Article Text
Abstract
Introduction Little is known about how changes in physiologic parameters affect venous sinus pressure measurements, waveforms, or gradients associated with sinus stenosis.
Objective To evaluate the effect of changes in cardiovascular and respiratory physiologic parameters on venous sinus pressure and caliber measurements in patients with idiopathic intracranial hypertension (IIH) undergoing venous sinus stenting.
Methods In a prospective, randomized pilot study, eight patients with IIH undergoing venous sinus stenting were randomized to one of two groups. Under general anesthesia, patients underwent venous manometry and waveform recordings twice in succession based on assigned physiologic groups immediately before stenting. The mean arterial pressure (MAP) group maintained normocapnia but modified MAPs in two arms to control for temporal confounding: group A1 (MAP 60-80 mm Hg then 100–110 mm Hg) and group A2 (MAP 100-110 mm Hg then 60–80 mm Hg). The end-tidal carbon dioxide (EtCO2) group maintained a high-normal MAP similar to standard neuroanesthesia goals and modified EtCO2: group B1 (EtCO2 24–26 mm Hg then 38–40 mm Hg) and B2 (EtCO2 28–40 mm Hg then 24–26 mm Hg).
Results In group A, superior sagittal sinus (SSS) pressures (ranging from 8 to 76 mm Hg) and trans-stenotic pressure gradients (TSPGs) (ranging from 2 to 67 mm Hg) were seen at MAP of 100–110 mm Hg compared with SSS pressures (4–38 mm Hg) and TSPGs (3–31 mm Hg) at 60–80 mm Hg. In group B, SSS pressures and TSPGs were considerably higher at EtCO2 levels of 38–40 mm Hg (15–57 mm Hg and 3–44 mm Hg, respectively) than at 24–26 mm Hg (8–26 mm Hg and 1–8 mm Hg, respectively).
Conclusions Despite the small sample size, this pilot study demonstrates a dramatic effect of both MAP and EtCO2 on venous sinus pressures obtained during venography. These findings underscore the importance of maintaining normal physiologic cardiovascular and respiratory parameters during venous sinus manometry.
- intracranial pressure
- stenosis
- angiography
- blood pressure
- stent
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Introduction
Idiopathic intracranial hypertension (IIH) is a syndrome characterized by headaches, visual symptoms, and other clinical signs and symptoms of raised intracranial pressure (ICP) in the absence of a mass lesion. The pathophysiology of this disease remains poorly understood, although the preponderance of evidence supports intracranial venous hypertension as the causative mechanism.1 In a subset of patients, venous sinus stenosis with a trans-stenotic gradient may be either causal or a consequence of a pathologic process of IIH leading to sinus compression.2 3 Sinus stenosis resolution after lumbar puncture with cerebrospinal fluid drainage has been observed, supporting the theory of a positive feedback loop in which increased ICP causes extramural sinus compression, leading to worsened venous congestion and further rises in ICP.4–6 Meta-analyses show venous sinus stenting is effective in relieving headaches, papilledema, and limiting vision loss, with an overall symptom improvement rate of 87%.7
Most practitioners identify candidates for venous sinus stenting by retrograde catheter venography and by documenting a trans-stenotic pressure gradient of at least 8 mm Hg,8 whereas other authors use stents for gradients as low as 4 mm Hg.9–11 Measurements of intracranial venous pressure are therefore the primary means through which candidacy for treatment is determined. However, little is known about normal intracranial venous physiology or factors that may affect pressure measurements during venography. Two retrospective reviews have demonstrated the potential influence of general anesthesia on the measurement of venous sinus pressures and the risk of underestimating the degree of venous outflow obstruction.12 13 Although a correlation was noted between the use of general anesthesia and changes in venous sinus pressures and trans-stenotic gradient, the causative mechanism was not identified. Although most neurointerventionalists now perform venography on patients under conscious or minimal sedation, there are no prospective or randomized data evaluating how or why different modes of anesthesia affect venous sinus pressures. Additionally, other than a recent case series detailing the pronounced effects of end-tidal carbon dioxide levels (EtCO2) on venous sinus pressure measurements and waveform morphology,14 there are few data studying the factors that may affect venous sinus pressures, waveform morphology, and pressure gradients across sinus stenoses. The purpose of this study is to evaluate the effect of changes in cardiovascular and respiratory physiologic parameters on venous sinus pressure and caliber measurements in patients with IIH undergoing venous sinus stenting.
Methods
Study population
A prospective, single-center, randomized pilot study of patients with IIH was performed following institutional review board approval. All patients with IIH who had been identified as candidates for venous sinus stenting, based on clinical diagnosis and a demonstrated pressure gradient ≥8 mm Hg across a venous sinus stenosis, were considered eligible for enrollment into this randomized pilot study. All participants underwent full informed consent and were then randomized into one of four groups. All participating patients were placed under general anesthesia and underwent venous manometry according to institutional protocol within their assigned physiologic parameter groups before undergoing venous sinus stenting.
Groups
The eight patients were randomized into one of four groups, with two patients in each group (table 1). Groups A1 and A2 had a physiologic EtCO2 (38–40 mm Hg) maintained but underwent controlled changes in mean arterial pressure (MAP) from the first recording to the subsequent recording. The order in which MAP changes occurred were opposite in these two groups to control for temporal confounding. MAP values of 60–80 mm Hg and 100–110 mm Hg were selected to represent low-normal and high-normal values, respectively. Groups B1 and B2 had a high-normal physiologic MAP maintained (100–110 mm Hg, similar to standard neuroanesthesia goals at our institution) but underwent controlled changes in EtCO2 from the first recording to the subsequent recording. The order in which EtCO2 changes occurred were opposite in groups B1 and B2 to control for temporal confounding. A lower EtCO2 of 24–26 mm Hg was chosen as this is a commonly used parameter during neuroanesthesia for craniotomy in the setting of malignant ICP elevations.
Cerebral venography and venous manometry
Each patient underwent cerebral venography and venous manometry under general anesthesia. The anesthesiologist was asked to maintain each patient’s initial recording parameters based on randomization to the physiologic parameter group. There is no standardization of MAP or EtCO2 values for these procedures at our institution or in the medical literature. EtCO2 was targeted to the protocol’s initial recording parameters by altering the patient’s minute ventilation by either increasing or decreasing respiratory rate and/or tidal volumes. The MAP was targeted towards the initial recording parameters using either a phenylephrine infusion (if the current MAP was less than the protocol MAP) or esmolol infusion (if the current MAP was higher than the protocol MAP).
The femoral vein was accessed with an 8 F sheath and a 5 F diagnostic catheter was advanced through an 8 F guiding catheter into the internal jugular vein (IJV) on the side of the venous sinus stenosis. A Rebar-27 microcatheter (Medtronic, Minneapolis, Minnesota, USA) was then navigated over a 0.014 microwire into the superior sagittal sinus (SSS). The goal EtCO2 and MAP were confirmed to have been present for at least 3 min before recording data. A cerebral venogram was then obtained in the anteroposterior (AP) and lateral views. Venous sinus manometric measurements were recorded through the microcatheter in the following order: SSS, torcula, ipsilateral transverse sinus (TS), transverse-sigmoid junction, sigmoid sinus (SS), and IJV. Pressures were allowed to normalize and then a single mean pressure was recorded at each location.
Once initial measurements were completed, the anesthesiologist was then asked to adjust the MAP or EtCO2 based on the randomized arm 'subsequent recording' parameters assigned to each patient. The microcatheter was again navigated into the SSS. Once the appropriate study physiologic parameters had been reached and maintained for 3 min, venography was repeated and venous pressures were recorded in the same locations as the microcatheter was withdrawn into the jugular bulb under the new assigned parameters. Once this was completed, each participant underwent stenting according to our institutional protocol.
Waveform recording
All venous manometry and waveform recordings were performed through the Rebar-27 microcatheter, which was flushed and attached to an arterial pressure monitor line positioned at the level of the patient’s heart. This system was then zeroed to atmospheric pressure. At each anatomic site, a minimum of four respiratory cycles were documented before proceeding to the next anatomic location. All manometric data were continuously collected using MediCollector (Boston, Massachusetts, USA). This was then exported into discrete files to be displayed graphically to expedite analysis and interpretation of the cerebral venous waveform characteristics with each change in physiologic parameters.
