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Background: Hypertonic saline (HTS) and mannitol are effective in reducing intracranial pressure (ICP) after severe traumatic brain injury (TBI). However, their simultaneous effect on the cerebral perfusion pressure (CPP) and ICP has not been studied rigorously., Objective: To determine the difference in effects of HTS and mannitol on the combined burden of high ICP and low CPP in patients with severe TBI., Methods: We performed a case-control study using prospectively collected data from the New York State TBI-trac® database (Brain Trauma Foundation, New York, New York). Patients who received only 1 hyperosmotic agent, either mannitol or HTS for raised ICP, were included. Patients in the 2 groups were matched (1:1 and 1:2) for factors associated with 2-wk mortality: age, Glasgow Coma Scale score, pupillary reactivity, hypotension, abnormal computed tomography scans, and craniotomy. Primary endpoint was the combined burden of ICPhigh (> 25 mm Hg) and CPPlow (< 60 mm Hg)., Results: There were 25 matched pairs for 1:1 comparison and 24 HTS patients matched to 48 mannitol patients in 1:2 comparisons. Cumulative median osmolar doses in the 2 groups were similar. In patients treated with HTS compared to mannitol, total number of days (0.6 ± 0.8 vs 2.4 ± 2.3 d, P < .01), percentage of days with (8.8 ± 10.6 vs 28.1 ± 26.9%, P < .01), and the total duration of ICPhigh + CPPlow (11.12 ± 14.11 vs 30.56 ± 31.89 h, P = .01) were significantly lower. These results were replicated in the 1:2 match comparisons., Conclusion: HTS bolus therapy appears to be superior to mannitol in reduction of the combined burden of intracranial hypertension and associated hypoperfusion in severe TBI patients., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Background: Intracranial hypertension is the final pathway of many neurocritical entities, such as spontaneous intracerebral hemorrhage (sICH) and severe traumatic brain injury (sTBI)., Objective: This study aimed to (1) determine alterations in intracranial pressure (ICP) and cerebral hemodynamics after an indomethacin (INDO) infusion test and the related association with survival in patients with refractory intracranial hypertension (RICH) secondary to sICH or sTBI and (2) assess the safety profile after INDO., Methods: INDO was administered in a loading dose (0.8 mg/kg/15 min), followed by a 2-hour continuous infusion (0.5 mg/kg/h) in RICH patients with ICP greater than 20 mm Hg who did not respond to first-line therapies. Changes in ICP, cerebral perfusion pressure (CPP), and cerebrovascular variables (assessed by transcranial Doppler and jugular bulb saturation) were observed. Clinical outcome was assessed at 1 and 6 months according to the Glasgow Outcome Scale and correlated with INDO infusion test response. Analysis of INDO safety profile was conducted., Results: Thirteen sICH and 10 sTBI patients were studied. The median GCS score at admission was 6. Within 30 minutes of INDO infusion, ICP decreased (42.0 ± 13.5 vs 27.70 ± 12.7 mm Hg; Δ%: -48.4%; P < .001), and both CPP (57.7 ± 4.8 vs 71.9 ± 7.0 mm Hg; Δ%: +26.0%; P < .001) and middle cerebral artery velocity (35.2 ± 5.6 vs 42.0 ± 5.1 cm·s(-1); Δ%: +26.1%; P < .001) increased. The CPP response to a 2-hour INDO infusion test was correlated (R2 = 0.72, P < .001) with survival. No adverse events were observed after INDO., Conclusion: Our findings support the effectiveness and feasibility of an INDO test in decreasing ICP and improving cerebral hemodynamics in surviving RICH patients. Future studies to evaluate different doses, lengths of infusion, and longer term effects are needed.

Therapy with hypertonic solutions is one of the mainstays of neurosurgical treatment for all types of neurological injury. Although the initial research with hypertonic agents in the early decades of the 20th century showed great promise for these agents to lower intracranial pressure, this research also showed a considerable rate of adverse effects and complications. By the 1940s and 1950s, hypertonic therapy had been discounted as unsafe and was rarely used in neurosurgery. In the late 1950s, Manucher J. Javid and Paul Settlage at the University of Wisconsin began experimenting with infusions of urea as an agent to control intracranial pressure. Their experiments were wildly successful, and urea became a drug of major importance to neurosurgeons worldwide in only a few years. This article chronicles the work of Javid and Settlage, including a discussion of the early research on hypertonic agents, the initial difficulty the Wisconsin researchers had in disseminating their results, the widespread acceptance that followed, and the impact that these discoveries had on the neurosurgical community. The prominent place that hypertonic agents now hold in the armamentarium of neurosurgeons is owed to the work of Dr Javid, as illustrated in this historical analysis.

