There are no randomized data for use of triple-H therapy in improving the long-term outcome in SAH (regardless of whether triple-H therapy was used as a prophylaxis or as a treatment)

3. There are nonrandomized, observational studies showing augmentation of CBF in hypoper-fused brain regions after triple-H therapy (or different parts of the triple-H therapy: ie, hyper-volemic therapy alone [normal saline boluses],⁵¹ or hyperdynamic therapy [increasing cardiac index without significantly increasing the blood pressure],⁵² or hypertensive therapy alone, or a combination of all of the above).

The following is a reasonable algorithm for managing patients with risk of developing symptom-atic vasospasm and delayed cerebral ischemia.

Intravascular Volume and Blood Pressure Management

Early Phase of SAH (typically bleed day 0-3, note the onset of symptomatic vasospasm may vary among patients) Low HH grade (the patient is doing well clinically, intact neurologic examination, s/p securing of the ruptured aneurysm in the ICU):

1. Keep euvolemic (does not need induced hypervolemia)

•   Avoid persistently low CVP (0-3): Note that CVP is a poor surrogate for volume status. Keeping CVP greater than 12  is a blind approach and may not provide euvolemia. However, avoiding persistently low CVP is probably helpful.

•  Avoid severe anemia (Hgb < 7).

•  Avoid low PA (pulmonary artery) wedge pressure (< 10).

•  Avoid low GEDVI (global end-diastolic volume index) < 680 mL/m².

•  Avoid high SVV (stroke volume variation) and pulse pressure variation > 13%.

•  Avoid low SVI (stroke volume index) (< 40 mL/m²).

•  Avoid low urine output < 0.5 mL/kg/h.

2. Keep normal BP

•  MAP 60-90 mm Hg (does not need induced hypertension).

3. Normal cardiac output and index

•  CO 5-8 L/min

•  CI (cardiac index) 3-5 L/min/m²

(Proceed to the next box if the patient has any signs of vasospasm.)

High HH Grade (no examination to follow as patient is in stupor and coma to begin with):

1. Make sure patient is not having vasospasm by following other diagnostic studies other than clinical examination such as CTA/CTP, and/or TCD, cEEG, etc.

2. Do what is written above for volume, BP, and CO.

(Proceed to next box if patient has any signs of vasospasm.)

Vasospasm Watch Period

This is typically bleed days 4-14, but symptomatic vasospasm with clinical deterioration can occur as late as day 21.

If the patient does not have any signs (clinical, TCD, CTA/P, or cEEG findings) of vasospasm, then manage the patient the same way as the early phase, targeting:

•  Euvolemic

•  Normotensive

•  Normal cardiac performance

If the patient has any signs (clinical, TCD, CTA/P, or cEEG) of vasospasm, then:

•  Hypervolemic

•  Hypertensive

•  Hyperdynamic cardiac performance

Optimizing Triple-H Therapy:

When the ICU team calls the interventional team for angiography for symptomatic vasospasm, one of the frequently asked (rightfully so) questions would be: “Have you maximized or fully optimized medical therapy for this patient?” This question is not unreasonable, as some patients with mild vasospasm may become asymptomatic and never really require any invasive procedure for their spasm.

How to Maximize or Fully Optimize Medical Therapy:

Use of either crystalloid or colloid is acceptable. It is highly recommended to consider using advanced dynamic variables such as stroke volume variation (SVV) and pulse pressure variation (PPV) in addition to commonly used stagnant variables such as central venous pressure (CVP) or pulmonary artery occlusion pressure.

Simply implementing CVP 10-14 would not be sufficient as CVP is a confounded variable with low reliability in terms of assessing preload responsiveness and other hemodynamic status. For patients who are being mechanically ventilated, in the absence of arrhythmia, the following recommendation is reasonable for active, symptomatic vasospasm:

•  SVV < 10%

•  PPV < 13%

•  GEDVI > 680 mL/m²

•  SVI > 40 mL/m²

•  CI > 3 L/min/m²

•  Urine output > 0.5 mL/kg/h

•  Reminder:

1. Reliability of advanced dynamic variables such as SVV and PPV requires controlled mechanical ventilation and the absence of arrhythmia.

