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The Journal of Physiology logoLink to The Journal of Physiology
. 2018 Nov 20;597(1):237–248. doi: 10.1113/JP276557

Lower body negative pressure to safely reduce intracranial pressure

Lonnie G Petersen 1,2,†, Justin S Lawley 3,4,5,†, Alexander Lilja‐Cyron 6, Johan C G Petersen 1,2, Erin J Howden 3,7, Satyam Sarma 3,4, William K Cornwell 3rd 3,8, Rong Zhang 3,4, Louis A Whitworth 4, Michael A Williams 9, Marianne Juhler 6, Benjamin D Levine 3,4,✉
PMCID: PMC6312426  PMID: 30286250

Abstract

Key points

  • During long‐term missions, some astronauts experience structural and functional changes of the eyes and brain which resemble signs/symptoms experienced by patients with intracranial hypertension.

  • Weightlessness prevents the normal cerebral volume and pressure ‘unloading’ associated with upright postures on Earth, which may be part of the cerebral and ocular pathophysiology.

  • By placing the lower body in a negative pressure device (LBNP) that pulls fluid away from cranial compartments, we simulated effects of gravity and significantly lowered pressure within the brain parenchyma and ventricle compartments.

  • Application of incremental LBNP demonstrated a non‐linear dose–response curve, suggesting 20 mmHg LBNP as the optimal level for reducing pressure in the brain without impairing cerebral perfusion pressure.

  • This non‐invasive method of reducing pressure in the brain holds potential as a countermeasure in space as well as having treatment potential for patients on Earth with traumatic brain injury or other pathology leading to intracranial hypertension.

Abstract

Patients with elevated intracranial pressure (ICP) exhibit neuro‐ocular symptoms including headache, papilloedema and loss of vision. Some of these symptoms are also present in astronauts during and after prolonged space‐flight where lack of gravitational stress prevents daily lowering of ICP associated with upright posture. Lower body negative pressure (LBNP) simulates the effects of gravity by displacing fluid caudally and we hypothesized that LBNP would lower ICP without compromising cerebral perfusion. Ten cerebrally intact volunteers were included: six ambulatory neurosurgical patients with parenchymal ICP‐sensors and four former cancer patients with Ommaya‐reservoirs to the frontal horn of a lateral ventricle. We applied LBNP while recording ICP and blood pressure while supine, and during simulated intracranial hypertension by 15° head‐down tilt. LBNP from 0 to 50 mmHg at increments of 10 mmHg lowered ICP in a non‐linear dose‐dependent fashion; when supine (n = 10), ICP was decreased from 15 ± 2 mmHg to 14 ± 4, 12 ± 5, 11 ± 4, 10 ± 3 and 9 ± 4 mmHg, respectively (P < 0.0001). Cerebral perfusion pressure (CPP), calculated as mean arterial blood pressure at midbrain level minus ICP, was unchanged (from 70 ± 12 mmHg to 67 ± 9, 69 ± 10, 70 ± 12, 72 ± 13 and 74 ± 15 mmHg; P = 0.02). A 15° head‐down tilt (n = 6) increased ICP to 26 ± 4 mmHg, while application of LBNP lowered ICP (to 21 ± 4, 20 ± 4, 18 ± 4, 17 ± 4 and 17 ± 4 mmHg; P < 0.0001) and increased CPP (P < 0.01). An LBNP of 20 mmHg may be the optimal level to lower ICP without impairing CPP to counteract spaceflight‐associated neuro‐ocular syndrome in astronauts. Furthermore, LBNP holds clinical potential as a safe, non‐invasive method for lowering ICP and improving CPP for patients with pathologically elevated ICP on Earth.

Keywords: Intracranial Pressure, Gravitational Physiology, Spaceflight, Countermeasure, Novel Treatment potential

Key points

  • During long‐term missions, some astronauts experience structural and functional changes of the eyes and brain which resemble signs/symptoms experienced by patients with intracranial hypertension.

  • Weightlessness prevents the normal cerebral volume and pressure ‘unloading’ associated with upright postures on Earth, which may be part of the cerebral and ocular pathophysiology.

  • By placing the lower body in a negative pressure device (LBNP) that pulls fluid away from cranial compartments, we simulated effects of gravity and significantly lowered pressure within the brain parenchyma and ventricle compartments.

  • Application of incremental LBNP demonstrated a non‐linear dose–response curve, suggesting 20 mmHg LBNP as the optimal level for reducing pressure in the brain without impairing cerebral perfusion pressure.

  • This non‐invasive method of reducing pressure in the brain holds potential as a countermeasure in space as well as having treatment potential for patients on Earth with traumatic brain injury or other pathology leading to intracranial hypertension.

