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The safety of intraosseous infusions: Risks of fat and bone marrow emboli to the lungs
ORIGINAL CONTRIBUTION intraosseous infusion, emboli, lungs
The Safety of Intraosseous Infusions: Risks of Fat and Bone Marrow Emboli to the Lungs The technique of intraosseous infusion is a life-saving emergency alternative when IV access is impossible or will be critically delayed. Concerns about its safety remain, especially concerning the risk of bone marrow and fat emboli to the lungs. We examined autopsy pulmonary specimens on two children who had received intraosseous infusions during resuscitation attempts and found an average of 0.23 to 0.7i bone marrow and fat emboli per m m 2 of lung. We studied normotensive dogs with intraosseous infusions of emergency drugs and solutions into the distal femur. Three dogs were studied with each of the following emergency drugs or solutions: controls with normal saline (0.9% NaCI), epinephrine 0.01 mg/kg, NaHCO 3 1 mEq/kg, CaC1 10 mg/kg, atropine 0.01 mg/kg, hydroxyethyl starch 6% in normal saline 10 mL/kg, 50% dextrose in water 0.25 g/kg, =and lidocaine i mg/kg. Four hours after infusion, the animals were killed, and representative sections of the lung were examined with oil red-O and hematoxylin and eosin stains for the presence of fat and bone marrow ernboli. Fat and bone marrow emboli were found in all lung sections, varying from 0.11 to 4.48 emboli/mm 2 lung (mean, 0.91 emboli/mm 2 lung) for the emergency drugs and solutions and 0.06 to 0.53 emboli/mm 2 (mean, 0.29 e m b o l i / m m 2 lung) for the controls. Analysis of variance revealed no significant difference (P = .07) in mean number of fat and bone marrow ernboli per square millimeter of lung among the emergency drugs and :ompared with controls. The 95% confidence limits for estimating the proportion of the population to develop bone marrow and fat emboli after intraosseous infusions is 0.89 to 1.00. Despite the universal finding of fat and bone marrow emboli in patients and animals in which emergency drugs were administered by the intraosseous route, there were no significant alterations in Pao 2 or intrapulmonary shunt during the four-hour study period. This suggests that although fat and bone marrow emboli are acommon occurrence after intraosseous drug administration, they are not of any immediate clinical importance, do not result in a pulmonary fat embolism syndrome or adult respiratory distress syndrome that might :ornpiicate resuscitation, and should not preclude the use of the intraosseous route for resuscitation drugs when l v access is delayed or impossible. However, the pulmonary fat embolism syndrome m a y complicate postresuscitation care, and bone marrow and fat emboli m a y be of clinical importance in patients with intracardiac right-to-left shunts because of 1the risk of cerebral emboli and emboli to other vital organs. Orlowski JP, Julius CJ, Petras RE, Porembka DT, Gallagher JM: The safety of intraosseous infusions: Risks of fat and bone marrow emboli to the lungs. Ann Emerg Med October 1989;I8:1062-1067.]
James P Orlowski, MD*t Carmen J Julius, MDt Robert E Petras, MDt David T Porembka, DO*lJean M Gallagher, RN*t Cleveland, Ohio From the Pediatric and Surgical Intensive Care Unit,* The Department of Pathology,t and the Division of Anesthesiology, t The Cleveland Clinic Foundation, Cleveland, Ohio. Received for publication February 27, 1989. Revision received June 2, 1989. Accepted for publication June 23, 1989. Address for reprints: James P Orlowski, MD, Director, Pediatric Intensive Care, The Cleveland Clinic Foundation, One Clinic Center -- G61-70, Cleveland, Ohio 44195-5086.
