Imaging

Aneurysmal subarachnoid hemorrhage is a devastating condition, with an estimated death rate of 30% during the initial episode.^1,2 Approximately the same number of patients survive but leave the hospital with disabling neurologic deficits.³

However, better outcomes can be achieved by systems that are able to work as a team on the collective goal of quick intervention to secure the ruptured aneurysm, followed by the implementation of measures to minimize secondary brain injury. Although the search for new diagnostic, prognostic, and therapeutic modalities continues, it is clear that there exists no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of small advances that will ultimately maximize the patient’s chances of survival and neurologic recovery.

This review focuses on the management of aneurysmal subarachnoid hemorrhage and its systemic and neurologic complications.

ANEURYSM IS THE MOST COMMON CAUSE OF SUBARACHNOID BLEEDING

Aneurysmal subarachnoid hemorrhage, ie, rupture of an intracranial aneurysm, flooding  the subarachnoid space with blood, affects about 24,000 Americans each year.^1,2 A ruptured aneurysm is the most common cause of subarachnoid hemorrhage, accounting for about 85% of cases. Less common causes include idiopathic benign perimesencephalic hemorrhage, arteriovenous malformation, dural arteriovenous fistula, and hemorrhagic mycotic aneurysm. These have their own natural history, pathophysiology, and specific treatment, and will not be addressed in this article.

Risk factors for aneurysmal subarachnoid hemorrhage include having a first-degree relative who had the disease, hypertension, smoking, and consuming more than 150 g of alcohol per week.⁴

CLINICAL PRESENTATION AND DIAGNOSIS

The key symptom of aneurysmal subarachnoid hemorrhage is the abrupt onset of severe headache that peaks in intensity over 1 hour,⁵ often described as “the worst headache of my life.” Headache is accompanied by brief loss of consciousness in 53% of cases (conversely, nearly half of patients maintain normal mental status), by nausea or vomiting in 77%, and by meningismus (neck pain or stiffness) in 35%.⁶

These clinical manifestations and risk factors have been incorporated into a decision rule:

Obtain brain imaging if the patient has acute headache reaching maximal intensity within 1 hour, associated with any of the following factors:

• Age 40 or older

• Neck pain or stiffness

• Witnessed loss of consciousness

• Onset during exertion

• “Thunderclap” headache (ie, instantly peaking pain)

• Limited neck flexion on examination.⁵

This decision rule has nearly 100% sensitivity for aneurysmal subarachnoid hemorrhage in clinical practice.⁵ All patients require brain imaging if they have a severe headache plus either abnormal neurologic findings (eg, a focal neurologic deficit) or a history of cerebral aneurysm.

Emergency physicians should have a low threshold for ordering noncontrast computed tomography (CT) of the head in patients with even mild symptoms suggesting aneurysmal subarachnoid hemorrhage. Failure to order CT is the most common diagnostic error in this situation.⁶ CT performed within 6 hours of headache onset is nearly 100% sensitive for this condition,⁷ but the sensitivity falls to 93% after the first 24 hours and to less than 60% after 5 days.⁸ In patients who have symptoms highly suggestive of aneurysmal subarachnoid hemorrhage but a normal CT, lumbar puncture is the next diagnostic step.

There are two alternatives to CT followed by lumbar puncture: ie, noncontrast CT followed by CT angiography,^9,10 and magnetic resonance imaging followed by magnetic resonance angiography. In patients with suspicious clinical symptoms but negative CT results, CT followed by CT angiography can rule out aneurysmal subarachnoid hemorrhage with a 99% probability.^9,10 However, CT followed by lumbar puncture remains the standard of care and carries a class I recommendation in the American Heart Association guidelines for ruling out subarachnoid hemorrhage.⁵

GRADING THE SEVERITY OF SUBARACHNOID HEMORRHAGE

Age, the thickness of the blood layer in the subarachnoid space, intraventricular hemorrhage and the findings of the neurologic examination at presentation are predictors of long-term outcomes in aneurysmal subarachnoid hemorrhage (Figure 1).

Different grading systems used in clinical practice are based on the findings on the initial neurologic examination and on the initial noncontrast CT (ie, the thickness of the blood, and whether intraventricular hemorrhage is present). Among the most widely used are those developed by Hunt and Hess¹² and by the World Federation of Neurological Surgeons¹¹ (WFNS), and the CT grading scales (Fisher¹³ or its modified version¹⁴)  (Tables 1 and 2). With either the Hunt and Hess scale or the WFNS scale, the higher the score, the worse the patient’s probable outcome. Scores on both Fisher scales correlate with the risk of angiographic vasospasm. The higher the grade, the higher the risk of angiographic vasospasm.

The VASOGRADE score—a combination of the WFNS score and the modified Fisher scale—stratifies patients at risk of delayed cerebral ischemia, allowing for a tailored monitoring strategy.¹⁵ There are three variations:

• VASOGRADE green—Modified Fisher 1 or 2 and WFNS 1 or 2

• VASOGRADE yellow—Modified Fisher 3 or 4 and WFNS 1, 2, or 3

• VASOGRADE red—WFNS 4 or 5. 

After the initial bleeding event, patients with aneurysmal subarachnoid hemorrhage are at high risk of delayed systemic and neurologic complications, with poor functional outcomes. Delayed cerebral ischemia holds the greatest risk of an unfavorable outcome and ultimately can lead to cerebral infarction, disability, and death.^6,7

INITIAL MANAGEMENT

After aneurysmal subarachnoid hemorrhage is diagnosed, the initial management (Figure 2) includes appropriate medical prevention of rebleeding (which includes supportive care, blood pressure management, and, perhaps, the early use of a short course of an antifibrinolytic drug) and early transfer to a high-volume center for securing the aneurysm. The reported incidence of rebleeding varies from 5% to 22% in the first 72 hours. “Ultra-early” rebleeding (within 24 hours of hemorrhage) has been reported, with an incidence as high as 15% and a fatality rate around 70%. Patients with poor-grade aneurysmal subarachnoid hemorrhage, larger aneurysms, and “sentinel bleeds” are at higher risk of rebleeding.16

Outcomes are much better when patients are managed in a high-volume center, with a specialized neurointensive care unit¹⁷ and access to an interdisciplinary team.¹⁸ Regardless of the initial grade, patients with aneurysmal subarachnoid hemorrhage should be quickly transferred to a high-volume center, defined as one treating at least 35 cases per year, and the benefit is greater in centers treating more than 60 cases per year.¹⁹ The higher the caseload in any given hospital, the better the clinical outcomes in this population.²⁰

Treating cerebral aneurysm: Clipping or coiling

Early aneurysm repair is generally considered the standard of care and the best strategy to reduce the risk of rebleeding. Further, early treatment may be associated with a lower risk of delayed cerebral ischemia²¹ and better outcomes.²²

Three randomized clinical trials have compared surgical clipping and endovascular repair (placement of small metal coils within the aneurysm to promote clotting).

The International Subarachnoid Aneurysm Trial²³ showed a reduction of 23% in relative risk and of 7% in absolute risk in patients who underwent endovascular treatment compared with surgery. The survival benefit persisted at a mean of 9 years (range 6–14 years), but with a higher annual rate of aneurysm recurrence in the coiling group (2.9% vs 0.9%).²⁴ Of note, this trial included only patients with aneurysms deemed suitable for both coiling and clipping, so that the exclusion rate was high. Most of the patients presented with good-grade (WFNS score 1–3), small aneurysms (< 5 mm) in the anterior circulation.

A single-center Finnish study²⁵ found no differences in rates of recovery, disability, and  death at 1 year, comparing surgery and endovascular treatment. Additionally, survival rates at a mean follow-up of 39 months were similar, with no late recurrences or aneurysmal bleeding.

Lastly, the Barrow Ruptured Aneurysm Trial26,27 found that patients assigned to endovascular treatment had better 1-year neurologic outcomes, defined as a modified Rankin score of 2 or less. Importantly, 37.7% of patients originally assigned to endovascular treatment crossed over to surgical treatment. The authors then performed intention-to-treat and as-treated analyses. Either way, patients treated by endovascular means had better neurologic outcomes at 1 year. However, no difference in the relative risk reduction in worse outcome was found on 3-year follow-up, and patients treated surgically had higher rates of aneurysm obliteration and required less aneurysm retreatment, both of which were statistically significant.

The question that remains is not whether to clip or whether to coil, but whom to clip and whom to coil.²⁸ That question must be answered on a patient-to-patient basis and requires the expertise of an interventional neuroradiologist and a vascular neurosurgeon—one of the reasons these patients are best cared for in high-volume centers providing such expertise.

MEDICAL PREVENTION OF REBLEEDING

Blood pressure management

There are no systematic data on the optimal blood pressure before securing an aneurysm. Early studies of hemodynamic augmentation in cases of ruptured untreated aneurysm reported rebleeding when the systolic blood pressure was allowed to rise above 160 mm Hg.^29,30 A recent study evaluating hypertensive intracerebral hemorrhage revealed better functional outcomes with intensive lowering of blood pressure (defined as systolic blood pressure < 140 mm Hg) but no significant reduction in the combined rate of death or severe disability.³¹ It is difficult to know if these results can be extrapolated to patients with aneurysmal subarachnoid hemorrhage. Current guidelines^3,32 say that before the aneurysm is treated, the systolic pressure should be lower than 160 mm Hg.

There is no specific drug of choice, but a short-acting, titratable medication is preferable. Nicardipine is a very good option, and labetalol might be an appropriate alternative.³³ Once the aneurysm is secured, all antihypertensive drugs should be held. Hypertension should not be treated unless the patient has clinical signs of a hypertensive crisis, such as flash pulmonary edema, myocardial infarction, or hypertensive encephalopathy.

Antifibrinolytic therapy

Risk factors: Family history, hypertension, smoking, heavy drinking

The role of antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage is controversial and has been studied in 10 clinical trials. In a Swedish study,³⁴ early use of tranexamic acid (1 g intravenously over 10 minutes followed by 1 g every 6 hours for a maximum of 24 hours) reduced the rebleeding rate substantially, from 10.8% to 2.4%, with an 80% reduction in the mortality rate from ultra-early rebleeding. However, a recent Cochrane review that included this study found no overall benefit.³⁵

An ongoing multicenter randomized trial in the Netherlands will, we hope, answer this question in the near future.³⁶ At present, some centers would consider a short course of tranexamic acid before aneurysm treatment.

DIAGNOSIS AND TREATMENT OF COMPLICATIONS

Medical complications are extremely common after aneurysmal subarachnoid hemorrhage. Between 75% and 100% of patients develop some type of systemic or further neurologic derangement, which in turn has a negative impact on the long-term outcome.^37,38 In the first 72 hours, rebleeding is the most feared complication, and as mentioned previously, appropriate blood pressure management and early securing of the aneurysm minimize its risk.

NEUROLOGIC COMPLICATIONS

Hydrocephalus

Hydrocephalus is the most common early neurologic complication after aneurysmal subarachnoid hemorrhage, with an overall incidence of 50%.³⁹ Many patients with poor-grade aneurysmal subarachnoid hemorrhage and patients whose condition deteriorates due to worsening of hydrocephalus require the insertion of an external ventricular drain (Figure 1).

Up to 30% of patients who have a poor-grade aneurysmal subarachnoid hemorrhage improve neurologically with cerebrospinal fluid drainage.⁴⁰ An external ventricular drain can be safely placed, even before aneurysm treatment, and placement does not appear to increase the risk of rebleeding.^39,41 After placement, rapid weaning from the drain (clamping within 24 hours of insertion) is safe, decreases length of stay in the intensive care unit and hospital, and may be more cost-effective than gradual weaning over 96 hours.⁴²

Increased intracranial pressure

Intracranial hypertension is another potential early complication, and is frequently due to the development of hydrocephalus, cerebral edema, or rebleeding. The treatment of increased intracranial pressure does not differ from the approach used in managing severe traumatic brain injury, which includes elevating the head of the bed, sedation, analgesia, normoventilation, and cerebrospinal fluid drainage.

Hypertonic saline has been tested in several studies that were very small but nevertheless consistently showed control of intracranial pressure levels and improvement in cerebral blood flow measured by xenon CT.^43–47 Two of these studies even showed better outcomes at discharge.^43,44 However, the small number of patients prevents any meaningful conclusion regarding the use of hypertonic saline and functional outcomes.

Outcomes are much better when patients are managed in a high-volume center

Barbiturates, hypothermia, and decompressive craniectomy could be tried in refractory cases.⁴⁸ Seule et al⁴⁹ evaluated the role of therapeutic hypothermia with or without barbiturate coma in 100 patients with refractory intracranial hypertension. Only 13 patients received hypothermia by itself. At 1 year, 32 patients had achieved a good functional outcome (Glasgow Outcome Scale score 4 or 5). The remaining patients were severely disabled or had died. Of interest, the median duration of hypothermia was 7 days, and 93% of patients developed some medical complication such as electrolyte disorders (77%), pneumonia (52%), thrombocytopenia (47%), or septic shock syndrome (40%). Six patients died as a consequence of one of these complications.

Decompressive craniectomy can be life-saving in patients with refractory intracranial hypertension. However, most of these patients will die or remain severely disabled or comatose.⁵⁰

Seizure prophylaxis is controversial

Seizures can occur at the onset of intracranial hemorrhage, perioperatively, or later (ie, after the first week). The incidence varied considerably in different reports, ranging from 4% to 26%.⁵¹ Seizures occurring perioperatively, ie, after hospital admission, are less frequent and are usually the manifestation of aneurysm rebleeding.²⁴

The question is not whether to clip or coil, but whom to clip and whom to coil

Seizure prophylaxis remains controversial, especially because the use of phenytoin is associated with increased incidence of cerebral vasospasm, infarction, and worse cognitive outcomes after aneurysmal subarachnoid hemorrhage.^52,53 Therefore, routine prophylactic use of phenytoin is not recommended in these patients,³ although the effect of other antiepileptic drugs is less studied and less clear. Patients may be considered for this therapy if they have multiple risk factors for seizures, such as intraparenchymal hematoma, advanced age (> 65), middle cerebral artery aneurysm, craniotomy for aneurysm clipping, and a short course (≤ 72 hours) of an antiepileptic drug other than phenytoin, especially while the aneurysm is unsecured.³

Levetiracetam may be an alternative to phenytoin, having better pharmacodynamic and kinetic profiles, minimal protein binding, and absence of hepatic metabolism, resulting in a very low risk of drug interaction and better tolerability.^54,55 Because of these advantages, levetiracetam has become the drug of choice in several centers treating aneurysmal subarachnoid hemorrhage in the United States.

Addressing this question, a survey was sent to 25 high-volume aneurysmal subarachnoid hemorrhage academic centers in the United States. All 25 institutions answered the survey, and interestingly, levetiracetam was the first-line agent for 16 (94%) of the 17 responders that used prophylaxis, while only 1 used phenytoin as the agent of choice.⁵⁶

A retrospective cohort study by Murphy-Human et al⁵⁷ showed that a short course of levetiracetam (≤ 72 hours) was associated with higher rates of in-hospital seizures compared with an extended course of phenytoin (eg, entire hospital stay). However, the study did not address functional outcomes.⁵⁷

Continuous electroencephalographic monitoring may be considered in comatose patients, in patients requiring controlled ventilation and sedation, or in patients with unexplained alteration in consciousness. In one series of patients with aneurysmal subarachnoid hemorrhage who received continuous monitoring, the incidence of nonconvulsive status epilepticus was 19%, with an associated mortality rate of 100%.⁵⁸

Continuous quantitative electroencephalography is useful to monitor and to detect angiographic vasospasm and delayed cerebral ischemia. Relative alpha variability and the alpha-delta ratio decrease with ischemia, and this effect can precede angiographic vasospasm by 3 days.^59,60

Delayed cerebral ischemia

Delayed cerebral ischemia is defined as the occurrence of focal neurologic impairment, or a decrease of at least 2 points on the Glasgow Coma Scale that lasts for at least 1 hour, is not apparent immediately after aneurysm occlusion, and not attributable to other causes (eg, hyponatremia, fever).⁶¹

Classically, neurologic deficits that occurred within 2 weeks of aneurysm rupture were ascribed to reduced cerebral blood flow caused by delayed large-vessel vasospasm causing cerebral ischemia.⁶² However, perfusion abnormalities have also been observed with either mild or no demonstrable vasospasm.⁶³ Almost 70% of patients who survive the initial hemorrhage develop some degree of angiographic vasospasm. However, only 30% of those patients will experience symptoms.

