SBIR Proposal

IV Cooling System for Hypothermia

Steve Huppman

Jermaine Johnson

Sylvia Kang

Erin Wacker

Advisor: Dr. James Menegazzi

April 17, 2007

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Table of Contents

Specific Aims ............................................................................................................................. 3

Significance ................................................................................................................................ 6

Preliminary Work ..................................................................................................................... 9

Methods .................................................................................................................................... 11

Results .………..........................................................................................................................17

Conclusion …………………………………………………………………………………... 21

References ................................................................................................................................ 22

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Specific Aims

In previous studies, researches have found that cardiac arrest often leads to severe

neurological damage.2 During cardiac arrest, a cession in blood flow for greater than five

minutes results in a chemical cascade in the body results in serious cerebral impairment.

However, if the body temperature could reach mild (34°C) to moderate (30°C)

therapeutic hypothermia immediately after cardiac arrest, the neurological outcome

would be much more improved as well as the mortality rate would be decreased.

Decreasing the body temperature lowers the amount of oxygen that is demanded by the

brain.

The proposed goal of this Phase I project is to create a cooling device to begin the

process of inducing mild hypothermia easily and quickly after cardiac arrest. This device

could be used by EMS and other first aid personals to help the patients before they get to

the hospital. In order to reach the best and fastest cooling results, this device functions by

cooling the body both internally and externally. Cooled saline flowing through standard

IV tubing, which is exposed to an ammonium nitrate – water solution (approximately 0°

C), will be infused into the body in an effort to induce mild hypothermia. Additional

external cooling will occur by placing the device on the patient’s chest.

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Our Phase I specific aims are:

1. Design an IV cooling system for cardiac arrest patients to achieve the

following goals:

Selection of the concentration of ammonium nitrate in the coolant

solution.

Three ratios (1:1, 2:1, 1:2) of ammonium nitrate to water

will be tested to determine which concentration will achieve

the minimum temperature for the longest period of time.

The less ammonium nitrate needed for the device the better

because it will lead to a cheaper manufacturing price.

Amount of tubing needed and the design of the device.

Multiple prototypes will be designed of similar nature to

decide which will cool the saline to the lowest temperature

while maintaining a good flow rate. It is desired to flow 2 L

of saline into the patient within 15 minutes (2.22 cc/ sec).

This is the typical amount infused in a cardiac arrest patient

on their way to the hospital. The final prototype will be

chosen based on flow rate and the temperature of the saline

as it would enter the patient.

The size of the casing and material selection.

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Size of the casing will be based on the size of an average

male’ chest. Material will be chosen on its thermal

conductivity, durability and ease of heat sealing.

The device will not induce mild hypothermia on its own.

However, it will begin the process on the patient’s trip to the

hospital at which time more advanced systems can be used to keep

the patient in the mild hypothermia state for 12-24 hrs.

2. Fabricate prototypes for testing.

A SolidWorks model will be created.

A prototype will be fabricated manually in the machine shop with

help from Andy Holmes. Various tools will be used to cut the

manifold and drill the holes.

3. Test prototypes in vitro.

Saline will flow from a one liter saline bag with a pressure bag

attached to it, through standard IV tubing to our activated

(ammonium nitrate and water already mixed) device which will

begin the cooling of the saline. The cooled saline will then flow

out of the device and into a patient (a beaker), where the average

temperature will be recorded. The goal is to have the saline reach

a temperature of 10° C less than normal room temperature with a

flow rate as close as possible to 2.22 cc/ sec.

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Significance

In their 2006 update, the American Heart Association estimates, 163,221 out-of-

hospital cardiac arrests will occur annually in the US.1 On average EMS treatment of

out-of hospital cardiac arrest occurs in 107,000 – 240,000 cases annually1. It has been

documented that after cardiac arrest with no blood flow for a period of time greater than

five minutes, cerebral brain damage due to ischemia will result.2

Therapeutic hypothermia has been in research literature as early as the 1950’s but

was widely ignored until the new millennium. In 2002, two publications shed light on the

possibility of the treatment of out-of-hospital cardiac arrest with mild therapeutic

hypothermia (30°C – 34°C).2,3 These publications both involved independent randomized

controlled studies and demonstrated significant improvement for comatose survivors of

