihood of having disability or death at 3 months. ⁶¹ Thus prophylactic administration of antiepileptic drugs is currently indicated for patients with Hunt and Hess grades IV and V.

Management of vasospasm

Previously, the occurrence of vasospasm was believed to be associated with the poorest outcomes as well as with the highest risk of death. Currently, however, evidence shows that rebleeding, and not vasospasm, is the greatest risk factor for death, and thus most management paradigms aim to prevent rebleeding events. However, managing vasospasm still remains a major concern and a pressing medical issue, as early and prolonged vasospasm is associated with the presentation of DCI in these patients. ⁵⁹ Although vasospasm does not cause DCI, approximately 30% of all SAH patients develop DCI. ⁵⁹ When comparing SAH patients who experience vasospasm with those who do not, 57% of patients who had severe cerebral vasospasm went on to develop DCI, whereas only 21% of patients without detectable vasospasm developed DCI. ⁶² Due to the poor outcomes associated with vasospasm and further development of DCI, SAH patients with Hunt and Hess grades IV and V are routinely monitored with imaging at day 7, and use of transcranial Doppler ultrasound for detection of vasospasm is performed daily. ¹

Prediction of vasospasm

Monitoring patients for vasospasm is critical because it can have detrimental consequences on patient outcome following SAH. The Fisher Scale and the modified Fisher Scale have been used to classify the degree of hemorrhage and can be used for prediction of vasospasm. A Fisher grade of 3 or 4 indicates a greater likelihood of developing worse complications associated with SAH, including development of vasospasm. Forty-eight percent of patients with a Fisher grade 3 or 4 hemorrhage develop a vasospasm-related problem. ⁶³ Although the Fisher Scale is widely used, incorporating other measures, such as increasing SAH thickness, allows a better predictive factor than the Fisher Scale alone. ⁴

The genetic differences between SAH patients may also be indicative of predicting development of vasospasm. Certain mutations in Apolipoprotein E (APOE), such as carrier for -219T allele, showed a significant 10.6% increase in development of cerebral vasospasm than people with -219G. ⁶³ Although no current approved predictive biomarker test currently exists, there is an increase in microRNA hsa-miR-3177-3p in patients with SAH who later develop vasospasm, alluding to a potential vasospasm predictive value in whole blood microRNA profiling. ⁶⁴

Vasospasm prophylaxis

The standard of care for all patients with SAH is to administer nimodipine (a calcium channel blocker) as it leads to a beneficial neurological outcome, but may also prevent vasospasm. ⁵⁸ Nimodipine should be administered orally or via nasogastric tube with 60 mg given every 4 h at the onset of SAH and continued for 3 weeks, as intravenous administration has been linked to negative severe side effects. Although recently continuous selective intra-arterial nimodipine therapy has been effective in reducing the chance of developing vasospasm,^65–68 the applicability of these results may not be relevant to grade V comatose patients. Other calcium antagonists yield similar beneficial results in preventing vasospasm, with a number needed to treat at 19. ⁶⁹ In addition, in patients with thick SAH clots treated with tissue plasminogen activator, there was a 56% reduced risk of developing vasospasm due to the increased clearance of SAH. A positive correlation exists between early administration and greater clearance at 48 h. ⁷⁰ , ⁷¹

Medical treatment of symptomatic vasospasm

Symptomatic vasospasm yields worse outcomes for poor-grade SAH patients. Traditional medical treatment for vasospasm was “triple-H” therapy: induction of hypervolemia, hypertension, and hemodilution. Previously, this combination therapy was used to prevent vasospasm, and although there is limited data on the efficacy of these claims, hypervolemia and induced hypertension are currently used to treat symptomatic vasospasm. ⁷² In one study, patients with symptomatic vasospasm showed a clinical response to euvolemia and hemodynamic augmentation in approximately 43% and 68% of patients, respectively. ⁷³ Hypervolemia and induction of hypertension should not be done prophylactically, and although enough evidence does not exist to support or refute the efficacy of these therapies, observational recommendations suggest that they be utilized on developing vasospasm. ⁵⁸ , ⁷⁴ Other treatments that can be added to these therapies, such as inotropic agents (e.g. dobutamine, magnesium sulfate), do not improve outcomes and are not recommended in the medical management of SAH. ⁷⁵ , ⁷⁶