Blinded venographic review
AP and lateral venographic imaging was reviewed by a senior neurointerventional-trained physician in a blinded fashion. On AP venography, five representative measurements of the SSS width throughout the S1 segment were performed followed by five measurements of the dominant TS height. On the lateral venogram, five measurements of S1 segment SSS depth and three SS height measurements were performed. The degree of venous collateralization present was noted by the reviewer.
Percent stenosis was calculated by previously published methods15 using lateral venographic imaging to determine the smallest diameter (in height) divided by normal TS height as demonstrated on AP imaging. For this study, the mean of the five TS measurements obtained from AP imaging was used as the denominator. Stenosis was then reported as a percent.
Statistical analysis
Descriptive statistics were calculated such that mean (range) was used for normally distributed variables and mean (SEM) for non-parametric data.
Results
Patient characteristics
Consent from eight patients who met criteria for venous sinus stenting was obtained for participation in the study. The patients were randomized into two physiologic groups to evaluate the effect of MAP and EtCO2 on venous sinus pressures and calibers. All enrolled patients were female, with mean age of 40 years (26–63 years). The mean body mass index (BMI) was 36.4 kg/m2 (range 24.8–51.5 kg/m2). The mean opening pressure on lumbar puncture at least 2 weeks before the intervention was 33.25 mm Hg (range 26–44 mm Hg). The mean baseline MAP recorded at the time of awake venography and manometry was 90.13 mm Hg (range 77–104 mm Hg). All enrolled and randomized patients completed the study.
Change in MAP parameters
A total of four patients were randomized into the MAP group (A1 and A2; table 2). Mean SSS venous pressures were higher at MAP of 100–110 mm Hg (mean 39 mm Hg (SEM 15.4)) than those recorded at 60–80 mm Hg (24.0 mm Hg (7.4)). The trans-stenotic pressure gradient (TSPG) was higher at a MAP of 100–110 mm Hg (figure 1A), with a mean pressure gradient of 29.8 mm Hg at MAP 100-110 mm Hg compared with 18.0 mm Hg at MAP 60-80 mm Hg.
Change in EtCO2 parameters
Four patients were randomized into the EtCO2 group (B1 and B2; table 2). Mean SSS pressures were noted to be considerably higher at EtCO2 levels of 38–40 mm Hg (36.8 mm Hg (SEM 10.0)) than those recorded at EtCO2 levels of 24–26 mm Hg (14.3 mm Hg (4.1)). The TSPG was observed to be higher at EtCO2 of 38–40 mm Hg (24.5 mm Hg (7.9)) than at EtCO2 levels of 24–26 mm Hg (3.0 mm Hg (0.8)). Figure 1B shows the absolute change in SSS pressure and gradient noted in these two groups.
Venous sinus caliber measurements
Patients in the EtCO2 group were found to have a noteworthy increase in the caliber of the SS at EtCO2 38–40 mm Hg. Otherwise, no substantial change was seen in venous sinus caliber or sinus stenosis measurements with MAP or EtCO2 changes.
Waveform changes
One patient had incomplete recordings due to equipment malfunction. Six of the eight patients had higher waveform amplitudes centrally, which decreased as the microcatheter was withdrawn proximally through the stenotic region, regardless of their physiologic parameter (figure 2). Patients in the EtCO2 group had higher waveform amplitudes at EtCO2 38–40 mm Hg than at EtCO2 24–26 mm Hg at the SSS (mean 21.1 mm Hg (SEM 6.7) vs 3.2 mm Hg (0.9)), torcula (20.8 mm Hg (6.7) vs 3.3 mm Hg (0.9)), and TS (20.9 mm Hg (6.4) vs 3.8 mm Hg (0.8)). Waveform morphology changes seen in this study mirrored waveform morphology previously described.14 16 No differences in waveform morphology were seen in the SS and IJV caudal to the stenosis.
