Pharmacokinetics of intraosseous and central venous drug delivery during cardiopulmonary resuscitation☆☆☆

Stephen L. Hoskins, Paulo do Nascimento Jr., Rodrigo M. Lima, Jonathan M. Espana-Tenorio, George C. Kramer

Dół formularza

Received 27 January 2011; received in revised form 20 July 2011; accepted 26 July 2011. published online 26 August 2011., http://www.resuscitationjournal.com/article/S0300-9572(11)00501-6/fulltext

Article Outline

1. Abstract

2. 1. Introduction

3. 2. Methods

1. 2.1. Animal preparation

2. 2.2. Protocol

3. 2.3. Tracers

4. 2.4. Statistics

2. 3. Results

1. 3.1. Appearance times

2. 3.2. Dose delivered

2. 4. Discussion

3. 5. Conclusions

4. Conflict of interest

5. Appendix A. Supplementary data

6. References

7. Copyright

Abstract 

We compared the pharmacokinetics of intraosseous (IO) drug delivery via tibia or sternum, with central venous (CV) drug delivery during cardiopulmonary resuscitation (CPR).

Methods

CPR of anesthetized KCl arrest swine was initiated 8
min post arrest. Evans blue and indocyanine green, each were simultaneously injected as a bolus with adrenaline through IO sternal and tibial needles, respectively, n
=
7. In second group (n
=
6) simultaneous IO sternal and IV central venous (CV) injections were made.

Results

Peak arterial blood concentrations were achieved faster for sternal IO vs. tibial IO administration (53
±
11
s vs. 107
±
27
s, p
=
0.03). Tibial IO dose delivered was 65% of sternal administration (p
=
0.003). Time to peak blood concentration was similar for sternal IO and CV administration (97
±
17
s vs. 70
±
12
s, respectively; p
=
0.17) with total dose delivered of sternal being 86% of the dose delivered via CV (p
=
0.22).

Conclusions

IO drug administrations via either the sternum or tibia were effective during CPR in anesthetized swine. However, IO drug administration via the sternum was significantly faster and delivered a larger dose.

Keywords: Intraosseous, Cardiopulmonary resuscitation, CPR, Pharmacokinetics, Tracers, Drug delivery

 

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1. Introduction 

Survival from out-of-hospital cardiac arrest depends on a sequence of therapeutic interventions termed the “chain of survival” by the American Heart Association (AHA). This sequence includes rapid access to emergency medical care, cardiopulmonary resuscitation (CPR), defibrillation, advanced care, and post resuscitation techniques such as hypothermia, percutaneous coronary interventions, and implantable cardioverter-defibrilators.¹, ²Â Unfortunately, survival rates after cardiac arrests are dismal (2.5-10.5%).³, ⁴, ⁵ More rapid vascular accesses for drug delivery during CPR may be one way of improving survival.

Intravenous access during CPR can be difficult even for an experienced caregiver. In one study, the median time required to establish an intravenous (IV) line by well-trained paramedics in the field was 2
min for first attempts and 5
min when further attempts were required.⁶ The overall success rate to establish an IV line in the field for medical emergencies is less than 75%.⁶,⁷, ⁸ There remains a need for more rapid vascular accesses for drug delivery during CPR may be one way of improving survival. Intravenous access during cardiopulmonary resuscitation (CPR) can be difficult even for an experienced caregiver. Intraosseous vascular (IO) access is an established rapid, safe, and effective alternative for peripheral intravenous drug delivery.⁸, ⁹ The American Heart Association and the European Resuscitation Council Guidelines for Pediatric Life Support recommend IO access via the tibia for pediatric patients.¹², ¹³Â In the last 10 years, several large bore IO needles for adult patients have become available that use IO access via the sternum, tibia and humerus. These devices have been evaluated in both patients and animals.⁸, ¹⁰, ¹¹Â Use of these devices provides rapid access to the systemic circulation during normovolemia.⁷, ⁸, ¹⁰, ¹⁴However, the effectiveness of IO drug delivery via different anatomical sites during CPR has been under evaluation.

We used a swine model of cardiac arrest to determine the pharmacokinetics of IO delivery of a double dye tracer method during CPR using simultaneous IO injections in the sternum and tibia. We also compared the pharmacokinetics of tracer administration via the sternum vs. central venous IV administration.

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2. Methods 

2.1. Animal preparation 

The study protocol was approved by the University of Texas Medical Branch's Institutional Animal Care and Use Committee (IACUC). UTMB animal facilities are accredited by the American Association for the Accreditation of Laboratory Animal Care.

The experimental model was Yorkshire swine (25-35
kg). The night before the experiment food was withheld from the animals, though they had free access to water. Pre sedation was induced the day of the experiment by an intramuscular injection of telazol, ketamine, and xylazine. A 22 gauge peripheral intravenous catheter was placed in the ear vein to deliver fluids and alpha chloralose. The animals were anesthetized for the surgical prep with 2-4% isoflurane by facial mask and then intubated orotracheally using direct laryngoscopy. Animals were placed supine on a heating blanket to maintain body temperature between 38 and 39
°C. Surgical areas were scrubbed and covered with sterile surgical drapes. Mechanical ventilation was established at a tidal volume of 15-20
ml/kg and a ventilatory rate of 12-16
breaths/min to maintain end tidal carbon dioxide between 30 and 40
mmHg. Thereafter, isoflurane was discontinued and anesthesia was maintained with an IV infusion of 1% alpha chloralose via the catheter in the ear, administered as an initial bolus of 50
mg/kg and sustained with a continuous infusion at 10
mg/kg/h.

The carotid artery was cannulated for arterial blood sampling via an incision of the right side of the neck. A central venous catheter was placed via the external jugular vein to provide dye tracer administration into the central venous circulation. Catheters were placed into the aorta, via right femoral artery, and femoral vein for acute monitoring and recording of mean arterial pressures and drug delivery by sampling arterial blood, respectively. IO needles Jamshidi (Baxter, Deerfield, IL) or EZ-IO^® (VidaCare, San Antonio, TX) were placed in the manubrium 5
cm caudal of the sternal notch, and at 3
cm distal of the tibial tuberosity, respectively. Correct placement was confirmed by cross section at necropsy. Lactated Ringer's solution was administered at a rate of 15
ml/kg/h during surgery. Standard hemodynamics were monitored (Hewlett Packard, Andover, MA) throughout the experiments. Data were recorded via a multi channel analog-digital data acquisition program using PowerLab (AD Instruments, UK).

2.2. Protocol 

Two protocols were employed with simultaneous injections; both of them were terminal studies. Protocol I (sternum vs. tibia) compared the pharmacokinetics of two different dye tracers administered intraosseously and simultaneously via the sternum and the tibia, respectively. Protocol II (sternum vs. central venous IV) compared the pharmacokinetics of IO administration of dye tracers via the sternum with a simultaneous administration via central venous IV. A 60-min baseline time period was established after completion of instrumentation. Lactate and blood gas variables were monitored to ensure that the animals had sufficiently recovered from the surgical procedure and reached a physiologic baseline before experimental data was collected. Heparin, 10,000
units was administered IV prior to the induction of cardiac arrest. During low flow states such as cardiac arrest, blood sampling can be difficult if the lines become clotted. Prior to the induction of cardiac arrest, the animals were administered a ketamine bolus (30
mg/kg) to achieve a deeper anesthesia plane and avoid any distress during the cardiac arrest and resuscitation.

Cardiac arrest was induced by rapid IV administration of 10
ml of saturated potassium chloride (KCl) (Hospira Inc., Lake Forest, IL) solution via central venous catheter followed by a 10
ml saline flush. Immediately following the injection of KCl the electrocardiogram (EKG) displayed a typical ventricular fibrillation (VF) waveform. Ventilator support was terminated at this time. Cardiac arrest was followed by an 8-min period of untreated ventricular fibrillation. CPR was then initiated and delivered by a mechanical chest compression device (Thumper^® Michigan Instruments, Grand Rapids, MI) at 100 compressions per min (without supplemental O₂) and at duty cycle rate of 50%. A compression depth was set at 2-in. and chest compressions were delivered in an anterior/posterior position centered on the sternal body. After 1-min of CPR pre-tracer arterial blood samples were taken. The volume of solution utilized was 1.5
ml followed by a 1.0
ml of saline flush.

2.3. Tracers 

Evans blue (EB) (Sigma-Aldrich, St. Louis, MO) 5.0
mg/ml, and indocyanine green (ICG) (Alkorn, Buffalo Grove, IL) 2.5
mg/ml were used randomly in each site for the consecutive experiments as tracers to determine the relative arterial appearance times and dose delivered from the IO and central venous routes. Both ICG and EB dyes are inert and have no known biological activity. Each bolus of tracer contained 0.014
mg/kg of adrenaline (epinephrine). At 2-min post CPR (0 time point) the tracers EB and ICG were co-administered simultaneously to the designated two paired sites in Protocol I (sternal IO and tibial IO) and in Protocol II (central venous IV and sternal IO). Rapid injection of the 2-3
ml of tracer solution was immediately followed by a 1
ml flush to clear the needle. Arterial blood samples were taken every 10-s for 5
1/2
min and then at every 30-s for the remainder of the 8-min time period. After completion of the study CPR was stopped and the animal was euthanized with a high dose of ketamine and KCl.

Plasma tracer concentrations in arterial blood were determined spectrophotometrically (Beckman Coulter DU 800 spectrophotometer, Brea, CA) using absorbance wavelengths of 805
nm for ICG and 620
nm for EB. Calibration standards of EB and ICG were prepared in plasma and used to calculate the concentrations of EB and ICG from arterial blood samples. The area under the curve (AUC) of arterial tracer concentration divided by the tracer dose was used as a measure of the drug delivered to the systemic circulation during the first 8
min after drug injection (0-480
s). The ratio of the AUC for both tracers was used as a measure of the relative drug delivery.

2.4. Statistics 

Summary data are expressed as means
±
standard error of the mean (SEM). To test for differences of appearance times a paired Student's t-test was conducted. Correlation coefficients for the relationship of mean arterial pressure (MAP) to appearance time were calculated utilizing Sigma plot software (Systat Software Inc., Version 11, San Jose, CA). A two-sided alpha level of significance of <0.05 was used for assessing statistical significance.

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3. Results 

Data on appearance time and dose delivered for all individual animals and groups are presented in figures and tables.

3.1. Appearance times 

Fig. 1(A and C) and Table 1 display data for each experiment of appearance times calculated in seconds, between injection and time to peak tracer concentration, in Protocol I—sternal IO and tibial IO injections (n
=
7). Mean time to maximum concentration was 53
±
11
s for the sternal injection compared to 107
±
27
s the tibial injection. The range was from 20 to 90
s and 40 to 240
s for the sternal and tibial routes, respectively (p
=
0.03). Time to half (50%) maximum concentration was 22
±
3
s using the sternal route and 50
±
8
s for the tibial route (p
=
0.006).

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• Fig. 1. 

The two upper graphs show appearance times of tracers vs. time: Protocol-I (tibial IO vs. the sternal IO): appearance times of tracers tibia (Graph-A) vs. sternum (Graph-C). Concentrations were normalized in this figure to the maximal concentration in order to better visualize time differences to peak concentration. The two lower graphs show dose delivered to the arterial blood calculated as dose injected (mg) by aortic blood concentration (μg/ml) for the same protocol tibia (Graph-B) and sternum (Graph-D).

Table 1. Appearance times in seconds from injection to maximum tracer concentrations and half (50%) maximal concentration.