In addition to vasospasm of large cerebral arteries, impaired autoregulation and early brain injury within the first 72 hours following subarachnoid hemorrhage may play important roles in the development of delayed cerebral ischemia.⁶⁴ Therefore, the modern concept of delayed cerebral ischemia monitoring should focus on cerebral perfusion rather than vessel diameter measurements. This underscores the importance of comprehensive, standardized monitoring techniques that provide information not only on microvasculature, but also at the level of the microcirculation, with information on perfusion, oxygen utilization and extraction, and autoregulation.

Although transcranial Doppler has been the most commonly applied tool to monitor for angiographic vasospasm, it has a low sensitivity and negative predictive value.³⁷ It is nevertheless a useful technique to monitor good-grade aneurysmal subarachnoid hemorrhage patients (WFNS score 1–3) combined with frequent neurologic examinations (Figure 3).

CT angiography is a good noninvasive alternative to digital subtraction angiography. However, it tends to overestimate the degree of vasoconstriction and does not provide information about perfusion and autoregulation.⁶⁵ Nevertheless, CT angiography combined with a CT perfusion scan can add information about autoregulation and cerebral perfusion and has been shown to be more sensitive for the diagnosis of angiographic vasospasm than transcranial Doppler and digital subtraction angiography (Figure 4).

Patients with a poor clinical condition (WFNS score 4 or 5) or receiving continuous sedation constitute a challenge in monitoring for delayed neurologic deterioration. Neurologic examination is not sensitive enough in this setting to detect subtle changes. In these specific and challenging circumstances, multimodality neuromonitoring may be useful in the early detection of delayed cerebral ischemia and may help guide therapy.⁶⁷

Several noninvasive and invasive techniques have been studied to monitor patients at risk of delayed cerebral ischemia after subarachnoid hemorrhage.⁶⁶ These include continuous electroencephalography, brain tissue oxygenation monitoring (Ptio₂), cerebral microdialysis, thermal diffusion flowmetry, and near-infrared spectroscopy. Of these techniques, Ptio₂, cerebral microdialysis, and continuous electroencephalography (see discussion of seizure prophylaxis above) have been more extensively studied. However, most of the studies were observational and very small, limiting any recommendations for using these techniques in routine clinical practice.⁶⁸

Ptio₂ is measured by inserting an intraparenchymal oxygen-sensitive microelectrode, and microdialysis requires a microcatheter with a semipermeable membrane that allows small soluble substances to cross it into the dialysate. These substances, which include markers of ischemia (ie, glucose, lactate, and pyruvate), excitotoxins (ie, glutamate and aspartate), and membrane cell damage products (ie, glycerol), can be measured. Low Ptio₂ values (< 15 mm Hg) and abnormal mycrodialysate findings (eg, glucose < 0.8 mmol/L, lactate-to-pyruvate ratio > 40) have both been associated with cerebral ischemic events and poor outcome.⁶⁸

Preventing delayed cerebral ischemia

Oral nimodipine 60 mg every 4 hours for 21 days, started on admission, carries a class I, level of evidence A recommendation in the management of aneurysmal subarachnoid hemorrhage.^3,32,69 It improves clinical outcome despite having no effect on the risk of angiographic vasospasm. The mechanism of improved outcome is unclear, but the effect may be a neuroprotective phenomenon limiting the extension of delayed cerebral ischemia.⁷⁰

If hypotension occurs, the dose can be lowered to 30 mg every 2 hours. Whether to discontinue nimodipine in this situation is controversial. Of note, the clinical benefits of nimodipine have not been replicated with other calcium channel blockers (eg, nicardipine).⁷¹

Prophylactic hyperdynamic fluid therapy, known as “triple-H” (hypervolemia, hemodilution, and hypertension) was for years the mainstay of treatment in preventing delayed cerebral ischemia due to vasospasm. However, the clinical data supporting this intervention have been called into question, as analysis of two trials found that hypervolemia did not improve outcomes or reduce the incidence of delayed cerebral ischemia, and in fact increased the rate of complications.^72,73 Based on these findings, current guidelines recommend maintaining euvolemia rather than prophylactic hypervolemia in patients with aneurysmal subarachnoid hemorrhage.^3,32,69

TREATING DELAYED CEREBRAL ISCHEMIA

Hemodynamic augmentation

In patients with neurologic deterioration due to delayed cerebral ischemia, hemodynamic augmentation is the cornerstone of treatment. This is done according to a protocol, started early, involving specific physiologic goals, clinical improvement, and escalation to invasive therapies in a timely fashion in patients at high risk of further neurologic insult (Figure 5).

The physiologic goal is to increase the delivery of oxygen and glucose to the ischemic brain. Hypertension seems to be the most effective component of hemodynamic augmentation regardless of volume status, increasing cerebral blood flow and brain tissue oxygenation, with reversal of delayed cerebral ischemic symptoms in up to two-thirds of treated patients.^74,75 However, this information comes from very small studies, with no randomized trials of induced hypertension available.

The effect of a normal saline fluid bolus in patients suspected of having delayed cerebral ischemia has been shown to increase cerebral blood flow in areas of cerebral ischemia.⁷⁴ If volume augmentation fails to improve the neurologic status, the next step is to artificially induce hypertension using vasopressors. The blood pressure target should be based on clinical improvement. A stepwise approach is reasonable in this situation, and the lowest level of blood pressure at which there is a complete reversal of the new focal neurologic deficit should be maintained.^3,29

Inotropic agents such as dobutamine or milrinone can be considered as alternatives in patients who have new neurologic deficits that are refractory to fluid boluses and vasopressors, or in a setting of subarachnoid hemorrhage-induced cardiomyopathy.^76,77

Once the neurologic deficit is reversed by hemodynamic augmentation, the blood pressure should be maintained for 48 to 72 hours at the level that reversed the deficit completely, carefully reassessed thereafter, and the patient weaned slowly. Unruptured unsecured aneurysms should not prevent blood pressure augmentation in a setting of delayed cerebral ischemia if the culprit aneurysm is treated.^3,32 If the ruptured aneurysm has not been secured, careful blood pressure augmentation can be attempted, keeping in mind that hypertension (> 160/95 mm Hg) is a risk factor for fatal aneurysm rupture.

Endovascular management of delayed cerebral ischemia

When medical augmentation fails to completely reverse the neurologic deficits, endovascular treatment can be considered. Although patients treated early in the course of delayed cerebral ischemia have better neurologic recovery, prophylactic endovascular treatment in asymptomatic patients, even if angiographic signs of spasm are present, does not improve clinical outcomes and carries the risk of fatal arterial rupture.⁷⁸

SYSTEMIC COMPLICATIONS

Hyponatremia and hypovolemia

Aneurysmal subarachnoid hemorrhage is commonly associated with abnormalities of fluid balance and electrolyte derangements. Hyponatremia (serum sodium < 135 mmol/L) occurs in 30% to 50% of patients, while the rate of hypovolemia (decreased circulating blood volume) ranges from 17% to 30%.⁷⁹ Both can negatively affect long-term outcomes.^80,81

Decreased circulating blood volume is a well-described contributor to delayed cerebral ischemia and cerebral infarction after aneurysmal subarachnoid hemorrhage.^80–82 Clinical variables such as heart rate, blood pressure, fluid balance, and serum sodium concentration are usually the cornerstones of intravascular volume status assessment. However, these variables correlate poorly with measured circulating blood volumes in those with aneurysmal subarachnoid hemorrhage.^83,84

The mechanisms responsible for the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage are not completely understood. Several factors have been described and may contribute to the increased natriuresis and, hence, to a reduction in circulating blood volume: increased circulating natriuretic peptide concentrations,^85–87 sympathetic nervous system hyperactivation,⁸⁸ and hyperreninemic hypo-
aldosteronism syndrome.^89,90

Guidelines: Before treating the aneurysm, the systolic pressure should be < 160 mm Hg

Lastly, the cerebral salt wasting syndrome, described in the 1950s,⁹¹ was thought to be a key mechanism in the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage. In contrast to the syndrome of inappropriate antidiuretic hormone, which is characterized by hyponatremia with a normal or slightly elevated intravascular volume, the characteristic feature of cerebral salt wasting syndrome is the development of hyponatremia in a setting of intravascular volume depletion.⁹² In critically ill neurologic and neurosurgical patients, this differential diagnosis is very difficult, especially in those with aneurysmal subarachnoid hemorrhage in whom the clinical assessment of fluid status is not reliable. These two syndromes might coexist and contribute to the development of hyponatremia after aneurysmal subarachnoid hemorrhage.^92,93

Hoff et al^83,84 prospectively compared the clinical assessment of fluid status by critical and intermediate care nurses and direct measurements of blood volume using pulse dye densitometry. The clinical assessment failed to accurately assess patients’ volume status. Using the same technique to measure circulating blood volume, this group showed that calculation of fluid balance does not provide adequate assessment of fluid status.^83,84

Hemodynamic monitoring tools can help guide fluid replacement in this population. Mutoh et al⁹⁴ randomized 160 patients within 24 hours of hemorrhage to receive early goal-directed fluid therapy (ie, preload volume and cardiac output monitored by transpulmonary thermodilution) vs standard therapy (ie, fluid balance or central venous pressure). Overall, no difference was found in the rates of delayed cerebral ischemia (33% vs 42%; P = .33) or favorable outcome (67% vs 57%; P = .22). However, in the subgroup of poor-grade patients (WFNS score 4 or 5), early goal-directed therapy was associated with a lower rate of delayed cerebral ischemia (5% vs 14%; P = .036) and with better functional outcomes at 3 months (52% vs 36%; P = .026).

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended because of the increased risk of cerebral infarction due to hypovolemic hypoperfusion.⁸²

Prophylactic use of mineralocorticoids (eg, fludrocortisone, hydrocortisone) has been shown to limit natriuresis, hyponatremia, and the amount of fluid required to maintain euvolemia.^95,96 Higher rates of hypokalemia and hyperglycemia, which can be easily treated, are the most common complications associated with this approach. Additionally, hypertonic saline (eg, 3% saline) can be used to correct hyponatremia in a setting of aneurysmal subarachnoid hemorrhage.⁷⁹

Cardiac complications

Cardiac complications after subarachnoid hemorrhage are most likely related to sympathetic hyperactivity and catecholamine-induced myocyte dysfunction. The pathophysiology is complex, but cardiac complications have a significant negative impact on long-term outcome in these patients.⁹⁷

Electrocardiographic changes and positive cardiac enzymes associated with aneurysmal subarachnoid hemorrhage have been extensively reported. More recently, data from studies of two-dimensional echocardiography have shown that subarachnoid hemorrhage can also be associated with significant wall-motion abnormalities and even overt cardiogenic shock.^98–100

There is no specific curative therapy; the treatment is mainly supportive. Vasopressors and inotropes may be used for hemodynamic augmentation.

Pulmonary complications

Pulmonary complications occur in 20% to 30% of all aneurysmal subarachnoid hemorrhage patients and are associated with a higher risk of delayed cerebral ischemia and death. Common pulmonary complications in this population are mild acute respiratory distress syndrome (27%), hospital-acquired pneumonia (9%), cardiogenic pulmonary edema (8%), aspiration pneumonia (6%), neurogenic pulmonary edema (2%), and pulmonary embolism (1%).^101–103

SUPPORTIVE CARE

Hyperthermia, hyperglycemia, and liberal use of transfusions have all been associated with longer stays in the intensive care unit and hospital, poorer neurologic outcomes, and higher mortality rates in patients with acute brain injury.¹⁰⁴ Noninfectious fever is the most common systemic complication after subarachnoid hemorrhage.

Antipyretic drugs such as acetaminophen and ibuprofen are not very effective in reducing fever in the subarachnoid hemorrhage population, but should still be used as first-line therapy. The use of surface and intravascular devices can be considered when fevers do not respond to nonsteroidal anti-inflammatory drugs.

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended

Although no prospective randomized trial has addressed the impact of induced normothermia on long-term outcome and mortality in aneurysmal subarachnoid hemorrhage patients, fever control has been shown to reduce cerebral metabolic distress, irrespective of intracranial pressure.¹⁰⁵ Maintenance of normothermia (< 37.5°C) seems reasonable, especially in aneurysmal subarachnoid hemorrhage patients at risk of or with active delayed cerebral ischemia.¹⁰⁶

Current guidelines^3,32,69 strongly recommend avoiding hypoglycemia, defined as a serum glucose level less than 80 mg/dL, but suggest keeping the blood sugar level below 180 or 200 mg/dL.

At the moment, there is no clear threshold for transfusion in patients with aneurysmal subarachnoid hemorrhage. Current guidelines suggest keeping hemoglobin levels between 8 and 10 g/dL.³

Preventing venous thromboembolism

The incidence of venous thromboembolism after aneurysmal subarachnoid hemorrhage varies widely, from 1.5% to 18%.¹⁰⁷ Active surveillance with venous Doppler ultrasonography has found asymptomatic deep vein thrombosis in up to 3.4% of poor-grade aneurysmal subarachnoid hemorrhage patients receiving pharmacologic thromboprophylaxis.¹⁰⁸

In a retrospective study of 170 patients, our group showed that giving drugs to prevent venous thromboembolism (unfractionated heparin 5,000 IU subcutaneously every 12 hours or dalteparin 5,000 IU subcutaneously daily), starting within 24 hours of aneurysm treatment, could be safe.¹⁰⁹ Fifty-eight percent of these patients had an external ventricular drain in place. One patient developed a major cerebral hemorrhagic complication and died while on unfractionated heparin; however, the patient was also on dual antiplatelet therapy with aspirin and clopidogrel.¹⁰⁹

Current guidelines suggest that intermittent compression devices be applied in all patients before aneurysm treatment. Pharmacologic thromboprophylaxis with a heparinoid can be started 12 to 24 hours after aneurysm treatment.^3,109

A TEAM APPROACH

Patients with subarachnoid hemorrhage need integrated care from different medical and nursing specialties. The best outcomes are achieved by systems that can focus as a team on the collective goal of quick intervention to secure the aneurysm, followed by measures to minimize secondary brain injury.

The modern concept of cerebral monitoring in a setting of subarachnoid hemorrhage should focus on brain perfusion rather than vascular diameter. Although the search continues for new diagnostic, prognostic, and therapeutic tools, there is no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of many small advances that will ultimately lead to better outcomes.

ACKNOWLEDGMENT

This work was supported by research funding provided by the Bitove Foundation, which has been supportive of our clinical and research work for several years.

Aneurysmal subarachnoid hemorrhage is a devastating condition, with an estimated death rate of 30% during the initial episode.^1,2 Approximately the same number of patients survive but leave the hospital with disabling neurologic deficits.³

However, better outcomes can be achieved by systems that are able to work as a team on the collective goal of quick intervention to secure the ruptured aneurysm, followed by the implementation of measures to minimize secondary brain injury. Although the search for new diagnostic, prognostic, and therapeutic modalities continues, it is clear that there exists no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of small advances that will ultimately maximize the patient’s chances of survival and neurologic recovery.

This review focuses on the management of aneurysmal subarachnoid hemorrhage and its systemic and neurologic complications.