Introduction

Intracranial pressure (ICP) is determined by the volumes of brain tissue, CSF and cerebral blood volume (Mokri 2001). When standing up, gravity displaces blood and fluid towards the feet thereby introducing a hydrostatic pressure gradient and reducing pressures in the cranial direction (Rowel 1986). These daily gravitational fluctuations in ICP are characterized by the balance between the volumes of intravascular cerebral blood and CSF; the intravascular component is regulated by arterial pressure, cerebral autoregulation and venous outflow resistance (Czosnyka et al. 1999) while CSF regulation is described by Davson's equation (Davson et al. 1973) as the balance between CSF formation rate (I a), outflow resistance (R out) and the venous pressure in the sagittal sinus (P sag) [ICP = I a * R out + P sag]. Venous pressure is a factor for both intracranial fluid systems and, given an open venous system, a strong correlation between central venous pressure and ICP has been demonstrated by us and others (Qvarlander et al. 2013; Petersen et al. 2016; Lawley et al. 2017).

In the absence of gravity (i.e. the microgravity environment associated with spaceflight) the persistent cephalic fluid shift and patent open venous system allows for consistent transmission of central venous pressures to the brain (Petersen et al. 2016). As central venous pressure in space is lower than supine values on Earth (Videbæk & Norsk 1985; Buckey et al. 1993), significant or pathological elevations in ICP during spaceflight do not seem likely. Indeed, our recent findings from short‐term microgravity by parabolic flights indicate that, when abolishing all hydrostatic pressure gradients, ICP assumes a value between that of upright and supine posture on Earth (Lawley et al. 2017). However, microgravity prevents habitual gravitational ‘unloading’ of cerebral structures and low (sometimes even negative) ICP associated with upright postures on Earth. Because humans spend two‐thirds of every day in upright postures, this suggests a mild, but chronic, elevation of the average 24‐h ICP in space compared to Earth. This inability to periodically ‘stand up and unload the brain’ in space may contribute to the visual impairment and cerebral remodelling experienced by some (∼50%) astronauts during long‐term spaceflight, commonly referred to as spaceflight‐associated neuro‐ocular syndrome (SANS; Mader et al. 2011; Lee et al. 2017). Indeed, symptoms presented by astronauts resemble those of patients on Earth with intracranial hypertension or perhaps hydrocephalus and include: oedema at the back of the eye, flattening of the globe, hyperoptic shift and remodelling of brain tissue (Mader et al. 2011; Roberts et al. 2017) .

The hydrostatic effects of gravity can be simulated by lower body negative pressure (LBNP); by placing the legs and pelvic region in a semi‐airtight chamber in which pressure can be reduced, blood and tissue fluids are displaced caudally, thereby reducing central venous pressure (Hirsch et al. 1989). LBNP could be used to simulate gravitational effects on the brain and counteract SANS during long‐term spaceflight (Macias et al. 2015). Furthermore, gravitational lowering of ICP is used in everyday clinical practice, where patients with pathological elevation of ICP from traumatic brain injury or other pathologies are commonly positioned with the head slightly elevated (Schwarz et al. 2002). We have shown that head‐up tilt by 20–30° lowers ICP corresponding to the hydrostatic pressure gradient within the venous system (Petersen et al. 2016). However, a limitation of head‐up tilt is the introduction of a hydrostatic pressure gradient between heart and brain, which reduces not only ICP but also arterial blood pressure at brain level (Petersen et al. 2014). The concurrent decrease in arterial feeding pressure decreases cerebral perfusion and oxygenation (Mehagnoul‐Schipper et al. 2000; Ogoh et al. 2015; Bronzwaer et al. 2017) and may be even more pronounced in patients with pathological or iatrogenic impairment of cardiovascular/pressor and ventilatory reflexes. Low levels of LBNP primarily affect venous pressures without impairing arterial blood pressures and could therefore provide an alternative, more protective, method to lower ICP. Because arterial feeding pressure to the brain is not impaired, LBNP could possibly increase cerebral perfusion pressure (CPP) and oxygen delivery to the brain tissue in patients with intracranial hypertension.

The aim of this study was to assess the efficacy and dose–response of LBNP to lower ICP in order to assess its potential as a countermeasure for spaceflight to re‐introduce the habitual gravitational ICP variability, as well as to assess potential for clinical use on Earth. While monitoring ICP and blood pressure, we applied LBNP from 0 to 50 mmHg at increments of 10 mmHg. To assess the potential of LBNP to reduce ICP and maintain/increase CPP as a potential future treatment option, intracranial hypertension was created experimentally by tilting the subjects 15° head‐down and repeating the LBNP protocol.

Methods

Ethical approval

The protocol of this intervention study was approved by the Committee on Health Research Ethics for The Capital Region of Denmark (H‐15001109) or the Institutional Review Board at the University of Texas Southwestern Medical Centre. The study was not registered in a publicly accessible database. All participants were informed of the purpose and risks involved with each procedure and provided oral and written informed consent in compliance with the Declaration of Helsinki.