2. Initiation of aggressive triple-H therapy does not mean one can delay providing more invasive therapy when necessary.

For patients who do not respond to triple-H therapy, any delay in getting angiography for more definitive treatment may increase the risk of developing irreversible ischemic damage.

3. Symptomatic vasospasm is a time-sensitive emergency, and timely treatment with balloon angioplasty within 2 hours of symptom onset has been shown to have sustained clinical improvement.⁵³

care

Invasive therapy options for symptomatic vasospasm

cerebral Angiography (Figure 1- )

There are a number of different vasodilators available for IA therapy of vasospasm in patients with aneurysmal SAH. These include papaverine, nicardipine, verapamil, and more recently milrinone.

These vasodilators often produce an immediate result in increasing the vessel calibers, but there is a limitation: the positive effect may not last long. It is not uncommon to see patients with vasospasm who respond to initial IA vasodilators become symptomatic the same day or the next day, requiring further multiple angiographic treatments. Unless the interventional suite is located in the middle of the NeuroICU with the team actually staying in the angiography suite 24/7, there may be some delay between the redetection of the symptomatic vasospasm and the actual time of reangiography. If the patient has aspiration pneumonia on a high-maintenance ventilator setting with multiple vasopres-sors, the presence of an anesthesiologist is needed for reangiography, and this can be another source of delay. Balloon angioplasty (BA), despite being more aggressive and associated with potentially fatal complication, may provide a longer lasting effect. It is true that BA does not guarantee that the vasospasm will not ever occur again. There are clearly angioplasty-refractory vasospasms. How-ever, it is usually fair to state that, in general, BA is superior in terms of the durability compared to injecting a few milligrams of any of the vasodilators mentioned above. It is difficult to quantify how long these vasodilators might work. Every practitioner has different thresholds for choosing different methods to address severe vasospasm. Ten milligrams of IA verapamil to the proximal M1 vaso-spasm may be perfectly fine for several days in some patients, but the positive effect may only last for 2 hours in others. Furthermore, the response rate among patients is unpredictable. IA infusion of vasodilation therapy may be considered safer in terms of performing the procedure com-pared to BA, as there is little to no risk of rupture of the vessel. However, if IA infusion of vasodilation therapy fails (and if it fails in the middle of night when no angiographic team members are available in-house), then there is a significant risk of stroke while preparing for repeat angiography.

Another important aspect to consider is the operator’s comfort level with each therapy. All of these pros and cons should be taken into account when choosing a therapy.

Intrathecal (It) Infusion and asal cistern Implants of calcium channel lockers Recently, injecting L-type dihydropyridine calcium channel blockers such as nicardipine via EVD as an intrathecal (IT) therapy for vasospasm has been reported.^54-56 Although generally considered as a new therapy, one of the first human cases dates back to early 1990s when IT nicardipine was injected

Figure 1- . Cerebral angiography. Conventional cerebral angiography shows severe right-sided internal carotid artery vasospasm in the carotid terminus. In addition, there is a severe spasm in the right A1 segment of the ACA.

prophylactically with positive results.⁵⁴ These reports were case series with small sample sizes, and there is currently lack of good evidence at this time for routinely implanting this therapy. Given anec-dotal reports of positive findings in both preventing and treating vasospasm, further studies are war-ranted to investigate the safety and efficacy of this therapy. As more Pbto₂ and other multimodality brain monitoring probes are used in clinical practice, there may be more information about how intraventricular use of vasodilators may improve the cerebral blood flow and whether it has more impact on the proximal versus distal vasculature. A recent randomized double-blind phase II study reported the use of prolonged-release implants of nicardipine and showed a reduced incidence of vasospasm and improved clinical outcome 1 year after SAH.⁵⁷ This study used nicardipine-releasing pellet implantation into the basal cisterns (10 implants placed directly onto the proximal vessels at the basal cisterns) after blood clots were washed out for both study and control groups. The implant group had a significantly reduced incidence of angiographic and symptomatic vasospasm with better short- and long-term outcome. Despite rather convincing data, it is important to remember that this therapy requires surgical clipping of the aneurysm, thorough washout of the fresh blood clots, fol-lowed by multiple implantation of nicardipine pellets.

