WO2017055450A1

WO2017055450A1 - Intracranial pressure adjustment infusion system and method

Info

Publication number: WO2017055450A1
Application number: PCT/EP2016/073256
Authority: WO
Inventors: Matthias Roth; Thomas REICHTHALHAMMER
Original assignee: SEIRATHERM GmbH
Priority date: 2015-09-30
Filing date: 2016-09-29
Publication date: 2017-04-06

Abstract

An adjustment device for controlling infusion fluid, in particular for temperature regulation therapy such as hypothermia treatment is adapted for intracranial hypertension (ICH) control. The device comprises a control unit configured to receive input signals indicating intracranial pressure (ICP) and to provide output signals indicating one or more recommendations for therapy based on said received input signals.

Description

Intracranial Pressure Adjustment Infusion System and Method

Field The invention is generally directed to devices and methods for controlling infusion fluid, in particular for temperature regulation therapy such as hypothermia treatment. The invention also concerns a hypothermia device, system or method that is adapted for intracranial hypertension (ICH) control.

Background

Intracranial pressure (ICP) is the pressure inside the skull and thus in the brain tissue and cerebrospinal fluid (CSF). ICP is measured in millimeters of mercury (mmHg) and, at rest, is normally 7-15 mmHg for a supine adult. The body has various mechanisms by which it keeps the ICP stable, with CSF pressures varying by about 1 mmHg in normal adults through shifts in production and absorption of CSF. Changes in ICP are attributed to volume changes in one or more of the constituents contained in the cranium.

Increased intracranial pressure (ICP) is one of the major causes of secondary brain ischemia that accompanies a variety of pathological conditions, most notably, traumatic brain injury (TBI), stroke, and intracranial hemorrhages. Increased intracranial pressure can cause such complications as (vision impairment and intracranial pressure (VHP), death, permanent neurological problems, reversible neurological problems, seizures, stroke. Cerebral edema and elevated intracranial pressure (ICP) are cardinal manifestations of severe brain injury in cases of traumatic brain injury (TBI), stroke (ischemic and hemorrhagic), aneurysmal subarachnoid hemorrhage, infection, and neoplasms. An elevated ICP may result in life-threatening compromised cerebral circulation and brainstem compression, and is the most common cause of death in patients with severe TBI.

A condition in which the body's core temperature drops below that required for normal metabolism and body functions is usually called hypothermia. This is generally considered to be less than about 35.0°C (about 95.0°F). Characteristic symptoms depend on the temperature. Targeted temperature management (TTM), previously known as therapeutic hypothermia or protective hypothermia is an active treatment that tries to achieve and maintain a specific body temperature in a person for a specific duration of time in an effort to improve health outcomes. This is done in an attempt to reduce the risk of tissue injury from lack of blood flow. Periods of poor blood flow may be due to cardiac arrest, or the blockage of an artery by a clot such as that may occur during stroke. Targeted temperature management improves survival and brain function following resuscitation from cardiac arrest. Evidence supports its use following certain types of cardiac arrest in which an individual does not regain consciousness. Targeted temperature management can advantageously prevent brain injury by several methods including decreasing the brain's oxygen demand, reducing the proportion of neurotransmitters like glutamate, as well as reducing free radicals that might damage the brain. In particular, therapeutic hypothermia can be an effective therapy for posttraumatic intracranial hypertension with an acceptable side-effect profile. The lowering of body temperature may be accomplished by many means including the use of cooling blankets, cooling helmets, cooling catheters, ice packs and ice water lavage. Medical events that targeted temperature management may effectively treat fall into five primary categories: neonatal encephalopathy, cardiac arrest, ischemic stroke, traumatic brain or spinal cord injury without fever, and neurogenic fever following brain trauma.

Applicants' prior application WO2012143479, incorporated herein, provides a useful general description of an apparatus for temperature therapy. Document US7896834 B2 discloses a pump system selectably controlling the temperature, flow rate, flow volume, and flow pressure of a fluid being infused into a patient's body. The apparatus comp ses means for delivering a predetermined volume or halting device operation when an excessive volume has been infused.

Document US8672884 B2 discloses methods for introducing fluids into a body cavity for hypothermic treatment. In one embodiment of the invention, at least one of the rate or volume of infusate is configured to increase a mean patient blood pressure. In another embodiment, the infusion parameter is at least one of a flow rate, a pressure, a total infused volume, an inflow duty cycle or a hypothermic solution temperature.

European Patent Application No. 2008849920 concerns a system and method that employ a monitoring device to monitor at least one patient physiological response to a change in temperature of the patient, e.g. pursuant to induced hypothermia therapy, wherein a monitoring signal is provided by the monitoring device. In turn, an output, e.g. a visual and/or auditory output, may be provided to a user indicative of at least one measure of a patient's response to the change in temperature.

The problem underlying the present invention is to provide an improved device and methods for controlling infusion fluid. The problem is solved by the subject matter of the present invention exemplified by the description and the claims.

Further features and advantages of the present disclosure will become apparent from the following detailed description.

Summary of the Invention

Intracranial hypertension is a common neurological complication in critically ill patients; it is the common pathway in the presentation of many neurologic and non-neurologic disorders. In the average adult, the skull encloses a total volume of 1450 ml_: 1300 ml_ of brain, 65 ml_ of CSF, and 1 10 mL of blood. ICH is generally defined as sustained intracranial pressures (ICPs) above 20-25 mm Hg. The normal range for ICP varies with age. Values for pediat c subjects are not as well established. Normal values are less than 10 to 15 mm Hg for adults and older children, 3 to 7 mm Hg for young children, and 1 .5 to 6 mm Hg for term infants. ICP values greater than 20 to 25 mm Hg require treatment in most circumstances. Sustained ICP values of greater than 40 mm Hg indicate severe, life-threatening intracranial hypertension.