Tibial IO vs. sternal IO injection
Animal (n = 7)	Peak concentration^*		50%Peak concentration^§
	Sternum	Tibia	Sternum	Tibia
86	80	110	36	57
21	90	150	22	68
18	80	240	25	85
34	20	40	15	25
35	30	100	18	50
39	20	50	22	33
36	50	60	13	35
Mean	53	107	22	50
SEM	11	27	3	8
CI	30-75	55-158	16-27	34-65

CI, confidence interval (confidence level
=
95%); SEM, standard error of the mean.

*p = 0.03 - peak concentration - tibia vs. sternum.

§p = 0.006 - 50% peak concentration - tibia vs. sternum.

Fig. 2(A and C) and Table 2 show the appearance times of tracers for Protocol II, sternal IO and central venous IV injections (n
=
6). Mean peak time to the maximum tracer concentrations after simultaneous injections, via IO and central vein were not significantly different 97
±
17
s and 70
±
12
s, respectively (p
=
0.17). Times for tracers to reach their 50% maximal concentrations were 36
±
4
s for sternal IO and 30
±
4
s for the central vein routes (p
=
0.06).

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• Fig. 2. 

The two upper graphs show appearance times of tracers vs. time: Protocol-II (sternal IO vs. central venous IV): appearance times of tracers central venous (Graph-A) vs. sternum (Graph-C). Concentrations were normalized in this figure to the maximal concentration in order to better visualize time differences to peak concentration. The two lower graphs show dose delivered to the arterial blood calculated as dose injected (mg) by aortic blood concentration (μg/ml) for the same protocol central venous (Graph-B) and sternum (Graph-D).

Table 2. Appearance times in seconds from injection to maximum tracer concentrations and half (50%) maximal concentration.

Sternal IO vs. central venous IV injection
Animal (n = 6)	Peak concentration		50%Peak concentration
	Sternum	IV	Sternum	IV
87	100	50	36.4	24
89	70	50	34	23
105	60	50	29	28
95	110	110	52	48
110	70	90	28	27
92	170	110	38	36
Mean	97	70	36	30
SEM	17	12	4	4
CI	64-129	45-94	28-42	22-37

p
=
0.17 - peak concentration - sternum vs. central venous infusion.

p
=
0.06 - 50% peak concentration - sternum vs. central venous infusion.

CI, confidence interval (confidence level
=
95%); SEM, standard error of the mean.

3.2. Dose delivered 

Dose delivered was determined by using an area under the curve analysis (AUC) for aortic concentration divided by injected dose.

Fig. 1(B and D) and Table 3 show the doses of tracer delivery to the aortic blood, for each animal of Protocol I, calculated as AUC. The ratio of the AUC between Protocol I (tibial IO vs. sternal IO) is a measure of the relative effectiveness of dose delivery via the two routes. The tibial IO route delivered less dose to the arterial blood or 65
±
5% as compared with the sternal route, mean AUC's difference was statically significant (p
=
0.003).

Table 3. Dose delivered for tibial vs. sternal IO injections calculated as area under the curve for aortic concentration μg/ml divided by dose injected (mg) over 480
s after injection. The relative effectiveness of the two routes is shown as a ratio of the area under the curve (AUC), tibial IO divided by sternal IO.

Relative dose delivered of tracers (Tibial IO vs. sternal IO injection—AUC0-480 s)
Animal	AUC^* (μg s/ml)		Ratio
	Sternum	Tibia	Tibia/sternum
21	912	450	0.49
18	776	382	0.49
34	601	400	0.67
35	645	368	0.57
39	509	423	0.83
36	511	418	0.82
86	783	545	0.70
Mean	677	427	0.65
SEM	57	22	0.05
CI	564-789	383-470	0.6-0.7

CI, confidence interval (confidence level
=
95%); SEM, standard error of the mean.

*p = 0.003 - comparison between AUC0-480 - tibia vs. sternum.