INTRODUCTION Difficulty and delay in establishing IV access is not an u n c o m m o n emergency problem, especially in pediatric patients. 1 We have recently seen the rejuvenation of intraosseous infusions as a technique for emergency access to the circulation when IV access cannot be established or will be critically delayed. 2-4 Intraosseous infusion has distinct advantages over the alternative route, intratracheal drug administration. 2 Any drug or solution that can be administered intravenously can be given by the intraosseous route, including crystalloid and colloid solutions for volume resuscitation. Intra-
18:10October 1989
Annals of Emergency Medicine
1062/73
INTRAOSSEOUS INFUSION Orlowski et al
FIGURE 1. Quantification of bone marrow and fat emboli to the lungs after intraosseous infusions of normal saline and various resuscitation drugs and solutions. Numbers of emboli per square millimeter of lung are the average results of three studies with each drug or solution.
LUNG EMBOLI
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5
FIGURE 2. Fat emboli in a pulmonary arteriole (original magnification, x 320). O~
tracheal drug administration is limited to epinephrine, atropine, lidocaine, and naloxone. Intraosseous infusions were commonplace in the 1930s and 1940s but fell out of use with the advent of improved IV needles and catheters. The only reports examining the risks of pulmonary emboli from intraosseous infusions are from older medical literature and are contradictory. A large clinical series of approximately 1,000 infusions in 495 patients reported no evidence of pulmonary emboli clinically or at autopsy in a limited number of patients; 5 other clinical studies had the same results.6, 7 However, a study in a rabbit model found pulmonary fat emboli in five of seven rabbits given arsenic by the intraosseous route. 8 Our study was designed to assess the risks of fat and bone marrow emboli to the lungs resulting from intraosseous infusions of common emergency drugs and solutions. We describe the frequency, amount, and sequelae of pulmonary fat and bone marrow emboli as a result of intraosseous infusions.
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MATERIALS A N D METHODS Thirty dogs weighing 18.4 to 26.8 kg were studied after intraosseous infusion of emergency drugs and solutions into the distal femur. Drugs administered by the intraosseous route w e r e e p i n e p h r i n e 0.01 m g / k g , N a H C O 3 1 mEq/kg, atropine 0.01 mg/kg, CaC12 10 mg/kg, lidocaine 1 mg/kg, 6% hydroxyethyl starch in normal saline 10 mL/kg, and 50% dextrose in water 0.25 g/kg. Three dogs were studied with each drug; control studies with intraosseous infusion of normal salin'6 (0.9% NaC1) were also conducted with three dogs. Additional studies with combination resuscitation drugs, epinephrine intraosseously in shock animals, and maintenance of the patency of the in74/1063
traosseous needle by pressurized infusion were also conducted. These studies were approved by the Animal Care and Research Projects Committees of the Cleveland Clinic Foundation. The animals were anesthetized with sodium pentobarbital (30 mg/ kg) and studied in the anesthetized, n o r m o t e n s i v e state. The a n i m a l s were not studied in the arrest, CPR, or shock states because shock is known to cause bone marrow riecrosis 9 and external cardiac compressions can cause rib and sternal fractures as well as pulmonary fat and bone marrow emboli.lo, 11 Although shock or cardiac arrest with CPR Annals of Emergency Medicine
would more clearly mimic the situations in which intraosseous infusions would be used, either of these states would potentially cause the complications we were looking for as a direct result of intraosseous infusions and could confound the results. We used 14-gauge reusable bone m a r r o w aspirate needles and 14gauge Jamshidi/Kormed disposable bone m a r r o w needles (American Pharmaceutical Laboratories, Glendale, California). After intraosseous administration of the drug by manual bolus push followed by a 5-mL normal saline flush, the animals were followed for four hours with sequential measurements of blood levels of 18:10 October 1989
FIGURE 3. Fat and bone m a r r o w emboli in t w o p u l m o n a r y arterioles (hem a t o x y l i n and eosin stain at original magnification, x 320). FIGURE 4. Fat and bone m a r r o w emboli in a p u l m o n a r y arteriole (original magnification, x 320).
