Non-invasive Measurement Of Intracranial Pressure Research Articles

How to use cerebral ultrasound in the ICU.

Cerebral ultrasound is a developing point of care tool for intensivists and emergency physicians, with an important role in the diagnosis of acute intracranial pathology, such as the assessment of cerebrovascular diseases and in the noninvasive intracranial pressure measurement both in the acute clinical settings and in intensive care unit (ICU). The traditional application of transcranial doppler (TCD) by assessing blood flow velocities in the main cerebral arteries, allows the evaluation and follow up of cerebral vasospasm, cerebral perfusion pressure, cerebral autoregulation and intracranial hypertension. The use of TCD, traditionally limited to the neurosonology laboratories settings, has expanded over the last years following the introduction of B-mode ultrasound and color Doppler, the transcranial color-coded duplex ultrasonography (TCCS), opening a new window to the assessment of cerebral anatomy not only in the neurocritical patients, but also in general ICU and emergency room patients. Here we report a brief review with the intent to up-to-date and describe the main applications and use of TCD/TCCS in the setting of Neurointensive Care.

Letter: Validation of Noninvasive Absolute Intracranial Pressure Measurements in Traumatic Brain Injury and Intracranial Hemorrhage

Letter: Validation of Noninvasive Absolute Intracranial Pressure Measurements in Traumatic Brain Injury and Intracranial Hemorrhage

Fluctuations in intracranial pressure can be estimated non-invasively using near-infrared spectroscopy in non-human primates

Intracranial pressure (ICP) is typically measured invasively through a sensor placed inside the brain or a needle inserted into the spinal canal, limiting the patient population on which this assessment can be performed. Currently, non-invasive methods are limited due to lack of sensitivity and thus only apply to extreme cases of increased ICP, instead of use in general clinical practice. We demonstrate a novel application for near-infrared spectroscopy (NIRS) to accurately estimate ICP changes over time. Using a non-human primate (Rhesus Macaque) model, we collected optical data while we induced ICP oscillations at multiple ICP levels obtained by manipulating the height of a fluid column connected via a catheter to the lateral ventricle. Hemodynamic responses to ICP changes were measured at the occipital pole and compared to changes detected by a conventional intraparenchymal ICP probe. We demonstrate that hemoglobin concentrations are highly correlated with induced ICP oscillations and that this response is frequency dependent. We translated the NIRS data into non-invasive ICP measurements via a fitted non-parametric transfer function, demonstrating a match in both magnitude and time alignment with an invasively measured reference. Our results demonstrate that NIRS has the potential for non-invasive ICP monitoring.

Reliability of Assessing Non-severe Elevation of Intracranial Pressure Using Optic Nerve Sheath Diameter and Transcranial Doppler Parameters.

Background/Aims: Non-invasive measurement of intracranial pressure (ICP) using ultrasound has garnered increasing attention. This study aimed to compare the reliability of ultrasonographic measurement of optic nerve sheath diameter (ONSD) and transcranial Doppler (TCD) in detecting potential ICP elevations.Methods: Patients who needed lumbar puncture (LP) in the Department of Neurology were recruited from December 2016 to July 2017. The ONSD and TCD measurements were completed before LP.Results: One hundred sixty-five participants (mean age, 41.96 ± 14.64 years; 80 men; 29 patients with elevated ICP) were included in this study. The mean ICP was 170 ± 52 mmH2O (range, 75–400 mmH2O). Univariate analyses revealed that ICP was non-significantly associated with TCD parameters and significantly associated with ONSD (r = 0.60, P < 0.001). The mean ONSD of the elevated ICP group was significantly higher than that of the normal ICP group (4.53 ± 0.40 mm vs. 3.97 ± 0.23 mm; P < 0.001). Multivariate linear regression determined that the difference between ICP and ONSD is significant.Conclusions: In the early stage of intracranial hypertension, ONSD is more reliable for evaluating ICP than TCD.

Ultrasonographic optic nerve sheath diameter correlation with ICP and accuracy as a tool for noninvasive surrogate ICP measurement in patients with decompressive craniotomy.