Fig. 2(B and D) and Table 4 show the actual values and ratio of the AUC between Protocol II (sternal IO vs. central venous IV). The sternal IO route was 86
±
10% as effective as the central venous route in tracer delivery, although the mean AUCs were not significantly different (p
=
0.22).

Table 4. Dose delivered for sternal IO versus central venous IV injections calculated as area under the curve for aortic concentration μg/ml divided by dose injected (mg) over 480
seconds after injection. The relative effectiveness of the two routes is shown as a ratio of the area under the curve (AUC), sternal IO divided by central venous IV.

Relative dose delivered of tracers (sternal IO vs. central venous IV injection—AUC0-480 s)
Animal	AUC μg s/ml		Ratio
	IV	Sternum	Sternum/IV
89	694	589	0.85
105	855	939	1.10
95	879	805	0.92
110	854	783	0.92
92	956	923	0.97
87	934	385	0.41
Mean	862	737	0.86
SEM	38	87	0.10
CI	788-935	566-907	0.7-1.0

p
=
0.22 - comparison between AUC_0-480 - sternum vs. central venous infusion.

CI, confidence interval (confidence level
=
95%); SEM, standard error of the mean.

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4. Discussion 

To the best of our knowledge the present study is the first to use a double tracer technique to assess effectiveness of simultaneous drug delivery, during CPR into two IO sites.

Overall the study demonstrated that the intraosseous (IO) route is an effective means of delivering drugs during CPR for tibia and sternum IO sites.

Peripheral IV lines are the most commonly used routes for drug delivery by EMS personnel. An absence of venous blood flow and low pressure during cardiac arrest can lengthen the time to obtain peripheral IV access and delay critically needed drug therapy. Experienced medics can achieve IV access rapidly under ideal conditions. However, prehospital conditions in the field transport to hospital, and the skill levels of medics can vary widely. Clinical studies have shown that peripheral IV access times can range from 2 to 49
min.⁶, ⁷, ⁸, ¹⁵ The success rate for establishing peripheral IV access after cardiac arrest and difficult IV is variable and ranges broadly between 30 and 75% in adult⁶, ⁷, ⁸ patients, with lower success rates for the pediatric patient population 18-65%.¹⁶, ¹⁷ A prospective study of successful prehospital IV placement in 583 patients showed that the success rate at first attempt was 74% (368 patients).⁶

Physicians have long sought alternate routes for the rapid administration of drugs during cardiac emergencies, circulatory shock, and low flow states. The endotracheal route is often used as a convenient and rapid alternative for IV delivery of selected drugs. However, efficacy of endotracheal delivery of drugs is controversial.¹⁸, ¹⁹ The IO route provides access to systemic circulation via the bone marrow cavity which provides a noncollapsible delivery point into the central circulation for emergency infusions and for drug delivery in the operation room setting.²⁰ Current American Heart Association guidelines and the International Resuscitation Council Guidelines recommend the IO route as first vascular access in pediatric emergencies such a cardiac arrest.¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹Â For adult cardiac arrest IO is the first alternative when intravenous access is delayed or impossible.¹³, ²²Â The success rate when IO access is used is 81-100%⁸, ¹⁰, ¹¹Â and the time to establish a IO line varies between 20
s and 1.5
min.⁸, ¹⁰, ²³Â The most common adverse effect associated with IO infusion is extravasation and this complication has been reported in 12% of patients.²⁴ Compartment syndrome, osteomyelitis, and tibial fracture are rare, but have been reported.⁹, ²⁴, ²⁵