ANEURYSM IS THE MOST COMMON CAUSE OF SUBARACHNOID BLEEDING

Aneurysmal subarachnoid hemorrhage, ie, rupture of an intracranial aneurysm, flooding  the subarachnoid space with blood, affects about 24,000 Americans each year.^1,2 A ruptured aneurysm is the most common cause of subarachnoid hemorrhage, accounting for about 85% of cases. Less common causes include idiopathic benign perimesencephalic hemorrhage, arteriovenous malformation, dural arteriovenous fistula, and hemorrhagic mycotic aneurysm. These have their own natural history, pathophysiology, and specific treatment, and will not be addressed in this article.

Risk factors for aneurysmal subarachnoid hemorrhage include having a first-degree relative who had the disease, hypertension, smoking, and consuming more than 150 g of alcohol per week.⁴

CLINICAL PRESENTATION AND DIAGNOSIS

The key symptom of aneurysmal subarachnoid hemorrhage is the abrupt onset of severe headache that peaks in intensity over 1 hour,⁵ often described as “the worst headache of my life.” Headache is accompanied by brief loss of consciousness in 53% of cases (conversely, nearly half of patients maintain normal mental status), by nausea or vomiting in 77%, and by meningismus (neck pain or stiffness) in 35%.⁶

These clinical manifestations and risk factors have been incorporated into a decision rule:

Obtain brain imaging if the patient has acute headache reaching maximal intensity within 1 hour, associated with any of the following factors:

• Age 40 or older

• Neck pain or stiffness

• Witnessed loss of consciousness

• Onset during exertion

• “Thunderclap” headache (ie, instantly peaking pain)

• Limited neck flexion on examination.⁵

This decision rule has nearly 100% sensitivity for aneurysmal subarachnoid hemorrhage in clinical practice.⁵ All patients require brain imaging if they have a severe headache plus either abnormal neurologic findings (eg, a focal neurologic deficit) or a history of cerebral aneurysm.

Emergency physicians should have a low threshold for ordering noncontrast computed tomography (CT) of the head in patients with even mild symptoms suggesting aneurysmal subarachnoid hemorrhage. Failure to order CT is the most common diagnostic error in this situation.⁶ CT performed within 6 hours of headache onset is nearly 100% sensitive for this condition,⁷ but the sensitivity falls to 93% after the first 24 hours and to less than 60% after 5 days.⁸ In patients who have symptoms highly suggestive of aneurysmal subarachnoid hemorrhage but a normal CT, lumbar puncture is the next diagnostic step.

There are two alternatives to CT followed by lumbar puncture: ie, noncontrast CT followed by CT angiography,^9,10 and magnetic resonance imaging followed by magnetic resonance angiography. In patients with suspicious clinical symptoms but negative CT results, CT followed by CT angiography can rule out aneurysmal subarachnoid hemorrhage with a 99% probability.^9,10 However, CT followed by lumbar puncture remains the standard of care and carries a class I recommendation in the American Heart Association guidelines for ruling out subarachnoid hemorrhage.⁵

GRADING THE SEVERITY OF SUBARACHNOID HEMORRHAGE

Age, the thickness of the blood layer in the subarachnoid space, intraventricular hemorrhage and the findings of the neurologic examination at presentation are predictors of long-term outcomes in aneurysmal subarachnoid hemorrhage (Figure 1).

Different grading systems used in clinical practice are based on the findings on the initial neurologic examination and on the initial noncontrast CT (ie, the thickness of the blood, and whether intraventricular hemorrhage is present). Among the most widely used are those developed by Hunt and Hess¹² and by the World Federation of Neurological Surgeons¹¹ (WFNS), and the CT grading scales (Fisher¹³ or its modified version¹⁴)  (Tables 1 and 2). With either the Hunt and Hess scale or the WFNS scale, the higher the score, the worse the patient’s probable outcome. Scores on both Fisher scales correlate with the risk of angiographic vasospasm. The higher the grade, the higher the risk of angiographic vasospasm.

The VASOGRADE score—a combination of the WFNS score and the modified Fisher scale—stratifies patients at risk of delayed cerebral ischemia, allowing for a tailored monitoring strategy.¹⁵ There are three variations:

• VASOGRADE green—Modified Fisher 1 or 2 and WFNS 1 or 2

• VASOGRADE yellow—Modified Fisher 3 or 4 and WFNS 1, 2, or 3

• VASOGRADE red—WFNS 4 or 5. 

After the initial bleeding event, patients with aneurysmal subarachnoid hemorrhage are at high risk of delayed systemic and neurologic complications, with poor functional outcomes. Delayed cerebral ischemia holds the greatest risk of an unfavorable outcome and ultimately can lead to cerebral infarction, disability, and death.^6,7

INITIAL MANAGEMENT

After aneurysmal subarachnoid hemorrhage is diagnosed, the initial management (Figure 2) includes appropriate medical prevention of rebleeding (which includes supportive care, blood pressure management, and, perhaps, the early use of a short course of an antifibrinolytic drug) and early transfer to a high-volume center for securing the aneurysm. The reported incidence of rebleeding varies from 5% to 22% in the first 72 hours. “Ultra-early” rebleeding (within 24 hours of hemorrhage) has been reported, with an incidence as high as 15% and a fatality rate around 70%. Patients with poor-grade aneurysmal subarachnoid hemorrhage, larger aneurysms, and “sentinel bleeds” are at higher risk of rebleeding.16

Outcomes are much better when patients are managed in a high-volume center, with a specialized neurointensive care unit¹⁷ and access to an interdisciplinary team.¹⁸ Regardless of the initial grade, patients with aneurysmal subarachnoid hemorrhage should be quickly transferred to a high-volume center, defined as one treating at least 35 cases per year, and the benefit is greater in centers treating more than 60 cases per year.¹⁹ The higher the caseload in any given hospital, the better the clinical outcomes in this population.²⁰

Treating cerebral aneurysm: Clipping or coiling

Early aneurysm repair is generally considered the standard of care and the best strategy to reduce the risk of rebleeding. Further, early treatment may be associated with a lower risk of delayed cerebral ischemia²¹ and better outcomes.²²

Three randomized clinical trials have compared surgical clipping and endovascular repair (placement of small metal coils within the aneurysm to promote clotting).

The International Subarachnoid Aneurysm Trial²³ showed a reduction of 23% in relative risk and of 7% in absolute risk in patients who underwent endovascular treatment compared with surgery. The survival benefit persisted at a mean of 9 years (range 6–14 years), but with a higher annual rate of aneurysm recurrence in the coiling group (2.9% vs 0.9%).²⁴ Of note, this trial included only patients with aneurysms deemed suitable for both coiling and clipping, so that the exclusion rate was high. Most of the patients presented with good-grade (WFNS score 1–3), small aneurysms (< 5 mm) in the anterior circulation.

A single-center Finnish study²⁵ found no differences in rates of recovery, disability, and  death at 1 year, comparing surgery and endovascular treatment. Additionally, survival rates at a mean follow-up of 39 months were similar, with no late recurrences or aneurysmal bleeding.

Lastly, the Barrow Ruptured Aneurysm Trial26,27 found that patients assigned to endovascular treatment had better 1-year neurologic outcomes, defined as a modified Rankin score of 2 or less. Importantly, 37.7% of patients originally assigned to endovascular treatment crossed over to surgical treatment. The authors then performed intention-to-treat and as-treated analyses. Either way, patients treated by endovascular means had better neurologic outcomes at 1 year. However, no difference in the relative risk reduction in worse outcome was found on 3-year follow-up, and patients treated surgically had higher rates of aneurysm obliteration and required less aneurysm retreatment, both of which were statistically significant.

The question that remains is not whether to clip or whether to coil, but whom to clip and whom to coil.²⁸ That question must be answered on a patient-to-patient basis and requires the expertise of an interventional neuroradiologist and a vascular neurosurgeon—one of the reasons these patients are best cared for in high-volume centers providing such expertise.

MEDICAL PREVENTION OF REBLEEDING

Blood pressure management

There are no systematic data on the optimal blood pressure before securing an aneurysm. Early studies of hemodynamic augmentation in cases of ruptured untreated aneurysm reported rebleeding when the systolic blood pressure was allowed to rise above 160 mm Hg.^29,30 A recent study evaluating hypertensive intracerebral hemorrhage revealed better functional outcomes with intensive lowering of blood pressure (defined as systolic blood pressure < 140 mm Hg) but no significant reduction in the combined rate of death or severe disability.³¹ It is difficult to know if these results can be extrapolated to patients with aneurysmal subarachnoid hemorrhage. Current guidelines^3,32 say that before the aneurysm is treated, the systolic pressure should be lower than 160 mm Hg.

There is no specific drug of choice, but a short-acting, titratable medication is preferable. Nicardipine is a very good option, and labetalol might be an appropriate alternative.³³ Once the aneurysm is secured, all antihypertensive drugs should be held. Hypertension should not be treated unless the patient has clinical signs of a hypertensive crisis, such as flash pulmonary edema, myocardial infarction, or hypertensive encephalopathy.

Antifibrinolytic therapy

Risk factors: Family history, hypertension, smoking, heavy drinking

The role of antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage is controversial and has been studied in 10 clinical trials. In a Swedish study,³⁴ early use of tranexamic acid (1 g intravenously over 10 minutes followed by 1 g every 6 hours for a maximum of 24 hours) reduced the rebleeding rate substantially, from 10.8% to 2.4%, with an 80% reduction in the mortality rate from ultra-early rebleeding. However, a recent Cochrane review that included this study found no overall benefit.³⁵

An ongoing multicenter randomized trial in the Netherlands will, we hope, answer this question in the near future.³⁶ At present, some centers would consider a short course of tranexamic acid before aneurysm treatment.

DIAGNOSIS AND TREATMENT OF COMPLICATIONS

Medical complications are extremely common after aneurysmal subarachnoid hemorrhage. Between 75% and 100% of patients develop some type of systemic or further neurologic derangement, which in turn has a negative impact on the long-term outcome.^37,38 In the first 72 hours, rebleeding is the most feared complication, and as mentioned previously, appropriate blood pressure management and early securing of the aneurysm minimize its risk.

NEUROLOGIC COMPLICATIONS

Hydrocephalus

Hydrocephalus is the most common early neurologic complication after aneurysmal subarachnoid hemorrhage, with an overall incidence of 50%.³⁹ Many patients with poor-grade aneurysmal subarachnoid hemorrhage and patients whose condition deteriorates due to worsening of hydrocephalus require the insertion of an external ventricular drain (Figure 1).

Up to 30% of patients who have a poor-grade aneurysmal subarachnoid hemorrhage improve neurologically with cerebrospinal fluid drainage.⁴⁰ An external ventricular drain can be safely placed, even before aneurysm treatment, and placement does not appear to increase the risk of rebleeding.^39,41 After placement, rapid weaning from the drain (clamping within 24 hours of insertion) is safe, decreases length of stay in the intensive care unit and hospital, and may be more cost-effective than gradual weaning over 96 hours.⁴²

Increased intracranial pressure

Intracranial hypertension is another potential early complication, and is frequently due to the development of hydrocephalus, cerebral edema, or rebleeding. The treatment of increased intracranial pressure does not differ from the approach used in managing severe traumatic brain injury, which includes elevating the head of the bed, sedation, analgesia, normoventilation, and cerebrospinal fluid drainage.

Hypertonic saline has been tested in several studies that were very small but nevertheless consistently showed control of intracranial pressure levels and improvement in cerebral blood flow measured by xenon CT.^43–47 Two of these studies even showed better outcomes at discharge.^43,44 However, the small number of patients prevents any meaningful conclusion regarding the use of hypertonic saline and functional outcomes.

Outcomes are much better when patients are managed in a high-volume center

Barbiturates, hypothermia, and decompressive craniectomy could be tried in refractory cases.⁴⁸ Seule et al⁴⁹ evaluated the role of therapeutic hypothermia with or without barbiturate coma in 100 patients with refractory intracranial hypertension. Only 13 patients received hypothermia by itself. At 1 year, 32 patients had achieved a good functional outcome (Glasgow Outcome Scale score 4 or 5). The remaining patients were severely disabled or had died. Of interest, the median duration of hypothermia was 7 days, and 93% of patients developed some medical complication such as electrolyte disorders (77%), pneumonia (52%), thrombocytopenia (47%), or septic shock syndrome (40%). Six patients died as a consequence of one of these complications.

Decompressive craniectomy can be life-saving in patients with refractory intracranial hypertension. However, most of these patients will die or remain severely disabled or comatose.⁵⁰

Seizure prophylaxis is controversial

Seizures can occur at the onset of intracranial hemorrhage, perioperatively, or later (ie, after the first week). The incidence varied considerably in different reports, ranging from 4% to 26%.⁵¹ Seizures occurring perioperatively, ie, after hospital admission, are less frequent and are usually the manifestation of aneurysm rebleeding.²⁴

The question is not whether to clip or coil, but whom to clip and whom to coil

Seizure prophylaxis remains controversial, especially because the use of phenytoin is associated with increased incidence of cerebral vasospasm, infarction, and worse cognitive outcomes after aneurysmal subarachnoid hemorrhage.^52,53 Therefore, routine prophylactic use of phenytoin is not recommended in these patients,³ although the effect of other antiepileptic drugs is less studied and less clear. Patients may be considered for this therapy if they have multiple risk factors for seizures, such as intraparenchymal hematoma, advanced age (> 65), middle cerebral artery aneurysm, craniotomy for aneurysm clipping, and a short course (≤ 72 hours) of an antiepileptic drug other than phenytoin, especially while the aneurysm is unsecured.³

Levetiracetam may be an alternative to phenytoin, having better pharmacodynamic and kinetic profiles, minimal protein binding, and absence of hepatic metabolism, resulting in a very low risk of drug interaction and better tolerability.^54,55 Because of these advantages, levetiracetam has become the drug of choice in several centers treating aneurysmal subarachnoid hemorrhage in the United States.

Addressing this question, a survey was sent to 25 high-volume aneurysmal subarachnoid hemorrhage academic centers in the United States. All 25 institutions answered the survey, and interestingly, levetiracetam was the first-line agent for 16 (94%) of the 17 responders that used prophylaxis, while only 1 used phenytoin as the agent of choice.⁵⁶

A retrospective cohort study by Murphy-Human et al⁵⁷ showed that a short course of levetiracetam (≤ 72 hours) was associated with higher rates of in-hospital seizures compared with an extended course of phenytoin (eg, entire hospital stay). However, the study did not address functional outcomes.⁵⁷

Continuous electroencephalographic monitoring may be considered in comatose patients, in patients requiring controlled ventilation and sedation, or in patients with unexplained alteration in consciousness. In one series of patients with aneurysmal subarachnoid hemorrhage who received continuous monitoring, the incidence of nonconvulsive status epilepticus was 19%, with an associated mortality rate of 100%.⁵⁸

Continuous quantitative electroencephalography is useful to monitor and to detect angiographic vasospasm and delayed cerebral ischemia. Relative alpha variability and the alpha-delta ratio decrease with ischemia, and this effect can precede angiographic vasospasm by 3 days.^59,60

Delayed cerebral ischemia

Delayed cerebral ischemia is defined as the occurrence of focal neurologic impairment, or a decrease of at least 2 points on the Glasgow Coma Scale that lasts for at least 1 hour, is not apparent immediately after aneurysm occlusion, and not attributable to other causes (eg, hyponatremia, fever).⁶¹

Classically, neurologic deficits that occurred within 2 weeks of aneurysm rupture were ascribed to reduced cerebral blood flow caused by delayed large-vessel vasospasm causing cerebral ischemia.⁶² However, perfusion abnormalities have also been observed with either mild or no demonstrable vasospasm.⁶³ Almost 70% of patients who survive the initial hemorrhage develop some degree of angiographic vasospasm. However, only 30% of those patients will experience symptoms.