Increased intracranial pressure (ICP) results in enlarged optic nerve sheath diameter (ONSD). In this study the authors aimed to assess the association of ONSD and ICP in severe traumatic brain injury (TBI) after decompressive craniotomy (DC). ONSDs were measured by ocular ultrasonography in 40 healthy control adults. ICPs were monitored invasively with a microsensor at 6 hours and 24 hours after DC operation in 35 TBI patients. ONSDs were measured at the same time in these patients. Patients were assigned to 3 groups according to ICP levels, including normal (ICP ≤ 13 mm Hg), mildly elevated (ICP = 14-22 mm Hg), and severely elevated (ICP > 22 mm Hg) groups. ONSDs were compared between healthy control adults and TBI cases with DC. Then, the association of ONSD with ICP was analyzed using Pearson's correlation coefficient, linear regression analysis, and receiver operator characteristic curves. Seventy ICP measurements were obtained among 35 TBI patients after DC, including 25, 27, and 18 measurements in the normal, mildly elevated, and severely elevated ICP groups, respectively. Mean ONSDs were 4.09 ± 0.38 mm in the control group and 4.92 ± 0.37, 5.77 ± 0.41, and 6.52 ± 0.44 mm in the normal, mildly elevated, and severely elevated ICP groups, respectively (p < 0.001). A significant linear correlation was found between ONSD and ICP (r = 0.771, p < 0.0001). Enlarged ONSD was a robust predictor of elevated ICP. With an ONSD cutoff of 5.48 mm (ICP > 13 mm Hg), sensitivity and specificity were 91.1% and 88.0%, respectively; a cutoff of 5.83 mm (ICP > 22 mm Hg) yielded sensitivity and specificity of 94.4% and 81.0%, respectively. Ultrasonographic ONSD is strongly correlated with invasive ICP measurements and may serve as a sensitive and noninvasive method for detecting elevated ICP in TBI patients after DC.

Validation of Noninvasive Absolute Intracranial Pressure Measurements in Traumatic Brain Injury and Intracranial Hemorrhage.

Increased intracranial pressure (ICP) causes secondary damage in traumatic brain injury (TBI), and intracranial hemorrhage (ICH). Current methods of ICP monitoring require surgery and carry risks of complications. To validate a new instrument for noninvasive ICP measurement by comparing values obtained from noninvasive measurements to those from commercial implantable devices through this pilot study. The ophthalmic artery (OA) served as a natural ICP sensor. ICP measurements obtained using noninvasive, self-calibrating device utilizing Doppler ultrasound to evaluate OA flow were compared to standard implantable ICP measurement probes. A total of 78 simultaneous, paired, invasive, and noninvasive ICP measurements were obtained in 11 ICU patients over a 17-mo period with the diagnosis of TBI, SAH, or ICH. A total of 24 paired data points were initially excluded because of questions about data independence. Analysis of variance was performed first on the 54 remaining data points and then on the entire set of 78 data points. There was no difference between the 2 groups nor was there any correlation between type of sensor and the patient (F[10, 43] = 1.516, P = .167), or the accuracy and precision of noninvasive ICP measurements (F[1, 43] = 0.511, P = .479). Accuracy was [-1.130; 0.539] mm Hg (CL = 95%). Patient-specific calibration was not needed. Standard deviation (precision) was [1.632; 2.396] mm Hg (CL = 95%). No adverse events were encountered. This pilot study revealed no significant differences between invasive and noninvasive ICP measurements (P < .05), suggesting that noninvasive ICP measurements obtained by this method are comparable and reliable.

Numerical evaluation of systematic errors of a non-invasive intracranial pressure measurement

Intracranial pressure (ICP) monitoring procedure can be applied to aid in secondary brain damage prevention. A high invasiveness of commonly used ICP measuring methods poses a risk of complications, and therefore new non-invasive methods are currently being developed. A promising non-invasive ICP measurement method is based on the existence of pressure balance state, which is driven by the unique morphological property of ophthalmic artery (OA). The value of ICP can be obtained by evaluating blood flow or artery characteristics in different OA segments, intracranial OA segment (IOA) and extracranial OA segment (EOA). In order to increase measurement accuracy, the systematic errors must be evaluated, which requires an implementation of a numerical model encompassing various physical phenomena. In this paper, a developed numerical model is presented, which was used to solve a transient fluid–structure interaction (FSI) problem of the pulsatile blood flow in a straight, physically meaningful anisotropic, hyperelastic OA, with ICP and external pressure (Pe) loads. It was found that the systematic error based on mean cross-sectional area difference between IOA and EOA segments was {–1.48, –1.37, –1.17} mmHg with ICP = {10, 20, 30} mmHg, respectively. The systematic error based on mean blood flow velocity difference between IOA and EOA segments was {–1.84, –1.76, –1.625} mmHg with ICP = {10, 20, 30} mmHg, respectively. The presented numerical model examined the worst-case scenario in terms of boundary conditions, which were immovable, while lengths of OA segments were physiologically relevant statistical means; however, the obtained systematic errors still met the clinical standards of ANSI/AAMI, where it is stated that the error should not exceed the ± 2 mmHg in the range of 0–20 mmHg of ICP. Boundary conditions and compliance affects the systematic error in both ways (reduce or increase it); this may explain the low systematic errors obtained in experimental studies by other authors.

OP02-1 - A novel method for noninvasive intracranial pressure measurement via in-vitro model experiments

OP02-1 - A novel method for noninvasive intracranial pressure measurement via in-vitro model experiments

Study of Optic Nerve Sheath Diameter in Normal Nepalese Adults Using Ultrasound

Introduction: Though invasive intracranial devices are gold standard to calculate intracranial pressure (ICP); these are not without any complications. Non-invasive measurement of ICP by Ultrasonography could be a safe and portable technique.Objectives: The objective of the study was to measure and compare values of optic nerve sheath diameter of both eyes in healthy Nepalese adults.Methodology: A prospective cross-sectional study of healthy adult Nepalese volunteers was performed using a 7.5 MHz linear Ultrasound probe on the closed eyelids; optic nerve sheath diameter (ONSD) was measured 3 mm behind the globe in each eye.Results: Optic nerve sheath diameter (ONSD) of both eyes was measured in 100 healthy volunteers of age ranged from 15 to 75 years with a mean of 30.21 ± 14.05 years. There were 18 (18%) male and 82 (82%) female. ONSD for right eye ranged from 3.20 to 4.90 mm with mean of 4.10 ± 0.50 mm and left eye from 3.20 to 4.80 mm with mean of 4.22 ± 0.49 mm. P value for right and left eye ONSD (P = 0.06) and male and female (P = 0.12 and 0.85 for right and left ONSD respectively) were within normal limits. ONSD has no correlation with age (P = 0.27 and 0.27 for right and left ONSD respectively).Conclusion Mean of optic nerve sheath diameter (ONSD) is 4.10mm and 4.22 mm for right and left eye respectively. There is no statistical significant difference in mean of ONSD between right and left eye. BJHS 2018;3(1)5 : 357-360

Graphical and statistical analyses of the oculocardiac reflex during a non-invasive intracranial pressure measurement.

PurposeThis study aimed to examine the incidence of the oculocardiac reflex during a non-invasive intracranial pressure measurement when gradual external pressure was applied to the orbital tissues and eye.MethodsPatients (n = 101) and healthy volunteers (n = 56) aged 20–75 years who underwent a non-invasive intracranial pressure measurement were included in this retrospective oculocardiac reflex analysis. Prespecified thresholds greater than a 10% or 20% decrease in the heart rate from baseline were used to determine the incidence of the oculocardiac reflex.ResultsNone of the subjects had a greater than 20% decrease in heart rate from baseline. Four subjects had a greater than 10% decrease in heart rate from baseline, representing 0.9% of the total pressure steps. Three of these subjects were healthy volunteers, and one was a glaucoma patient.ConclusionThe incidence of the oculocardiac reflex during a non-invasive intracranial pressure measurement procedure was very low and not associated with any clinically relevant effects.

Reference intervals for the evoked tympanic membrane displacement measurement: a non-invasive measure of intracranial pressure**Portions of this work were presented in poster form at the 16th International Symposium on Intracranial Pressure and Neuromonitoring (Cambridge, Massachusetts, 29 June 2016).

