Locally induced hypothermia for treatment of acute ischaemic stroke: a physical feasibility study

Abstract

During the treatment of stroke by local intra-arterial thrombolysis (LIT) it is frequently possible to pass the blood clot with a micro-catheter, allowing perfusion of brain tissue distally to the occlusion. This possibility allows for new early treatments of ischaemic brain tissue, even before the blood clot has been removed. One potential new approach to preserve brain tissue at risk may be locally induced endovascular hypothermia. Physical parameters such as the required micro-catheter input pressure, output velocity and flow rates, and a heat exchange model, applicable in the case of a micro-catheter placed within a guiding catheter, are presented. Also, a simple cerebral temperature model is derived that models the temperature response of the brain to the perfusion with coolant fluids. Based on this model, an expression has been derived for the time needed to reach a certain cerebral target temperature. Experimental in vitro measurements are presented that confirm the usability of standard commercially available micro-catheters to induce local hypothermia of the brain. If applied in vivo, the model predicts a local cooling rate of ischaemic brain tissue of 300 g of approximately 1°C in 1 min, which is up to a factor 30-times faster than the time-consuming systemic hypothermia via the skin. Systemic body temperature is only minimally affected by application of local hypothermia, thus avoiding many limitations and complications known in systemic hypothermia.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2a–c
Fig. 3a–c
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Walpoth B, Walpoth-Aslan B, Mattle H, Radanov B, Schroth G, Schaeffler L, Fisher A, Segesser L, Althaus U (1997) Outcome of survivors of accidental deep hypothermia and circulatory arrest treated with extracorporal blood warming. N Engl J Med 337:1500–1505

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Dietrich WD, Busto R, Halley M, Valdes I (1990) The importance of brain temperature in alterations of the blood–brain barrier following cerebral ischemia. J Neuropathol Exp Neurol 49:486–497

    CAS  PubMed  Google Scholar 

  3. 3.

    Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W (1998) Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 29:2461–2466

    CAS  PubMed  Google Scholar 

  4. 4.

    Maher J, Hachinski V (1993) Hypothermia as a potential treatment for cerebral ischemia. Cerebrovasc Brain Metab Rev 5:277–300

    CAS  PubMed  Google Scholar 

  5. 5.

    Ginsberg MD, Sternau LL, Globus YT, Dietrich WD, Busto R (1992) Therapeutic modulation of brain temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev 4:189–225

    CAS  PubMed  Google Scholar 

  6. 6.

    Krieger DW, DeGeorgia MA, Abou-Chebl A, Andrefsky JC, Sila CA, Katzan IL, Mayberg MR, Furlan AJ (2001) Cooling for acute ischemic brain damage (COOL AID): an open pilot study of induced hypothermia in acute ischemic stroke. Stroke 32:1847–1854

    CAS  PubMed  Google Scholar 

  7. 7.

    Gillooly JF, Brown JH, West GB, Savage VM, Charnov EL (2001) Effects of size and temperature on metabolic rate. Science 293:2248–2251

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Ganong WF (1995) Review of medical physiology, textbook. Prentice-Hall International, p 258

    Google Scholar 

  9. 9.

    Dixon SR, Whitbourn RJ, Dae MW, Grube E, Sherman W, Schaer GL, Jenkins JS, Baim DS, Gibbons RJ, Kuntz RE, Popma JJ, Nguyen TT, O’Neill WW (2002) Induction of mild hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol 40:1928–1934

    Article  PubMed  Google Scholar 

  10. 10.

    Hammer M, Krieger DW (2002) Acute ischemic stroke: is there a role for hypothermia? Cleve Clin J Med 69:770–785

    PubMed  Google Scholar 

  11. 11.

    Wang H, Olivero W, Lanzino G, Elkins W, Rose J, Honings D, Rodde M, Burnham J, Wang D (2004) Rapid and selective cerebral hypothermia achieved using a cooling helmet. J Neurosurg 100:272–277

    PubMed  Google Scholar 

  12. 12.

    Noguchi Y, Nishio S, Kawauchi M, Asari S, Ohmoto T (2002) A new method of inducing selective brain hypothermia with saline perfusion into subdural space: effects on transient cerebral ischemia in cats. Acta Med Okayama 56:279–286

    PubMed  Google Scholar 

  13. 13.

    Ding Y, Li J, Luan X, Lai Q, McAllister JP II, Phillis JW, Clark JC, Guthikonda M, Diaz FG. (2004) Local saline infusion into ischemic territory induces regional brain cooling and neuroprotection in rats with transient middle cerebral artery occlusion. Neurosurgery 54:956–964, discussion 964–965

    Article  PubMed  Google Scholar 

  14. 14.

    Furlan A, Higashida R, Wechsler L, Gent W, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark M, Silver F, Rivera F (1999) Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomised controlled trial. Prolyse in acute cerebral thromboembolism. JAMA 282:2003–2011

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Gönner F, Remonda L, Mattle H, Sturzenegger M, Ozdoba C, Lövblad KO, Baumgartner R, Bassetti C, Schroth G (1998) Local intra-arterial thrombolysis in acute ischemic stroke. Stroke 29:1894–1900

    PubMed  Google Scholar 

  16. 16.

    Arnold M, Schroth G, Nedeltchev K, Loher T, Remonda L, Stepper F, Sturzenegger M, Mattle HP (2002) Intra-arterial thrombolysis in 100 patients with acute stroke due to middle cerebral artery occlusion. Stroke 33:1828–1833

    Article  PubMed  Google Scholar 

  17. 17.

    Arnold M, Nedeltchev K, Schroth G, Baumgartner R, Remonda L, Loher T, Stepper F, Sturzenegger M, Schuknecht B, Mattle HP (2004) Clinical and radiological predictors of recanalisation and outcome of 40 patients with acute basilar artery occlusion treated with intra-arterial thrombolysis (editorial commentary p 811). J Neurol Neurosurg Psychiatry 75:857–862

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Schroth G, Berlis A, Mayer T, Remonda L, Brekenfeld C, Ozdoba C, Wiest R, Slotboom J (2003) Interventionelle Neuroradiologische Techniken zur frühen Behandlung des Schlaganfalles. Therapeutische Umschau 60:569–583

    CAS  PubMed  Google Scholar 

  19. 19.

    Benziger TH (1969) Heat regulation homeostasis of central temperature in man. Physiol Rev 49:671

    PubMed  Google Scholar 

  20. 20.

    Lienhard IV JH, Lienhard V JH (2003) A heat transfer textbook, 3rd edn. Phlogiston, Cambridge

    Google Scholar 

  21. 21.

    Watts DD, Trask A, Socken K, Perdue P, Dols S, Kaufmann C (1998) Hypothermia coagulopathy in trauma: effect of varying level of hypothermia on enzyme speed, platelet function and fibrinolytic activity. J Trauma 44:846–854

    CAS  PubMed  Google Scholar 

  22. 22.

    Patt A, McCroskey BL, Moore EE (1988) Hypothermia induced coagulopathies in trauma. Surg Clin North Am 68:775–785

    CAS  PubMed  Google Scholar 

  23. 23.

    Reuler JB (1978) Hypothermia: pathophysiology, clinical settings, and management. Ann Intern Med 89:519–527

    CAS  PubMed  Google Scholar 

  24. 24.

    Granberg PO (1991) Human physiology under cold exposure. Arctic Med Res 50:23–27

    PubMed  Google Scholar 

  25. 25.

    Clifton GL, Allen S, Barrodale P, Plenger P, Berry J, Koch S, Fletcher J, RL Hayes, Choi SC (1993) A phase II study of moderate hypothermia in severe brain injury. J Neurotrauma 10:263–271

    CAS  PubMed  Google Scholar 

  26. 26.

    Goldstein D, Frank SM (2001) The wisdom of the body revisited: the adrenomedullary response to mild core hypothermia in humans. Endocr Regul 35:3–7

    CAS  PubMed  Google Scholar 

  27. 27.

    Marion DW, Penrod LE, Kelsery SF, Obrist WD, Kochanek PM, Palmer AM, Wisniewski SR, DeKosky ST (1997) Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 336:540–546

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Gunel E, Caglayan F, Caglayan O, Dilsiz A, Duman S, Aktan M (1998) Treatment of intestinal reperfusion injuries using antioxidant agents. J Pediatr Surg 33:1536–1539

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Zausinger S, Westermaier T, Plesnila N, Steiger HJ, Schmid-Elsaesser R (2003) Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia. Stroke 34:1526–1532

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Hastie LE, Patton WF, Hechtman HB, Shepro D (1997) Filamin redistribution in an endothelial cell reoxygenation injury model. Free Radic Biol Med 22:955–966

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Guyton AC (1971) Basic human physiology: normal function and mechanisms of disease. Saunders

    Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to J. Slotboom.