The Monroe-Kellie hypothesis states the sum of the intracranial volumes of blood, brain, cerebrospinal fluid (CSF), and other components is constant, and that an increase in any one of these must be offset by an equal decrease in another, or else pressure increases. An increase in pressure caused by an expanding intracranial volume is distributed evenly throughout the intracranial cavity.

Cerebral perfusion pressure (CPP) depends on mean systemic arterial pressure (MAP) and ICP by the following relationship:

CPP = MAP - ICP

Cerebral perfusion pressure, or CPP, is the net pressure gradient causing cerebral blood flow to the brain (brain perfusion). It must be maintained within narrow limits because too little pressure could cause brain tissue to become ischemic (having inadequate blood flow), and too much could raise intracranial pressure (ICP). The mean arterial pressure (MAP) is a term used in medicine to describe an average blood pressure in an individual. It is defined as the average arterial pressure during a single cardiac cycle. MAP is considered to be the perfusion pressure seen by the organs in the body. MAP that is greater than 60 mmHg is enough to sustain the organs of the average person. Under normal circumstances, average cerebral blood flow (e.g. the average recorded over 5 minutes or over hours) is relatively constant due to protective autoregulation. MAP is normally between 65 and 1 10 mmHg. If the MAP falls below this number for an appreciable time, vital organs will not get enough Oxygen perfusion, and will become hypoxic, a condition called ischemia. Various methods for TTM exist, e.g. surface techniques, intravascular heat exchange catheters etc. In case TTM is being done with tempered fluids, e.g. cold saline in order to achieve a hypothermia temperature level, a deep level of hypothermia could require substantial amounts of fluid. The fluid consumption is highly patient specific, as well as the individual effect on ICP adjustment. However, the general physiological assumption according to the Monroe- Kellie hypothesis would be that an excess of fluid could lead to a MAP increase and in case of insufficient auto-regulation to an ICP increase.

Thus, there is a need to monitor and control the level of ICP during targeted temperature management. The present invention provides an improved device for controlling and managing administration of infusion fluids which are to be infused to a patient, especially a patient suffering from elevated ICP, while taking into account that infusion of fluids may lead to increased ICP. The device advantageously incorporates a control unit which allows a feedback-controlled delivery of infusion fluids.

The device of the invention is adapted to receive inputs of signals that indicate the level of intracranial pressure and optionally blood pressure of the patient. The input signals may be provided by a user, from an external computer system, or internally from a component of the device.

The invention provides a device for controlling and managing administration of infusion fluid for temperature regulation therapy, comprising at least one flow control unit for regulating volume, flow rate and/or temperature of infusion fluid, and at least one control unit for receiving input signals and providing output signals, wherein the control unit is configured to receive input signals indicating the intracranial pressure and optionally blood pressure of the patient and to provide output signals indicating one or more recommendation for therapy based on said received input signals.

The device according to the present invention comp ses a control unit configured to receive input signals and to provide output signals. The control unit generally comp ses a processor and a memory, for receiving and storing signal data, and for storing and executing programs for processing the received signals and controlling the flow control unit, and providing any suitable output signals and/or information as may be desired to implement. The control unit provides output signals that indicate at least recommendations for the therapy. Based on the input information received, the device provides recommendations to a user that include information as to which action can be taken in response to the ICP level that is received. Temperature regulation therapy can be applied to patients with intracranial hypertension. The term "temperature regulation therapy" in the present application refers to a process of controlling a patient's body temperature below the normal body temperature. This can be achieved by using invasive temperature management treatments which, among others, include the infusion of cold intravenous fluids (also referred to herein as infusion fluids). The infusion fluid can be any known fluids such as blood/blood derivates, pharmacological fluids, nutritional fluids, and fluid infusion systems and/or an infusion system for infusing, e.g., saline or other balanced fluids like Ringer's solution. Also the kind, shape, material and volume can vary. An infusion fluid can be any fluid administered intravenously to a patient, such as saline solution or other type of conventional IV solution or any solution such as a blood solution, dissolved drug or the like, administered to a patient via intravenous infusion. For instance, the infusion fluid could be blood, particularly extra corporal fluids like blood, dialysis liquids or substitute liquids, more preferably an infusion liquid such as electrolyte solutions such as NaCI, Ringer solutions, or Jonosteril^®. According to the present invention, the infusion of a fluid may be used for controlling the body temperature.

The device according to the present invention comprises a flow control unit. A flow control unit in general refers to a device or arrangement that enables the device to actively maintain a certain flow rate, i.e. a pumping mechanism, which allows controlled, variable flow rate of the infusion fluid. The pumping mechanism can comprise a pump of any kind available in the market, such as a peristaltic pump, piston pumps etc. The pump can be adapted to deliver the infusion fluid continuously and/or intermittently and/or sequentially, the latter preferably on the basis of pulses and intermediate pauses with volumes during the pulses of between 1 ml to 50ml. A flow control unit may for example regulate the volume and/or temperature of infusion fluid. The control unit may be configured to receive input signals indicating the level of intracranial pressure. ICP can be measured with invasive or noninvasive methods. Invasive methods normally require an insertion of an ICP sensor into the brain ventricle or parenchymal tissue. The intraventricular catheter is the most accurate monitoring method. To insert an intraventricular catheter, a hole is drilled through the skull and the catheter can be inserted through the brain into the lateral ventricle, an area of the brain that contains liquid (cerebrospinal fluid or CSF) which protects the brain and spinal cord. The intracranial pressure (ICP) can be measured at the same time as monitoring by draining fluid out through the catheter. The catheter may be hard to get into place when the intracranial pressure is high. Another method involves the use of subdural screw, where the hollow screw that is inserted through a hole drilled in the skull. It is placed through the membrane that protects the brain and spinal cord (dura mater). This allows the sensor to record from inside the subdural space. Another invasive method involves inserting an epidural sensor between the skull and dural tissue. The epidural sensor is placed through a hole drilled in the skull. This procedure is less invasive than other methods. It is preferred that lidocaine or another local anesthetic is injected at the site where the cut will be made.