Objective: Evoked tympanic membrane displacement (TMD) is a non-invasive technique for assessing intracranial pressure (ICP). The aim of this study was to define reference intervals (RIs) in the healthy population. Approach: Measurements were made in 154 healthy adults. Results were quantified by Vm, which is the most frequently described TMD measurement. Distributions were determined for sitting and supine posture. Differences between right and left ears were explored using a Wilcoxon signed-rank test. Postural changes were used to assess pressure transfer between the cerebral spinal fluid (CSF) and the perilymph. Main results: The range in which 95% of scores fall is −283 to 722 nl (M = 132 nl) left sitting, −232 to 623 nl (M = 97 nl) right sitting, −543 to 717 nl (M = 37 nl) left supine and −584 to 504 nl (M = −15 nl) right supine. No significant difference was seen between the left and right ears in the sitting position; a significant difference was seen in the supine position. A significant effect of posture was seen for both the left and right ears. Postural changes indicated pressure transfer between the CSF and perilymph more often in the right ear (75.3%) than the left (61.9%). Pressure transfer could not be assumed in either ear for 13.4% of participants. Significance: We present the largest dataset of evoked TMD in healthy individuals and the first set of RIs for Vm. A patient cohort with both invasive ICP and evoked TMD measurements is needed to validate the technique for clinical use.

Non-invasive Intracranial Pressure Assessment in Brain Injured Patients Using Ultrasound-Based Methods.

Non-invasive measurement of intracranial pressure (ICP) can be invaluable in the management of critically ill patients. Invasive measurement of ICP remains the "gold standard" and should be performed when clinical indications are met, but it is invasive and brings some risks. In this project, we aim to validate the non-invasive ICP (nICP) assessment models based on arterious and venous transcranial Doppler ultrasonography (TCD) and optic nerve sheath diameter (ONSD). We included brain injured patients requiring invasive ICP monitoring (intraparenchymal or intraventricular). We assessed the concordance between ICP measured non-invasively with arterious [flow velocity diastolic formula (ICPFVd) and pulsatility index (PI)], venous TCD (vPI) and ICP derived from ONSD (nICPONSD) compared to invasive ICP measurement. Linear regression showed a positive relationship between nICP and ICP for all the methods, except PIv. ICPONSD showed the strongest correlation with invasive ICP (r = 0.61) compared to the other methods (ICPFVd, r = 0.26, p value = 0.0015; PI, r = 0.19, p value = 0.02, vPI, r = 0.056, p value = 0.510). The ability to predict intracranial hypertension was highest for ICPONSD (AUC = 0.91; 95% CI, 0.85-0.97 at ICP > 20 mmHg), with a sensitivity and specificity of 85%, followed by ICPFVd (AUC = 0.67; 95% CI, 0.54-0.79). Our results demonstrate that among the non-invasive methods studied, ONSD showed the best accuracy in the detection of ICP.

Ultrasonographic optic nerve sheath diameter for predicting elevated intracranial pressure during laparoscopic surgery: a systematic review and meta-analysis.

Laparoscopic surgery involves the creation of a carbon dioxide (CO2) pneumoperitoneum to facilitate a clear surgical view, which may result in an elevated intracranial pressure (ICP). Depending on the surgical area, steep Trendelenburg positioning may be used as well, further increasing the ICP. The objective of this study was to assess the effects of laparoscopic surgery on changes in ICP assessed by ultrasonographic measurement of optic nerve sheath diameter (ONSD), which is a generally accepted simple, reliable, and non-invasive ICP measurement technique. A computerized literature search was performed in August 2016 to identity prospective studies that measured ONSD to assess ICP changes during laparoscopic surgery. The primary outcome was the change in ONSD during the early (0-30min) and late (30-120min) periods after initiating pneumoperitoneum, compared with baseline values measured after anesthesia induction. Mean differences (MDs) with 95% confidence intervals [CIs] were calculated. Nine observational studies and one randomized controlled trial, with a total of 460 subjects, were analyzed. Compared to the baseline value after anesthesia induction, significant increases in ONSD were observed in both the early period (MD 0.46, 95% CI 0.31-0.61, P<0.001, I 2=97.3%) and late period (MD 0.67, 95% CI 0.20-1.14, P=0.005, I 2=99.2%). Comparing the ONSD during the early and late periods revealed no significant differences over time. The current meta-analysis revealed that ICP elevation during laparoscopy could be anticipated through a significant increase in the ONSD in the early (0-30min) and late (30-120min) periods during CO2 pneumoperitoneum.