Appendices

Appendix 1

Radiation

The body radiates electromagnetic waves. This radiated power by the human body, denoted by Pradiation, can be calculated by:

$$ P_{{\text{radiation}}} = \varepsilon \sigma S\left( {T_{{\text{body}}}^4 - T_{{\text{ambient}}}^4 } \right) $$
(5)

where ɛ is the emissivity of the human skin having a value of 0.97, σ is Boltzmann’s constant (5.67×10−8 W m−2 K−4), S is the surface of the human body (assumed to be roughly 2.0 m2 for an adult), Tbody is the skin temperature, and Tambient is the ambient temperature. For a skin temperature of 34.0°C and an ambient temperature of 23°C, Pradiation is 132.9 W.

Conduction

The heat transfer rate of the human body due to conduction can be calculated in the following way:

$$ P_{{\text{conduction}}} = \frac{{k_{{\text{air}}} S\left( {T_{{\text{body}}} - T_{{\text{ambient}}} } \right)}} {d} $$
(6)

in which kair=24×10−3 W m−1 K−1. The distance parameter d accounts for the distance from the skin surface where the air temperature drops from Tbody to Tambient. Assuming d=0.045 m and the same ambient and skin temperature as in the radiation example, Pconduction=11.7 W.

Convection

Convection involves the transport of energy by means of the motion of the heat transfer medium. In the case of the human body this is the surrounding air. The heat losses due to convection are more difficult to calculate. Convection can be approximated using (Eq. 6) by introducing an effective heated air layer deff. The stronger the air motion, the smaller the heated air layer, and the larger the energy loss due to convection. Under surgical conditions, this term is normally negligible.

Perspiration

As soon as the skin temperature reaches 37°C, the skin will begin to sweat. Perspiration will increase rapidly with increasing skin temperature. A healthy person has a perspiration volume rate \(\dot M\) of approximately 600 g/day, but the perspiration volume rate can be up to 1.5 l/h under extreme conditions [31]. The body is cooled by the vaporization of water. The vaporization heat Cvap of water at body temperature is 2.436×103 kJ kg−1. The perspiration heat transfer rate Pperspiration, expressed in watts, of a healthy person can thus be calculated as:

$$ P_{{\text{perspiration}}} = C_{{\text{vap}}} \dot M = 16.9\,{\text{W}} $$
(7)

If the skin temperature drops below 37°C, sweating will stop. A direct consequence of the physical facts presented above is that, under surgical conditions, the heat loss due to radiation alone (132.9 W) is larger than the basal metabolic rate (80–100 W), which means that the patients have to be warmed actively in order to prevent unwanted systemic hypothermia.

Appendix 2

Required micro-catheter input pressure

Since the inner radii of micro-catheters are very small, the input pressures needed to pump coolant fluid through them are very high. The relationship between the liquid volume per time unit ϕV (flow rate) that passes through a circular tube and the required pressure difference ΔP over the tube is given by the Poiseuille–Hagen formula:

$$ \phi _{\text{V}} = \Delta P\frac{{8\eta L}} {{\pi R^4 }} $$
(8)

in which η is the viscosity of the fluid transported through the micro-catheter, L is the length of the micro-catheter, and R is the inner radius of the micro-catheter.

Coolant fluid outflow velocity

The output speed, vout, with which the coolant leaves the micro-catheter, measured in metres per second, depends on the radius R of the micro-catheter as well as on the coolant flow rate ϕV and is given by:

$$ v_{{\text{out}}} = \frac{{\phi _{\text{V}} }} {{\pi R^2 }} $$
(9)

In order to prevent damage to the blood vessel wall distal to the occlusion site, the maximum outflow velocity should not exceed a certain maximum value. Realistic outflow velocity values for micro-catheters are in the order of 1–5 m s−1. The maximum tolerable outflow velocity will depend on the ratio between the micro-catheter’s inner radius and the arterial inner radius. The smaller this ratio, the higher the maximum tolerable micro-catheter output velocity, as the coolant fluid jet at the micro-catheter tip will be slowed down very rapidly by the eddies that are produced in the non-moving blood behind the occlusion. To the best of the authors’ knowledge, there exists no safety guideline for the maximum tolerable micro-catheter output velocity. When the technique is used clinically, before the therapeutic injection of cool saline solution is started, the position of the tip of the catheter relative to the vessel wall, as well as the size of each, has to be visualized by subtle contrast injection as shown in Figs. 2b and 3c.