Subjects

Ten subjects with implanted devices allowing direct measurement of ICP were included [eight male; mean ± SD (range): age 38 ± 17 years (20–67); height 179 ± 8 cm (170–189); weight 79.9 ± 12 kg (58–90)]. Strict inclusion criteria, requiring access to direct recordings of ICP in generally healthy patients with structurally normal brains, limited the number of included subjects. All were free of cardiovascular disease and took no medication with effects on cerebral haemodynamics at the time of the investigation (Table 1).

Table 1.

Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria
Age > 18 and < 70 years Supine ICP > 18 mmHg
Access to invasive ICP recording; either from lateral ventricle or parenchyma Shunt treatment
Glasgow Coma Scale 15, normal cognitive function and mentally fit to cooperate in the investigation CT/MRI indications of global oedema or focal lesions
No medications with effect on cerebrovascular parameters at the time of the study Headache, nausea or other adverse reactions to head‐down tilt
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From ambulatory neurosurgical patients undergoing 24–48 h of parenchymal ICP monitoring (Fig. 1) as part of their diagnostic work‐up, six patients were carefully selected following the inclusion and exclusion criteria described in Table 1 and they were considered to be ‘as normal as possible’. Clinical indications for extended ICP monitoring for these patients were for diagnostic purposes, including a need for 24‐h ICP profile, nocturnal ICP or capturing abnormal pressure wave patterns. The six patients were those who at the end of the diagnostic procedure were found not to be surgical candidates including being free of focal lesions or global oedema on computed tomography/magnetic resonance imaging (CT/MRI) scan, having a normal 24‐h ICP‐profile and normal cognitive function (we have followed and described the selection procedure in a previous study; Petersen et al. 2016)

Figure 1. Sites of measurement of intracranial pressure.

Figure 1

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A, fluid‐filled Ommaya reservoir implanted under the skin and with the tip of the catheter in the frontal horn of the lateral ventricle. B, cabled parenchymal tip‐transducer placed 2–3 cm into the brain parenchyma.

The remaining four subjects were former cancer patients with an Ommaya reservoir inserted though the skull for the purpose of delivering prophylactic chemotherapy into the CNS as part of their treatment for haematological malignancy (Fig. 1). The participants had no metastasis to the CNS and had been free of their malignant disease for at least 1 year at the time of the investigation (the selection process has been described in a previous study; Lawley et al. 2017).

Measurements

Parenchymal ICP (cerebral interstitial pressure) was measured in the six ambulatory neurosurgical patients using a tip‐transducer catheter (Neurovent‐P, Raumedic, Helmbrechts, Germany) inserted under local anaesthesia and sterile conditions through a right frontal burr hole. CSF pressure (cerebral fluid pressure) was measured in the four patients with Ommaya‐reservoirs using fluid‐filled pressure transduction with the external pressure transducer fixed and zeroed at the external auditory meatus (Fig. 1).

Beat‐by‐beat arterial blood pressure and heart rate were measured continuously by photoplethysmography and the volume‐clamp method from a cuff around the third finger. Pulse contour analysis provided cardiac stroke volume, cardiac output and total peripheral resistance (Nexfin, BMeye, Amsterdam, the Netherlands). A height‐sensor at the 4th intercostal space was used to correct arterial blood pressure to heart level while the distance between the 4th intercostal space and the external auditory meatus was used to estimate blood pressure at mid‐brain level (Petersen et al. 2016).

Protocol

After collecting upright seated baseline data, the participants were positioned on a standard whole‐body tilt table with the lower body inside a semi‐airtight chamber sealed at the level of the iliac crest. Pressure inside the chamber was reduced below ambient pressure by a standard vacuum pump. Baseline measurements at ambient pressure in supine and 15° head‐down tilt (HDT) posture were performed after at least 15 min of rest. HDT of 15° was chosen based on previous work (Petersen et al. 2014, 2016) and is a compromise between achieving the desired increase in ICP while minimizing confounding influence from mechanical compression of the heart and lungs by abdominal content and thus effects on cardiac filling and ventilation. During the rest period and data collection, participants were instructed to maintain a relaxed body posture and minimize conversation, but keep their eyes open and stay awake. LBNP was applied at increments of 10 mmHg from 0 to 50 mmHg during two separate sessions either with the subject in the supine position or at 15° HDT. We have previously reported significant reduction of ICP by slight head‐elevation by adding a pillow (Lawley et al. 2017). In one patient in the present study, we further tested the combined (and potential synergistic) effect of both a gravitationally induced hydrostatic pressure gradient (real gravitational stress) and LBNP (simulated gravitational stress).

All measurements were recorded as analog data and transferred to a laptop at 1000 Hz using a standard AD converter (Powerlab, ADInstruments, Sydney, Australia, and Biopac Systems, Goleta, CA, USA). Data are reported as an average of the final minute of each 10‐min experimental condition (i.e. minute 9–10 of each experimental condition).

Statistical analysis

To examine the effect of LBNP while lying in the supine position, all variables were analysed using a single‐factor (phase: Supine, 10 LBNP, 20 LBNP, 30 LBNP, 40 LBNP and 50 mmHg LBNP) linear mixed‐effects models with the participant modelled as random effect. Planned contrasts derived from the models’ least square means estimates were used to examine the difference between supine and each phase of LBNP. Values for the upright posture are presented for reference only. To examine the effect of LBNP while lying in the 15° HDT position (simulated intracranial hypertension), all variables were analysed using a single factor (phase: HDT, 10 LBNP‐HDT, 20 LBNP‐HDT, 30 LBNP‐HDT, 40 LBNP‐HDT and 50 LBNP‐HDT) linear mixed‐effects models with the participant modelled as random effect. Planned contrasts derived from the models’ least square means estimates were used to examine the difference between 15° HDT and each phase of LBNP. All post hoc testing following a significant outcome from the ANOVA were part of the original study design and thus were planned a priori.

Baseline measurements during standing and supine were repeated after application of LBNP. All values returned to baseline, demonstrating no carryover effects of the intervention. All values are expressed as mean ± SD. All statistical procedures were completed with JMP 12 (JMP Pro; SAS 268 Institute Inc., Cary, NC, USA). Statistical significance was set at P < 0.05.

Results

Impact of LBNP in the supine posture

While in the supine posture, LBNP caused an immediate and consistent reduction in ICP (P < 0.0001, n = 10, Fig. 2 A). LBNP of 10 mmHg reduced ICP by 1.5 ± 1.7 mmHg and an additional 1.7 ± 1.6 at 20 mmHg LBNP. With increasing levels of LBNP, ICP was further reduced, but following a non‐linear pattern in which effects on ICP somewhat tapered off as LBNP was increased to 30, 40 and 50 mmHg, thus attenuating the reduction in ICP to 1 ± 1, 0.8 ± 0.6 and 0.6 ± 0.4 mmHg, respectively. CPP, calculated as the difference between mean arterial pressure (MAP) at mid‐brain level and ICP, tended to increase slightly although not reaching statistical significance with the exception of at 40 mmHg where CPP increased by 3 ± 1 mmHg (P = 0.02, n = 10, Fig. 2 B). MAP values both at heart level and corrected to mid‐brain level are presented in Tables 2 and 3.

Figure 2. Lower body negative pressure consistently lowers intracranial pressure and maintains cerebral perfusion pressure in the supine posture.

Figure 2

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A and B, intracranial pressure (ICP) (A) and cerebral perfusion pressure (CPP) (B) during progressive lower body negative pressure (LBNP), n = 10. The upright posture is presented for reference only; asterisks indicate a significant difference compared to supine posture: ** P ≤ 0.01, * P ≤ 0.05. Closed circles represent Raumedic volunteers; open diamonds represent Ommaya volunteers. C and D, ICP (B) and CPP (D) after 2 and 10 min at −40 mmHg LBNP to demonstrate acute and sustained steady state effect of LBNP, n = 2. E, original recordings of ICP and CPP during graded LBNP. At the end of 10 min at −40 mmHg, this subject's head was placed on a pillow. Note the large fall in ICP, confirming the additive effect of LBNP and head elevation.

Table 2.

Haemodynamic variables during graded lower body negative pressure in the supine position

Seated (90°) Supine (0°) Supine (0°) −10 LBNP Supine (0°) −20 LBNP ‐ Supine (0°) −30 LBNP Supine (0°) −40 LBNP Supine (0°) −50 LBNP
ICP (mmHg) 0.23 ± 3.46 15.03 ± 2.45 13.77 ± 3.7** 11.79 ± 4.06** 10.92 ± 3.65** 10.39 ± 3.38** 9.44 ± 3.95**
MAP_EAM (mmHg) 61.77 ± 9.12 84.86 ± 11.76 80.88 ± 7.8* 81.1 ± 9.82* 81.33 ± 10.98* 82.8 ± 12.22 83.05 ± 12.61
CPP (mmHg) 61.55 ± 9.66 69.83 ± 12.17 67.11 ± 9.27 69.31 ± 10.49 70.41 ± 11.8 72.41 ± 12.89* 73.61 ± 14.59
MAP (mmHg) 92.35 ± 8.22 84.86 ± 11.76 80.88 ± 7.8** 81.1 ± 9.82** 81.33 ± 10.98** 82.8 ± 12.22 83.05 ± 12.61**
SBP (mmHg) 125.48 ± 15.44 124.84 ± 20.42 116.83 ± 13.57* 114.86 ± 15.03** 115.27 ± 17.37** 115.81 ± 21.07** 114.91 ± 22.42**
DBP (mmHg) 75.82 ± 7.12 67.03 ± 7.56 64.24 ± 4.79 65.11 ± 5.97 66.05 ± 6.2 67.94 ± 7.07 65.93 ± 4.39
HR (beats/min) 74.93 ± 11.34 64.1 ± 9.13 64.23 ± 9.55 68.08 ± 9.87 73.65 ± 9.25** 76.76 ± 9.46** 82.34 ± 8.83**
SV (ml) 80.97 ± 14.84 104.47 ± 13.88 103.13 ± 13.51 92.18 ± 11.03* 84.40 ± 12.1** 82.19 ± 11.01** 75.31 ± 8.98**
Qc (l/min) 5.99 ± 0.69 6.62 ± 0.65 6.54 ± 0.78 6.21 ± 0.61 6.26 ± 0.68 6.25 ± 0.84 6.12 ± 0.96
TPR (dyne·s/cm5) 1258.39 ± 236.1 1057.06 ± 228.77 1006.32 ± 231.71 1065.65 ± 226.75 1061.61 ± 225.05 1093.17 ± 261.94 1192.26 ± 348.4
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ICP (intracranial pressure); MAP_EAM (mean arterial pressure at the level of the external acoustic meatus; CPP (cerebral perfusion pressure); MAP (mean arterial pressure at heart‐level); SBP (systolic blood pressure); DBP (diastolic blood pressure); HR (heart rate); SV (cardiac stroke volume); Qc (cardiac output); TPR (total peripheral resistance). Data are presented as mean ± SD. Asterisks indicate a significant difference compared to supine posture: * P < 0.05, ** P < 0.01.