Intra-aortic alloon counterpulsation therapy

Patients with high-grade SAH may also have depressed cardiac function—a typical model for this is that of the neurogenic stunned myocardium phenomenon (sometimes described as neurogenic stress cardiomyopathy or takotsubo cardiomyopathy) with mid to moderately elevated troponin and severely depressed ejection fraction (EF) and reversible left ventricular wall motion abnormality (see below for further details). Depressed cardiac function poses an additional challenge in managing symptomatic vasospasm. Triple-H therapy (hypertensive, hypervolemic, hemodilution) can con-tribute to developing severe pulmonary edema, and yet patients require induced hypertension and hypervolemia, which increases the afterload and results in further cardiac injury. Intra-aortic balloon counterpulsation was first described in human cerebral vasospasm cases in the mid to late 1990s in order to “allow continuation of triple-H therapy and to maintain adequate cerebral perfusion.”⁵⁸ Imaging studies of both animals and humans reported significantly augmented cerebral blood flow in vasospasm cases by using different methods of brain perfusion scans.^59,60 Inflation at the beginning of diastole and deflation at the end of diastole have been shown to increase the cardiac perfusion, reduce afterload, maintain cardiac performance, and optimize end-organ perfusion including the brain. This therapy is not used routinely, and there are no large studies demonstrating safety and outcome ben-efits in vasospasm patients. Nevertheless, it is reasonable to be aware and consider this therapy when patients are having severely depressed cardiac function and symptomatic vasospasm refractory to other less invasive medical therapy (for more details, refer to Chapter 35).

neuroFlo Device

This is an intra-aortic catheter with two small balloons designed to augment CBF during the acute phase of ischemic brain injury. The distal balloon is placed above the renal arteries and the proximal balloon is placed below the renal arteries. Partial occlusion of the descending abdominal aorta by inflation of the balloons leads to redirected flow, providing increased CBF as a result (Figures 1-9 and 1-10).

In March 2005, the US Food and Drug Administration approved this device for clinical use under the humanitarian device exemption program after a pilot study in 2004 showed feasibility. In the pilot study, 1 hour of partial aortic occlusion in 17 patients with acute ischemic stroke led to improved blood flow and brain perfusion along with reduced neurologic deficits.⁶¹ A randomized controlled trial, SENTIS (Safety and Efficacy of NeuroFlo for Treatment of Ischemic Stroke), is currently in progress for more data in acute stroke. A single-arm, observational study on symptomatic vasospasm after aneurysmal SAH has been reported in 24 patients, showing increased mean flow velocity and improvement in NIH stroke scale 20 minutes post-procedure with sustained clinical benefit on a 30-day follow-up in most patients.⁶²

care

A high-grade SAH (HH I , F 3, mFS 4) patient survived the IcP crisis, brain hypoxia, brain metabolic stress, and vasospasm. on the regular floor, the patient is recovering well but develops hyponatremia (na 125 mE L). It is bleed day 14 today. the patient is clinically stable but has had recurrent sei-zures in the past and the decision is made to treat the hyponatremia prior to transferring the patient to an inpatient rehabilitation facility. How would you approach this? What are the important points regarding cerebral salt wasting (cSW) versus syndrome of inappropriate antidiuretic hormone (SIADH)?

cerebral (or Renal) Salt Wasting (cSW) Syndrome

Altered plasma and cerebrospinal fluid (CSF) concentration of natriuretic peptide has been thought to be the etiology of this syndrome, which is seen after any severe brain injury but more commonly described in patients with aneurysmal SAH. Sodium wasting is accompanied by free water loss leading

Partial balloon occlusion Renal arteries

Pre treatment Post treatment Penumbra

Cone

Figure 1-9. NeuroFlo device. (Reproduced with permission from Coaxia, Inc., and Richard Klucznik, MD.)