ICP can also be measured non-invasively. Several methods for noninvasive measuring of elevated ICP have been proposed: radiologic methods including computed tomography and magnetic resonance imaging, transcranial Doppler, electroencephalography power spectrum analysis, and the audiological and ophthalmological techniques. For example, one may use the ICP monitoring system manufactured by Codman & Shurtell, Inc., that uses a transducer to sense ICP in an intraparenchymal sensing mode, a pressure transducer-tipped catheter to sense ICP in an intravent cular sensing mode, an ICP sensor system using an external ICP sensor, and any other suitable ICP sensor. ICP can also be measured by minimally-invasive probes (NeMo Probe) manufactured by NeMo Devices AG, Switzerland.

Methods of measuring ICP are known to the person skilled in the art and are for example described in Raboel et al., Intracranial Pressure Monitoring: Invasive versus Non-Invasive Methods - A Review. Critical Care Research and Practice and U.S: 20150018697. The control unit may be configured to receive input signals indicating the level of blood pressure or mean systemic arterial pressure (MAP). An input signal provides the level of blood pressure, the control unit may calculate the MAP based on said level.

In one preferred embodiment, the control unit is configured to receive input signals from at least one external computer system. This is particularly useful when used in hospitals using electronic patient journal systems that store and make available patient data such as biosignals (blood pressure, pulse, level of shivering, hemoglobin values, etc.), data from analyzed patient samples, and data concerning administered therapy, including but not limited to medicaments and fluids that have been or are being administered. It will be appreciated that the control unit is, in some embodiments, able to receive directly input from such at least one external computer system, with a suitable program interface to query the external system for the desired data. In other embodiments, the control unit prompts a user to feed the unit with desired data from such external computer system, manually, or by entering data files in suitable format.

The control unit may additionally be configured to receive input data indicating the core body temperature and/or the desired therapeutic body temperature of the patient. In contrast to core body temperature, which generally refers to the temperature of the internal environment of the body, including organs such as the heart and liver, body surface temperature generally refers to the temperature of the skin at various body parts, including limbs, hands, feet or extremities.

In addition, a control unit according to the present invention may be configured to provide output signals, also termed herein as compensation signals, which provide one or more suggestions or recommendations intended for decreasing intracranial pressure when it is over a predetermined limit or maintaining intracranial pressure within an acceptable limit. This can be achieved by increasing or maintaining the cooling effect of the infusion fluid.

In one embodiment, the control unit is configured to provide a signal to the flow control unit to increase flow rate of the infusion fluid. This may take place when the ICP is over a predetermined limit. For example, the control unit can be configured to provide a signal to the flow control unit to increase flow rate of the infusion fluid, especially when the ICP is over a limit. The limit may be 15 mm Hg, 16 mm Hg, 17 mm Hg, 18 mm Hg, 19 mm Hg, 20 mm Hg, 21 mm Hg, 22 mm Hg, 23 mm Hg, 24 mm Hg, 25 mm Hg, 26 mm Hg, 27 mm Hg, 28 mm Hg, 29 mm Hg, or 30 mm Hg. Preferably, the limit is between 15-25 mm Hg, such as 20-25 mm Hg. Typically, normal adult ICP is defined as 5 to 15 mm Hg. ICP values of 20 to 30 mm Hg represent mild intracranial hypertension and should be monitored. However, the limit is generally dependent on the condition of the patient. For example, when a temporal mass lesion is present, herniation can occur with ICP values less than 20 mm Hg.

In another embodiment, the control unit can be configured to provide a signal to the flow control unit to decrease the temperature of the infusion fluid. In general, the control unit is preferably configured to receive input data indicating temperature of infusion fluid being administered and/or connected to the device. The cooled infusion fluid may be delivered between -1 to 14°C, such as -1 °C, 0°C, 1 °C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 1 1 °C, 12°C, 13°C, or 14°C. Infusion fluid is preferably delivered with a minimum temperature of 3.5°C, preferably 3.6°C, more preferably 3.7°C, more preferably 3.8°C, more preferably 3.9°C and most preferably 4°C and/or cooled infusion fluid is provided at a maximum temperature of 6°C, preferably 5.5°C, more preferably 5.0°C, more preferably 4.5°C, more preferably 4.25°C and most preferably 4.0°C. The temperature of the infusion fluid can be decreased by 0.1 °C, 0.2°C, 0.3°C, 0.4°C, 0.5°C, 0.6 °C, 0.7°C, 0.8°C, 0.9°C, 1 .0°C, 1 .1 °C, 1 .2°C, 1 .3 °C, 1.4°C, 1.5°C, 1.6°C, 1 .7°C, 1 .8°C, 1 .9°C, 2.0°C or more. The control unit may provide an output signal to the flow control unit to maintain the flow rate, while decreasing the temperature of the infusion fluid. The control unit may provide an output signal to the flow control unit to increase the flow rate, while maintaining the temperature of the infusion fluid. In another alternative embodiment, the control unit may provide an output signal to the flow control unit to increase the flow rate and/or decrease the temperature of the infusion fluid.

Osmolarity is the term defining concentration of combined solutes in water, as amount of solute per L. In bodily fluids this is similarto osmolality which is the amount of solute per kg of solution. Water crosses cell membranes freely from areas of low solute concentration to areas of high solute concentration. Thus, osmolality tends to equalize across different body fluid compartments, resulting primarily from movement of water, not solutes. Solutes such as urea that freely diffuse across cell membranes have little or no effect on water shifts (little or no osmotic activity), whereas solutes that are restricted primarily to one fluid compartment, such as Na and K, have the greatest osmotic activity. Tonicity, or effective osmolality, reflects osmotic activity and determines the force drawing water across fluid compartments defined as the osmotic force. Hyperosmolar therapy is used to reduce elevated ICP. The osmotic agents create an osmotic gradient across an intact blood-brain barrier and thus draw water from the cerebral interstitium into the vascular space.