In addition to vasospasm of large cerebral arteries, impaired autoregulation and early brain injury within the first 72 hours following subarachnoid hemorrhage may play important roles in the development of delayed cerebral ischemia.⁶⁴ Therefore, the modern concept of delayed cerebral ischemia monitoring should focus on cerebral perfusion rather than vessel diameter measurements. This underscores the importance of comprehensive, standardized monitoring techniques that provide information not only on microvasculature, but also at the level of the microcirculation, with information on perfusion, oxygen utilization and extraction, and autoregulation.

Although transcranial Doppler has been the most commonly applied tool to monitor for angiographic vasospasm, it has a low sensitivity and negative predictive value.³⁷ It is nevertheless a useful technique to monitor good-grade aneurysmal subarachnoid hemorrhage patients (WFNS score 1–3) combined with frequent neurologic examinations (Figure 3).

CT angiography is a good noninvasive alternative to digital subtraction angiography. However, it tends to overestimate the degree of vasoconstriction and does not provide information about perfusion and autoregulation.⁶⁵ Nevertheless, CT angiography combined with a CT perfusion scan can add information about autoregulation and cerebral perfusion and has been shown to be more sensitive for the diagnosis of angiographic vasospasm than transcranial Doppler and digital subtraction angiography (Figure 4).

Patients with a poor clinical condition (WFNS score 4 or 5) or receiving continuous sedation constitute a challenge in monitoring for delayed neurologic deterioration. Neurologic examination is not sensitive enough in this setting to detect subtle changes. In these specific and challenging circumstances, multimodality neuromonitoring may be useful in the early detection of delayed cerebral ischemia and may help guide therapy.⁶⁷

Several noninvasive and invasive techniques have been studied to monitor patients at risk of delayed cerebral ischemia after subarachnoid hemorrhage.⁶⁶ These include continuous electroencephalography, brain tissue oxygenation monitoring (Ptio₂), cerebral microdialysis, thermal diffusion flowmetry, and near-infrared spectroscopy. Of these techniques, Ptio₂, cerebral microdialysis, and continuous electroencephalography (see discussion of seizure prophylaxis above) have been more extensively studied. However, most of the studies were observational and very small, limiting any recommendations for using these techniques in routine clinical practice.⁶⁸

Ptio₂ is measured by inserting an intraparenchymal oxygen-sensitive microelectrode, and microdialysis requires a microcatheter with a semipermeable membrane that allows small soluble substances to cross it into the dialysate. These substances, which include markers of ischemia (ie, glucose, lactate, and pyruvate), excitotoxins (ie, glutamate and aspartate), and membrane cell damage products (ie, glycerol), can be measured. Low Ptio₂ values (< 15 mm Hg) and abnormal mycrodialysate findings (eg, glucose < 0.8 mmol/L, lactate-to-pyruvate ratio > 40) have both been associated with cerebral ischemic events and poor outcome.⁶⁸

Preventing delayed cerebral ischemia

Oral nimodipine 60 mg every 4 hours for 21 days, started on admission, carries a class I, level of evidence A recommendation in the management of aneurysmal subarachnoid hemorrhage.^3,32,69 It improves clinical outcome despite having no effect on the risk of angiographic vasospasm. The mechanism of improved outcome is unclear, but the effect may be a neuroprotective phenomenon limiting the extension of delayed cerebral ischemia.⁷⁰

If hypotension occurs, the dose can be lowered to 30 mg every 2 hours. Whether to discontinue nimodipine in this situation is controversial. Of note, the clinical benefits of nimodipine have not been replicated with other calcium channel blockers (eg, nicardipine).⁷¹

Prophylactic hyperdynamic fluid therapy, known as “triple-H” (hypervolemia, hemodilution, and hypertension) was for years the mainstay of treatment in preventing delayed cerebral ischemia due to vasospasm. However, the clinical data supporting this intervention have been called into question, as analysis of two trials found that hypervolemia did not improve outcomes or reduce the incidence of delayed cerebral ischemia, and in fact increased the rate of complications.^72,73 Based on these findings, current guidelines recommend maintaining euvolemia rather than prophylactic hypervolemia in patients with aneurysmal subarachnoid hemorrhage.^3,32,69

TREATING DELAYED CEREBRAL ISCHEMIA

Hemodynamic augmentation

In patients with neurologic deterioration due to delayed cerebral ischemia, hemodynamic augmentation is the cornerstone of treatment. This is done according to a protocol, started early, involving specific physiologic goals, clinical improvement, and escalation to invasive therapies in a timely fashion in patients at high risk of further neurologic insult (Figure 5).

The physiologic goal is to increase the delivery of oxygen and glucose to the ischemic brain. Hypertension seems to be the most effective component of hemodynamic augmentation regardless of volume status, increasing cerebral blood flow and brain tissue oxygenation, with reversal of delayed cerebral ischemic symptoms in up to two-thirds of treated patients.^74,75 However, this information comes from very small studies, with no randomized trials of induced hypertension available.

The effect of a normal saline fluid bolus in patients suspected of having delayed cerebral ischemia has been shown to increase cerebral blood flow in areas of cerebral ischemia.⁷⁴ If volume augmentation fails to improve the neurologic status, the next step is to artificially induce hypertension using vasopressors. The blood pressure target should be based on clinical improvement. A stepwise approach is reasonable in this situation, and the lowest level of blood pressure at which there is a complete reversal of the new focal neurologic deficit should be maintained.^3,29

Inotropic agents such as dobutamine or milrinone can be considered as alternatives in patients who have new neurologic deficits that are refractory to fluid boluses and vasopressors, or in a setting of subarachnoid hemorrhage-induced cardiomyopathy.^76,77

Once the neurologic deficit is reversed by hemodynamic augmentation, the blood pressure should be maintained for 48 to 72 hours at the level that reversed the deficit completely, carefully reassessed thereafter, and the patient weaned slowly. Unruptured unsecured aneurysms should not prevent blood pressure augmentation in a setting of delayed cerebral ischemia if the culprit aneurysm is treated.^3,32 If the ruptured aneurysm has not been secured, careful blood pressure augmentation can be attempted, keeping in mind that hypertension (> 160/95 mm Hg) is a risk factor for fatal aneurysm rupture.

Endovascular management of delayed cerebral ischemia

When medical augmentation fails to completely reverse the neurologic deficits, endovascular treatment can be considered. Although patients treated early in the course of delayed cerebral ischemia have better neurologic recovery, prophylactic endovascular treatment in asymptomatic patients, even if angiographic signs of spasm are present, does not improve clinical outcomes and carries the risk of fatal arterial rupture.⁷⁸

SYSTEMIC COMPLICATIONS

Hyponatremia and hypovolemia

Aneurysmal subarachnoid hemorrhage is commonly associated with abnormalities of fluid balance and electrolyte derangements. Hyponatremia (serum sodium < 135 mmol/L) occurs in 30% to 50% of patients, while the rate of hypovolemia (decreased circulating blood volume) ranges from 17% to 30%.⁷⁹ Both can negatively affect long-term outcomes.^80,81

Decreased circulating blood volume is a well-described contributor to delayed cerebral ischemia and cerebral infarction after aneurysmal subarachnoid hemorrhage.^80–82 Clinical variables such as heart rate, blood pressure, fluid balance, and serum sodium concentration are usually the cornerstones of intravascular volume status assessment. However, these variables correlate poorly with measured circulating blood volumes in those with aneurysmal subarachnoid hemorrhage.^83,84

The mechanisms responsible for the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage are not completely understood. Several factors have been described and may contribute to the increased natriuresis and, hence, to a reduction in circulating blood volume: increased circulating natriuretic peptide concentrations,^85–87 sympathetic nervous system hyperactivation,⁸⁸ and hyperreninemic hypo-
aldosteronism syndrome.^89,90

Guidelines: Before treating the aneurysm, the systolic pressure should be < 160 mm Hg

Lastly, the cerebral salt wasting syndrome, described in the 1950s,⁹¹ was thought to be a key mechanism in the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage. In contrast to the syndrome of inappropriate antidiuretic hormone, which is characterized by hyponatremia with a normal or slightly elevated intravascular volume, the characteristic feature of cerebral salt wasting syndrome is the development of hyponatremia in a setting of intravascular volume depletion.⁹² In critically ill neurologic and neurosurgical patients, this differential diagnosis is very difficult, especially in those with aneurysmal subarachnoid hemorrhage in whom the clinical assessment of fluid status is not reliable. These two syndromes might coexist and contribute to the development of hyponatremia after aneurysmal subarachnoid hemorrhage.^92,93

Hoff et al^83,84 prospectively compared the clinical assessment of fluid status by critical and intermediate care nurses and direct measurements of blood volume using pulse dye densitometry. The clinical assessment failed to accurately assess patients’ volume status. Using the same technique to measure circulating blood volume, this group showed that calculation of fluid balance does not provide adequate assessment of fluid status.^83,84

Hemodynamic monitoring tools can help guide fluid replacement in this population. Mutoh et al⁹⁴ randomized 160 patients within 24 hours of hemorrhage to receive early goal-directed fluid therapy (ie, preload volume and cardiac output monitored by transpulmonary thermodilution) vs standard therapy (ie, fluid balance or central venous pressure). Overall, no difference was found in the rates of delayed cerebral ischemia (33% vs 42%; P = .33) or favorable outcome (67% vs 57%; P = .22). However, in the subgroup of poor-grade patients (WFNS score 4 or 5), early goal-directed therapy was associated with a lower rate of delayed cerebral ischemia (5% vs 14%; P = .036) and with better functional outcomes at 3 months (52% vs 36%; P = .026).

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended because of the increased risk of cerebral infarction due to hypovolemic hypoperfusion.⁸²

Prophylactic use of mineralocorticoids (eg, fludrocortisone, hydrocortisone) has been shown to limit natriuresis, hyponatremia, and the amount of fluid required to maintain euvolemia.^95,96 Higher rates of hypokalemia and hyperglycemia, which can be easily treated, are the most common complications associated with this approach. Additionally, hypertonic saline (eg, 3% saline) can be used to correct hyponatremia in a setting of aneurysmal subarachnoid hemorrhage.⁷⁹

Cardiac complications

Cardiac complications after subarachnoid hemorrhage are most likely related to sympathetic hyperactivity and catecholamine-induced myocyte dysfunction. The pathophysiology is complex, but cardiac complications have a significant negative impact on long-term outcome in these patients.⁹⁷

Electrocardiographic changes and positive cardiac enzymes associated with aneurysmal subarachnoid hemorrhage have been extensively reported. More recently, data from studies of two-dimensional echocardiography have shown that subarachnoid hemorrhage can also be associated with significant wall-motion abnormalities and even overt cardiogenic shock.^98–100

There is no specific curative therapy; the treatment is mainly supportive. Vasopressors and inotropes may be used for hemodynamic augmentation.

Pulmonary complications

Pulmonary complications occur in 20% to 30% of all aneurysmal subarachnoid hemorrhage patients and are associated with a higher risk of delayed cerebral ischemia and death. Common pulmonary complications in this population are mild acute respiratory distress syndrome (27%), hospital-acquired pneumonia (9%), cardiogenic pulmonary edema (8%), aspiration pneumonia (6%), neurogenic pulmonary edema (2%), and pulmonary embolism (1%).^101–103

SUPPORTIVE CARE

Hyperthermia, hyperglycemia, and liberal use of transfusions have all been associated with longer stays in the intensive care unit and hospital, poorer neurologic outcomes, and higher mortality rates in patients with acute brain injury.¹⁰⁴ Noninfectious fever is the most common systemic complication after subarachnoid hemorrhage.

Antipyretic drugs such as acetaminophen and ibuprofen are not very effective in reducing fever in the subarachnoid hemorrhage population, but should still be used as first-line therapy. The use of surface and intravascular devices can be considered when fevers do not respond to nonsteroidal anti-inflammatory drugs.

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended

Although no prospective randomized trial has addressed the impact of induced normothermia on long-term outcome and mortality in aneurysmal subarachnoid hemorrhage patients, fever control has been shown to reduce cerebral metabolic distress, irrespective of intracranial pressure.¹⁰⁵ Maintenance of normothermia (< 37.5°C) seems reasonable, especially in aneurysmal subarachnoid hemorrhage patients at risk of or with active delayed cerebral ischemia.¹⁰⁶

Current guidelines^3,32,69 strongly recommend avoiding hypoglycemia, defined as a serum glucose level less than 80 mg/dL, but suggest keeping the blood sugar level below 180 or 200 mg/dL.

At the moment, there is no clear threshold for transfusion in patients with aneurysmal subarachnoid hemorrhage. Current guidelines suggest keeping hemoglobin levels between 8 and 10 g/dL.³

Preventing venous thromboembolism

The incidence of venous thromboembolism after aneurysmal subarachnoid hemorrhage varies widely, from 1.5% to 18%.¹⁰⁷ Active surveillance with venous Doppler ultrasonography has found asymptomatic deep vein thrombosis in up to 3.4% of poor-grade aneurysmal subarachnoid hemorrhage patients receiving pharmacologic thromboprophylaxis.¹⁰⁸

In a retrospective study of 170 patients, our group showed that giving drugs to prevent venous thromboembolism (unfractionated heparin 5,000 IU subcutaneously every 12 hours or dalteparin 5,000 IU subcutaneously daily), starting within 24 hours of aneurysm treatment, could be safe.¹⁰⁹ Fifty-eight percent of these patients had an external ventricular drain in place. One patient developed a major cerebral hemorrhagic complication and died while on unfractionated heparin; however, the patient was also on dual antiplatelet therapy with aspirin and clopidogrel.¹⁰⁹

Current guidelines suggest that intermittent compression devices be applied in all patients before aneurysm treatment. Pharmacologic thromboprophylaxis with a heparinoid can be started 12 to 24 hours after aneurysm treatment.^3,109

A TEAM APPROACH

Patients with subarachnoid hemorrhage need integrated care from different medical and nursing specialties. The best outcomes are achieved by systems that can focus as a team on the collective goal of quick intervention to secure the aneurysm, followed by measures to minimize secondary brain injury.

The modern concept of cerebral monitoring in a setting of subarachnoid hemorrhage should focus on brain perfusion rather than vascular diameter. Although the search continues for new diagnostic, prognostic, and therapeutic tools, there is no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of many small advances that will ultimately lead to better outcomes.

ACKNOWLEDGMENT

This work was supported by research funding provided by the Bitove Foundation, which has been supportive of our clinical and research work for several years.

Aneurysmal subarachnoid hemorrhage is a devastating condition, with an estimated death rate of 30% during the initial episode.^1,2 Approximately the same number of patients survive but leave the hospital with disabling neurologic deficits.³

However, better outcomes can be achieved by systems that are able to work as a team on the collective goal of quick intervention to secure the ruptured aneurysm, followed by the implementation of measures to minimize secondary brain injury. Although the search for new diagnostic, prognostic, and therapeutic modalities continues, it is clear that there exists no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of small advances that will ultimately maximize the patient’s chances of survival and neurologic recovery.

This review focuses on the management of aneurysmal subarachnoid hemorrhage and its systemic and neurologic complications.

ANEURYSM IS THE MOST COMMON CAUSE OF SUBARACHNOID BLEEDING

Aneurysmal subarachnoid hemorrhage, ie, rupture of an intracranial aneurysm, flooding  the subarachnoid space with blood, affects about 24,000 Americans each year.^1,2 A ruptured aneurysm is the most common cause of subarachnoid hemorrhage, accounting for about 85% of cases. Less common causes include idiopathic benign perimesencephalic hemorrhage, arteriovenous malformation, dural arteriovenous fistula, and hemorrhagic mycotic aneurysm. These have their own natural history, pathophysiology, and specific treatment, and will not be addressed in this article.