to intravascular volume depletion. If CSW and intravascular volume depletion is treated like the syn-drome of inappropriate antidiuretic hormone (SIADH) with water restriction, systemic hypotension and end-organ hypoperfusion may occur without improving hyponatremia. One should attempt to accurately assess intravascular volume status as the first step. Treatment should focus on replacing the sodium and targeting euvolemia for overall volume state. Oral salt tablets (2 to 4 g PO q4 to 8h) and isotonic saline via IV infusion is reasonable as the first step. If salt wasting gets worse, then 2% to 3%

continuous IV infusion of hypertonic saline can be given (start 2% to 3% at 50 mL/h, then titrate up or down). Mineralocorticoids promote sodium absorption at the level of the distal tubule in the kidney and can be used to treat CSW (fludrocortisone 0.05 to 0.2 mg PO qd).

A wrong (and dangerous) fluid management would be to misdiagnose CSW as SIADH and per-form water restriction with the use of a vasopressin receptor antagonist. Such therapy would lead to profound intravascular volume depletion in the setting of ICP crisis, brain hypoxia, brain metabolic crisis, and symptomatic vasospasm. This can lead to devastating ischemic brain injury. Recently, the term cerebral salt wasting syndrome has been challenged, with the term renal salt wasting syndrome being suggested as there have been cases where the same syndrome occurred in the absence of any brain disease.⁶³ In the setting of acute cerebral injury such as SAH, cerebral, or renal, salt wasting syndrome may be more common than what has been reported.

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

SIADH is another important differential diagnosis for hyponatremia in the NeuroICU. The same etiolo-gies that can lead to CSW can also cause SIADH (eg, SAH, ischemic stroke, traumatic brain injury [TBI], tumor). Differentiating SIADH from CSW can be challenging. A traditional teaching regarding this is the concept of difference in volume status: SIADH has either a euvolemic or hypervolemic state and salt wasting syndrome has volume depletion.

Figure 1-1 . Magnetic resonance perfusion scan before and after placement of the NeuroFlo device. Diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC), relative mean transit time (MTT), and mean cerebral blood volume (CBV) maps obtained pretreatment and posttreatment. The 30-day CT images are in the far right column. Volumetric measurements reveal decreases of 27% and 45% in lesion volumes on the ADC and MTT maps, respectively, within the right MCA region posttreatment. The final infarct volume (30-day CT) was considerably smaller than the lesion volume observed on the pretreatment ADC maps and corresponds well to the lesion seen on the initial CBV maps. With permission courtesy of Dr. Muhammad S. Hussain.

care Applying volume restriction and promoting free water loss (aquauresis) by antagonizing the vaso-pressin receptor (V2 receptors in the kidney) with IV conivaptan (20 mg IV loading over 30 minutes followed by 20 mg/day, may increase to 40 mg/day) or PO tolvaptan (15 mg PO qd, may increase to 30 mg/day with maximum of 60 mg/day) are appropriate therapies. As these aquauretic agents lead to effective free water loss, one needs to be cautious about aggressive fluid restriction.

With all the laboratory findings for both CSW and SIADH being similar, only volume status can be a hint for differentiating these two syndromes. However, there is no one gold standard parameter that is believed to be always accurate in assessing volume status. Assessing intravascu-lar volume status is a daily challenge for any ICU. As such, for serum hyponatremia occurring in neurologic patients (eg, aneurysmal SAH), it should really be treated with one good old therapy:

salt. Hyponatremia is often well tolerated and only patients who are symptomatic, or patients who have a low threshold for recurrent seizures, or patients with severe and worsening hyponatremia (< 125 mEq/L typically) should be treated. If hyponatremia is to be treated in a patient who needs adequate CPP and good intravascular volume (eg, in the middle of active symptomatic vasospasm), giving salt by hypertonic saline is preferred over aggressive volume management. Losing significant free water might be appropriate for SIADH, but can be harmful for patients without SIADH who really are experiencing CSW.

In general, the following tips can be helpful: