SBIR Proposal
IV Cooling System for Hypothermia
Steve Huppman
Jermaine Johnson
Sylvia Kang
Erin Wacker
Advisor: Dr. James Menegazzi
April 17, 2007
Table of Contents
Specific Aims 3
Significance 6
Preliminary Work 9
Methods 11
Results .………...... 17
Conclusion …………………………………………………………………………………... 21
References 22
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.
Our Phase I specific aims are:
1. Design an IV cooling system for cardiac arrest patients to achieve the following goals:
Ø Selection of the concentration of ammonium nitrate in the coolant solution.
l 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.
Ø Amount of tubing needed and the design of the device.
l 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.
Ø The size of the casing and material selection.
l 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.
Ø 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.
Ø A SolidWorks model will be created.
Ø 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.
Ø 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.
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 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 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.
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 / 14.0
2 / 18.6
4 / 18.6
Trial 1 (pressurized)
Time (min / Temperature (°C)0 / 20.2
2 / 20.2
Trial 2 (unpressurized, gravity driven):
Time (min) / Temperature (°C)1 / 19.6
2 / 19.5
Trial 2 (pressurized)
Time (min) / Temperature (°C)0 / 20.1
1 / 19.8
2 / 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.
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 / 500
2 / 666 / 333
3 / 333 / 666
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
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) 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.
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.