Table 3.

Haemodynamic variables during graded lower body negative pressure in the −15° head down tilt position

Supine (0°) −15° HDT −15° HDT −10 LBNP −15° HDT −20 LBNP −15° HDT −30 LBNP −15° HDT −40 LBNP −15° HDT −50 LBNP
ICP (mmHg) 15.22 ± 2.86 26.14 ± 4.19 21.4 ± 3.82** 19.63 ± 3.99** 18.32 ± 3.88** 16.62 ± 3.87** 16.79 ± 3.89**
MAP_EAM (mmHg) 85.87 ± 11.64 90.47 ± 7.85 91.91 ± 8.94 88.89 ± 6.3 86.6 ± 11.35 91.41 ± 9.2 88.64 ± 9.16
CPP (mmHg) 70.65 ± 13.19 64.33 ± 8.62 70.51 ± 11.4** 69.26 ± 8.06** 68.28 ± 11.94 74.79 ± 11.22** 71.85 ± 9.78**
MAP (mmHg) 85.87 ± 11.64 82.53 ± 7.82 83.97 ± 9.05 82.27 ± 9.41 78.66 ± 11.2 83.52 ± 9.39 80.7 ± 9.27
SBP (mmHg) 122.19 ± 22.79 119.8 ± 15.38 122.46 ± 15.97 120.27 ± 16.63 113.34 ± 20.41* 117.4 ± 17.57 114.85 ± 18.53
DBP (mmHg) 66.55 ± 6.39 63.33 ± 4.47 65.33 ± 4.56 63.49 ± 5.28 60.87 ± 8.61 66.22 ± 5.31 63.68 ± 4.43
HR (beats/min) 65.1 ± 8.84 62.52 ± 8.38 62.41 ± 9.74 63.23 ± 11.15 66.96 ± 9.78 77.74 ± 7.73** 68.43 ± 4.95*
SV (ml) 101.48 ± 13.3 109.29 ± 10.57 108.13 ± 19.61 103.94 ± 13.7 97.11 ± 10.06** 83.03 ± 15.92** 91.17 ± 9.16**
Qc (l) 6.57 ± 0.84 6.82 ± 0.97 6.58 ± 1.08 6.5 ± 0.98 6.48 ± 0.93 6.32 ± 0.74 6.22 ± 0.8
TPR (dyne·s/cm5) 1099.22 ± 276.23 993.38 ± 224.8 1059.4 ± 297.37 1050.21 ± 249.29 1023.15 ± 284.76 1088.89 ± 201.54 1044.69 ± 210.77
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Data are presented as mean ± SD. Asterisks indicate significant difference compared to supine −15° head‐down tilt posture: * P < 0.05, ** P < 0.01.

Lowering of ICP occurred almost instantaneously (within seconds) with application of an increase in LBNP and remained below baseline for the duration of LBNP application (Fig. 2 C, D). Moreover, adding a pillow in order to combine a hydrostatic pressure gradient between the heart and the brain with LBNP caused a further reduction (5.5 mmHg) in ICP and improvement in CPP (7 mmHg) when compared to LBNP alone (n = 1, Fig. 2 E).

As expected, LBNP at ≥20 mmHg reduced stroke volume (P < 0.0001, n = 10), accompanied by a reflex increase in heart rate (P < 0.0001, n = 10) to maintain cardiac output (P = 0.14, n = 10).