the drug and arterial blood gases. After four hours, the animals were killed with an overdose of pentobarbital and potassium chloride, and the lungs and section of femur in which the intraosseous infusion had occurred were resected and fixed in formalin. One representative section of the right upper, right lower, left upper, and left lower lobes of the lung were routinely processed, embedded in paraffin, cut, and stained with hematoxylin and eosin (H + E). One additional random lung section was taken from each dog and stained by the oil red-0 method. Representative sections of bone surrounding the needle puncture site were placed in de!8:10October 1989
calcification solution, trimmed and routinely processed, embedded in paraffin, cut, and stained with H + E. Bone marrow and fat emboli were quantitated in the following manner. Each vascular lumen containing bone marrow or fat elements was counted. Quantitative counts were taken of the H + E-stained Sections to determine the total number of bone marrow and fat emboli per slide. Slides stained by the oil red-0 m e t h o d served to verify that areas appearing as fat emboli in H + E sections did contain fat. The total area of lung tissue per slide was measured using a digitizing pad, microcomputer, and image analysis software (R & M BioAnnals of Emergency Medicine
metrics, Nashville, Tennessee). The number of bone marrow and fat emboli per square millimeter of tissue was t h e n c a l c u l a t e d . Values expressed from both right and left lungs represent the average number of emboli per square millimeter in the total sampled lung tissue. Slides from each section of bone (one per dog studied) were examined for cortical and trabecular bone necrosis or bone marrow or marrow fat necrosis. Arterial blood gases over the four h o u r s of s t u d y w i t h the a n i m a l breathing 100% oxygen were used to c a l c u l a t e c h a n g e in Pao2, PAo 2 - Pao2, and i n t r a p u l m o n a r y shunt (Qs/Qt) as measures of clinically significant pulmonary fat embolism syndrome or adult respiratory distress syndrome. Two children who w e r e resuscitated using intraosseous infusions and CPR, but s u b s e q u e n t l y died within four hours and had autopsies, also were studied with stains and quantification of bone marrow and fat emboli in a similar manner to the dog study. Results were analyzed statistically by analysis of variance for comparing the n u m b e r of emboli among the emergency drugs and solutions and with controls and by the binomial distribution to define the 95% confidence limits for the occurrence of emboli after intraosseous infusions.
RESULTS Fat and bone marrow emboli to the lungs were found in all animals and both pediatric patients. Fat and bone marrow emboli varied from 0.11 to 4.48 emboli/mm 2 lung (mean, 0.91 e m b o l i / m m 2 lung). This compared with control values of 0.06 to 0.53 e m b o l i / m m 2 l u n g ( m e a n , 0.29 emboli/mm 2 lung). As shown (Figure 1), the combination therapy of epinephrine and sodium bicarbonate was associated with an a m o u n t of emboli to the lungs that was not only greater than other amounts but was also greater than the sum of ef1064/75
INTRAOSSEOUS INFUSION Orlowski et al
FIGURE 5. Effect of pressurized and nonpressurized m a i n t e n a n c e infusions into the intraosseous needle on the occurrence of pulmonary fat and bone m a r r o w emboli. Pressurized m a i n t e n a n c e infusions did not ii~crease the risk of emboli. fects of the drugs separately. Of the single-drug therapies, calcium chloride and lidocaine were associated with the m o s t emboli. Amazingly, sodium bicarbonate alone was associated w i t h the fewest emboli. Epinephrine intraosseously resulted in the same number of emboli whether the animal was normotensive or in shock. Even the c o n t r o l a n i m a l s w h o s e only i n t r a o s s e o u s infusion was isotonic normal saline developed bone marrow and fat emboli to the lungs. Analysis of variance indicated no significant difference (P = .07) in mean number of emboli per square millimeter of lung among the emergency drugs or solutions and compared with controls. Examples of the fat and b o n e m a r r o w e m b o l i are shown (Figures 2 through 4). We also examined the effects of pressurizing