Voelckel et al. showed that bone marrow blood flow was reduced by 70-80% after hemorrhage.²⁶ During CPR the bone marrow flow is expected to be lower than in hemorrhagic shock. Sato et al. and Del Guercio et al. showed in dogs and humans, respectively that during CPR the cardiac output is only approximately 20-30% of normal.²⁷, ²⁸ In our study mean aortic appearance times to the peak concentration of the tracer was 97
±
17
s for the sternal IO route which was not statistically significant (p
=
0.17) compared to 70
±
12
s for central venous route. Barsan et al. showed similar result in dogs with mean time to peak times for central venous infusion of 84
s with range between 53 and 100
s.²⁹ Kuhn et al. showed that the peak concentration of dye obtained with central venous injection of indocyanine green during CPR in humans was at 30
s. However, only three patients were included on the study.³⁰ Emerman et al. demonstrated in dogs that the interval of central venous injection to first appearance of the indocyanine green during CPR was 37
±
17
s.³¹Â Zuercher et al. showed mean time from adrenaline injection to peak coronary perfusion of 60
±
6
s when the drug was delivered via IO vs. 43
±
4 after IV injection during CPR.³²Â These results are similar to our finding of time to the 50% peak concentration, i.e. central venous (30
s), sternal (22
s—Protocol I; 36
s—Protocol II), and tibia (50
s).

Some factors can affect the appearance times and the dose delivery in this study. One is that sternum is located closer to the central circulation when compared with the tibia location, which may facilitate the faster appearance of the drug on the systemic circulation when the drug is delivered into the sternum. Second, there is a difference of blood perfusion between the two bones. It is likely that the sternum perfusion is better than the tibia perfusion and this may facilitate the absorption of the drug to the systemic circulation. Gross et al. showed a wide heterogeneity of bone blood flow comparing hematopoietic cancellous bones (red marrow) such as sternum, rib, ilium, and femur epiphysis (24
ml
min^−1
100
g^−1) vs. nonhematopoietic bones (yellow marrow) such as tibia and mandible (2
ml
min^−1
100
g^−1). The authors also described a significant decrease in blood flow and an increase in vascular resistance in bone during hemorrhagic hypotension.³³

A key point during the CPR maneuvers is the quality of the chest compressions. To give effective chest compression is important that the rescuers or the devices used to perform the CPR push hard (≥5
cm) and fast (≥100/min).²²Â The chest should be allowed to recoil freely after each compression. Besides, approximately equal compressions and relaxation times should be used and interruptions in chest compressions should be minimized. If these chest compressions are not effective all the circulatory blood flow can be affected including the bone marrow flow.²², ³⁴ Any anatomic difference between the animals or any other factor that impair the dynamic of the chest compressions might result in differences in cardiac output during this period, which might consequently delay the appearance time of tracers on the systemic circulation.

The dose delivered of tracer via the IO route was similar to that delivered by central venous route. The sternal IO route delivered 86% of the tracer to the aorta compared with central vein drug delivery. However, in one animal, the ratio between sternum/central venous infusions was 0.41 (Table 4). When we exclude this outlier data point from the analysis, the resultant sternum dose delivered via the route was 95% that of the central venous. The effectiveness of the IO sternal route for drug delivery during CPR may be due to one or more factors. The red bone marrow of the sternum could provide sufficient blood flow for rapid delivery of drugs to the great veins. Further, chest compressions may facilitate the drug egress out of the marrow and into the vasculature.³⁵ Alternatively, the IO delivery of tracer may be independent of marrow blood flow. It may be that a 1.5
ml bolus of tracer followed by the 1
ml flush used in our study is sufficient volume to advance most of the tracer through the marrow, out of the injection site and into the venous circulation.

The mean dose delivered via the tibial route was 65% and 53% of the drug delivery via the sternum and central venous route, respectively. However, even for the tibial route the half maximal concentrations were achieved in less than 1
min. Andropoulos et al. used HPLC analysis for the determination of tibial adrenaline delivery during CPR in lambs. The authors determined that the maximum arterial plasma adrenaline concentrations were similar between central venous and tibial IO delivery. However, they noted reduced appearance time, after central venous administration compared to tibial IO injection after adrenaline injection.³⁶