Background: Mannitol has traditionally been the mainstay of medical therapy for intracranial hypertension in patients with head injury. We previously demonstrated that mannitol reduces brain volume in patients with cerebral edema, although whether this occurs because of a reduction in brain water, blood volume, or both remains poorly understood., Objective: To test the hypothesis that mannitol acts by lowering blood viscosity leading to reflex vasoconstriction and a fall in cerebral blood volume (CBV)., Methods: We used O positron emission tomography to study 6 patients with traumatic brain injuries requiring treatment for intracranial hypertension. Cerebral blood flow (CBF), CBV, and cerebral metabolic rate for oxygen (CMRO2) were measured before and 1 hour after administration of 1.0 g/kg 20% mannitol., Results: CBV rose from 4.1 ± 0.4 to 4.2 ± 0.2 mL/100 g (P = .3), while intracranial pressure fell from 21.5 ± 4.9 to 13.7 ± 5.1 mm Hg (P < .003) after mannitol. Blood pressure, PaCO2, oxygen content, CBF, and CMRO2 did not change., Conclusion: A single bolus of 1 g/kg of 20% mannitol does not acutely lower CBV. Another mechanism, such as a reduction in brain water, may better explain mannitol's ability to lower intracranial pressure and reduce mass effect.

Background: In patients with aneurysmal subarachnoid hemorrhage (SAH), preliminary results indicate that the amplitude of the single intracranial pressure (ICP) wave is a better predictor of the early clinical state and 6-month outcome than the mean ICP., Objective: To perform a randomized and blinded single-center trial comparing the effect of mean ICP vs mean ICP wave amplitude (MWA)-guided intensive care management on early clinical state and outcome in patients with aneurysmal SAH., Methods: Patients were randomized to 2 different types of ICP management: maintenance of mean ICP less than 20 mm Hg and MWA less than 5 mm Hg. Early clinical state was assessed daily using the Glasgow Coma Scale. The primary efficacy variable was 12-month outcome in terms of the Rankin Stroke Score., Results: Ninety-seven patients were included in the study. There were no significant differences in treatment between the 2 groups apart from a larger volume of cerebrospinal fluid drained during week 1 in the MWA group. There was a tendency toward higher Glasgow Coma Scale scores in the MWA group during weeks 1 (P = .08) and 2 (P = .07). Outcome in terms of Rankin Stroke Score at 12 months was significantly better in the MWA group (P < .05)., Conclusion: This randomized and blinded trial disclosed a significant better primary efficacy variable (Rankin Stroke Score after 12 months) in the MWA patient group. We suggest that proactive intensive care management with MWA-tailored cerebrospinal fluid drainage during the first week improves aneurysmal SAH outcome.

Objective: Barbiturate-induced coma can be used in patients to treat intractable intracranial hypertension when other therapies, such as osmotic therapy and sedation, have failed. Despite control of intracranial pressure, cerebral infarction may still occur in some patients, and the effect of barbiturates on outcome remains uncertain. In this study, we examined the relationship between barbiturate infusion and brain tissue oxygen (PbtO2)., Methods: Ten volume-resuscitated brain-injured patients who were treated with pentobarbital infusion for intracranial hypertension and underwent PbtO2 monitoring were studied in a neurosurgical intensive care unit at a university-based Level I trauma center. PbtO2, intracranial pressure (ICP), mean arterial pressure, cerebral perfusion pressure (CPP), and brain temperature were continuously monitored and compared in settings in which barbiturates were or were not administered., Results: Data were available from 1595 hours of PbtO2 monitoring. When pentobarbital administration began, the mean ICP, CPP, and PbtO2 were 18 +/- 10, 72 +/- 18, and 28 +/- 12 mm Hg, respectively. During the 3 hours before barbiturate infusion, the maximum ICP was 24 +/- 13 mm Hg and the minimum CPP was 65 +/- 20 mm Hg. In the majority of patients (70%), we observed an increase in PbtO2 associated with pentobarbital infusion. Within this group, logistic regression analysis demonstrated that a higher likelihood of compromised brain oxygen (PbtO2 < 20 mm Hg) was associated with a decrease in pentobarbital dose after controlling for ICP and other physiological parameters (P < 0.001). In the remaining 3 patients, pentobarbital was associated with lower PbtO2 levels. These patients had higher ICP, lower CPP, and later initiation of barbiturates compared with patients whose PbtO2 increased., Conclusion: Our preliminary findings suggest that pentobarbital administered for intractable intracranial hypertension is associated with a significant and independent increase in PbtO2 in the majority of patients. However, in some patients with more compromised brain physiology, pentobarbital may have a negative effect on PbtO2, particularly if administered late. Larger studies are needed to examine the relationship between barbiturates and cerebral oxygenation in brain-injured patients with refractory intracranial hypertension and to determine whether PbtO2 responses can help guide therapy.