Risk factors for aneurysmal subarachnoid hemorrhage include having a first-degree relative who had the disease, hypertension, smoking, and consuming more than 150 g of alcohol per week.⁴

CLINICAL PRESENTATION AND DIAGNOSIS

The key symptom of aneurysmal subarachnoid hemorrhage is the abrupt onset of severe headache that peaks in intensity over 1 hour,⁵ often described as “the worst headache of my life.” Headache is accompanied by brief loss of consciousness in 53% of cases (conversely, nearly half of patients maintain normal mental status), by nausea or vomiting in 77%, and by meningismus (neck pain or stiffness) in 35%.⁶

These clinical manifestations and risk factors have been incorporated into a decision rule:

Obtain brain imaging if the patient has acute headache reaching maximal intensity within 1 hour, associated with any of the following factors:

• Age 40 or older

• Neck pain or stiffness

• Witnessed loss of consciousness

• Onset during exertion

• “Thunderclap” headache (ie, instantly peaking pain)

• Limited neck flexion on examination.⁵

This decision rule has nearly 100% sensitivity for aneurysmal subarachnoid hemorrhage in clinical practice.⁵ All patients require brain imaging if they have a severe headache plus either abnormal neurologic findings (eg, a focal neurologic deficit) or a history of cerebral aneurysm.

Emergency physicians should have a low threshold for ordering noncontrast computed tomography (CT) of the head in patients with even mild symptoms suggesting aneurysmal subarachnoid hemorrhage. Failure to order CT is the most common diagnostic error in this situation.⁶ CT performed within 6 hours of headache onset is nearly 100% sensitive for this condition,⁷ but the sensitivity falls to 93% after the first 24 hours and to less than 60% after 5 days.⁸ In patients who have symptoms highly suggestive of aneurysmal subarachnoid hemorrhage but a normal CT, lumbar puncture is the next diagnostic step.

There are two alternatives to CT followed by lumbar puncture: ie, noncontrast CT followed by CT angiography,^9,10 and magnetic resonance imaging followed by magnetic resonance angiography. In patients with suspicious clinical symptoms but negative CT results, CT followed by CT angiography can rule out aneurysmal subarachnoid hemorrhage with a 99% probability.^9,10 However, CT followed by lumbar puncture remains the standard of care and carries a class I recommendation in the American Heart Association guidelines for ruling out subarachnoid hemorrhage.⁵

GRADING THE SEVERITY OF SUBARACHNOID HEMORRHAGE

Age, the thickness of the blood layer in the subarachnoid space, intraventricular hemorrhage and the findings of the neurologic examination at presentation are predictors of long-term outcomes in aneurysmal subarachnoid hemorrhage (Figure 1).

Different grading systems used in clinical practice are based on the findings on the initial neurologic examination and on the initial noncontrast CT (ie, the thickness of the blood, and whether intraventricular hemorrhage is present). Among the most widely used are those developed by Hunt and Hess¹² and by the World Federation of Neurological Surgeons¹¹ (WFNS), and the CT grading scales (Fisher¹³ or its modified version¹⁴)  (Tables 1 and 2). With either the Hunt and Hess scale or the WFNS scale, the higher the score, the worse the patient’s probable outcome. Scores on both Fisher scales correlate with the risk of angiographic vasospasm. The higher the grade, the higher the risk of angiographic vasospasm.

The VASOGRADE score—a combination of the WFNS score and the modified Fisher scale—stratifies patients at risk of delayed cerebral ischemia, allowing for a tailored monitoring strategy.¹⁵ There are three variations:

• VASOGRADE green—Modified Fisher 1 or 2 and WFNS 1 or 2

• VASOGRADE yellow—Modified Fisher 3 or 4 and WFNS 1, 2, or 3

• VASOGRADE red—WFNS 4 or 5. 

After the initial bleeding event, patients with aneurysmal subarachnoid hemorrhage are at high risk of delayed systemic and neurologic complications, with poor functional outcomes. Delayed cerebral ischemia holds the greatest risk of an unfavorable outcome and ultimately can lead to cerebral infarction, disability, and death.^6,7

INITIAL MANAGEMENT

After aneurysmal subarachnoid hemorrhage is diagnosed, the initial management (Figure 2) includes appropriate medical prevention of rebleeding (which includes supportive care, blood pressure management, and, perhaps, the early use of a short course of an antifibrinolytic drug) and early transfer to a high-volume center for securing the aneurysm. The reported incidence of rebleeding varies from 5% to 22% in the first 72 hours. “Ultra-early” rebleeding (within 24 hours of hemorrhage) has been reported, with an incidence as high as 15% and a fatality rate around 70%. Patients with poor-grade aneurysmal subarachnoid hemorrhage, larger aneurysms, and “sentinel bleeds” are at higher risk of rebleeding.16

Outcomes are much better when patients are managed in a high-volume center, with a specialized neurointensive care unit¹⁷ and access to an interdisciplinary team.¹⁸ Regardless of the initial grade, patients with aneurysmal subarachnoid hemorrhage should be quickly transferred to a high-volume center, defined as one treating at least 35 cases per year, and the benefit is greater in centers treating more than 60 cases per year.¹⁹ The higher the caseload in any given hospital, the better the clinical outcomes in this population.²⁰

Treating cerebral aneurysm: Clipping or coiling

Early aneurysm repair is generally considered the standard of care and the best strategy to reduce the risk of rebleeding. Further, early treatment may be associated with a lower risk of delayed cerebral ischemia²¹ and better outcomes.²²

Three randomized clinical trials have compared surgical clipping and endovascular repair (placement of small metal coils within the aneurysm to promote clotting).

The International Subarachnoid Aneurysm Trial²³ showed a reduction of 23% in relative risk and of 7% in absolute risk in patients who underwent endovascular treatment compared with surgery. The survival benefit persisted at a mean of 9 years (range 6–14 years), but with a higher annual rate of aneurysm recurrence in the coiling group (2.9% vs 0.9%).²⁴ Of note, this trial included only patients with aneurysms deemed suitable for both coiling and clipping, so that the exclusion rate was high. Most of the patients presented with good-grade (WFNS score 1–3), small aneurysms (< 5 mm) in the anterior circulation.

A single-center Finnish study²⁵ found no differences in rates of recovery, disability, and  death at 1 year, comparing surgery and endovascular treatment. Additionally, survival rates at a mean follow-up of 39 months were similar, with no late recurrences or aneurysmal bleeding.

Lastly, the Barrow Ruptured Aneurysm Trial26,27 found that patients assigned to endovascular treatment had better 1-year neurologic outcomes, defined as a modified Rankin score of 2 or less. Importantly, 37.7% of patients originally assigned to endovascular treatment crossed over to surgical treatment. The authors then performed intention-to-treat and as-treated analyses. Either way, patients treated by endovascular means had better neurologic outcomes at 1 year. However, no difference in the relative risk reduction in worse outcome was found on 3-year follow-up, and patients treated surgically had higher rates of aneurysm obliteration and required less aneurysm retreatment, both of which were statistically significant.

The question that remains is not whether to clip or whether to coil, but whom to clip and whom to coil.²⁸ That question must be answered on a patient-to-patient basis and requires the expertise of an interventional neuroradiologist and a vascular neurosurgeon—one of the reasons these patients are best cared for in high-volume centers providing such expertise.

MEDICAL PREVENTION OF REBLEEDING

Blood pressure management

There are no systematic data on the optimal blood pressure before securing an aneurysm. Early studies of hemodynamic augmentation in cases of ruptured untreated aneurysm reported rebleeding when the systolic blood pressure was allowed to rise above 160 mm Hg.^29,30 A recent study evaluating hypertensive intracerebral hemorrhage revealed better functional outcomes with intensive lowering of blood pressure (defined as systolic blood pressure < 140 mm Hg) but no significant reduction in the combined rate of death or severe disability.³¹ It is difficult to know if these results can be extrapolated to patients with aneurysmal subarachnoid hemorrhage. Current guidelines^3,32 say that before the aneurysm is treated, the systolic pressure should be lower than 160 mm Hg.

There is no specific drug of choice, but a short-acting, titratable medication is preferable. Nicardipine is a very good option, and labetalol might be an appropriate alternative.³³ Once the aneurysm is secured, all antihypertensive drugs should be held. Hypertension should not be treated unless the patient has clinical signs of a hypertensive crisis, such as flash pulmonary edema, myocardial infarction, or hypertensive encephalopathy.

Antifibrinolytic therapy

Risk factors: Family history, hypertension, smoking, heavy drinking

The role of antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage is controversial and has been studied in 10 clinical trials. In a Swedish study,³⁴ early use of tranexamic acid (1 g intravenously over 10 minutes followed by 1 g every 6 hours for a maximum of 24 hours) reduced the rebleeding rate substantially, from 10.8% to 2.4%, with an 80% reduction in the mortality rate from ultra-early rebleeding. However, a recent Cochrane review that included this study found no overall benefit.³⁵

An ongoing multicenter randomized trial in the Netherlands will, we hope, answer this question in the near future.³⁶ At present, some centers would consider a short course of tranexamic acid before aneurysm treatment.

DIAGNOSIS AND TREATMENT OF COMPLICATIONS

Medical complications are extremely common after aneurysmal subarachnoid hemorrhage. Between 75% and 100% of patients develop some type of systemic or further neurologic derangement, which in turn has a negative impact on the long-term outcome.^37,38 In the first 72 hours, rebleeding is the most feared complication, and as mentioned previously, appropriate blood pressure management and early securing of the aneurysm minimize its risk.

NEUROLOGIC COMPLICATIONS

Hydrocephalus

Hydrocephalus is the most common early neurologic complication after aneurysmal subarachnoid hemorrhage, with an overall incidence of 50%.³⁹ Many patients with poor-grade aneurysmal subarachnoid hemorrhage and patients whose condition deteriorates due to worsening of hydrocephalus require the insertion of an external ventricular drain (Figure 1).

Up to 30% of patients who have a poor-grade aneurysmal subarachnoid hemorrhage improve neurologically with cerebrospinal fluid drainage.⁴⁰ An external ventricular drain can be safely placed, even before aneurysm treatment, and placement does not appear to increase the risk of rebleeding.^39,41 After placement, rapid weaning from the drain (clamping within 24 hours of insertion) is safe, decreases length of stay in the intensive care unit and hospital, and may be more cost-effective than gradual weaning over 96 hours.⁴²

Increased intracranial pressure

Intracranial hypertension is another potential early complication, and is frequently due to the development of hydrocephalus, cerebral edema, or rebleeding. The treatment of increased intracranial pressure does not differ from the approach used in managing severe traumatic brain injury, which includes elevating the head of the bed, sedation, analgesia, normoventilation, and cerebrospinal fluid drainage.

Hypertonic saline has been tested in several studies that were very small but nevertheless consistently showed control of intracranial pressure levels and improvement in cerebral blood flow measured by xenon CT.^43–47 Two of these studies even showed better outcomes at discharge.^43,44 However, the small number of patients prevents any meaningful conclusion regarding the use of hypertonic saline and functional outcomes.

Outcomes are much better when patients are managed in a high-volume center

Barbiturates, hypothermia, and decompressive craniectomy could be tried in refractory cases.⁴⁸ Seule et al⁴⁹ evaluated the role of therapeutic hypothermia with or without barbiturate coma in 100 patients with refractory intracranial hypertension. Only 13 patients received hypothermia by itself. At 1 year, 32 patients had achieved a good functional outcome (Glasgow Outcome Scale score 4 or 5). The remaining patients were severely disabled or had died. Of interest, the median duration of hypothermia was 7 days, and 93% of patients developed some medical complication such as electrolyte disorders (77%), pneumonia (52%), thrombocytopenia (47%), or septic shock syndrome (40%). Six patients died as a consequence of one of these complications.

Decompressive craniectomy can be life-saving in patients with refractory intracranial hypertension. However, most of these patients will die or remain severely disabled or comatose.⁵⁰

Seizure prophylaxis is controversial

Seizures can occur at the onset of intracranial hemorrhage, perioperatively, or later (ie, after the first week). The incidence varied considerably in different reports, ranging from 4% to 26%.⁵¹ Seizures occurring perioperatively, ie, after hospital admission, are less frequent and are usually the manifestation of aneurysm rebleeding.²⁴

The question is not whether to clip or coil, but whom to clip and whom to coil

Seizure prophylaxis remains controversial, especially because the use of phenytoin is associated with increased incidence of cerebral vasospasm, infarction, and worse cognitive outcomes after aneurysmal subarachnoid hemorrhage.^52,53 Therefore, routine prophylactic use of phenytoin is not recommended in these patients,³ although the effect of other antiepileptic drugs is less studied and less clear. Patients may be considered for this therapy if they have multiple risk factors for seizures, such as intraparenchymal hematoma, advanced age (> 65), middle cerebral artery aneurysm, craniotomy for aneurysm clipping, and a short course (≤ 72 hours) of an antiepileptic drug other than phenytoin, especially while the aneurysm is unsecured.³

Levetiracetam may be an alternative to phenytoin, having better pharmacodynamic and kinetic profiles, minimal protein binding, and absence of hepatic metabolism, resulting in a very low risk of drug interaction and better tolerability.^54,55 Because of these advantages, levetiracetam has become the drug of choice in several centers treating aneurysmal subarachnoid hemorrhage in the United States.

Addressing this question, a survey was sent to 25 high-volume aneurysmal subarachnoid hemorrhage academic centers in the United States. All 25 institutions answered the survey, and interestingly, levetiracetam was the first-line agent for 16 (94%) of the 17 responders that used prophylaxis, while only 1 used phenytoin as the agent of choice.⁵⁶

A retrospective cohort study by Murphy-Human et al⁵⁷ showed that a short course of levetiracetam (≤ 72 hours) was associated with higher rates of in-hospital seizures compared with an extended course of phenytoin (eg, entire hospital stay). However, the study did not address functional outcomes.⁵⁷

Continuous electroencephalographic monitoring may be considered in comatose patients, in patients requiring controlled ventilation and sedation, or in patients with unexplained alteration in consciousness. In one series of patients with aneurysmal subarachnoid hemorrhage who received continuous monitoring, the incidence of nonconvulsive status epilepticus was 19%, with an associated mortality rate of 100%.⁵⁸

Continuous quantitative electroencephalography is useful to monitor and to detect angiographic vasospasm and delayed cerebral ischemia. Relative alpha variability and the alpha-delta ratio decrease with ischemia, and this effect can precede angiographic vasospasm by 3 days.^59,60

Delayed cerebral ischemia

Delayed cerebral ischemia is defined as the occurrence of focal neurologic impairment, or a decrease of at least 2 points on the Glasgow Coma Scale that lasts for at least 1 hour, is not apparent immediately after aneurysm occlusion, and not attributable to other causes (eg, hyponatremia, fever).⁶¹

Classically, neurologic deficits that occurred within 2 weeks of aneurysm rupture were ascribed to reduced cerebral blood flow caused by delayed large-vessel vasospasm causing cerebral ischemia.⁶² However, perfusion abnormalities have also been observed with either mild or no demonstrable vasospasm.⁶³ Almost 70% of patients who survive the initial hemorrhage develop some degree of angiographic vasospasm. However, only 30% of those patients will experience symptoms.

In addition to vasospasm of large cerebral arteries, impaired autoregulation and early brain injury within the first 72 hours following subarachnoid hemorrhage may play important roles in the development of delayed cerebral ischemia.⁶⁴ Therefore, the modern concept of delayed cerebral ischemia monitoring should focus on cerebral perfusion rather than vessel diameter measurements. This underscores the importance of comprehensive, standardized monitoring techniques that provide information not only on microvasculature, but also at the level of the microcirculation, with information on perfusion, oxygen utilization and extraction, and autoregulation.

Although transcranial Doppler has been the most commonly applied tool to monitor for angiographic vasospasm, it has a low sensitivity and negative predictive value.³⁷ It is nevertheless a useful technique to monitor good-grade aneurysmal subarachnoid hemorrhage patients (WFNS score 1–3) combined with frequent neurologic examinations (Figure 3).