A fluid-structure interaction model of the internal carotid and ophthalmic arteries for the noninvasive intracranial pressure measurement method

Accurate and clinically safe measurements of intracranial pressure (ICP) are crucial for secondary brain damage prevention. There are two methods of ICP measurement: invasive and noninvasive. Invasive methods are clinically unsafe; therefore, safer noninvasive methods are being developed. One of the noninvasive ICP measurement methods implements the balance principle, which assumes that if the velocity of blood flow in both ophthalmic artery segments – the intracranial (IOA) and extracranial (EOA) – is equal, then the acting ICP on the IOA and the external pressure (Pe) on the EOA are also equal.To investigate the assumption of the balance principle, a generalized computational model incorporating a fluid-structure interaction (FSI) module was created and used to simulate noninvasive ICP measurement by accounting for the time-dependent behavior of the elastic internal carotid (ICA) and ophthalmic (OA) arteries and their interaction with pulsatile blood flow.It was found that the extra balance pressure term, which incorporates the hydrodynamic pressure drop between measurement points, must be added into the balance equation, and the corrections on a difference between the velocity of blood flow in the IOA and EOA must be made, due to a difference in the blood flow rate.

Location of the internal carotid artery and ophthalmic artery segments for non-invasive intracranial pressure measurement by multi-depth TCD

ABSTRACTThe aim of the present study was to locate the ophthalmic artery by using the edge of the internal carotid artery (ICA) as the reference depth to perform a reliable non-invasive intracranial pressure measurement via a multi-depth transcranial Doppler device and to then determine the positions and angles of an ultrasonic transducer (UT) on the closed eyelid in the case of located segments. High tension glaucoma (HTG) patients and healthy volunteers (HVs) undergoing non-invasive intracranial pressure measurement were selected for this prospective study. The depth of the edge of the ICA was identified, followed by a selection of the depths of the IOA and EOA segments. The positions and angles of the UT on the closed eyelid were measured. The mean depth of the identified ICA edge for HTG patients was 64.3 mm and was 63.0 mm for HVs (p = 0.21). The mean depth of the selected IOA segment for HTG patients was 59.2 mm and 59.3 mm for HVs (p = 0.91). The mean depth of the selected EOA segment for HTG patients was 48.5 mm and 49.8 mm for HVs (p = 0.14). The difference in the located depths of the segments between groups was not statistically significant. The results showed a significant difference in the measured UT angles in the case of the identified edge of the ICA and selected ophthalmic artery segments (p = 0.0002). We demonstrated that locating the IOA and EOA segments can be achieved using the edge of the ICA as a reference point.Abbreviations: OA: ophthalmic artery; IOA: intracranial segments of the ophthalmic artery; EOA: extracranial segments of the ophthalmic artery; ICA: internal carotid artery; UT: ultrasonic transducer; HTG: high tension glaucoma; SD: standard deviation; ICP: intracranial pressure; TCD: transcranial Doppler

Can intracranial pressure be measured non-invasively bedside using a two-depth Doppler-technique?

Measurement of intracranial pressure (ICP) is necessary in many neurological and neurosurgical diseases. To avoid lumbar puncture or intracranial ICP probes, non-invasive ICP techniques are becoming popular. A recently developed technology uses two-depth Doppler to compare arterial pulsations in the intra- and extra-cranial segments of the ophthalmic artery for non-invasive estimation of ICP. The aim of this study was to investigate how well non-invasively-measured ICP and invasively-measured cerebrospinal fluid (CSF) pressure correlate. We performed multiple measurements over a wide ICP span in eighteen elderly patients with communicating hydrocephalus. As a reference, an automatic CSF infusion apparatus was connected to the lumbar space. Ringer's solution was used to create elevation to pre-defined ICP levels. Bench tests of the infusion apparatus showed a random error (95% CI) of less than ±0.9mmHg and a systematic error of less than ±0.5mmHg. Reliable Doppler signals were obtained in 13 (72%) patients. An infusion test could not be performed in one patient. Thus, twelve patients and a total of 61 paired data points were studied. The correlation between invasive and non-invasive ICP measurements was good (R=0.74), and the 95% limits of agreements were -1.4±8.8mmHg. The within-patient correlation varied between 0.47 and 1.00. This non-invasive technique is promising, and these results encourage further development and evaluation before the method can be recommended for use in clinical practice.

Clinical review of non-invasive intracranial pressure measurement in medical cases

AbstractIntracranial pressure (ICP) measurement plays a vital role in decision making in neurological emergencies. Invasive methods of ICP monitoring have been the gold standard. Advent of various non-invasive techniques has widened the option of ICP measurement in medical cases as well. We illustrate two cases where optic nerve sheath measurements helped in managing raised ICP and time the need for surgical intervention and review the literature on non-invasive ICP measurement.

