Non-invasive assessment of intracranial pressure - a plugin function of ICM+ system B. Schmidt, M. Czosnyka*, P. Smielewski*, R. Plontke, J. Schwarze, J. Klingelhöfer Dept. of Neurology, Medical Centre Chemnitz, Germany * Ac. Neurosurgical Unit, Addenbrooke’s Hospital, Cambridge, UK

Non-invasive ICP assessment procedure - for scientific use only -  The procedure calculates Intracranial Pressure from Arterial Blood Pressure and Transcranial Doppler Blood Flow Velocitiy of Middle Cerebral Artery  Patented: by Patent Nr. DE 196 00 983  Distributed by the authors as a Plugin of ICM+ Monitoring Software / University Cambridge, UK - for scientific use only -

The list of functions in ICM+ can be extended by plugins The list of functions in ICM+ can be extended by plugins. One such plugin already available for ICM+ enables non-invasive calculation of ICP from TCD FV and ABP signals in real time. ICP Non-invasive ICP ICP Non-invasive ICP

How to insert nICP plugin into ICM+:. - The non-invasive ICP plugin is a DLL file, developed in a C++ Borland environment. - Copy the plugin into the ICM+ plugin folder, e.g. pathname is "C:\Documents and Settings\All Users\Documents\ICM+\Plugins\" - Now start ICM+. The plugin should be shown in the registration dialogue under "3rd Party Plugins”. You send us the registration data of your ICM+ license, which contains name, company and ICM+ install code. The data should be exactly the same as it is in the ICM+ registration form. - Using this data we calculate your registration key for the nICP plugin and send it back to you by email. - You enter the registration key of this plugin in the ICM+ dialogue. This activates the nICP plugin, unlimited in time.   DE 19600983

Basic principle of the procedure Calculate the signal of intracranial pressure (ICP) from signals of arterial blood pressure (ABP) and blood flow velocity (FV) of the middle cerebral artery (MCA)

Non-invasive ICP assessment – basic method TCD-characteristics { tcdj } j = 0, ..., m FV ABP weight function ABP ® ICP { wi } i = 0, ..., n nICP (non-invasive ICP) FV : blood flow velocity in middle cerebral artery ABP: arterial blood pressure ICP: intracranial pressure TCD: transkranial Doppler ultrasound weight function = impulse response: signal transformation, time domain equivalent of transfer function

S Generation of the nICP Procedure FV ABP ICP w  A * tcd + B Signal data of reference patients FV ABP ICP ICPj = ABPj-k * wk k=0 S n TCD characteristics tcd = (tcd0, tcd1, ..., tcdm) weight function ABP ® ICP w = (w0, w1, ..., wn) Multiple Regression analyses w  A * tcd + B A (n+1) x (m+1) Matrix B n+1-dim. Vektor (A,B) : nICP Matrix, (n+1) x (m+2) Dim

non-invasive ICP assessment – basic method weight function ABP ® FV { tj } j = 0, ..., 12 FV ABP { wi } = A * ( {tj}x , PI, dFV, . . . ) + B weight function ABP ® ICP { wi } i = 0, ..., n nICP Matrix A, Vector B generated by multiple regression analyses of reference data TCD-characteristics ® weight function ABP ® ICP PI: Pulsatility index dFV: diastolic FV

Results 1 - non-invasive ICP assessment on average of  315 patient-day recordings: mean DICP = 5.2 ± 3.7 mm Hg 95% CI = 12.4 mm Hg median DICP = 4.2 mm Hg  137 patient recordings: mean DICP = 5.0 ± 3.3 mm Hg 95% CI = 10.8 mm Hg DICP = mean abs (ICP-nICP)

Bland-Altman Plot of nICP - ICP comparison -30 -25 -20 -15 -10 -5 5 10 15 20 25 30 40 50 95% CI Bland-Altman Plot of nICP - ICP comparison on average of Daily Recordings: N = 315 nICP-ICP [mm Hg] (nICP+ICP)/2 [mm Hg] -20 -15 -10 -5 5 10 15 20 25 30 40 Bland-Altman Plot of nICP - ICP comparison on average of Patient Recordings: N = 137 nICP-ICP [mm Hg] 95% CI (nICP+ICP)/2 [mm Hg]

nICP - ICP comparison in recordings nICP - ICP comparison in patients 40 ICP [mm Hg] y = 0,863x + 1 35 30 25 20 15 10 5 5 10 15 20 25 30 35 40 45 nICP - ICP comparison in patients 40 ICP [mm Hg] 35 30 25 20 15 10 5 5 10 15 20 25 30 35 40 nICP [mm Hg]