CT angiography is a good noninvasive alternative to digital subtraction angiography. However, it tends to overestimate the degree of vasoconstriction and does not provide information about perfusion and autoregulation.⁶⁵ Nevertheless, CT angiography combined with a CT perfusion scan can add information about autoregulation and cerebral perfusion and has been shown to be more sensitive for the diagnosis of angiographic vasospasm than transcranial Doppler and digital subtraction angiography (Figure 4).

Patients with a poor clinical condition (WFNS score 4 or 5) or receiving continuous sedation constitute a challenge in monitoring for delayed neurologic deterioration. Neurologic examination is not sensitive enough in this setting to detect subtle changes. In these specific and challenging circumstances, multimodality neuromonitoring may be useful in the early detection of delayed cerebral ischemia and may help guide therapy.⁶⁷

Several noninvasive and invasive techniques have been studied to monitor patients at risk of delayed cerebral ischemia after subarachnoid hemorrhage.⁶⁶ These include continuous electroencephalography, brain tissue oxygenation monitoring (Ptio₂), cerebral microdialysis, thermal diffusion flowmetry, and near-infrared spectroscopy. Of these techniques, Ptio₂, cerebral microdialysis, and continuous electroencephalography (see discussion of seizure prophylaxis above) have been more extensively studied. However, most of the studies were observational and very small, limiting any recommendations for using these techniques in routine clinical practice.⁶⁸

Ptio₂ is measured by inserting an intraparenchymal oxygen-sensitive microelectrode, and microdialysis requires a microcatheter with a semipermeable membrane that allows small soluble substances to cross it into the dialysate. These substances, which include markers of ischemia (ie, glucose, lactate, and pyruvate), excitotoxins (ie, glutamate and aspartate), and membrane cell damage products (ie, glycerol), can be measured. Low Ptio₂ values (< 15 mm Hg) and abnormal mycrodialysate findings (eg, glucose < 0.8 mmol/L, lactate-to-pyruvate ratio > 40) have both been associated with cerebral ischemic events and poor outcome.⁶⁸

Preventing delayed cerebral ischemia

Oral nimodipine 60 mg every 4 hours for 21 days, started on admission, carries a class I, level of evidence A recommendation in the management of aneurysmal subarachnoid hemorrhage.^3,32,69 It improves clinical outcome despite having no effect on the risk of angiographic vasospasm. The mechanism of improved outcome is unclear, but the effect may be a neuroprotective phenomenon limiting the extension of delayed cerebral ischemia.⁷⁰

If hypotension occurs, the dose can be lowered to 30 mg every 2 hours. Whether to discontinue nimodipine in this situation is controversial. Of note, the clinical benefits of nimodipine have not been replicated with other calcium channel blockers (eg, nicardipine).⁷¹

Prophylactic hyperdynamic fluid therapy, known as “triple-H” (hypervolemia, hemodilution, and hypertension) was for years the mainstay of treatment in preventing delayed cerebral ischemia due to vasospasm. However, the clinical data supporting this intervention have been called into question, as analysis of two trials found that hypervolemia did not improve outcomes or reduce the incidence of delayed cerebral ischemia, and in fact increased the rate of complications.^72,73 Based on these findings, current guidelines recommend maintaining euvolemia rather than prophylactic hypervolemia in patients with aneurysmal subarachnoid hemorrhage.^3,32,69

TREATING DELAYED CEREBRAL ISCHEMIA

Hemodynamic augmentation

In patients with neurologic deterioration due to delayed cerebral ischemia, hemodynamic augmentation is the cornerstone of treatment. This is done according to a protocol, started early, involving specific physiologic goals, clinical improvement, and escalation to invasive therapies in a timely fashion in patients at high risk of further neurologic insult (Figure 5).

The physiologic goal is to increase the delivery of oxygen and glucose to the ischemic brain. Hypertension seems to be the most effective component of hemodynamic augmentation regardless of volume status, increasing cerebral blood flow and brain tissue oxygenation, with reversal of delayed cerebral ischemic symptoms in up to two-thirds of treated patients.^74,75 However, this information comes from very small studies, with no randomized trials of induced hypertension available.

The effect of a normal saline fluid bolus in patients suspected of having delayed cerebral ischemia has been shown to increase cerebral blood flow in areas of cerebral ischemia.⁷⁴ If volume augmentation fails to improve the neurologic status, the next step is to artificially induce hypertension using vasopressors. The blood pressure target should be based on clinical improvement. A stepwise approach is reasonable in this situation, and the lowest level of blood pressure at which there is a complete reversal of the new focal neurologic deficit should be maintained.^3,29

Inotropic agents such as dobutamine or milrinone can be considered as alternatives in patients who have new neurologic deficits that are refractory to fluid boluses and vasopressors, or in a setting of subarachnoid hemorrhage-induced cardiomyopathy.^76,77

Once the neurologic deficit is reversed by hemodynamic augmentation, the blood pressure should be maintained for 48 to 72 hours at the level that reversed the deficit completely, carefully reassessed thereafter, and the patient weaned slowly. Unruptured unsecured aneurysms should not prevent blood pressure augmentation in a setting of delayed cerebral ischemia if the culprit aneurysm is treated.^3,32 If the ruptured aneurysm has not been secured, careful blood pressure augmentation can be attempted, keeping in mind that hypertension (> 160/95 mm Hg) is a risk factor for fatal aneurysm rupture.

Endovascular management of delayed cerebral ischemia

When medical augmentation fails to completely reverse the neurologic deficits, endovascular treatment can be considered. Although patients treated early in the course of delayed cerebral ischemia have better neurologic recovery, prophylactic endovascular treatment in asymptomatic patients, even if angiographic signs of spasm are present, does not improve clinical outcomes and carries the risk of fatal arterial rupture.⁷⁸

SYSTEMIC COMPLICATIONS

Hyponatremia and hypovolemia

Aneurysmal subarachnoid hemorrhage is commonly associated with abnormalities of fluid balance and electrolyte derangements. Hyponatremia (serum sodium < 135 mmol/L) occurs in 30% to 50% of patients, while the rate of hypovolemia (decreased circulating blood volume) ranges from 17% to 30%.⁷⁹ Both can negatively affect long-term outcomes.^80,81

Decreased circulating blood volume is a well-described contributor to delayed cerebral ischemia and cerebral infarction after aneurysmal subarachnoid hemorrhage.^80–82 Clinical variables such as heart rate, blood pressure, fluid balance, and serum sodium concentration are usually the cornerstones of intravascular volume status assessment. However, these variables correlate poorly with measured circulating blood volumes in those with aneurysmal subarachnoid hemorrhage.^83,84

The mechanisms responsible for the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage are not completely understood. Several factors have been described and may contribute to the increased natriuresis and, hence, to a reduction in circulating blood volume: increased circulating natriuretic peptide concentrations,^85–87 sympathetic nervous system hyperactivation,⁸⁸ and hyperreninemic hypo-
aldosteronism syndrome.^89,90

Guidelines: Before treating the aneurysm, the systolic pressure should be < 160 mm Hg

Lastly, the cerebral salt wasting syndrome, described in the 1950s,⁹¹ was thought to be a key mechanism in the development of hyponatremia and hypovolemia after aneurysmal subarachnoid hemorrhage. In contrast to the syndrome of inappropriate antidiuretic hormone, which is characterized by hyponatremia with a normal or slightly elevated intravascular volume, the characteristic feature of cerebral salt wasting syndrome is the development of hyponatremia in a setting of intravascular volume depletion.⁹² In critically ill neurologic and neurosurgical patients, this differential diagnosis is very difficult, especially in those with aneurysmal subarachnoid hemorrhage in whom the clinical assessment of fluid status is not reliable. These two syndromes might coexist and contribute to the development of hyponatremia after aneurysmal subarachnoid hemorrhage.^92,93

Hoff et al^83,84 prospectively compared the clinical assessment of fluid status by critical and intermediate care nurses and direct measurements of blood volume using pulse dye densitometry. The clinical assessment failed to accurately assess patients’ volume status. Using the same technique to measure circulating blood volume, this group showed that calculation of fluid balance does not provide adequate assessment of fluid status.^83,84

Hemodynamic monitoring tools can help guide fluid replacement in this population. Mutoh et al⁹⁴ randomized 160 patients within 24 hours of hemorrhage to receive early goal-directed fluid therapy (ie, preload volume and cardiac output monitored by transpulmonary thermodilution) vs standard therapy (ie, fluid balance or central venous pressure). Overall, no difference was found in the rates of delayed cerebral ischemia (33% vs 42%; P = .33) or favorable outcome (67% vs 57%; P = .22). However, in the subgroup of poor-grade patients (WFNS score 4 or 5), early goal-directed therapy was associated with a lower rate of delayed cerebral ischemia (5% vs 14%; P = .036) and with better functional outcomes at 3 months (52% vs 36%; P = .026).

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended because of the increased risk of cerebral infarction due to hypovolemic hypoperfusion.⁸²

Prophylactic use of mineralocorticoids (eg, fludrocortisone, hydrocortisone) has been shown to limit natriuresis, hyponatremia, and the amount of fluid required to maintain euvolemia.^95,96 Higher rates of hypokalemia and hyperglycemia, which can be easily treated, are the most common complications associated with this approach. Additionally, hypertonic saline (eg, 3% saline) can be used to correct hyponatremia in a setting of aneurysmal subarachnoid hemorrhage.⁷⁹

Cardiac complications

Cardiac complications after subarachnoid hemorrhage are most likely related to sympathetic hyperactivity and catecholamine-induced myocyte dysfunction. The pathophysiology is complex, but cardiac complications have a significant negative impact on long-term outcome in these patients.⁹⁷

Electrocardiographic changes and positive cardiac enzymes associated with aneurysmal subarachnoid hemorrhage have been extensively reported. More recently, data from studies of two-dimensional echocardiography have shown that subarachnoid hemorrhage can also be associated with significant wall-motion abnormalities and even overt cardiogenic shock.^98–100

There is no specific curative therapy; the treatment is mainly supportive. Vasopressors and inotropes may be used for hemodynamic augmentation.

Pulmonary complications

Pulmonary complications occur in 20% to 30% of all aneurysmal subarachnoid hemorrhage patients and are associated with a higher risk of delayed cerebral ischemia and death. Common pulmonary complications in this population are mild acute respiratory distress syndrome (27%), hospital-acquired pneumonia (9%), cardiogenic pulmonary edema (8%), aspiration pneumonia (6%), neurogenic pulmonary edema (2%), and pulmonary embolism (1%).^101–103

SUPPORTIVE CARE

Hyperthermia, hyperglycemia, and liberal use of transfusions have all been associated with longer stays in the intensive care unit and hospital, poorer neurologic outcomes, and higher mortality rates in patients with acute brain injury.¹⁰⁴ Noninfectious fever is the most common systemic complication after subarachnoid hemorrhage.

Antipyretic drugs such as acetaminophen and ibuprofen are not very effective in reducing fever in the subarachnoid hemorrhage population, but should still be used as first-line therapy. The use of surface and intravascular devices can be considered when fevers do not respond to nonsteroidal anti-inflammatory drugs.

Fluid restriction to treat hyponatremia in aneurysmal subarachnoid hemorrhage is no longer recommended

Although no prospective randomized trial has addressed the impact of induced normothermia on long-term outcome and mortality in aneurysmal subarachnoid hemorrhage patients, fever control has been shown to reduce cerebral metabolic distress, irrespective of intracranial pressure.¹⁰⁵ Maintenance of normothermia (< 37.5°C) seems reasonable, especially in aneurysmal subarachnoid hemorrhage patients at risk of or with active delayed cerebral ischemia.¹⁰⁶

Current guidelines^3,32,69 strongly recommend avoiding hypoglycemia, defined as a serum glucose level less than 80 mg/dL, but suggest keeping the blood sugar level below 180 or 200 mg/dL.

At the moment, there is no clear threshold for transfusion in patients with aneurysmal subarachnoid hemorrhage. Current guidelines suggest keeping hemoglobin levels between 8 and 10 g/dL.³

Preventing venous thromboembolism

The incidence of venous thromboembolism after aneurysmal subarachnoid hemorrhage varies widely, from 1.5% to 18%.¹⁰⁷ Active surveillance with venous Doppler ultrasonography has found asymptomatic deep vein thrombosis in up to 3.4% of poor-grade aneurysmal subarachnoid hemorrhage patients receiving pharmacologic thromboprophylaxis.¹⁰⁸

In a retrospective study of 170 patients, our group showed that giving drugs to prevent venous thromboembolism (unfractionated heparin 5,000 IU subcutaneously every 12 hours or dalteparin 5,000 IU subcutaneously daily), starting within 24 hours of aneurysm treatment, could be safe.¹⁰⁹ Fifty-eight percent of these patients had an external ventricular drain in place. One patient developed a major cerebral hemorrhagic complication and died while on unfractionated heparin; however, the patient was also on dual antiplatelet therapy with aspirin and clopidogrel.¹⁰⁹

Current guidelines suggest that intermittent compression devices be applied in all patients before aneurysm treatment. Pharmacologic thromboprophylaxis with a heparinoid can be started 12 to 24 hours after aneurysm treatment.^3,109

A TEAM APPROACH

Patients with subarachnoid hemorrhage need integrated care from different medical and nursing specialties. The best outcomes are achieved by systems that can focus as a team on the collective goal of quick intervention to secure the aneurysm, followed by measures to minimize secondary brain injury.

The modern concept of cerebral monitoring in a setting of subarachnoid hemorrhage should focus on brain perfusion rather than vascular diameter. Although the search continues for new diagnostic, prognostic, and therapeutic tools, there is no “silver bullet” that will help all patients. Instead, it is the systematic integration and application of many small advances that will ultimately lead to better outcomes.

ACKNOWLEDGMENT

This work was supported by research funding provided by the Bitove Foundation, which has been supportive of our clinical and research work for several years.

A 38-year-old woman presents to the emergency department after experiencing several days of swelling and mild discomfort in her left calf. She denies chest pain or shortness of breath. She does not recall antecedent trauma, is a nonsmoker, is healthy, and takes no medications apart from a multivitamin. She has not undergone any surgical procedure, has not been hospitalized recently, and has no history of venous thromboembolic disease. She says she started an aerobics program 1 week ago.

On examination, her left lower leg is mildly swollen, but the difference in calf circumference between the right and left legs is less than 1 cm. There is no erythema, no pitting edema, and only mild and rather diffuse tenderness of the calf. A urine pregnancy test is negative and her D-dimer level is 350 ng/mL (reference range < 500 ng/mL). Does she require ultrasonography of the left leg to evaluate for deep vein thrombosis (DVT)?

This patient does not need confirmatory ultrasonography, as her normal D-dimer level of 350 ng/mL is enough to rule out DVT. Her low probability of having DVT is further supported by her Wells score (Table 1), a tool that can help rule out DVT and reduce the need for further testing. DVT is unlikely if a patient’s Wells score is less than 2, and this patient’s score is –1. She receives 1 point for swelling of her left lower leg, but injury from her recent aerobic exercise is at least as likely as DVT to account for her symptoms (–2 points).

GUIDELINES AND CHOOSING WISELY

Compression ultrasonography is the study most commonly used to evaluate for DVT. The diagnosis is made if either the femoral or popliteal vein is noncompressible.¹ In a patient with no history of DVT, the sensitivity of compression ultrasonography is 94%, and its specificity is 98%.