Appendix 3

The bio-heat equation

For the time-dependent and spatially dependent temperature T in any point of living tissue to be calculated, the bio-heat equation needs to be solved and is given by:

$$ \rho _{{\text{IB}}} c_{{\text{IB}}} \frac{{\partial T}} {{\partial t}} = \nabla \left( {k_{{\text{IB}}} \nabla T} \right) - c_{{\text{Blood}}} W_{{\text{Blood}}} \left( {T - T_{{\text{Blood}}} } \right) + P $$
(10)

in which ρ IB is the density of the infarcted brain tissue (kg m−3), cIB the specific heat (J kg−1 K−1), kIB the thermal conductivity (W K−1 m−1), cBlood the specific heat (J kg−1 K−1) of blood, and WBlood the volumetric perfusion rate (kg m−3 s−1). The first term on the right-hand side accounts for thermal conductivity, the second term for heat exchange of the tissue with the arterial blood and P is the brain tissue’s metabolic heat production. Finding solutions to the partial differential equation is far from trivial. Here we present an approximate solution by making the following assumptions. Since the blood vessel is totally occluded the volumetric perfusion rate of the blood is zero. The ischaemic brain tissue that was perfused by the artery before it became occluded is assumed to have total mass MIB. This brain tissue is during hypothermia treatment solely artificially perfused by the micro-catheter having an output flow rate ϕmc,out (ml min−1). Since the tissue is in an ischaemic state we assume the metabolic rate P to be negligible. We also assume conductive heat transport to be negligible and further assume that the heat is uniformly in space transferred via the arterioles and capillaries. Under these assumptions, Eq. 10 can be written as

$$ M_{{\text{IB}}} c_{{\text{IB}}} \frac{{{\text{d}}T_{{\text{IB}}} }} {{{\text{d}}t}} = \phi _{{\text{mc,out}}} c\left( {T_{{\text{IB}}} - T_{{\text{Artery}}} } \right) $$
(11)

This equation can be rewritten as:

$$ \frac{{{\text{d}}T_{{\text{IB}}} }} {{{\text{d}}t}} = \frac{{\phi _{{\text{mc,out}}} }} {{M_{{\text{IB}}} }}\left( {T_{{\text{IB}}} - T_{{\text{mc,out}}} } \right) = \kappa \left( {T_{{\text{IB}}} - T_{{\text{mc,out}}} } \right) $$
(12)

with ccBlood. With TIB (0)=TIB, 0 and Tmc,out not time dependent, the following solution is found:

$$ T_{{\text{IB}}} (t) = T_{{\text{IB,}}0} + \left( {{\text{exp}}\,( - \kappa \,t) - 1} \right)\left( {T_{{\text{IB,}}0} - T_{{\text{mc,out}}} } \right) $$
(13)

Time to reach target hypothermia temperature

Of more practical use than Eq. 13 is an expression that relates to the time necessary to reach a specific hypothermia temperature Thypothermia, while given the mass of the tissue jeopardized by ischaemia, the coolant temperature, and the coolant flow rate. It can be proven that the time t needed to reach a target temperature of Thypothermia (with the additional condition that Tmc,out < Thypothermia < TIB) is given by:

$$ t\left( {T_{{\text{hypothermia}}} } \right) = - \frac{{M_{{\text{IB}}} }} {{\phi _{{\text{mc,out}}} }}\ln \left( {\frac{{T_{{\text{hypothermia}}} - T_{{\text{IB}}} (0)}} {{T_{{\text{IB}}} (0) - T_{{\text{mc,out}}} }} + 1} \right) $$
(14)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Slotboom, J., Kiefer, C., Brekenfeld, C. et al. Locally induced hypothermia for treatment of acute ischaemic stroke: a physical feasibility study. Neuroradiology 46, 923–934 (2004). https://doi.org/10.1007/s00234-004-1286-z

Download citation

Keywords

  • Hypothermia
  • Heat transfer
  • Brain
  • Stroke
  • Physical modelling
  • Local intra-arterial thrombolysis (LIT)