Discussion
This is the first randomized study to evaluate the effects of blood pressure and arteriovenous carbon dioxide content on venous sinus pressures, waveforms, and venous calibers in patients with IIH and venous sinus stenosis. Although the sample size is small, dramatic changes in venous pressure measurements, trans-stenotic pressure gradients, and waveform morphology were identified with changes in MAP or EtCO2 measurements. Changes in EtCO2 had the most profound effect on these metrics, with the SSS and gradient pressures higher under normal physiologic EtCO2 values than when lowered to 24–26 mm Hg. Measurements performed under high MAP showed similar findings. This study confirms findings from our previous case series14 and strongly suggests that venous manometry and venography should be performed under normal physiologic conditions to mitigate the influence of these confounders on determining candidacy for stenting.
Changes in EtCO2 led to profound changes in sinus pressures, TSPG, and waveform morphology. Arteriovenous carbon dioxide content has a well-described powerful effect on ICP through its vasodilatory effects, with raised arteriovenous carbon dioxide leading to increased cerebral blood flow (CBF), cerebral blood volume, and subsequent rise in ICP. Reducing EtCO2 by increasing minute ventilation results in a concomitant reduction in arterial carbon dioxide pressure, triggering vasoconstriction of the intracranial resistance arterioles through perivascular pH shifts. This intracranial vasoconstriction leads to a decrease in cerebral blood volume and resultant decrease in ICP.17 According to the hypothesis through which venous sinus stenosis arises, decreases in ICP through reductions in EtCO2 would cause subsequent reduction of extramural compression of the venous sinuses and venous congestion. As a result, we would expect to see lower venous pressures and trans-stenotic gradients. These physiologic effects in response to changes in EtCO2 are quite dramatic, with mean increase of pressure of 166%, mean increase in trans-stenotic gradient of 19.25 mm Hg, and an average increase in venous waveform amplitude of 17.9 mm Hg on normalization of EtCO2. These data strongly suggest that venography should be performed on awake patients in order to nullify any potential confounding effects due to hypocapnia. One could hypothesize that the opposite situation is also likely—hypercapnia may result in increased extramural compression of venous sinuses, with resulting exaggeration of the trans-stenotic gradient and pressures. In patients who require anesthesia, conscious sedation may be preferred, but attention should be directed towards potential hypercapnia if the patient were to hypoventilate with sedation. If general anesthesia is necessary, maintenance of normal physiologic parameters (EtCO2 38–40 mm Hg) is strongly recommended in order to best approximate normal physiology during the awake state.
Raising MAPs also increased sinus pressures and trans-stenotic pressure gradients, but to a lesser degree than seen with normocapnia. Cerebral autoregulation maintains CBF across a wide spectrum of blood pressures. Such factors are reliant on cerebral perfusion pressure, which is highly dependent on ICP and MAP. ICP is a measure of intracranial compliance, and will increase as intracranial volume increases (owing to space-occupying lesion, edema, or vessel blood volume). In a feedback mechanism, as ICP increases, in order to maintain cerebral perfusion pressure and CBF within normal range, MAP also increases.18 However, in the presence of chronic hypertension, the cerebral autoregulatory mechanism becomes impaired. This loss increases the transmission of pressure across the capillaries, leading to a blood–brain barrier and cerebral edema. Secondly, chronic systemic hypertension causes structural changes in the vasculature, including (a) decreased density of cerebral arterioles and capillaries,19 and (b) increased distensibility of the cerebral arterioles and capillaries despite hyalinization of the microvasculature.20 Although there is little documentation of the hypertensive effects on the cerebral venous circulation, it is likely that the above effects would lead to increased venous pressures.