Conventional invasive temperature management treatments often require constant personnel involvement and attention to perform successfully, it would be preferred that no constant personnel involvement is needed. To achieve this, the control unit can be configured to provide a signal to the flow control unit to automatically increase the osmolarity of the infusion fluid.

In some embodiments, the control unit may be configured to receive input signals from at least one sensor that determines concentration of at least one electrolyte and provides a signal indicating said concentration. Such sensor can be arranged to determine the concentration of an electrolyte in an infusion fluid connected to the device, such as by arranging a special sampling duct delivering a quantity of fluid to the sensor, which can be, but is not limited to, at least one ion specific electrode, such as a sodium selective electrode, potassium selective electrode or chloride selective electrode. The sampling duct can be arranged in parallel with a delivery duct, such that fluid entering the sampling duct is consumed and discarded, or in-line with the delivery duct, analyzing the fluid before it is delivered. Care must be taken to ensure that fluid administered to the patient remains sterile. The control unit may recommend, as IV fluid, a fluid comprising higher concentration of electrolytes. The control unit, for example, can be configured to receive input signals from at least one sensor that determines concentration of at least one electrolyte and provides a signal indicating said concentration. Although in another embodiment, the control unit can be configured to provide output signals indicating one or more recommendations for therapy, wherein the recommendation comprises an instruction to administer hyperosmolar infusion fluid. This can be done by increasing the osmolarity of the infusion fluid. Hypertonic saline is mostly preferred as such hyperosmolar infusion fluid. Hypertonic saline appears to be safe, and elevations of serum sodium with the use of hypertonic saline have not been associated with significant neurologic, cardiac, or renal injury. Va ous saline concentrations, from 3 to 23.4%, can be used. Such concentration causes intravascular expansion by osmotically drawing free waterfrom the tissues into the plasma, thus resulting in a decrease in blood viscosity and improved cerebral perfusion. If cerebral autoregulation is intact, these hemodynamic changes result in vasoconstriction and a decrease in CBV and ICP.

Hypertonic saline, given in concentrations for example ranging from 3% to 23.4%, creates an osmotic force to draw water from the interstitial space of the brain parenchyma into the intravascular compartment in the presence of an intact blood-brain barrier, reducing intracranial volume and ICP.

Some common infusion fluids and its osmolarity are defined below in a non-limiting list.

Table 1

There are slight variations for the exact composition for some of the above mentioned solutions (such as Ringer's solution, Ringer's lactate solution, etc.) as supplied by different manufacturers, thus such terms should not be equated with one precise formulation. It would be within scope for a skilled person in the art to determine the osmolarity and which hyperosmolar infusion fluid can be infused.

The device and method of the present invention is able to monitor the patient's intracranial pressure (ICP) at a level appropriate for the patient's medical condition and send output signals indicating one or more recommendations for therapy based on the level of intracranial pressure. In one embodiment, the recommendation provided by the control unit comprises an instruction to administer ICP-reducing medication. As used herein, the term ICP-reducing medication is intended to mean any biologically active agent or drug or combination of agents or drugs that is administered to a patient for the purpose of reducing ICP. Any ICP-reducing agents can be used, such as agents commonly used in hyperosmolar therapy (such as mannitol, Tris buffer) or sedative agents.

Mannitol has rheologic and osmotic effects. Immediately after infusion of mannitol, there is an expansion of plasma volume and a reduction in hematocrit and in blood viscosity, which may increase CBF and on balance increase oxygen delivery to the brain. In patients with intact pressure autoregulation, infusion of mannitol induces cerebral vasoconstriction, which maintains CBF constant, and the decrease in ICP is large. In patients with absent pressure autoregulation, infusion of mannitol increases cerebral blood flow (CBF), and the decrease in ICP is less pronounced. Mannitol also may improve microcirculatory rheology and has free radical scavenging effects. The osmotic effect of mannitol increases serum tonicity, which draws edema fluid from cerebral parenchyma. This process takes 15 to 30 minutes until gradients are established. Serum osmola ty of 300 to 320 mOsm is preferred to avoid side effects of therapy, such as hypovolemia, hyperosmolarity, and renal failure.

Tris buffer corrects intracellular acidosis and increases the buffering capacity of CSF. For example, 50 ml TRIS 36.34% i.v. bolus can be infused in patients with elevated ICP. Intravenous bolus administration of mannitol lowers the ICP in 1 to 5 minutes with a peak effect at 20 to 60 minutes. The effect of mannitol on ICP lasts 1 .5 to 6 hours, depending on the clinical condition. Mannitol may be given as a bolus of 0.25 g/kg to 1 g/kg body weight. When urgent reduction of ICP is needed, an initial dose of 1 g/kg body weight should be given. Arterial hypotension (systolic blood pressure < 90 mm Hg) should be avoided. Another ICP-reducing agent which can be used is barbiturate. It is believed to be due to a decrease in both cerebral blood flow and cerebral metabolic rate of oxygen. It has also been suggested that barbiturates have a neuroprotective effect at the cellular level. In practice, pentobarbital may be given in a loading dose of 10 mg/kg body weight followed by 5 mg/kg body weight each hour for 3 doses. The maintenance dose is 1 to 2 mg/kg/h, titrated to a serum level of 30 to 50 pg/mL or until the electroencephalogram shows a burst suppression pattern. Using barbiturates is less preferred because of a higher risk for hypotension. Barbiturate coma should only be considered for patients with refractory intracranial hypertension because of the serious complications associated with high-dose barbiturates, and because the neurologic examination becomes unavailable for several days. Hypotension caused by pentobarbital can be treated first with volume replacement and then with vasopressors if necessary. ICP-reducing medications which can be used in the art are known, including anti-histaminics for example described in US 7476662 B2, sedative agents, or steroids. Several different classes of drugs are used as sedatives in patients, including propofol, benzodiazepines, opioid narcotics, etomidate, ketamine, dexmedetomidine (see Oliver Flower and Simon Hellings, "Sedation in Traumatic Brain Injury," Emergency Medicine International, vol. 2012). Sedative agents can be used to prevent secondary brain injury by facilitating and optimising ventilation, reducing cerebral metabolic rate and reducing intracranial pressure. Maintenance of sedation may permit manipulation of ventilation, optimisation of cerebral metabolic rate (CMR02), cerebral blood flow (CBF), and intracranial pressure (ICP). Preferred sedative agents include propofol, midazolam, flunitrazepam, lorazepam, diazepam, opioid and ketamine. Examples of steroids includes glucocorticoids (Acta Neurol Scand. 1997 Sep;96(3):167-70).