Interventional treatment of symptomatic vasospasm

In patients refractory to hypervolemic and hypertensive therapies, there is an indication for treatment with intra-arterial vasodilators, or treatment with cerebral angioplasty. Elevated transcranial Doppler velocity recordings, with an average of 208 cm/s, are indications that hemodynamic augmentation is ineffective, and insertion of an intra-aortic balloon pump (IABP) may be effective in these patients. ⁷⁷ Administration of intra-arterial vasodilators (IADs) is another viable option for these patients. IADs lead to a robust response and have been shown to have 66% good outcomes, with only a 5% mortality rate throughout the follow-up periods reported. ⁷² Although there is no statistical significance between IABPs and IADs, both methods had increased outcomes when transcranial Doppler ultrasound was used in detection and monitoring of patient conditions. ⁷⁸

Asymptomatic cerebral ischemia in poor-grade SAH patients

In patients without detectable vasospasm, monitoring angioplasties is still acceptable in order to prophylactically treat vasospasm, as 25% of poor-grade SAH patients have asymptomatic cerebral ischemia. ⁶⁷ Prophylactic triple H therapy in addition to other vasospasm prophylaxis is a reasonable course of treatment for patients who are at high risk of asymptomatic ischemia or high risk of DCI. ⁵⁸ Patients with coma, Hunt and Hess grade V, are at especially high risk for poor outcome and have a high chance of developing DCI, and these patients are more likely to experience asymptomatic vasospasm which has a 33% increased chance of having a worse outcome on the modified Rankin Scale at 3-month follow-up. ⁷⁹ Therefore, vasospasm prophylaxis, routine transcranial Doppler ultrasound, and continuous EEG monitoring should be considered in all of these patients due to their high risk. ⁵⁸

Multimodality neuromonitoring

Advances in neuromonitoring allow physicians to more effectively detect and treat secondary cerebral injury in poor-grade SAH patients. Parameters that can be measured in real time include ICP, CPP, P_btO₂, CBF, and jugular venous oxygen saturation. Metabolites that are early markers for secondary brain injury, such as lactate/pyruvate ratio >40 can also be measured via cerebral microdialysis. ⁸⁰ Continuous EEG monitoring has many uses, such as assessing consciousness of comatose patients and detecting CBF. These metrics allow physicians to proactively prevent complications which are evident in the patient’s neurological examination. ⁸¹

Continuous EEG monitoring

Ictal-interictal continuum abnormalities, such as sporadic epileptiform discharges, generalized periodic discharges, or seizures, may help predict whether patients are at risk for delayed ischemic events. ²¹ Alpha/delta ratios are the best predictors of vasospasm and delayed ischemic events and are lower in patients who are at risk for delayed cerebral infarct within the first four days post injury. ⁸² Alpha/delta ratios in intracortical EEG decrease approximately 42% in patients with vasospasm compared with 17% in those without. ⁸³ EEGs can also be conducted on comatose patients to determine levels of consciousness, arousability, and awareness. There is potential to quantify patient consciousness using EEG monitoring and neurological examination. ⁸⁴ EEGs can be analyzed along with somatosensory evoked potentials to predict neurological deterioration, which may allow physicians to detect and protect against future neurological damage. ⁸⁵

Regional measurement of brain tissue oxygenation (P_btO₂) and cerebral blood flow (CBF) monitoring

There has recently been a reduction in mortality of patients with severe traumatic brain injury due to an increased adherence to CPP and ICP monitoring guidelines. ⁸⁶ Abnormalities in both P_btO₂ and CBF are correlated with decreased CPP. CBF levels are usually normal immediately following injury, but can decrease 3–5 days after SAH. ⁸⁷ P_btO₂ can be measured commercially using the Licox system or the Neurovent-PTO system, and used as a surrogate measure of CBF. ⁸⁸ Current CBF guidelines recommend the measurement of P_btO₂ when conducting hyperventilative treatments. ³⁴ Non-invasive probes use near-infrared spectroscopy to measure CBF. ⁸² Although P_btO₂ can be used to estimate CBF, the inverse is not true, as P_btO₂ is a multidimensional variable that incorporates multiple factors including CBF, diffusion capability, and capillary, cellular, and tissue needs. ¹⁴ , ⁸⁹ , ⁹⁰ Treatment of P_btO₂ below 1.33 kPa was effective in reducing secondary ischemic damage. ⁸⁸