Objective: Mannitol is the standard of care for patients with increased intracranial pressure (ICP), but multiple administrations of mannitol risk renal toxicity and fluid accumulation in the brain parenchyma with consequent worsening of cerebral edema. This preliminary study assessed the safety and efficacy of small-volume injections of 23.4% sodium chloride solution for the treatment of intracranial hypertension in patients with traumatic brain injury who became tolerant to mannitol., Methods: We retrospectively reviewed the charts of 13 adult patients with traumatic brain injury who received mannitol and 23.4% sodium chloride independently for the treatment of intracranial hypertension at San Francisco General Hospital between January and October 2003. Charts were reviewed to determine ICP, cerebral perfusion pressure, mean arterial pressure, serum sodium values, and serum osmolarity before and after treatment with 23.4% sodium chloride and mannitol. Complications were noted., Results: The mean reductions in ICP after treatment were significant for both mannitol (P < 0.001) and hypertonic saline (P < 0.001); there were no significant differences between reductions in ICP when comparing the two agents (P = 0.174). The ICP reduction observed for hypertonic saline was durable, and its mean duration of effect (96 min) was significantly longer than that of mannitol treatment (59 min) (P = 0.016). No complications were associated with treatment with hypertonic saline., Conclusion: This study suggests that 23.4% hypertonic saline is a safe and effective treatment for elevated ICP in patients after traumatic brain injury. These results warrant a rigorous evaluation of its efficacy as compared to mannitol in a prospective randomized controlled trial.

Objective: Elevated intracranial pressure (ICP) is related to mortality after intracerebral hemorrhage (ICH). To develop effective strategies for the medical treatment of ICP in cases of ICH, we evaluated the therapeutic efficacy of mannitol and hypertonic saline in a canine model of ICH., Methods: We introduced ICH in three groups of anesthetized mongrel dogs, consisting of seven animals each, by autologous blood injection (5.5-7.5 ml) under arterial pressure in the deep white matter adjacent to the left basal ganglia. We evaluated the effect of iso-osmolar doses (5.5 mOsm/kg) of intravenously administered mannitol (1 gm/kg), 3% NaCl (5.3 ml/kg), or 23.4% NaCl (0.7 ml/kg) administered 2 hours after the introduction of hematoma, on the following: ICP, cerebral perfusion pressure, cerebral oxygen extraction and oxygen consumption, and regional cerebral blood flow in regions around and distant to the hematoma. All measurements were recorded at baseline, before treatment, and 15, 30, 60, and 120 minutes after treatment. We also evaluated the water content (wet/dry weight) and blood-brain barrier permeability (Evans blue method) in pathologically demarcated regions of brain., Results: There was an immediate reduction in ICP (mm Hg +/- standard error of the mean) in the 23.4% NaCl (27.6+/-4 to 11.0+/-2 mm Hg, P = 0.001), 3% NaCl (23.7+/-3 to 14.7+/-2 mm Hg, P = 0.009), and mannitol (25.6+/-3 to 15.9+/-4 mm Hg, P = 0.02) groups. Compared with pretreatment values, ICP was significantly lower in both the 23.4% NaCl (12.3+/-2 mm Hg, P = 0.002) and 3% NaCl (17.6+/-2 mm Hg, P = 0.008) groups but not in the mannitol group (18.7+/-4 mm Hg, P = 0.08) 15 minutes after the administration of treatment. There was a gradual rise in ICP observed in the 23.4% NaCl and mannitol groups with time. Only in the 3% NaCl group was the ICP significantly lower than the pretreatment value at 120 minutes (18.0+/-2 mm Hg, P = 0.02). A significantly higher cerebral perfusion pressure (108.4+/-4 versus 79.6+/-10 mm Hg, P = 0.048) and lower water content in the lesioned white matter (65.5+/-1% versus 67.9+/-1%, P = 0.07) was observed 2 hours after treatment in animals receiving 3% NaCl compared with animals receiving mannitol. There were no significant differences observed in regional cerebral blood flow, oxygen extraction, or oxygen consumption at any time point among the three groups., Conclusion: Hypertonic saline, in both 3 and 23.4% concentrations, is as effective as mannitol in the treatment of intracranial hypertension observed in association with ICH. Hypertonic saline may have a longer duration of action, particularly when used in 3% solution. None of three treatment regimens influence regional cerebral blood flow or cerebral metabolism.