In a preferred embodiment, the control unit is configured to provide output signals to a drug delivery device adapted to administer said ICP-reducing medication, where the delivery device is not part of the overall device.

A drug delivery device includes any means for containing and releasing a drug, wherein the drug is released to a subject. The term "drug delivery device" refers to any means for containing and releasing a drug, wherein the drug is released into a subject. The means for containing is not limited to containment in a walled vessel, but may be any type of containment device, including non-injectable devices (pumps etc.) and injectable devices, including a gel, a viscous or semi-solid material or even a liquid. Drug delivery devices may be inhaled, oral, transdermal, parenteral and suppository. Inhaled devices include gaseous, misting, emulsifying and nebulizing bronchial (including nasal) inhalers; oral includes mostly pills; whereas transdermal includes mostly patches. Parenteral includes injectable and non-injectable devices. Non-injectable devices may be "implants" or "non- injectable implants" and include e.g., pumps and solid biodegradable polymers. Injectable devices are split into bolus injections, that are injected and dissipate, releasing a drug all at once, and depots, that remain discrete at the site of injection, releasing the drug over time. Depots include e.g., oils, gels, liquid polymers and non- polymers, and microspheres. Many drug delivery devices are described in Encyclopedia of Controlled Drug Delivery (1999), Edith Mathiowitz (Ed.), John Wiley & Sons, Inc. The term "drug" as used herein, refers to any substance meant to alter animal physiology. The term "dosage form" refers to a drug plus a drug delivery device. The term "formulation" (or "drug formulation") means any drug together with a pharmaceutically acceptable excipient or carrier such as a solvent such as water, phosphate buffered saline or other acceptable substance. A formulation may contain a drug and other active agents. It may also contain an excipient, solvent or buffer or stabilizing agent. In another preferred embodiment, the control unit is configured to provide output signals to a drug delivery device which is part of the overall device. In other words, the device according to present invention comprises a drug delivery device and wherein the control unit is configured to provide output signals to said drug delivery device. Such device may be semi-automated or automated, such that when the ICP exceeds a certain given value, the control unit automatically provides an output signal to the drug delivery device adapted to deliver ICP-reducing medication to the patient without or with only minimal intervention of medical personnel.

In one embodiment, the recommendation can comprise an instruction to perform lumbar cerebrospinal fluid drainage on the patient to decrease intracranial pressure. CSF drainage lowers ICP immediately by reducing intracranial volume and more long-term by allowing edema fluid to drain into the ventricular system. Drainage of even a small volume of CSF can lower ICP significantly, especially when intracranial compliance is reduced by injury. However, this is a less preferred recommendation given its invasive nature. In another embodiment, the recommendation can comp se an instruction to perform decompressive craniectomy on the patient. The surgery removes part of the calvaria to create a window in the cranial vault to reduce ICP. It is the most radical intervention for intracranial hypertension and thus a less preferred option. Decompressive craniectomy is generally considered a very aggressive means to treating intracranial hypertension. There are some complications associated with decompressive craniectomy, including intracranial infection, infection of the bone flap, subdural or subgaleal hygroma, increased cerebral edema, hemorrhage, and hydrocephalus. In addition, the patient will require a second operation for cranioplasty.

Increased intracranial pressure can be caused by a space occupying lesion. Therefore, in another embodiment, the recommendation can comp se an instruction to remove a space-occupying lesion of the brain, such as a tumor or hemorrhage.

In one embodiment, the recommendation can comphse an instruction to hyperventilate or hyperoxygenate the patient. In general, hyperoxygenating is administering greater amounts of Oxygen and increasing the blood oxygen levels higher than normal. Hyperventilating is the excessive ventilation of the lungs, beyond what is required to achieve normal arterial blood gases. These measures decrease PaC02, which can induce constriction of cerebral arteries by alkalinizing the CSF. The resulting reduction in cerebral blood volume decreases ICP. In general, they are less preferred, because the effect on ICP is time limited.

In a preferred embodiment, the control unit is configured to receive input signal indicating the intracranial pressure entered by a user. Preferably, the control unit prompts a user to enter the input signal. In some embodiments, the control unit is configured to receive input signals that are entered by a doctor or other caretaker. In such embodiments, the device comphses a user interface with a user information output such as a screen, for prompting the user for input signals to be entered, suitably via a touchpad screen or keyboard. Various arrangements are possible and within the scope of the invention. In some embodiments, the user is prompted at least whenever a fresh infusion bag is to be connected to the device and/or at regular time intervals.

In one embodiment, the control unit is configured to receive an input signal indicating the intracranial pressure from an intracranial pressure sensor, where sensor is not part of the overall device.

In another embodiment, the control unit is configured to receive an input signal indicating the intracranial pressure from an intracranial pressure sensor, where sensor is part of the overall device. Preferably, the signal is from a non-invasive ICP sensor such as a NeMo probe manufactured by NeMo Devices AG, Switzerland.