out-of-hospital cardiac arrest with ventricular fibrillation. Based on the evidence

supported by the aforementioned publications, the Advanced Life Support Task Force of

the International Liaison Committee on Resuscitation (ILCOR) recommended in 2003,

unconscious adult patients of cardiac arrest caused by ventricular fibrillation with

spontaneous circulation should be cooled between (32°C – 34°C) for 12 to 24 hours and

cooling may benefit other types of in-hospital cardiac arrest.4

The benefit of therapeutic hypothermia for out-of-hospital comatose cardiac arrest

patients focuses on the ability to limit cerebral ischemia. The chemical effect of cerebral

ischemia has been shown to cause an energy depletion, ion pump failure, and release of

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free radicals. These free radicals and also the creation of excitotoxic agent created also

invoke an increase in body temperature.7 Mild hypothermia treatment for cardiac arrest

has shown a decrease in length of hospital stay, reduction of hospital mortality, and

survival rates after one year.8

The cooling of intravenous fluids has evolved into an increasingly viable and

beneficial method because it can be preformed before the patient arrives at the hospital.

Examples of these types of products such as the ice cold Ringer solution demonstrate

this.9 The device forming the basis of this Phase I proposal relies on the principle of

attempting to quickly cool intravenous fluid in an effort to lower the blood temperature

and thereby decreasing the oxygen demand of the brain. This device enables the patient

to be treated with therapeutic hypothermia while being transported to a hospital. The

quicker a cardiac arrest victim can be treated with therapeutic hypothermia the greater the

potential neurological benefit that can be received. Since brain damage occurs with no

blood flow for more than five minutes, the issue of time is of utmost importance and

implementation of mild therapeutic hyperthermia as close in time to the cardiac arrest is

critical.

Surveys have been conducted of the health care industry exploring the lack of

compliance with the recommendations of the ILCOR.5,6 Abella et al. noted to the question

of “Have you ever utilized hypothermia in a patient after resuscitation?”, Over 71% of

critical care providers and 95% of emergency medicine provides stated no.6 The

conclusions that the Abella group reached for the above mentioned statistics were the

following: lack of awareness of supporting data, technical constraints, and lack of

hypothermia protocol led to an under-use of mild hypothermia. We have developed a

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protocol for implementation of our device and a method of usage, which does not

infringe on their natural ability of the emergency medical professional, provides to

perform their life support tasks.

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Preliminary Work

Under a specified set of parameters, we tested the saline temperature cooled by the

chemical bag model. The total tubing length is 4ft, which makes 6 turns inside the device.

The initial temperature inside the device is 8°C, and the temperature of saline external to

the device is 20.6°C. The model setup is shown below:

Figure 1. The chemical cooling package and IV tubing. Outside view (left). Inside View (right).

We ran four trials to test the temperature drop of saline. Two of them were under

pressurized condition and two of them were not. The test results are shown in Table 1:

Table 1: Four trials and the results in preliminary study.

Trial 1 (unpressurized, gravity driven):

Time (min) Temperature (°C)0 14.02 18.64 18.6

Trial 1 (pressurized)

Time (min Temperature (°C)0 20.2

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2 20.2Trial 2 (unpressurized, gravity driven):

Time (min) Temperature (°C)1 19.62 19.5

Trial 2 (pressurized)

Time (min) Temperature (°C)0 20.11 19.82 19.6

From the results above, the saline was not cooled enough to reach the temperature we

want (10° C less than standard room temperature). The number of tubing turns inside the

device may need to be increased and the IV fluid temperature needs to be much colder to

achieve hypothermia.

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Methods

Specific Aim 1: Design

Ammonium Nitrate Concentration Selection.

In order to maximally decrease the patient’s body temperature simply by the

saline entering the body through a peripheral IV, it is necessary that the temperature of

the saline is as close to freezing (0°C) as possible. We will do this by taking advantage

of the endothermic chemical reaction that occurs between the coolant composed of

ammonium nitrate and water. When the two chemicals are mixed together, they

immediately react to rapidly decrease the temperature of the solution. To determine how

close to freezing this chemical reaction can get, we will experiment using numerous

ratios of coolant to water, keeping volume constant: 1:1, 1:2, and 2:1. The different

ratios are shown in Table 2. It should be noted that commercially sold ice packs, as well

as information listed in patents, that the ratio of ammonium nitrate to water is not a molar

ratio, but instead a gram ratio. Therefore, the ratios (1:1, 1:2, 2:1) listed here are gram

ratios. We will test each of these ratios, recording the average temperature in the beaker

(“patient”), plotting this average temperature over a 15 minute period and determining

which ratio achieves the most amount of cooling for the longest period of time.