Several guidelines recommend using a clinical decision rule to establish the probability of venous thromboembolic disease before any additional diagnostic testing such as D-dimer measurement or ultrasonography.^2–4 A number of clinical decision rules exist for DVT, but the Wells score is the most studied and validated.¹ It incorporates the patient’s risk factors, symptoms, and signs to categorize the probability of DVT as low, moderate, or high and has been further modified to classify the risk as either likely or unlikely (Table 1).⁵

Guidelines from the American College of Chest Physicians (2012), Scottish Intercollegiate Guidelines Network (2010), and American Academy of Family Physicians and American College of Physicians (2007) recommend against performing imaging if a high-sensitivity D-dimer test is negative in a patient in whom the pretest probability of DVT is unlikely.^2–4 Enzyme-linked immunofluorescence assays, microplate enzyme-linked immunosorbent assays, and latex quantitative assays are considered high-sensitivity D-dimer tests, having 96%, 94%, and 93% sensitivity, respectively, in ruling out DVT.¹ Other D-dimer tests have lower sensitivity and cannot comfortably rule out DVT even if the results are negative.

Since D-dimer measurement is a sensitive but not specific test, it should be used only to rule out DVT—not to rule it in. Moreover, compression ultrasonography may be indicated to rule out other causes of the patient’s symptoms.

The guidelines caution against D-dimer testing if the patient has a comorbid condition that can by itself raise or lower the D-dimer level, leading one to falsely conclude the patient has or does not have DVT (Table 2).^1–4 In these instances, the pretest probability of  DVT may be higher than calculated by a clinical prediction rule, and compression ultrasonography may be an appropriate initial test.⁴ Compression ultrasonography is also recommended as a confirmatory test in low-risk patients who have a positive D-dimer test or as an initial test in patients at higher risk for DVT.^2–4

If a patient has a low pretest probability of DVT as defined by the Wells score and a normal high-sensitivity D-dimer measurement, then ordering imaging studies is a questionable practice according to statements by the American College of Physicians, American College of Emergency Physicians, European Society of Cardiology, American Academy of Family Physicians, and Scottish Intercollegiate Guidelines Network.

HARMS OF ULTRASONOGRAPHY

Although ultrasonography is generally well tolerated, it may be unnecessary. Combining a prediction rule (to assess the probability) with D-dimer testing (to rule out DVT) can significantly reduce the use of ultrasonography and the associated cost.

Wells et al⁵ calculated that clinicians could cut back on ultrasonographic testing by 39% by not doing it in those who had a low pretest probability and a negative D-dimer test result.⁵ In that patient population, fewer than 1% of patients were later found to have DVT.

Ordering compression ultrasonography as additional testing may lead to a false-positive result and to additional unnecessary testing and treatments that would inconvenience the patient, increase the risk of serious complications such as bleeding, and incur increased costs. Cost considerations should include not only the cost of the test and its interpretation, but also the workup and treatment of false-positive results, patient time missed from work while being tested, and potential associated costs for patients who need to be evaluated in the emergency department to obtain same-day testing.

THE CLINICAL BOTTOM LINE

Our patient’s Wells score indicates that DVT is unlikely. A negative D-dimer test is sufficient to rule out DVT, and further testing is unnecessary.

A 38-year-old woman presents to the emergency department after experiencing several days of swelling and mild discomfort in her left calf. She denies chest pain or shortness of breath. She does not recall antecedent trauma, is a nonsmoker, is healthy, and takes no medications apart from a multivitamin. She has not undergone any surgical procedure, has not been hospitalized recently, and has no history of venous thromboembolic disease. She says she started an aerobics program 1 week ago.

On examination, her left lower leg is mildly swollen, but the difference in calf circumference between the right and left legs is less than 1 cm. There is no erythema, no pitting edema, and only mild and rather diffuse tenderness of the calf. A urine pregnancy test is negative and her D-dimer level is 350 ng/mL (reference range < 500 ng/mL). Does she require ultrasonography of the left leg to evaluate for deep vein thrombosis (DVT)?

This patient does not need confirmatory ultrasonography, as her normal D-dimer level of 350 ng/mL is enough to rule out DVT. Her low probability of having DVT is further supported by her Wells score (Table 1), a tool that can help rule out DVT and reduce the need for further testing. DVT is unlikely if a patient’s Wells score is less than 2, and this patient’s score is –1. She receives 1 point for swelling of her left lower leg, but injury from her recent aerobic exercise is at least as likely as DVT to account for her symptoms (–2 points).

GUIDELINES AND CHOOSING WISELY

Compression ultrasonography is the study most commonly used to evaluate for DVT. The diagnosis is made if either the femoral or popliteal vein is noncompressible.¹ In a patient with no history of DVT, the sensitivity of compression ultrasonography is 94%, and its specificity is 98%.

Several guidelines recommend using a clinical decision rule to establish the probability of venous thromboembolic disease before any additional diagnostic testing such as D-dimer measurement or ultrasonography.^2–4 A number of clinical decision rules exist for DVT, but the Wells score is the most studied and validated.¹ It incorporates the patient’s risk factors, symptoms, and signs to categorize the probability of DVT as low, moderate, or high and has been further modified to classify the risk as either likely or unlikely (Table 1).⁵

Guidelines from the American College of Chest Physicians (2012), Scottish Intercollegiate Guidelines Network (2010), and American Academy of Family Physicians and American College of Physicians (2007) recommend against performing imaging if a high-sensitivity D-dimer test is negative in a patient in whom the pretest probability of DVT is unlikely.^2–4 Enzyme-linked immunofluorescence assays, microplate enzyme-linked immunosorbent assays, and latex quantitative assays are considered high-sensitivity D-dimer tests, having 96%, 94%, and 93% sensitivity, respectively, in ruling out DVT.¹ Other D-dimer tests have lower sensitivity and cannot comfortably rule out DVT even if the results are negative.

Since D-dimer measurement is a sensitive but not specific test, it should be used only to rule out DVT—not to rule it in. Moreover, compression ultrasonography may be indicated to rule out other causes of the patient’s symptoms.

The guidelines caution against D-dimer testing if the patient has a comorbid condition that can by itself raise or lower the D-dimer level, leading one to falsely conclude the patient has or does not have DVT (Table 2).^1–4 In these instances, the pretest probability of  DVT may be higher than calculated by a clinical prediction rule, and compression ultrasonography may be an appropriate initial test.⁴ Compression ultrasonography is also recommended as a confirmatory test in low-risk patients who have a positive D-dimer test or as an initial test in patients at higher risk for DVT.^2–4

If a patient has a low pretest probability of DVT as defined by the Wells score and a normal high-sensitivity D-dimer measurement, then ordering imaging studies is a questionable practice according to statements by the American College of Physicians, American College of Emergency Physicians, European Society of Cardiology, American Academy of Family Physicians, and Scottish Intercollegiate Guidelines Network.

HARMS OF ULTRASONOGRAPHY

Although ultrasonography is generally well tolerated, it may be unnecessary. Combining a prediction rule (to assess the probability) with D-dimer testing (to rule out DVT) can significantly reduce the use of ultrasonography and the associated cost.

Wells et al⁵ calculated that clinicians could cut back on ultrasonographic testing by 39% by not doing it in those who had a low pretest probability and a negative D-dimer test result.⁵ In that patient population, fewer than 1% of patients were later found to have DVT.

Ordering compression ultrasonography as additional testing may lead to a false-positive result and to additional unnecessary testing and treatments that would inconvenience the patient, increase the risk of serious complications such as bleeding, and incur increased costs. Cost considerations should include not only the cost of the test and its interpretation, but also the workup and treatment of false-positive results, patient time missed from work while being tested, and potential associated costs for patients who need to be evaluated in the emergency department to obtain same-day testing.

THE CLINICAL BOTTOM LINE

Our patient’s Wells score indicates that DVT is unlikely. A negative D-dimer test is sufficient to rule out DVT, and further testing is unnecessary.

A 38-year-old woman presents to the emergency department after experiencing several days of swelling and mild discomfort in her left calf. She denies chest pain or shortness of breath. She does not recall antecedent trauma, is a nonsmoker, is healthy, and takes no medications apart from a multivitamin. She has not undergone any surgical procedure, has not been hospitalized recently, and has no history of venous thromboembolic disease. She says she started an aerobics program 1 week ago.

On examination, her left lower leg is mildly swollen, but the difference in calf circumference between the right and left legs is less than 1 cm. There is no erythema, no pitting edema, and only mild and rather diffuse tenderness of the calf. A urine pregnancy test is negative and her D-dimer level is 350 ng/mL (reference range < 500 ng/mL). Does she require ultrasonography of the left leg to evaluate for deep vein thrombosis (DVT)?

This patient does not need confirmatory ultrasonography, as her normal D-dimer level of 350 ng/mL is enough to rule out DVT. Her low probability of having DVT is further supported by her Wells score (Table 1), a tool that can help rule out DVT and reduce the need for further testing. DVT is unlikely if a patient’s Wells score is less than 2, and this patient’s score is –1. She receives 1 point for swelling of her left lower leg, but injury from her recent aerobic exercise is at least as likely as DVT to account for her symptoms (–2 points).

GUIDELINES AND CHOOSING WISELY

Compression ultrasonography is the study most commonly used to evaluate for DVT. The diagnosis is made if either the femoral or popliteal vein is noncompressible.¹ In a patient with no history of DVT, the sensitivity of compression ultrasonography is 94%, and its specificity is 98%.

Several guidelines recommend using a clinical decision rule to establish the probability of venous thromboembolic disease before any additional diagnostic testing such as D-dimer measurement or ultrasonography.^2–4 A number of clinical decision rules exist for DVT, but the Wells score is the most studied and validated.¹ It incorporates the patient’s risk factors, symptoms, and signs to categorize the probability of DVT as low, moderate, or high and has been further modified to classify the risk as either likely or unlikely (Table 1).⁵

Guidelines from the American College of Chest Physicians (2012), Scottish Intercollegiate Guidelines Network (2010), and American Academy of Family Physicians and American College of Physicians (2007) recommend against performing imaging if a high-sensitivity D-dimer test is negative in a patient in whom the pretest probability of DVT is unlikely.^2–4 Enzyme-linked immunofluorescence assays, microplate enzyme-linked immunosorbent assays, and latex quantitative assays are considered high-sensitivity D-dimer tests, having 96%, 94%, and 93% sensitivity, respectively, in ruling out DVT.¹ Other D-dimer tests have lower sensitivity and cannot comfortably rule out DVT even if the results are negative.

Since D-dimer measurement is a sensitive but not specific test, it should be used only to rule out DVT—not to rule it in. Moreover, compression ultrasonography may be indicated to rule out other causes of the patient’s symptoms.

The guidelines caution against D-dimer testing if the patient has a comorbid condition that can by itself raise or lower the D-dimer level, leading one to falsely conclude the patient has or does not have DVT (Table 2).^1–4 In these instances, the pretest probability of  DVT may be higher than calculated by a clinical prediction rule, and compression ultrasonography may be an appropriate initial test.⁴ Compression ultrasonography is also recommended as a confirmatory test in low-risk patients who have a positive D-dimer test or as an initial test in patients at higher risk for DVT.^2–4

If a patient has a low pretest probability of DVT as defined by the Wells score and a normal high-sensitivity D-dimer measurement, then ordering imaging studies is a questionable practice according to statements by the American College of Physicians, American College of Emergency Physicians, European Society of Cardiology, American Academy of Family Physicians, and Scottish Intercollegiate Guidelines Network.

HARMS OF ULTRASONOGRAPHY

Although ultrasonography is generally well tolerated, it may be unnecessary. Combining a prediction rule (to assess the probability) with D-dimer testing (to rule out DVT) can significantly reduce the use of ultrasonography and the associated cost.

Wells et al⁵ calculated that clinicians could cut back on ultrasonographic testing by 39% by not doing it in those who had a low pretest probability and a negative D-dimer test result.⁵ In that patient population, fewer than 1% of patients were later found to have DVT.

Ordering compression ultrasonography as additional testing may lead to a false-positive result and to additional unnecessary testing and treatments that would inconvenience the patient, increase the risk of serious complications such as bleeding, and incur increased costs. Cost considerations should include not only the cost of the test and its interpretation, but also the workup and treatment of false-positive results, patient time missed from work while being tested, and potential associated costs for patients who need to be evaluated in the emergency department to obtain same-day testing.

THE CLINICAL BOTTOM LINE

Our patient’s Wells score indicates that DVT is unlikely. A negative D-dimer test is sufficient to rule out DVT, and further testing is unnecessary.

A 57-year-old man with long-standing systemic sclerosis presented with worsening diffuse abdominal pain associated with several episodes of nonbloody emesis for 5 days. He had been hospitalized numerous times over the past 2 years for similar symptoms. In those instances, abdominal radiography and computed tomography (CT) had revealed nonspecific intestinal pseudo-obstruction that had resolved within a few days with bowel rest, antibiotics for small-intestinal bacterial overgrowth, and supportive care.

At the time of this presentation, physical examination showed stable vital signs, a tympanic, distended abdomen with diffuse tenderness, and diminished bowel sounds with no sign of peritonitis. Complete blood cell counts, renal function testing, and serum lactate levels were unremarkable.

Abdominal radiography showed mildly dilated loops of small bowel with multiple fluid levels, raising concern for intestinal obstruction. Interestingly, abdominal CT revealed extensive pneumatosis cystoides intestinalis of the entire small bowel with sparing of the colon, which raised concern for acute bowel ischemia (Figure 1). However, given the patient’s underlying systemic sclerosis and current stable condition, the general surgeon recommended conservative management with bowel rest, rifaximin to treat the small-intestinal bacterial overgrowth, and intravenous fluids, which resulted in significant clinical improvement. A liquid diet was initiated and advanced as tolerated to a soft diet before he was discharged home after 8 days of hospitalization.

A RARE, USUALLY BENIGN COMPLICATION OF SYSTEMIC SCLEROSIS

Pneumatosis cystoides intestinalis is a rare gastrointestinal complication of systemic sclerosis characterized by intramural accumulation of gas within thin-walled cysts. It is postulated to result either from excess hydrogen gas produced by intraluminal bacterial fermentation and altered partial pressure of nitrogen within the intestinal wall (the bacterial theory),¹ or from the transgression of gas cysts through the layers of bowel wall as a result of high luminal pressure from intestinal obstruction (the mechanical theory).²

The more widespread use of diagnostic CT in recent years has led to increased recognition of this condition, a finding that also often raises concern for intestinal necrosis or perforation.3 Meticulous correlation of the clinical presentation with corroborative laboratory testing should determine whether a conservative medical approach or emergency surgical exploration is appropriate.4

Pneumatosis cystoides intestinalis in patients with systemic sclerosis is a benign condition that generally resolves with bowel rest, antibiotics, inhalational oxygen therapy, and supportive care.⁵ An elevated venous oxygen concentration from high-flow oxygen therapy is believed to attenuate the gaseous cysts by decreasing the partial pressure of the nitrogenous gases and by being toxic to the anaerobic gut bacteria.

About 3% of patients with pneumatosis cystoides intestinalis develop complications such as pneumoperitoneum, intestinal volvulus, obstruction, or hemorrhage. Evidence of pneumoperitoneum or bowel infarction—such as the presence of portomesenteric venous gas, a decreased arterial pH, or an elevated lactic acid or amylase level—warrants immediate surgical intervention. Overall, early recognition and watchful monitoring for bowel necrosis or perforation are preferred over reflexive surgical exploration.

A 57-year-old man with long-standing systemic sclerosis presented with worsening diffuse abdominal pain associated with several episodes of nonbloody emesis for 5 days. He had been hospitalized numerous times over the past 2 years for similar symptoms. In those instances, abdominal radiography and computed tomography (CT) had revealed nonspecific intestinal pseudo-obstruction that had resolved within a few days with bowel rest, antibiotics for small-intestinal bacterial overgrowth, and supportive care.

At the time of this presentation, physical examination showed stable vital signs, a tympanic, distended abdomen with diffuse tenderness, and diminished bowel sounds with no sign of peritonitis. Complete blood cell counts, renal function testing, and serum lactate levels were unremarkable.