The control unit is preferably configured to receive input data indicating the volume of the infusion fluid being administered and/or connected to the device. This may be useful for maintaining a desired targeted volume balance. The device may additionally incorporate means for measuring and monitoring volume or weight of one or more bodily fluids from the patient, in particular urine and in some embodiments also other fluids discharged from the body such as through perspiration, defecation, and blood loss. It would be possible to improve the administration of a medical fluid such as an infusion fluid, in particular, for the purpose of providing cooling of the patient, by ensuring optimal flow of the medical fluid taking into account the desired effect in terms of desired delivery volume and desired effect on body temperature, and an optimal volume balance of hydration of the patient.

The control unit may further store data indicating the medication administered to the patient. The output signals generated by the control unit which indicate recommendation for therapy may be determined based on said data. If the intracranial pressure continues for a prolonged period of time over a limit which is undesired for the patient, the control unit may be configured to automatically stop the infusion or to provide an output signal indicating a recommendation to adjust infusion treatment. For example, the control unit may further store data indicating the ICP reducing medication or other medications already administered to the patient. If the patient has already received ICP-reducing medication exceeding recommended limits, the control unit would refrain from providing recommendation which comprises an instruction to administer further ICP-reducing medication. Instead, the control unit may send a signal to provide an output signal indicating a recommendation which comprises an instruction to perform SDF drainage or decompressive craniectomy.

In some embodiments, the control unit is configured to receive input signals from at least one sensor that indicates the blood pressure. In one preferred embodiment, the input signals may further comprise signals selected from the group consisting of signals indicating medical condition of the patient, signals indicating desired therapeutic body temperature of the patient, and signals indicating blood status of the patient, signals indicating concentration of at least one electrolyte, signals indicating additional infusion fluid that the patient is being administered, and signals indicating the level of shivering. Input signals that can be entered in the device and which the device may prompt the user for may be selected from but are not limited to one or more of the following: signal indicating concentration of at least one electrolyte, signal indicating additional infusion fluid that the patient is being or is to be administered, signal indicating medication that the patient is being administered or has received, signal indicating medical condition of patient, signal indicating desired therapeutic body temperature of patient, and signal indicating blood status of patient. "Blood status" in this context may refer to any of various parameters describing status of blood, such as hemoglobin value, platelet count, etc. "Medical condition" in the context herein may refer to any vital signal such as but not limited to pulse, blood pressure, body temperature, or other relevant input parameter defining medical condition. In useful embodiments, the device is connected to one or more temperature sensors that provide the control unit with values indicating the body temperature of the patient.

The device of the present invention may suitably be arranged also with means to monitor and/or adjust volume being administered, by controlling flow rate of IV fluid and monitoring fluid loss from the patient by suitable sensors, or prompting for relevant data to be entered representing fluid loss. Accordingly, in some embodiments of the invention, the device is configured to adjust the volume of one or more medical infusion fluids, the device comprising a. at least one first determining unit adapted to measure and/or determine the volume of the medical infusion fluid flowing through a delivery duct and adapted to provide a respective first signal; at least one second determining unit adapted to measure and/or determine the volume and/or weight of at least one released body fluid and/or a physiological parameter and further adapted to provide a respective second signal; and at least one volume controlling unit adapted to control the flow of the medical infusion fluid through the delivery duct on the basis of the first and the second signals. It is advantageous that the device be configured to minimize shivering of the patient. Shivering is a normal reflex reaction of the body to feeling cold, triggered to maintain homeostasis. Skeletal muscles begin to shake in small movements, creating warmth by expending energy. Thus, shivering will counteract the desired effect of hypothermia treatment in addition to being uncomfortable to the patient. In an embodiment of the invention, the control unit of the device is configured to receive input signals indicating levels of shivering and to provide output signals indicating one or more recommendations for therapy based on said received input signals, to counteract the shivering. In one such embodiment, the control unit may react by forwarding an output signal to the flow control unit, signaling that the flow rate is to be altered (reduced), and/or the control unit may signal that the temperature of the infusion fluid is to be raised. In another embodiment, the control unit provides an output signal indicating a recommendation, or a signal to a drug delivery device, that the patient be administered an anti-shivering medication, such as but not limited to a medication selected from opiates, tramadol, magnesium sulfate, a 2-agonists, physostigmine, doxapram, methylphenidate, and/or 5-HT3 antagonists. In other embodiments, output signal indicates a recommendation that surface temperature of the patient be affected, such as through the use of blankets, heating pads, or the like. In other embodiments, the control unit is configured to receive input signals directly (without user input) from sensors, such as but not limited to sensors for sensing vital signals or other patient signals (e.g. heart rate, blood pressure, breathing rhythm, level of shivering... etc.). In some embodiments, the control unit is able to receive a combination of input signals, both manually entered and received from sensors and/or external computers, systems, etc. Such signals can be used by the control unit for providing recommendations. For example, such sensors may detect an adverse event, such as heart rate irregularities, which may indicate lack of potassium, then the control unit can respond by giving an output signal with instructions to change the infusion fluid to a fluid with higher potassium content. This can happen either such that the device will start administering potassium containing fluid instead of or in addition to non-potassium fluid, or by providing output signals to a user instructing to change infusion fluid.