Our measurements of appearance times and doses delivered, coupled with an additional one or more minutes for establishing a peripheral IV, suggest that even when using the slower tibial IO route, one would effectively deliver drugs into the arterial circulation during CPR in a shorter time than the time needed to successfully start a peripheral IV. As such, the tibial IO route is both an efficacious and rapid means of delivering drug therapy during CPR. The size of the saline bolus after the drug infusion may also have an important role on the time for maximum concentration of the dye. If we had used a larger flush the effectiveness of the IO tibial delivery may have increased. Wenzel et al. demonstrated comparable vasopressin plasma level and hemodynamic variables when the drug was delivered both by the intravenous and the tibial IO routes during CPR. However, the authors infused 20
ml of saline bolus compared with 1.0
ml used in the present study.³⁷

Based on the present data, we recommend that sternal IO route be considered as the first choice of drug delivery during CPR when IV access has not been established, and that the tibial IO route is also justified as second choice. The practical choices of which route to use in adults also depend on which IO devices are available. There are currently 6 adult IO devices allowed for marketing by the Food and Drug Administration (FDA). This includes two IO devices for adult sternal access (FAST1 (Pyng Medical Corp., Richmond, BC, Canada) and Sternal EZ-IO (Vidacare Corp., San Antonio, TX)) and four IO devices for tibial access (SurFast (Cook Critical Care, Bloomington, IN), Jamishidi (Baxter Allegiance, McGraw Park), Bone Injection Gun (B.I.G., Waismed, Houston, TX), EZ-IO (Vidacare Corp., San Antonio, TX)).⁹, ³⁸, ³⁹ In pediatric patients, standard butterfly needle, spinal needle, and pediatric versions of adult IO needles can be used. Most recently the humerus has been suggested as a route for IO delivery. Further work will be required to assess the relative success of this route vs. the sternal and the tibial route.

There are limitations to our study. First, swine are not humans and conclusive extrapolation to human patient responses cannot be made. The shape of the pig thorax is different from the human thorax. In pigs, the ventricles are positioned in the center of the thoracic cavity, surrounded by lung tissues on all sides. In humans, the right ventricle is positioned just under the sternum. This anatomic difference makes it more difficult to get a compression effect on the heart of pigs. Chest compressions in pigs increase intrathoracic pressure (thoracic pump mechanism), which in turns affects the heart. In humans we have not only the thoracic pump effect but also the direct heart pump mechanism affecting the heart by chest compression.³⁴ Moreover, we did not measure the plasma concentrations of adrenaline. We used dye tracers as a surrogate of drug delivery in place of the biologically active drug. However, measurement of adrenaline would preclude comparison of simultaneous injections. The significant variability of cardiac output during CPR results in an animal to animal variability of time to peak concentration and dose delivered; while simultaneous 2 tracer paired studies provides for great precision for comparing differences. Further, high background levels of endogenous adrenaline during CPR make precise assessment exogenous drug epinephrine impossible. Our study suggests that either bone marrow blood flow or the volume of injectate, or both, are sufficient for tracer delivery through the emissary veins to the superior vena cava. We studied young pigs with healthy hearts and peripheral vessels, while clinical ventricular fibrillation occurs largely in older patients with some amount of peripheral artery disease. The pig is the most often used animal model of cardiac arrest and CPR.²⁶, ³⁷ Finally, data on tibial IO injections in swine with their short legs may not be comparable to that of adult humans with longer legs farther from the heart. Blood flow in the leg and bone marrow cavities below the diaphragm could be less in humans than in pigs during CPR.

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5. Conclusions 

Both tibial and sternal IO routes are an effective means of delivering life saving drugs during CPR. Dye tracers delivered via tibial IO or sternal IO routes of anesthetized swine reached maximal concentrations in the arterial blood during CPR in less than 2
min with both, a faster and a greater dose delivered using the sternum route than with the tibial route. Sternal IO and central venous routes are not different considering pharmacokinetics of tracers during CPR in swine.

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Conflict of interest 

Dr. Kramer is an inventor on patents for intraosseous technologies and a compensated consultant to Vidacare 2007-2010.

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Appendix A. Supplementary data 

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