Cerebral microdialysis

Cerebral microdialysis is an invasive procedure that allows the measurement of metabolites and proteins in the brain. Lactate/pyruvate ratios >40 are associated with computed tomography (CT)–verified infarcts and delayed ischemic neurological events. ⁹¹ A threshold of three events of lactate/pyruvate ratio >40 greatly increases specificity, from 40% to 71%. Relative hyperglycolysis is noted in 33% of patients with unfavorable outcomes as compared with 4% of patients with favorable outcomes at a metabolic ratio threshold >3.44. Using a composite of lactate/pyruvate ratio and metabolic ratio or hypoxic lactate events, patient outcomes can be predicted. ⁹² Cerebral microdialysis can also be used to measure cytokine levels. Levels of IL-6 are correlated with severity of SAH, development of DCI, and poor outcomes. ⁷ Levels of TNF-α on days 4–6 post injury are also correlated with an increased risk in cerebral vasospasm. ⁹³ By monitoring the levels of metabolites and cytokines in real time, physicians will be able to predict risk of negative outcomes and take necessary steps to prevent them.

Medical complications

Medical complications are frequent occurrences after SAH, and can play as big a factor in poor outcomes as rebleeds, EBI, and DCI. ⁹⁴ Poor-grade SAH is associated with neurogenic pulmonary edema, due to increased sympathetic output. Physicians must distinguish this from pneumonia, as neurogenic pulmonary edema is successfully treated with positive end-expiratory pressure ventilation. ⁹⁵ Hyperoxemia and hypooxemia are also independently associated with worse outcomes, so proper oxygen management is critical to good outcomes. ¹¹ Poor-grade SAH is also associated with metabolic distress, which can be managed by insulin infusion therapy, but further study is needed to optimize this treatment method. ¹⁴ , ⁹⁰ Hyponatremic and hypernatremic patients are found to have 88.2% unfavorable outcomes, compared with 15.6% of patients with normal sodium levels. ⁹⁶ Patients develop anemia from loss of red blood cells due to bleeding from SAH. Blood transfusions are associated with poor outcomes, but it is unclear if this is due to the blood transfusion itself or from the anemia due to blood loss. ⁹⁵

Infections and fevers are other important factors in the management of SAH patients. Fevers are directly correlated with poor outcomes. ⁹⁷ Hospital-acquired infections are significant factors of extended length of stay, but worse outcomes are not necessarily associated with hospital infections. ⁴⁶ , ⁹⁴ SAH patients are found to have several different infectious sources including pneumonia (20%), urinary tract infections (13%), bloodstream infections (8%), and bacterial meningitis/ventriculitis (5%). ⁹⁵ SIRS is common in the initial four days post onset in poor-grade SAH patients, and a higher SIRS score is correlated with a worse outcome. ⁹⁸ Physicians should monitor and manage patients accordingly to prevent extracerebral organ damage and the onset of DCI. ⁹⁹

End-of-life care

The current standard of care for poor-grade SAH patients must be reevaluated. The introduction of an early, aggressive surgical option has made the Hunt and Hess grade less important in regard to outcome. ¹⁰⁰ Physicians are more likely to underestimate patient outcomes and withdraw care. Outcome predictions based on clinical and diagnostic criteria at admission have been shown to result in withholding care from up to 30% of patients, who would otherwise have favorable outcomes. ¹⁰¹ , ¹⁰²

Conclusion

Advancements of care in SAH patients make it unethical to deny treatment to poor Hunt and Hess grade patients. A majority, if not all, of major complications arise within 24–72 h of ictus, indicating the feasibility for early intensive management and treatment in these patients. Early and aggressive treatment (early insertion of an EVD, early aneurysm treatment, and application of advanced therapeutic capabilities in the intensive care unit) result in a significant improvement in survival rate (number needed to treat = 2) and favorable outcome (number needed to treat = 3 for a modified Rankin Scale score of 0–3) in patients with Hunt and Hess grade V SAH.

ORCID iD

Fawaz Al-Mufti https://orcid.org/0000-0003-4461-7005