The device may further comprise a user interface which prompts the user for input information and outputs visual information indicating said output signals. Preferably, the device disclosed in the present invention is adapted to be mounted into a rack. There is generally a need to standardize the different components used in hospitals and being placed next to patients for the delivery of different medications. Moreover, racks with a plurality of components for medical devices become more and more used. Typically, they offera slotfor introducing medical devices such as syringes or pumps pumping infusion fluids with different medicaments for their intravenous delivery. For example, in US patent 4,756,706 a central processing unit is described for centrally controlling and monitoring the different components mentioned before. WO 2013/102495 concerns an arrangement of a rack and a medical device to be attached to the rack. Thus, an arrangement of a rack and a medical device may be advantageously provided to allow for an easy attachment of the medical device to the rack, by providing a secure and reliable and at the same time versatile electrical connection between the medical device and the rack. Thus, in one preferred embodiment, the device is adapted to be mounted into a rack. For example, a frame can be provided and assembled and/or adapted to introduce the device into one or more slots of a rack of given dimension and/or shape. The rack can be of any shape, either with a single post for assembling the medical device and other medical devices and/or a shelf-like structure with more than one post and/or at least one or more walls. Moreover, the rack can be adapted to allow several medical devices to be placed in at least one vertical and/or at least one ho zontal row(s). The frame of the medical device comp ses at least one, preferably at least two rail(s) and/or hook(s) for inserting the device into the rack. In case the rack comphses essentially one post, one or more hooks can be provided. In case of a shelf-like rack, one or more rail(s) can be provided for slidingly placing or allowing the device to be placed in the rack. The rail(s) and/or the respective counterpart(s) at the rack can be of any known structure with sliding or bearing-supported structure(s) and/or of expandable and/or telescoping nature. Moreover, the medical device can comphse at least one releasable lock for releasably locking the device in the rack. This can prevent the accidental removing of the medical device in or at the rack and/or the defined position of the device and/or its other components interfering with the rack and other elements. The term locking does not necessarily mean that a specific element is provided. It can also be enabled by a mechanical and/or electronic indicator indicating the defined position of the medical device at and/or in the rack. The present invention also provides a rack which includes one or more of the devices described herein.

Preferred embodiments

The present invention will become more fully understood from the description before and particularly below and the accompanying drawings that are given by way of illustration only and show and/or exemplify preferred aspects thereof. Fig. 1 illustrates an embodiment of the configuration of the device of the invention.

The device 1 as shown in Fig. 1 comprises a control unit 20, a flow control unit 40 and an input/output screen21. A typical infusion fluid bag 10 is hung on a conventional supporting device. From the bag, a duct 1 1 provides infusion fluid through the flow control unit 40, which passes the infusion fluid onwards to a patient (not shown) through duct 14. An optional input line 61 from an external computer 60 is shown. Adjacent to the bag 10 is a barcode scanner S1 for detecting and registering type of IV fluid bag, providing a signal to the control unit. Alternatively and optionally, input data concerning the type of IV fluid bag is input via the input screen 21.

Intracranial pressure sensors S2 and temperature sensor S3 are shown. They can be applied to the patient to measure the intracranial pressure and the core body temperature.

Bed 30 is shown to schematically illustrate the patient.

Target temperature for hypothermia ranges between 30.0°C and 36.5°C, depending on the specific condition being treated, preferably 30.0°C, 30.5°C, 31.0°C, 31 .5°C, 32°C, 32.5°C, 33.0°C, 33.5°C, 34.0°C, 34.5°C, 35.0°C or 35.5°C, 36.0°C, and 36.5°C. A target temperature for cooling lower than 30°C should be avoided because of the increased risk of cardiac arrhythmias, coagulation abnormalities and infections. More preferably, the target temperature is between 33.0°C to 36.0°C, such as 33.0°C, 33.5°C, 34.0°C, 34.5°C, 35.0°C or 35.5°C, and 36.0°C. Cooling is achieved with a device as described in the present application. Decisions regarding the method and duration of cooling will likely vary among individual patients depending on the pathophysiology of the brain injury and may be under the discretion of the attending neurointensivist on another medical specialist.

ICP is preferably monitored continuously or at least every 15 mins. When the device receives input signals indicating the intracranial pressure of the patient which is above 20 mmHg, such as 20 mmHg, 21 mmHg, 22 mmHg, 23 mmHg, 24 mmHg, 25 mmHg, the device provides output signals indicating a recommendation which is an instruction to increase the hypothermia effect. ICP level should be maintained under 20-25 mmHg. It is also preferred that CCP is monitored and maintained above 50 mmHg. As alternative recommendations, osmotherapy with either mannitol or hypertonic saline can be considered. Preferably, the following substance can be used

1 . mannitol 20 %, sorbit 40 % (each i.v. bolus 0.5 - 0.75 g/kg KG, max 4 - 6 * daily)

2. glycerol 10 % (i.v. 1000 -1500 ml/d, max 3 - 4 * daily)

3. NaCI 7,5-10 % (i.v. bolus 3 ml/kg KG, up to 250 ml/d)

For intracranial hypertension refractory to initial medical management, sedation, barbiturate coma, drainage of CSF or decompressive craniectomy should be considered.

Rewarming should be done slowly (e.g., over 12-24 h) so as to decrease the risk of rebound ICH. It is imperative to monitor ICP during rewarming. The device of the invention is preferably configured so as to fit in a conventional hospital rack system, i.e. a bedside rack for containing one or more modular devices for patient care and/or monitoring. In such embodiments, the device is configured and designed as a modular unit to fit in such rack. The device can, in certain such embodiments, comprise more than one modular unit, for example when it is desired to actively cool the infusion fluid by keeping it in a cooled storage compartment while the fluid is administered. Such a cooling compartment can be an add-on module.

As used herein, including in the claims, singular forms of terms are to be construed as also including the plural form and vice versa, unless the context indicates otherwise. Thus, it should be noted that as used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

Throughout the description and claims, the terms "comprise", "including", "having", and "contain" and their variations should be understood as meaning "including but not limited to", and are not intended to exclude other components.

The present invention also covers the exact terms, features, values and ranges etc. in case these terms, features, values and ranges etc. are used in conjunction with terms such as about, around, generally, substantially, essentially, at least etc. (i.e., "about 3" shall also cover exactly 3 or "substantially constant" shall also cover exactly constant).

The term "at least one" should be understood as meaning "one or more", and therefore includes both embodiments that include one or multiple components. Furthermore, dependent claims that refer to independent claims that describe features with "at least one" have the same meaning, both when the feature is referred to as "the" and "the at least one".