Impact of LBNP on ICP during elevated ICP by HDT

HDT by 15° significantly increased ICP (∆11 mmHg, P < 0.001, n = 6). Whilst tilted head‐down, application of graded LBNP significantly reduced ICP (P < 0.0001, n = 6, Fig. 3 A) following a similar non‐linear pattern as during supine posture and demonstrating the steepest decline in ICP around 20 mmHg of LBNP. MAP was maintained (P = 0.24), resulting in an overall increase in CPP (P < 0.0009, n = 6, Fig. 3 B). Stroke volume started to decline at 30 mmHg LBNP and higher pressures (P < 0.0001, n = 6), accompanied by a reflex increase in heart rate so that cardiac output was maintained (P = 0.34, n = 6, Table 2). Figure 3 C demonstrates the well‐described exponential pressure–volume relationship of the intracranial space; a given volume reduction along the steep rightward part of the curve leads to a larger reduction in pressure than along the leftward side and flat portion of the pressure–volume curve. This explains the augmented effect in the simulated intracranial hypertension situation and indicates the potential for use in patients with elevated ICP.

Figure 3. Lower body negative pressure consistently lowers intracranial pressure and cerebral perfusion pressure in an experimental model of intracranial hypertension.

Figure 3

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A and B, intracranial pressure (ICP) (A) cerebral perfusion pressure (CPP) (B) during progressive lower body negative pressure (LBNP), n = 6. The supine posture is presented for reference only. Asterisks indicate a significant difference compared to −15° head‐down tilt posture: ** P ≤ 0.01. Closed circles represent the individual cases with an implanted parenchymal ICP sensor. C, pressure–volume relationship within the rigid skull and intracranial compliance curve, demonstrating the potential for larger decrease in ICP at a given volume displacement and thus potential benefits of applying LBNP in individuals with elevated ICP.

Discussion

This study is the first to demonstrate the efficacy and dose–response relationship of LBNP to lower ICP by direct, invasive measurements of CSF pressure and CPP in humans. Caudal displacement of blood and fluid translated to a significant decrease in both CSF and parenchymal pressure. The data suggest 20 mmHg LBNP as the optimal level to decrease ICP without impairing CPP or cardiac stroke volume. LBNP treatment holds potential for use in space to re‐introduce gravitational fluid and pressure variability and counteract the detrimental effects of microgravity on cerebral and ocular structures (i.e. SANS). Furthermore, LBNP may hold potential as a new non‐invasive way to manage intracranial hypertension in various pathologies for patients on Earth.

Effects of gravity, weightlessness and simulated gravity

Fluid distribution and regional pressures are affected by body posture relative to the gravitational field. When standing up, gravity displaces blood and fluid towards the feet thereby decreasing central and cephalic venous volumes and pressures (Rowel 1986). Humans spend two‐thirds of every day in upright postures, and thereby are adapted to a relatively low average 24‐h ICP along with large diurnal fluctuations in ICP (Andresen et al. 2015; Petersen et al. 2016). This ICP variability is lost in the microgravity environment of space, and probably plays an important role in the pathophysiology behind SANS (Mader et al. 2011; Lee et al. 2017; Roberts et al. 2017). Because SANS appears to be closely related to this headward fluid shift and failure to unload the brain during the day, countermeasures should focus on reversing the fluid shift and reintroducing intracranial pressure and fluid variability. LBNP has been used for decades to mimic gravitational stress and hypovolaemia by displacing blood and fluid caudally (Wolthuis et al. 1970). This study supports the concept that a decrease in central venous pressures translates directly to a corresponding decrease in pressure of both the CSF and brain tissue. Previous studies have demonstrated a 2 mmHg reduction in central venous pressure for every 10 mmHg of LBNP from 10 to 30 mmHg (Norsk et al. 1986; Hirsch et al. 1989). These observations correlate well with our current ICP measurements which demonstrated a 1.5 ± 1.7 mmHg reduction by application of 10 mmHg LBNP and a further 1.7 ± 1.6 reduction at 20 mmHg LBNP. When LBNP was increased to 30, 40 and 50 mmHg, the reduction in ICP was attenuated to 1 ± 1, 0.8 ± 0.6 and 0.6 ± 0.4 mmHg, respectively. A secondary mechanism could be a direct effect of the negative pressure on lumbar and pelvic segments of the spine and epidural venous beds or even the CSF fluid‐filled spinal canal itself; as the seal of the LBNP is created at the iliac crest, the lower spine extends into the pressure chamber and despite being encapsulated in bony structure, the external negative pressure could possibly directly affect cranial–spinal compliance by displacing venous blood to caudal segments of epidural plexus thereby decreasing filling and pressure more cranially. It is also possible that CSF is directly affected and displaced caudally, thus adding to the decrease in ICP at the level of the brain.