Table 2: Concentrations that will be tested to determine ratio of ammonium nitrate to water

Test Water (mL) Ammonium Nitrate (g)

1 500 5002 666 3333 333 666

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In general, we expect the temperature to decrease as the amount of coolant

increases. Using a digital temperature probe, the temperature will be continuously

monitored for 15 minutes from the time the chemicals are mixed. The chemicals will be

mixed manually at first then left alone to simulate what will actually occur when using

the device in vivo. We will only measure the temperature for the first 15 minutes because

the maximum amount of cooling occurs between 10 and 15 minutes and the device is

only specified to be used for 15 minutes. After 15-20 minutes, the temperature will

slowly increase until it reaches room temperature. The final concentration of coolant to

water will be chosen based on the experimentally lowest recorded temperature for the

longest amount of time.

Tubing Length and Number of Turns

The IV fluid must be exposed to the coolant for a period of time long enough to

adequately decrease the patient’s core body temperature. This amount of time has been

approximated to be 15 minutes Standard IV tubing (4 mm internal diameter) will be used

in the device. There will be two different prototypes of the device, the tubing set up in

series and also set up in parallel like a classic heat exchanger.

Figure 1: Diagram showing the tubing set up in series. In this prototype the tubing will be snaked in series

Intravenous Fluid

Tubing

Chemical Ice-Bag with Internal Tubing

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Figure 2: Manifolds used to set the tubing up in parallel.

There is a balance between tubing length and amount of time required for the

saline to reach the patient, which depends on the flow rate. The longer the tubing inside

the device, the slower the flow rate, the longer it will take the saline to enter the body.

The goal is to have the fluid enter the body at a maximum flow rate, while still having a

cooling effect. We will control these factors by altering the total tubing length for the

prototype where the tubing is set up in series and altering the length of tubing on each

bridge of the manifold. The length of tubing will be determined theoretically estimating

the surface area needed to achieve the required cooling, then determining the length of

each tube. It has been estimated from theoretical calculations, using an equation derived

from the conservation of mass through a tube, that the length of each tube in the manifold

should be about 10 inches long or the length of tubing for the prototype in series should

be about 4 feet long. These two prototypes will be testing along with some slight

variations. We will also test minivolume tubing (same length as the standard IV tubing)

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for the prototype with tubing in series to test if the increase in surface area decreases

saline temperature. We will also test connecting 2 manifolds together to increase the

residence time of the saline in the device as shown in Figure () and ().

Figure 3: Prototype with tubing in parallel. In this device, there are two rows of 16 tubes.

Figure 4: Prototype with tubing in parallel. In this device, there is one row with 32 tubes across and each manifold is connected by a T-connector.

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The flow rate will be controlled by adjusting the amount of force that the

pressure bag is exerting on the saline. There is an indicator on the pressure bag, a white

zone, a green zone, and a red zone. The white zone indicates minimal pressure on the

bag, the green zone indicates maximal pressure without the bursting of the bag, and the

red zone is a danger zone where the pressure will automatically deflate. The flow rate

will be kept at a maximum by keeping the pressure in the green zone (about 300 mmHg).

Case Size and Material Selection

We will create a rectangular case that will lie across the patient’s chest which

should maximize the cooling effects. The case will be created to fit the tubing inside the

device, but the case has been estimated to be about one foot by one foot (based solely on

an estimation of adult patient’s chest sizes). The case will be flexible, because it needs to

be able to be cracked and shaken to break the water sac inside that will induce a chemical

reaction. Although a non conductive material would be best to maintain a cool

temperature inside the device, we also want there to be external cooling to the patient so

the simplest material will be selected. In this case, the simplest material is the same

material currently used in the commercially available ice packs. Polyethylene will be the

material used in the device. It is flexible, thermally conductive, water-resistant, durable,

and can be easily sealed so heat will easily transfer from the device to the tubing as well

as the patient’s chest.