Abdominal radiography showed mildly dilated loops of small bowel with multiple fluid levels, raising concern for intestinal obstruction. Interestingly, abdominal CT revealed extensive pneumatosis cystoides intestinalis of the entire small bowel with sparing of the colon, which raised concern for acute bowel ischemia (Figure 1). However, given the patient’s underlying systemic sclerosis and current stable condition, the general surgeon recommended conservative management with bowel rest, rifaximin to treat the small-intestinal bacterial overgrowth, and intravenous fluids, which resulted in significant clinical improvement. A liquid diet was initiated and advanced as tolerated to a soft diet before he was discharged home after 8 days of hospitalization.

A RARE, USUALLY BENIGN COMPLICATION OF SYSTEMIC SCLEROSIS

Pneumatosis cystoides intestinalis is a rare gastrointestinal complication of systemic sclerosis characterized by intramural accumulation of gas within thin-walled cysts. It is postulated to result either from excess hydrogen gas produced by intraluminal bacterial fermentation and altered partial pressure of nitrogen within the intestinal wall (the bacterial theory),¹ or from the transgression of gas cysts through the layers of bowel wall as a result of high luminal pressure from intestinal obstruction (the mechanical theory).²

The more widespread use of diagnostic CT in recent years has led to increased recognition of this condition, a finding that also often raises concern for intestinal necrosis or perforation.3 Meticulous correlation of the clinical presentation with corroborative laboratory testing should determine whether a conservative medical approach or emergency surgical exploration is appropriate.4

Pneumatosis cystoides intestinalis in patients with systemic sclerosis is a benign condition that generally resolves with bowel rest, antibiotics, inhalational oxygen therapy, and supportive care.⁵ An elevated venous oxygen concentration from high-flow oxygen therapy is believed to attenuate the gaseous cysts by decreasing the partial pressure of the nitrogenous gases and by being toxic to the anaerobic gut bacteria.

About 3% of patients with pneumatosis cystoides intestinalis develop complications such as pneumoperitoneum, intestinal volvulus, obstruction, or hemorrhage. Evidence of pneumoperitoneum or bowel infarction—such as the presence of portomesenteric venous gas, a decreased arterial pH, or an elevated lactic acid or amylase level—warrants immediate surgical intervention. Overall, early recognition and watchful monitoring for bowel necrosis or perforation are preferred over reflexive surgical exploration.

A 57-year-old man with long-standing systemic sclerosis presented with worsening diffuse abdominal pain associated with several episodes of nonbloody emesis for 5 days. He had been hospitalized numerous times over the past 2 years for similar symptoms. In those instances, abdominal radiography and computed tomography (CT) had revealed nonspecific intestinal pseudo-obstruction that had resolved within a few days with bowel rest, antibiotics for small-intestinal bacterial overgrowth, and supportive care.

At the time of this presentation, physical examination showed stable vital signs, a tympanic, distended abdomen with diffuse tenderness, and diminished bowel sounds with no sign of peritonitis. Complete blood cell counts, renal function testing, and serum lactate levels were unremarkable.

Abdominal radiography showed mildly dilated loops of small bowel with multiple fluid levels, raising concern for intestinal obstruction. Interestingly, abdominal CT revealed extensive pneumatosis cystoides intestinalis of the entire small bowel with sparing of the colon, which raised concern for acute bowel ischemia (Figure 1). However, given the patient’s underlying systemic sclerosis and current stable condition, the general surgeon recommended conservative management with bowel rest, rifaximin to treat the small-intestinal bacterial overgrowth, and intravenous fluids, which resulted in significant clinical improvement. A liquid diet was initiated and advanced as tolerated to a soft diet before he was discharged home after 8 days of hospitalization.

A RARE, USUALLY BENIGN COMPLICATION OF SYSTEMIC SCLEROSIS

Pneumatosis cystoides intestinalis is a rare gastrointestinal complication of systemic sclerosis characterized by intramural accumulation of gas within thin-walled cysts. It is postulated to result either from excess hydrogen gas produced by intraluminal bacterial fermentation and altered partial pressure of nitrogen within the intestinal wall (the bacterial theory),¹ or from the transgression of gas cysts through the layers of bowel wall as a result of high luminal pressure from intestinal obstruction (the mechanical theory).²

The more widespread use of diagnostic CT in recent years has led to increased recognition of this condition, a finding that also often raises concern for intestinal necrosis or perforation.3 Meticulous correlation of the clinical presentation with corroborative laboratory testing should determine whether a conservative medical approach or emergency surgical exploration is appropriate.4

Pneumatosis cystoides intestinalis in patients with systemic sclerosis is a benign condition that generally resolves with bowel rest, antibiotics, inhalational oxygen therapy, and supportive care.⁵ An elevated venous oxygen concentration from high-flow oxygen therapy is believed to attenuate the gaseous cysts by decreasing the partial pressure of the nitrogenous gases and by being toxic to the anaerobic gut bacteria.

About 3% of patients with pneumatosis cystoides intestinalis develop complications such as pneumoperitoneum, intestinal volvulus, obstruction, or hemorrhage. Evidence of pneumoperitoneum or bowel infarction—such as the presence of portomesenteric venous gas, a decreased arterial pH, or an elevated lactic acid or amylase level—warrants immediate surgical intervention. Overall, early recognition and watchful monitoring for bowel necrosis or perforation are preferred over reflexive surgical exploration.

For about one in five patients with known atherosclerotic coronary artery disease, standard-dose therapy with statins did not result in significant lowering of LDL cholesterol.

Furthermore, the results of this large pooled data sample showed that for statin hyporesponders, statin therapy did not prevent progression of intravascular plaque volume as measured by grayscale intravascular ultrasound.

Patients exhibit a wide range of response to standard statin dosing, and the effect of minimal LDL-C lowering on atherosclerotic disease progression had not previously been determined, according to Dr. Yu Kataoka of the University of Adelaide, Australia, and his colleagues (Arterioscler. Thromb. Vasc. Biol. 2015 [doi:10.1161/ATVBAHA.114.304477]).

Investigators pooled data from seven clinical trials that examined 647 total patients with angiographically confirmed CAD who were initiated on statins and followed by serial intravascular ultrasound. The present study analyzed baseline characteristics, serial lipid profile, and atheroma burden for the group.

In all, 130 patients of the 647 (20%) had minimal LDL-C lowering with statin therapy, showing nonsignificant lowering or even an increase in LDL-C levels during the study period. This group of hyporesponders differed in being slightly younger, more obese, less likely to have hypertension and dyslipidemia, and less likely to be receiving beta-blockers than were the statin responders. Other patient characteristics were similar between the two groups. A variety of agents were used, including atorvastatin, rosuvastatin, simvastatin, and pravastatin. Concurrent administration of other antiatherosclerotic agents was permitted and was similar between the groups. Atheroma burden at baseline was also similar between the two groups.

Measuring serial changes in atheroma burden showed a significant difference between statin responders and hyporesponders. The adjusted change in atheroma volume was –0.21% for the responders, compared with +0.83% for the hyporesponders (P = .006). Lumen volume decreased 11.64 mm³ for the responders, while the reduction was 16.54 mm³ for the hyporesponders (P = .006). Of those who responded to lipid therapy with LDL-C lowering, 29.8% had substantial atheroma regression, while 25.9% had substantial plaque progression; among hyporesponders, however, just 13.8% experienced significant plaque regression, while 37.7% had significant atheroma progression, both significant differences.

Dr. Kataoka and his colleagues emphasized that the factors contributing to poor statin response are not well understood. They noted that for this study, the pooled trials all showed adherence rates over 90%, eliminating patient compliance as a variable. Rigorous statistical techniques were used to control for comorbidities and coadministered medications. There are known genetic polymorphisms and phenotypic variations in statin metabolism, though these were not reported here. Although the results were not statistically significant, C-reactive protein levels were higher for the hyporesponse group, suggesting that another factor may be individual response to the anti-inflammatory effect that is among the known pleiotropic effects of this drug class.

In an interview, lead author Stephen Nicholls noted that many clinicians are still reluctant to treat to full effect. Citing the concept of “clinical inertia,” Dr. Nicholls pointed out that “Even when statins are prescribed, they are often at lower doses than ideal. That translated to more plaque growth, which leads directly to more heart attacks and more revascularization procedures.”

Study limitations included the potential residual confounding effects of pooling data from seven discrete clinical trials, though mixed modeling techniques attempted to correct for this effect. The present study also reported atheroma burden, but not actual clinical events. The study authors noted, however, that they had previously reported a direct relationship between atheroma progression and the occurrence of cardiovascular events.

Dr. Nicholls has received speaking honoraria and research support from many pharmaceutical companies, and from Infraredx. Dr. Steven E. Nissen of the Cleveland Clinic was a coinvestigator and has received research support from and is a consultant/adviser to numerous pharmaceutical companies; all honoraria or consulting fees go directly to charity so that he receives neither income nor a tax deduction. The other authors report no conflicts.

For about one in five patients with known atherosclerotic coronary artery disease, standard-dose therapy with statins did not result in significant lowering of LDL cholesterol.

Furthermore, the results of this large pooled data sample showed that for statin hyporesponders, statin therapy did not prevent progression of intravascular plaque volume as measured by grayscale intravascular ultrasound.

Patients exhibit a wide range of response to standard statin dosing, and the effect of minimal LDL-C lowering on atherosclerotic disease progression had not previously been determined, according to Dr. Yu Kataoka of the University of Adelaide, Australia, and his colleagues (Arterioscler. Thromb. Vasc. Biol. 2015 [doi:10.1161/ATVBAHA.114.304477]).

Investigators pooled data from seven clinical trials that examined 647 total patients with angiographically confirmed CAD who were initiated on statins and followed by serial intravascular ultrasound. The present study analyzed baseline characteristics, serial lipid profile, and atheroma burden for the group.

In all, 130 patients of the 647 (20%) had minimal LDL-C lowering with statin therapy, showing nonsignificant lowering or even an increase in LDL-C levels during the study period. This group of hyporesponders differed in being slightly younger, more obese, less likely to have hypertension and dyslipidemia, and less likely to be receiving beta-blockers than were the statin responders. Other patient characteristics were similar between the two groups. A variety of agents were used, including atorvastatin, rosuvastatin, simvastatin, and pravastatin. Concurrent administration of other antiatherosclerotic agents was permitted and was similar between the groups. Atheroma burden at baseline was also similar between the two groups.

Measuring serial changes in atheroma burden showed a significant difference between statin responders and hyporesponders. The adjusted change in atheroma volume was –0.21% for the responders, compared with +0.83% for the hyporesponders (P = .006). Lumen volume decreased 11.64 mm³ for the responders, while the reduction was 16.54 mm³ for the hyporesponders (P = .006). Of those who responded to lipid therapy with LDL-C lowering, 29.8% had substantial atheroma regression, while 25.9% had substantial plaque progression; among hyporesponders, however, just 13.8% experienced significant plaque regression, while 37.7% had significant atheroma progression, both significant differences.

Dr. Kataoka and his colleagues emphasized that the factors contributing to poor statin response are not well understood. They noted that for this study, the pooled trials all showed adherence rates over 90%, eliminating patient compliance as a variable. Rigorous statistical techniques were used to control for comorbidities and coadministered medications. There are known genetic polymorphisms and phenotypic variations in statin metabolism, though these were not reported here. Although the results were not statistically significant, C-reactive protein levels were higher for the hyporesponse group, suggesting that another factor may be individual response to the anti-inflammatory effect that is among the known pleiotropic effects of this drug class.

In an interview, lead author Stephen Nicholls noted that many clinicians are still reluctant to treat to full effect. Citing the concept of “clinical inertia,” Dr. Nicholls pointed out that “Even when statins are prescribed, they are often at lower doses than ideal. That translated to more plaque growth, which leads directly to more heart attacks and more revascularization procedures.”

Study limitations included the potential residual confounding effects of pooling data from seven discrete clinical trials, though mixed modeling techniques attempted to correct for this effect. The present study also reported atheroma burden, but not actual clinical events. The study authors noted, however, that they had previously reported a direct relationship between atheroma progression and the occurrence of cardiovascular events.

Dr. Nicholls has received speaking honoraria and research support from many pharmaceutical companies, and from Infraredx. Dr. Steven E. Nissen of the Cleveland Clinic was a coinvestigator and has received research support from and is a consultant/adviser to numerous pharmaceutical companies; all honoraria or consulting fees go directly to charity so that he receives neither income nor a tax deduction. The other authors report no conflicts.

For about one in five patients with known atherosclerotic coronary artery disease, standard-dose therapy with statins did not result in significant lowering of LDL cholesterol.

Furthermore, the results of this large pooled data sample showed that for statin hyporesponders, statin therapy did not prevent progression of intravascular plaque volume as measured by grayscale intravascular ultrasound.

Patients exhibit a wide range of response to standard statin dosing, and the effect of minimal LDL-C lowering on atherosclerotic disease progression had not previously been determined, according to Dr. Yu Kataoka of the University of Adelaide, Australia, and his colleagues (Arterioscler. Thromb. Vasc. Biol. 2015 [doi:10.1161/ATVBAHA.114.304477]).

Investigators pooled data from seven clinical trials that examined 647 total patients with angiographically confirmed CAD who were initiated on statins and followed by serial intravascular ultrasound. The present study analyzed baseline characteristics, serial lipid profile, and atheroma burden for the group.

In all, 130 patients of the 647 (20%) had minimal LDL-C lowering with statin therapy, showing nonsignificant lowering or even an increase in LDL-C levels during the study period. This group of hyporesponders differed in being slightly younger, more obese, less likely to have hypertension and dyslipidemia, and less likely to be receiving beta-blockers than were the statin responders. Other patient characteristics were similar between the two groups. A variety of agents were used, including atorvastatin, rosuvastatin, simvastatin, and pravastatin. Concurrent administration of other antiatherosclerotic agents was permitted and was similar between the groups. Atheroma burden at baseline was also similar between the two groups.

Measuring serial changes in atheroma burden showed a significant difference between statin responders and hyporesponders. The adjusted change in atheroma volume was –0.21% for the responders, compared with +0.83% for the hyporesponders (P = .006). Lumen volume decreased 11.64 mm³ for the responders, while the reduction was 16.54 mm³ for the hyporesponders (P = .006). Of those who responded to lipid therapy with LDL-C lowering, 29.8% had substantial atheroma regression, while 25.9% had substantial plaque progression; among hyporesponders, however, just 13.8% experienced significant plaque regression, while 37.7% had significant atheroma progression, both significant differences.

Dr. Kataoka and his colleagues emphasized that the factors contributing to poor statin response are not well understood. They noted that for this study, the pooled trials all showed adherence rates over 90%, eliminating patient compliance as a variable. Rigorous statistical techniques were used to control for comorbidities and coadministered medications. There are known genetic polymorphisms and phenotypic variations in statin metabolism, though these were not reported here. Although the results were not statistically significant, C-reactive protein levels were higher for the hyporesponse group, suggesting that another factor may be individual response to the anti-inflammatory effect that is among the known pleiotropic effects of this drug class.

In an interview, lead author Stephen Nicholls noted that many clinicians are still reluctant to treat to full effect. Citing the concept of “clinical inertia,” Dr. Nicholls pointed out that “Even when statins are prescribed, they are often at lower doses than ideal. That translated to more plaque growth, which leads directly to more heart attacks and more revascularization procedures.”

Study limitations included the potential residual confounding effects of pooling data from seven discrete clinical trials, though mixed modeling techniques attempted to correct for this effect. The present study also reported atheroma burden, but not actual clinical events. The study authors noted, however, that they had previously reported a direct relationship between atheroma progression and the occurrence of cardiovascular events.

Dr. Nicholls has received speaking honoraria and research support from many pharmaceutical companies, and from Infraredx. Dr. Steven E. Nissen of the Cleveland Clinic was a coinvestigator and has received research support from and is a consultant/adviser to numerous pharmaceutical companies; all honoraria or consulting fees go directly to charity so that he receives neither income nor a tax deduction. The other authors report no conflicts.