Charles & Lathers (1994) estimated that 50 mmHg of LBNP produced the same caudal fluid shift as upright standing. Johnson et al. (2014) even achieved a slightly negative central venous pressure (−0.6 ± 0.8 mmHg) by application of 45 mmHg LBNP, which is close to normal upright values (Petersen et al. 2014). At head‐up tilt angles above 20–30° the internal jugular veins start to collapse and intravascular pressure approaches zero (Dawson et al. 2004; Gisolf et al. 2004). While some flow persists (Valdueza et al. 2000), the hydrostatic gradient is interrupted and this may protect ICP from reaching very negative values when upright (Petersen et al. 2016). In the present study, we were not able to reduce ICP to upright standing values by application even of high levels of LBNP (50 mmHg). Indeed, application of LBNP above 30 mmHg did not cause much further reduction in ICP, but did significantly reduce stroke volume as an indication of impaired venous return to the heart (Table 2). Combining ‘real gravitational stress’ via slight head elevation by adding a pillow and ‘simulated gravitational stress’ by LBNP in the case‐study demonstrated additive effects on lowering ICP. Elevation of the head, even if only temporary, facilitates drainage of cerebral structures and reduces pressure. This mechanism may explain why subjects included in bedrest trials to simulate effects of weightlessness typically do not present with SANS. These subjects typically are allowed use of a pillow as well as periodic slight head elevation for the purpose of personal hygiene or eating. Periodic cerebral unloading or drainage in this manor may be sufficient to prevent SANS or keep symptoms at pre‐clinical levels.

A decrease in cerebral blood flow velocity in response to LBNP was demonstrated early on by Wolthuis et al. (1970, 1975), while others confirmed the dose–response correlation of LBNP and cerebral blood flow (Levine et al. 1994; Zhang et al. 1997; Mitsis et al. 2006). In the current study, LBNP was well tolerated and CPP was maintained throughout the LBNP protocol. Our data indicate low‐level LBNP (around 20 mmHg) as the optimal one to safely reduce ICP while maintaining cerebral perfusion and cardiac stroke volume. This was particular evident during simulated intracranial hypertension by HDT, where the downward slope of ICP as a function of LBNP showed a steeper trend between 0–10 and 10–20 mmHg LBNP compared to higher levels of LBNP (30–50 mmHg) (Fig. 3) Moreover, increasing LBNP levels to above some 20 or 30 mmHg is well known to be associated with reduced cardiac filling (also shown in the current trial; Tables 2 and 3) and increased sympathetic drive, but ultimately leading to cerebral hypoperfusion and syncope at higher levels of LBNP (Zhang et al. 1997; Ogoh et al. 2015). Taken together, we therefore recommend a low level of around 20 mmHg LBNP to safely reduce ICP. The reduction in ICP by LBNP occurred immediately (within seconds) and lasted for the duration of application of up to about 1 h in the current experimental trial.

LBNP holds important potential as a countermeasure during long‐term spaceflight to reverse the cephalad fluid shift and re‐introduce diurnal ICP variability to prevent development of SANS. The feasibility of LBNP is currently being tested on board the International Space Station using the Russian ‘Chibis’ device to apply short‐term (up to 30 min), low‐level (20–25 mmHg) LBNP to create the desired caudal fluid shift. Additionally, in ground‐based simulation trials using slight HDT bedrest, we are currently investigating the effects of long‐term (8 h per day), low‐level (20 mmHg) LBNP to counteract the time‐dependent fluid build up and swelling of posterior ocular structures which are believed to be a precursor of SANS. The feasibility of LBNP as a countermeasure during long‐term space flight will require re‐configuration of currently available bulky LBNP devices.

Intracranial hypertension and clinical applications of LBNP

Intracranial hypertension is a symptom or consequence of a wide range of conditions from traumatic or spontaneous haemorrhage, stroke, cerebral oedema, tumours or congenital disturbances to CSF flow. Damage to the brain tissue is caused both directly by ‘mechanical compression’ and ultimately herniation of the brainstem into the foramen magnum and by ‘ischaemic damage’ when blood flow and oxygen delivery fails to meet the metabolic demand (Stocchetti & Maas 2014). Therefore, a timely intervention to reduce ICP and maintain cerebral perfusion is recommended when ICP exceeds 20 mmHg (Fleischman et al. 2012; Brain Trauma Foundation Guidelines, http://tbiguidelines.org). Therapeutic interventions fall into one of two categories with the aim to either reduce intracranial volumes (e.g. by CSF drainage, hyperventilation‐induced vasoconstriction, hyperosmolar therapy) or to increase available space by decompressive craniectomy (Brain Trauma Foundation Guidelines; Czosnyka et al. 1999; Stocchetti et al. 2008). All current treatment options carry significant risk of adverse effects, require admission to highly specialized hospital wards, and/or have varying or short‐lasting effects in reducing ICP.