Within study groups, we observed variability between patients in response to changes in MAP and EtCO2 of unclear etiology. Under the same conditions, SSS pressures ranged from 4 to 38 mm Hg at low MAP to 8–76 mm Hg at high MAP (groups A1 and A2), and TSPG changes ranged from 3 to 31 mm Hg to 2–67 mm Hg, respectively. Similarly, when going from low EtCO2 to high EtCO2 (groups B1 and B2), SSS pressures ranged from 8 to 26 mm Hg to 15–57 mm Hg, respectively, and TSPG changes ranged from 1 to 8 mm Hg to 3–44 mm Hg, respectively. The cause of this wide variability is unclear and the small sample size precludes statistical testing to evaluate the reason for these noted differences. Potential causes of the pronounced variability could be secondary to patient differences in BMI, central venous pressures, intracranial compliance, baseline ICP, or type/degree of stenosis, which may mitigate or exaggerate the effect of changes in blood pressure or carbon dioxide content on individual intracranial venous systems. Alternatively, other confounding factors not directly controlled for in the study, such as type of inhalational agent or paralytic agents, procedural length, or other physiologic parameters, such as tidal volumes or pulse pressure, may play a role. It is clear that future studies will need to focus on the effect of these parameters and must also have the power to evaluate for confounding factors that may help to explain the marked variability seen in this pilot study.
This study and other commentaries21 highlight the lack of published knowledge defining venous sinus pressures and their correlation with ICP and disease. This lack of knowledge is critical as venous pressure relationships are the primary substrate in which candidacy for venous sinus stenting is determined, yet we have a limited understanding of normal values or of what factors alter or confound these measurements. Few studies have evaluated normal venous sinus pressures in adults. Previously performed cerebrospinal fluid dynamic studies from lumbar catheter protocols suggest that in the majority of patients, SSS pressure is normally <11 mm Hg,22 23 whereas studies performed in the setting of intracranial pathology have indicated that mean awake SSS pressures are <15 mm Hg.24 25 In a recent series of over 100 patients with IIH undergoing venography,1 patients with opening pressure of ≤20 cm H2O and all adjacent pressure gradients of ≤4 mm Hg were selected in order to understand venous sinus pressures in those with milder IIH disease. Data from these patients suggest that in normal individuals, SSS pressures should probably be <18 mm Hg, overall pressure gradients <8 mm Hg, and total cranial gradients <5 mm Hg. Future studies will be necessary to understand what is considered 'normal' intracranial venous physiology in the absence of intracranial abnormalities or IIH in order to improve on our understanding of the pathophysiology of IIH.
This study has important limitations, most notably the small sample size. It was designed as a pilot study to test the feasibility of changing parameters during venous sinus stenting and therefore enrolled only eight patients. As such, this severely limits the ability to perform statistical testing due to the low power. Future studies enrolling more patients with more varied parameter thresholds are necessary to expand the effects of changes in EtCO2 or MAP over a wider spectrum. Second, another important limitation of this study is the use of standardized MAPs, which does not take into account the inherent individual variability in what is considered physiologic baseline. Further studies to better understand the relation between venous sinus pressures and MAP would benefit from a study design that tailored 'non-physiologic' parameters to baseline values specific to an individual. Third, in an effort to control a single physiologic variable at any given time to allow for direct comparison across all patients, we standardized the MAP range, and arbitrarily chose the MAP goal of 100–110 mm Hg across all EtCO2 groups. As elevating the MAP may raise venous sinus pressures, use of the higher MAP parameter (100–110 mm Hg) might have resulted in overestimations of the effect of changes in EtCO2 on venous sinus pressures. Fourth, other important factors might have affected venous sinus pressures (eg, BMI, vascular anatomy, type of stenosis, etc). However, given the small number of patients, this study was not designed to evaluate the influence of these factors on pressures or gradients independently. Finally, methods used for recording pressures and measuring venographic stenosis have been published previously.16 No rigorous guidelines are available in the published literature and therefore these methods may not be directly comparable to methods or results at other centers.
Conclusions
Changes in EtCO2 and MAP have dramatic effects on venous sinus pressures, trans-stenotic gradients, and venous waveform morphologies in patients with IIH and venous sinus stenosis. These findings underscore the importance of maintaining normal physiologic cardiovascular and respiratory parameters during venous sinus manometry. Future studies are needed to confirm the findings of this pilot study.
References
Footnotes
Contributors CT: data collection, data analysis, manuscript preparation. RMG: data collection, manuscript preparation. CK: design, data analysis. JRT: data collection, manuscript preparation. SQW: conception, design, data collection, manuscript preparation. KMF: conception, study design, data collection, data analysis, manuscript preparation.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Unpublished data are available upon request from the corresponding author.