Clinical Validation of a Transcranial Doppler-Based Noninvasive Intracranial Pressure Meter: A Prospective Cross-Sectional Study

Noninvasive intracranial pressure (ICP) measurement would represent a major advance for patients with neurological problems. The Vittamed ICP meter is an ultrasound-based device reported to have high agreement with lumbar puncture cerebrospinal fluid (CSF) pressure measurement. However, previous studies included mostly patients with normal levels of ICP. The purpose of our study was to perform an independent clinical validation study of a transcranial Doppler-based noninvasive ICP meter in patients anticipated to have a wide range of ICP. In a prospective cross-sectional design, we simultaneously measured ICP with the Vittamed device and the invasive lumbar CSF pressure. The operator of each procedure was blinded to the result of the other method. Data were analyzed using Bland-Altman plots, Pearson correlation coefficients, and receiver operator characteristic curves. Twenty-four independent paired measurements of Vittamed and lumbar CSF pressure were obtained; with mean absolute difference between paired measures of 4.5 mmHg (standard deviation 3.1). The 95% limits of agreement were-10.5 to+11.0. The systematic bias (mean of paired differences) was negligible at 0.25 mmHg. The sensitivity, specificity, and area under the curve for ICP >20 mmHg were 0.73, 0.77, and 0.71, respectively. The Vittamed ICP meter had fair agreement with lumbar CSF pressure measurement. The wide limits of agreement would preclude using this version of the device as a stand-alone method for ICP determination, but may be useful if combined with other ICP screening methods. Ongoing improvements to the Vittamed hardware and software may lead to improvements in accuracy and clinical utility of this device.

Non-invasive assessment of intracranial pressure.

Monitoring of intracranial pressure (ICP) is invaluable in the management of neurosurgical and neurological critically ill patients. Invasive measurement of ventricular or parenchymal pressure is considered the gold standard for accurate measurement of ICP but is not always possible due to certain risks. Therefore, the availability of accurate methods to non-invasively estimate ICP has the potential to improve the management of these vulnerable patients. This review provides a comparative description of different methods for non-invasive ICP measurement. Current methods are based on changes associated with increased ICP, both morphological (assessed with magnetic resonance, computed tomography, ultrasound, and fundoscopy) and physiological (assessed with transcranial and ophthalmic Doppler, tympanometry, near-infrared spectroscopy, electroencephalography, visual-evoked potentials, and otoacoustic emissions assessment). At present, none of the non-invasive techniques alone seem suitable as a substitute for invasive monitoring. However, following the present analysis and considerations upon each technique, we propose a possible flowchart based on the combination of non-invasive techniques including those characterizing morphologic changes (e.g., repetitive US measurements of ONSD) and those characterizing physiological changes (e.g., continuous TCD). Such an integrated approach, which still needs to be validated in clinical practice, could aid in deciding whether to place an invasive monitor, or how to titrate therapy when invasive ICP measurement is contraindicated or unavailable.

Ultrasound assessment of optic nerve sheath diameter in healthy volunteers

BackgroundUltrasound assessment of optic nerve sheath diameter (ONSD) has been suggested as a non-invasive measure of intracranial pressure. Numerous small studies suggest its validity; however, discrepancy exists around normal values for ONSD. In this study we sought to define a normal value range for ONSD in a population of healthy adult volunteers. MethodsONSD was measured in healthy adult volunteers and a normal range was defined using descriptive statistics. A regression analysis was used to determine relationship between ONSD measurements and sex, age, height and weight. ResultsOne hundred twenty adults were recruited (age 18-65 [mean 29.3]) with 55 male and 65 female subjects. Mean ONSD was 3.68 mm (95% confidence interval [CI], 2.85-4.40). Upon regression analysis, mean ONSD did not vary with age, weight, or height but did vary with sex. Mean ONSD measurements for men were 3.78 mm (95% CI, 3.23-4.48) compared with 3.60 mm (95% CI, 2.83-4.11) for women. ConclusionThis study has defined the range of ONSD in a healthy cohort of volunteers. The lack of relationship to age, weight and height is similar to other studies but this is the first study to find a difference depending on sex suggesting the possible need for separate reference ranges for men and women.