Results 3 - non-invasive ICP assessment nICP assessment replicates ICP trends in recordings with high ICP dynamic:  95th perc ICP > 5th perc ICP + 10 mm Hg , 33 recordings, mean nICP - ICP correlation R = 0.53 ± 0.47  90th perc ICP > 10th perc ICP + 9 mm Hg , 27 recordings, mean nICP - ICP correlation R = 0.57 ± 0.46

Example 1 033040AL.1L5

Example 2 038080JM.0L5

Example 2 038080JM.0L5

Example 4 053022AW.0L5

Conclusions  in the clinically relevant range of ICP the nICP assessment showed a reasonable accuracy  nICP assessment replicates ICP changes and trends  nICP plugin of ICM+ may be used for clinical studies * in patients without implanted ICP probes * Pfister D, Schmidt B, Smielewski P, Siegemund M, Strebel SP, Rüegg S, Marsch SCU, Pargger H, Steiner LA. Intracranial Pressure in Patients with Sepsis. Acta Neurochir Suppl. 102:71-75, 2008 Schmidt B, Weinhold M, Czosnyka M, May SA, Steinmeier R, Klingelhöfer J. Accuracy of non-invasive ICP assessment can be increased by an initial individual calibration. Acta Neurochir Suppl. 102: 49-52, 2008 Schmidt B, Klingelhöfer J, Perkes I, Czosnyka M. Cerebral Autoregulatory Response Depends on the Direction of Change in Perfusion Pressure. J Neurotrauma. 26:1-6, 2009 Reinhard M, Neunhoeffer F, Gerds TA, Niesen WD, Buttler KJ, Timmer J, Schmidt B, Czosnyka M, Weiller C, Hetzel A (2010). Secondary decline of cerebral autoregulation is associated with worse outcome after intracerebral hemorrhage. Intensive Care Med 36(2):264-71, 2010 Oeinck M, Neunhoeffer F, Buttler K-J, Meckel S, Schmidt B, Czosnyka M, Weiller C and Reinhard M. Dynamic Cerebral Autoregulation in Acute Intracerebral Hemorrhage. Stroke. published online August 13, 2013;  

Pfister D, Schmidt B, Smielewski P, Siegemund M, Strebel SP, Rüegg S, Marsch SCU, Pargger H, Steiner LA (2008). Intracranial Pressure in Patients with Sepsis. Acta Neurochir Suppl. 102:71-75 Schmidt B, Weinhold M, Czosnyka M, May SA, Steinmeier R, Klingelhöfer J (2008). Accuracy of non-invasive ICP assessment can be increased by an initial individual calibration. Acta Neurochir Suppl. 102: 49-52 Schmidt B, Klingelhöfer J, Perkes I, Czosnyka M (2009). Cerebral Autoregulatory Response Depends on the Direction of Change in Perfusion Pressure. J Neurotrauma. 26:1-6 Reinhard M, Neunhoeffer F, Gerds TA, Niesen WD, Buttler KJ, Timmer J, Schmidt B, Czosnyka M, Weiller C, Hetzel A (2010). Secondary decline of cerebral autoregulation is associated with worse outcome after intracerebral hemorrhage. Intensive Care Med 36(2):264-71 Maximilian Oeinck, Florian Neunhoeffer, Klaus-Juergen Buttler, Stephan Meckel, Bernhard Schmidt, Marek Czosnyka, Cornelius Weiller and Matthias Reinhard. Dynamic Cerebral Autoregulation in Acute Intracerebral Hemorrhage. Stroke. published online August 13, 2013;  

S Flow diagram of the nICP procedure FV ABP nICP w  A * tcd + B Signal data of current patient FV ABP nICP every 10 Seconds ICPj = ABPj-k * wk k=0 S n weight function ABP ® ICP w = (w0, w1, ..., wn) TCD characteristics tcd = (tcd0, tcd1, ..., tcdm) w  A * tcd + B A (n+1) x (m+1) Matrix B n+1-dim. Vektor (A,B) : nICP Matrix, (n+1) x (m+2) Dim