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Specific Aim 2: Fabrication

We will fabricate the device by hand. Using the machine shop, with the help of

Andy Holmes, we will hand fabricate and assemble the device. A band saw will be used

to cut the hard portion of the manifold (dacron tubing). Holes will be cut into the dacron

tubing with a mill and a lathe, and various hand tools will be used to tap the holes in

order to get connectors to connect to the holes.

Specific Aim 3: Testing

All testing will be done in vitro. In each of these tests, the experiment will be set

up as shown in Figure (), including a pressure bag with one liter of saline, an extension

set to connect the saline bag to the device (ID of 4 mm), the device, and another

extension set (ID of 4 mm) to connect the device to the arm of the patient (“the beaker”)

where the core body temperature (“temperature of saline inside the beaker”) will be

measured. This same set-up exists for each of the prototypes. The average temperature of

the saline inside the beaker will be measured using a digital thermometer each minute for

15 minutes.

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Results

Ammonium Nitrate Concentration Selection

The first test was performed to select the proper ammonium nitrate concentration

that would optimize our ratio to provide the maximum amount of cooling for the longest

period of time. Table 3 (A, B and C) shows the temperature of the coolant solution over

15 minutes for three separate ammonium nitrate and water ratios. It was found that both

the 1 NH4NO3: 1 H2O ratio and the 2 NH4NO3: 1 H2O ratio resulted in similar outcomes.

In both the temperature dropped to a minimum of -4° C and remained under 0° C for 15

minutes. These were much better than the 1 NH4NO3: 2 H2O ratio in which the

temperature never went under 2° C. In the end, a 1 NH4NO3: 1 H2O was decided to be

best because it would result in a cheaper manufacturing cost as not as much ammonium

nitrate would be needed.

Standard IV Tubing vs. Minivolume IV Tubing

It was thought that by increasing the surface area exposed to the coolant by using

minivolume IV tubing it would result in a lower saline temperature. Table 4 shows the

temperature of the saline after flowing through 71” of tubing (A – standard, B-

minivolume). The outer diameters, inner diameters and wall thicknesses are also

reported. It was discovered that after 15 minutes the temperature of the saline flowing

through the minivolume tubing was only 0.2° C cooler than that flowing through the

standard IV tubing. It was decided this was not worth the 0.4 cc/min decrease in the flow

rate. Flow rate was already the greatest concern and any further decrease from a 0.5

cc/min flow rate would be unacceptable.

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Table 3: Temperatures of ammonium nitrate and water solutions over 15 minute time periods.

A

1 NH4NO3: 1 H2O

B

2 NH4NO3: 1 H2O

C

1 NH4NO3: 2 H2O

Elapsed Time (min)

Temperature (Celsius)

0 101 02 -33 -44 -45 -46 -37 -38 -2.59 -210 -1.511 -112 -0.513 -0.514 -0.515 016 0.517 118 119 1.520 2

Average -1.2

Elapsed Time (min)

Temperature (Celsius)

0 81 -22 -43 -34 -35 -36 -27 -28 -29 -1.510 -111 -112 -113 -0.514 015 016 017 0.518 119 120 1.5

Average -1.1

Elapsed Time (min)

Temperature (Celsius)

0 101 42 43 44 25 26 27 28 29 210 211 212 213 314 215 416 417 518 519 420 5

Average 3.1

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Table 4: Temperature recorded as a function of time for the prototype where the tubing is in series. Note that the length is 2 feet longer than proposed in the methods section due to ordering restraints. It was assumed to be more beneficial to have tubing that was longer than shorter for heat transport purposes.

Standard IV Tubing   Minivolume IV Tubing  OD= 0.140"   OD=0.0895"  ID=0.1165"   ID=0.0645"  

wall=0.0235"   wall=0.025"         

Time (min) Temp (deg C) Time (min) Temp (deg C)1 16.2 1 17.92 14.9 2 17.83 14.1 3 15.54 14.8 4 13.95 14.3 5 12.96 14.5 6 12.77 14.4 7 12.98 14.5 8 13.39 14.8 9 13.9

10 14.9 10 14.611 15 11 14.912 15.4 12 15.113 15.1 13 14.914 15.1 14 14.915 15.3 15 15.1