It will be appreciated that variations to the foregoing embodiments of the invention can be made while still falling within the scope of the invention. Alternative features serving the same, equivalent or similar purpose can replace features disclosed in the specification, unless stated otherwise. Thus, unless stated otherwise, each feature disclosed represents one example of a generic series of equivalent or similar features.

Use of exemplary language, such as "for instance", "such as", "for example" and the like, is merely intended to better illustrate the invention and does not indicate a limitation on the scope of the invention unless so claimed. Any steps described in the specification may be performed in any order or simultaneously, unless the context clearly indicates otherwise.

All of the features and/or steps disclosed in the specification can be combined in any combination, except for combinations where at least some of the features and/or steps are mutually exclusive. In particular, preferred features of the invention are applicable to all aspects of the invention and may be used in any combination.

Claims

1 . Device for controlling and managing administration of infusion fluid for temperature

regulation therapy, comprising:

at least one flow control unit for regulating the volume, flow rate and/or temperature of infusion fluid, and

at least one control unit for receiving input signals and providing output signals, wherein the control unit is configured to receive input signals indicating intracranial pressure (ICP) and optionally blood pressure of a patient and to provide output signals indicating one or more recommendation for therapy based on said received input signals.

2. The device according to claim 1 , wherein the control unit is configured to receive input signals from at least one external computer system.

3. The device according to any of the preceding claims, wherein the control unit is configured to receive input data indicating the core body temperature or body surface temperature of the patient.

4. The device according to any of the preceding claims, wherein the control unit is configured to provide a signal to the flow control unit.

5. The device according to any of the preceding claims, wherein the control unit is configured to provide a signal to the flow control unit to increase flow rate of the infusion fluid.

6. The device according to any of the preceding claims, wherein the control unit is configured to provide a signal to the flow control unit to decrease the temperature of the infusion fluid.

7. The device according to any of the preceding claims, wherein the control unit is configured to provide a signal to the flow control unit to increase the osmolarity of the infusion fluid.

8. The device according to any of the preceding claims, wherein the recommendation

comprises an instruction to increase the osmolarity of the infusion fluid.

9. The device according to any of the preceding claims, wherein the recommendation

comprises an instruction to administer ICP-reducing medication.

10. The device according to claim 9, wherein the ICP-reducing medication is mannitol, propofol, midazolam, flunitrazepam, lorazepam, diazepam, opioid, ketamine, glucocorticoid and/or barbiturate.

1 1 . The device according to any of the preceding claims, wherein the control unit is configured to provide output signals to a drug delivery device adapted to administer said ICP- reducing medication.

12. The device according to any of the preceding claims, further comprising a drug delivery device, and wherein the control unit is configured to provide output signals to said drug delivery device.

13. The device according to any of the preceding claims, wherein the recommendation

comprises an instruction to perform lumbar cerebrospinal fluid drainage on the patient.

14. The device according to any of the preceding claims, wherein the recommendation

comprises an instruction to perform decompressive craniectomy on the patient or to remove a space occupying lesion.

15. The device according to any of the preceding claims, wherein the recommendation

comprises an instruction to hyperventilate or hyperoxygenate the patient.

16. The device according to any of the preceding claims, wherein the control unit is configured to receive input signal indicating the intracranial pressure entered by a user, and, optionally, wherein the control unit prompts a user for input signals to be entered.

17. The device according to any of the preceding claims, wherein the control unit is configured to receive input signal indicating the intracranial pressure from an intracranial pressure sensor, and wherein the device optionally comprises the intracranial pressure sensor.

18. The device according to any of the preceding claims, wherein the control unit is configured to receive an input signal indicating the intracranial pressure from a non-invasive ICP sensor such as a NeMo probe.

19. The device according to any of the preceding claims, wherein the control unit is configured to receive input data indicating volume of infusion fluid administered to the device.

20. The device according to any of the preceding claims, wherein the control unit further stores data indicating the medication administered to the patient, and wherein said recommendation is determined based on said data.

21 . The device according to any of the preceding claims, wherein the input signals comp se signals selected from the group consisting of signals indicating medical condition of patient, signals indicating desired therapeutic body temperature of patient, and signals indicating blood status of patient, signals indicating concentration of at least one electrolyte, signals indicating additional infusion fluid that the patient is being

administered, and signals indicating the level of shivering of the patient.

22. The device according to any of the preceding claims, comprising a user interface which prompts the user for input information and outputs visual information indicating said output signals.

23. The device according to any of the preceding claims, wherein the control unit is configured to receive input signals indicating the level of shivering of the patient and to provide output signals indicating one or more recommendation for therapy based on said received input signals.

24. The device according to any of the preceding claims, wherein the control unit is configured to receive input signals that define infusion fluid to be administered or which is being administered, and store such information, and provide output signals to control electrolyte content of the infusion fluid based on said received input signals.

25. The device according to any of the preceding claims, further comprising at least one first determining unit adapted to measure and/or determine the volume of the medical infusion fluid flowing through a delivery duct and adapted to provide a respective first signal, and

at least one second determining unit adapted to measure and/or determine the volume and/or weight of at least one released body fluid and/or a physiological parameter and further adapted to provide a respective second signal, and

at least one volume controlling unit adapted to control the flow of the medical infusion fluid through the delivery duct on the basis of the first and the second signals, and optionally, wherein the second determining unit is adapted to measure and/or determine the volume and/or weight of at least one released body fluid selected from urine, sweat, wound liquid, blood, breath vapors, evaporation and/or liquid content of stools.

26. The device according to any of the preceding claims adapted to be mounted into a rack.

27. A rack comprising the device according to any of the preceding claims.

28. A method of controlling and managing administration of infusion fluid for temperature regulation therapy, comprising:

regulating volume, flow rate and/or temperature of infusion fluid, and

receiving input signals and providing output signals,

wherein the input signals indicate the intracranial pressure of the patient,

providing output signals indicating one or more recommendation for therapy based on said received input signals.

29. A method of treating a mammal comprising using a device and/or a method according to any one of the preceding claims.