Gravitational lowering of ICP by head elevation is part of current standard of care for most patients with intracranial hypertension, but is limited by the concurrent decrease in arterial blood pressure at brain level and thus decreased cerebral perfusion and oxygenation (Mehagnoul‐Schipper et al. 2000; Olavarria et al. 2014; Bronzwaer et al. 2017). As a result, guidelines for patient positioning following, for example, stroke remain ambiguous (Jauch et al. 2013; Anderson et al. 2017). Similar to head elevation, LBNP lowers ICP but causes a significantly smaller decline in cerebral blood perfusion (Bronzwaer et al. 2017) and low‐level LBNP may therefore have advantages over head elevation in lowering ICP and maintaining cerebral blood flow. Compared to LBNP, head elevation causes a larger reduction in arterial CO2 partial pressure and constriction of cerebral arteries (Frerichs et al. 2005), and a reduction in arterial feeding pressure at brain‐level due to the hydrostatic pressure gradient between the heart and the brain (Petersen et al. 2014). Despite similar effects on central haemodynamics, LBNP may therefore better protect cerebral perfusion compared to head elevation. Cerebral compliance is expressed as the exponential relationship between intracranial volume and pressure (compliance = ΔV/ΔP). Due to the non‐linear relationship between pressure and volume within the rigid skull (Fig. 3 C) we propose that LBNP might be even more efficient when applied to patients with intracranial hypertension (Table 3).

This study introduces low‐level LBNP as a potential new, non‐invasive, robust and safe alternative method to lower ICP and improve cerebral perfusion in patients with pathologically elevated ICP. Moreover, LBNP can be combined with most other therapeutic interventions. Although only in one individual, our case‐study documented that a combination of LBNP and head elevation caused a synergistic lowering of ICP and increase in CPP (Fig. 2 E and Table 3). A combination of these non‐invasive interventions could provide an effective first response to head trauma, which could be applied anywhere from the site of injury, during transportation, to the emergency department and intensive care unit. Furthermore, LBNP could be applied when head‐up tilt is not feasible, such as during transportation of the patient from the site of an accident or during CT/MRI scans. Note that the present study only included awake and cerebrally intact volunteers. Application of LBNP may hold greater risks for comatose patients who have pathological or iatrogenic reduction of cardiovascular‐pressor reflexes or reduction of respiratory or cerebral haemodynamic autonomic control. Caution is therefore advised for future testing of LBNP in clinical trials and both feasibility and relevant clinical outcomes should be considered and tested.

Limitations

A limitation to this study is the small number of included test subjects. The current study included neurosurgical patients who were ‘as normal as possible’ and healthy volunteers who had previously received intrathecal treatment for a malignant disease via an Ommaya reservoir; all were considered to have normal ICP. Strict inclusion and exclusion criteria ensured intact cerebral anatomy and physiology, while still allowing for recording of invasive ICP. A strength of the study is that ICP was measured both in the CSF of the frontal horn of the lateral ventricle (Ommaya patients using open fluid pressure transduction) as well as in the brain parenchyma (Raumedic tip transducer sensors for interstitial pressure). ICP response to LBNP was robust and reproducible between subjects and sites of measurements within the brain.

The reduction in ICP was maintained for the duration of LBNP application, but in this study, a maximum of 50 min of LBNP was applied (the cumulative time line of incremental LBNP from 10 to 50 mmHg). Ongoing studies will determine if long‐term (several hours) application of LBNP will persistently reduce ICP or be blunted by compensatory mechanisms. Additionally, the tolerance and efficacy of daily application of low‐level, long‐term LBNP are currently being investigated to further define potential for use both in space and on Earth.

Conclusion

We have demonstrated the efficacy of LBNP to reduce parenchyma and CSF pressure of the brain. Application of graded LBNP reduced ICP following a non‐linear dose–response curve. Based on these data, we recommend 20 mmHg LBNP to lower ICP without impairing arterial blood pressure. LBNP simulates the effects of gravitational stress on ICP, but better protects and maintains cerebral perfusion than head elevation. It therefore holds potential as a novel non‐invasive method to lower ICP and maintain perfusion of brain tissue and could be used alone or in combination with other current treatment regimes. Furthermore, LBNP might be applied for astronauts during long‐term space flight to reintroduce diurnal gravitational cerebral volume and pressure variability, thereby maintaining cerebral and ocular health.

Additional information

Conflict of interest

The authors declare no financial conflict of interest.

Author contributions

LGP, JSL and BDL conceived and designed the experiments. LGP, JSL, ALC, JCGP, EJH, LAW and MJ performed the experiments. All authors contributed to writing the paper.

Funding

LGP was supported by Novo Nordic Foundation grant number NNF15OC0019196; JSL and BDL were supported by National Space Biomedical Research Institute grant number NCC 9‐58. Neither funding source had any influence on data collection, interpretation or decision to submit the manuscript for publication.

Acknowledgements

We thank the patients and volunteers for participating in this trial.

Biography

Lonnie G. Petersen completed her MD from the University of Copenhagen, Denmark, in 2007 and has worked in Emergency Medicine and Intensive Care. Dr Petersen received her PhD in Gravitational Physiology and Space Medicine from the Department of Anesthesiology and Neurosurgery in 2016. She is currently working at the University of California, San Diego supported by the Novo Nordic Foundation and National Research Council (Sapera Aude fellow) as well as several NASA grants. Her research is rooted in cardiovascular physiology with a focus on pressure and blood flow regulation of the brain and always with an integrative physiology approach.

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Edited by: Michael Hogan & Philip Ainslie.

This is an Editor's Choice article from the 1 January 2019 issue.

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