AVERAGE 14.9 AVERAGE 14.7FLOW RATE (cc/min) 0.5 FLOW RATE (cc/min) 0.1

Starting Temp of Saline 22.6Length 71"

Testing

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The results of our final prototype may be found in Table 5. This was a single

manifold design with sixteen 10” standard IV tubes. The Solid Works design may be

seen back in Figure 2. Two alternative designs were also tested (Figure 3 - 2 rows of 16

tubes and Figure 1- 1 row of 32 tubes) but the pressure drop was too large to obtain a

flow rate any where near acceptable for these designs to work. Our prototype cooled the

saline to a minimum of 10.4° C while remaining under 10.3° C for 15 minutes. The flow

rate was 1.11 cc/sec which was half of the 2.22 cc/sec that we had wished to achieve.

Table 5: Temperature recorded as a function of time for the final device (1 row of 16 tubes).

Time (min) Temp (F) Temp ( C )1 72 22.22 51.2 10.73 51.1 10.64 50.8 10.45 50.1 10.16 50 10.07 50.8 10.48 51.4 10.89 50.4 10.2

10 50.8 10.411 50.3 10.212 50.8 10.413 50.6 10.314 50.9 10.515 50.5 10.3

AVG   10.4Q   1.11 cc/sec

Conclusion

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After thorough testing, we developed a device that will begin the process of

inducing mild hypothermia in patients suffering from cardiac arrest. The device is best

used when administered within 5 minutes of the stoppage of blood flow in the patient and

when not used for a period of time over 15 minutes. Saline will flow from a pressurized

saline bag through standard IV tubing into our device. Our device will cool the saline to

~10° C as the tubing it flows through is exposed to a 1:1 ratio of ammonium nitrate and

water. The saline will exit the device through standard IV tubing flowing at 1.11 cc/ min

with an temperature of 10.4° C over 15 minutes. In summary, 1 L of cooled saline will

be infused in 15 minutes. This is a decrease of 50% from the normal 2 L of saline that is

infused to cardiac arrest victims, but we believe that this process will better the

neurological outcome of the patient as well as reduce the chance of mortality. It should be

noted that further in vivo tests still need to be performed to gain a better understanding of

the situation. These tests are planned and will be done before the device is put on the

market.

References:

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1. American Heart Association. Heart Disease and Stroke Statistics – 2006 Update. www.americanheart.org 2006

2. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med, Vol. 346, No. 8, 2002

3. Bernard, SA. Gray, TW. Buist, MD. Jones, BM. Silvester, W. Gutteridge, G. Smith, K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med, Vol. 346, No. 8, 2002

4. Nolan, JP. Morley, PT. Vanden Hoek, TL, et al. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Resuscitation. Vol. 57, No. 3, 2003

5. Wolfrum, S. Radke, PW. Pishchon, T. Willich, SN. Schunkert, H. Kurowski, V. Mild therapeutic hypothermia after cardiac arrest – A nationwide survey of the implementation of the ILCOR guidelines in German intensive care units. Resuscitation. 2006 (in press)

6. Abella, BS. Rhee, JW. Huang, KN. Vanden Hoek, TL. Becker, LB. Induced hypothermia is underused after resuscitation from cardiac arrest: a current practice survey. Resuscitation. Vol. 64, 2005

7. Alzaga, A. Cerdan, M. Varon, J. Therapeutic hypothermia. Resuscitation. Vol. 70, 2006

8. Tanimoto, H. Ichinose, K. Okamoto, T. Yoshitake, A. Tashiro, M. Sakanashi, Y. Ao, H. Terasaki, H. Rapidly induced hypothermia with extracorporeal lung and heart assist (ECLHA) improves the neurological outcome after prolonged cardiac arrest in dogs. Resuscitation. 2006 (in press)

9. Virkkunen, I. Yri-Hankala, A. Silfast, T. Induction of therapeutic hypothermia after cardiac arrest in prehospital patients using ice-cold Ringer’s solution: a pilot study. Resuscitation, Vol. 62, 2004

10. Busch, M. Soreide, E. Lossius, HM. Lexow, K. Dickstein, K. Rapid implementation of therapeutic hypothermia in comatose out-of hospital cardiac arrest survivors. Acta Anaesthesiol Scand. Vol. 50, 2006

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