the m a i n t e n a n c e infusion into the intraosseous needle to maintain the patency of the needle throughout the four hours of study. W i t h o u t pressurization, the intraosseous needle tends to occlude and needs to be flushed manually occasionally during use. A pressurized m a i n t e n a n c e infusion did not increase the incidence of emboli in either lidocaine or epinephrine drug studies compared with nonpressurized m a i n t e n a n c e infusion (Figure 5). The examination of the section of femur into which the bone marrow needle was placed and the drug administered revealed that the greatest degree of bone marrow necrosis and hemorrhage occurred w i t h the sodium bicarbonate infusions either alone or in c o m b i n a t i o n w i t h epinephrine. The second greatest bone marrow damage occurred with 50% dextrose in w a t e r and; third, epin e p h r i n e and lidocaine. The bone marrow was normal j n some of the epinephrine, DsoW, and lidocaine infusions and in the calcium chloride and hydroxyethyl starch infusions. Ventilation-perfusion abnormalities associated with intraosseous infusions were assessed by analyzing 76H065
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a r t e r i a l b l o o d gases. As s h o w n ( T a b l e ) , t h e c h a n g e s in Pao2, PAo 2 - Pao2, and Qs/Qt were insignificant. The greatest detriment in ventilation-perfusion abnormalities resulted from NaHCO8 intraosseous infusion and resulted in an average decrease in Pao 2 of 28 m m Hg (less than 10% change), a 19 m m Hg increase in P A o 2 - P a o 2 and a 1% increase in Qs/Qt. The 95% confidence limits based on the binomial distribution revealed that one can be reasonably confident that a high proportion (0.89 to 1.00) of intraosseous infusions will result in fat and bone marrow emboli to the lungs. DISCUSSION
I n t r a o s s e o u s infusion is a technique for obtaining access to the circulation. Unlike peripheral veins, intramedullary blood vessels do not collapse in shock. Intraosseous infusion is a c t u a l l y an IV i n f u s i o n t h r o u g h blood vessels w i t h i n the bone marrow, which are held open by a rigid, noncollapsible ,bony wall. It was first described m o r e t h a n 50 years ago,12,la and most of the experimental and clinical experience with the technique was described during the 1940s. 1¢-22 These studies showed the technique of intraosseous infusion to be safe, easy, and effective. As IV catheters and needles were developed and improved during the 1950s and 1960s, intraosseous infusion was largely forgotten. With the present Annals of Emergency Medicine
resurgence of interest in the technique, animal and clinical studies have again d e m o n s t r a t e d its effectiveness. 23 While the IV route is still the route i of choice for administering drugs and l fluids, vascular access m a y be diffi-] cult or impossible to establish rap-J idly in children in circulatory col-] lapse or cardiac arrest. 1 For these c h i l d r e n and s o m e adults, intraosseous infusion is a practical and ef-i fective initial alternative. It is an ef-i fective route for the administration] of sodium bicarbonate,24, 25 calcium, I and glucose, none of which can be given by the endotracheal route. In: addition, infusions of crystalloid, colloid, blood, dopamine, 26 epinephrine, and dobutamine 26 can be given intraosseously while attempts at IV cannulation are under way. 2z Because the t e c h n i q u e of intraosseous infusion is recommended for life-threatening emergencies where vascular access is critical, there are few relative contraindications One~ of the unanswered questions about I its safety is the risk of bone marrow] and fat emboli to the lungs. The risks[ of these complications might the0.} retically be greatest with hypertonic, lipophilic, or lipolytic substances. / The only studies to address these] complications were performed in the I 1940s and produced contradictory re. I sults. Heinild et al s reported no evi-] dence of fat emboli in approximately l 1,000 pediatric infusions using post-T m o r t e m examination of patients who 18:10 October 1989
TABLE. V e n t i l a t i o n - p e r f u s i o n a b n o r m a l i t i e s occurring w i t h i n f o u r h o u r s o f intraosseous infusions
A PAO2-PaO2
A Qs/Qt (%)
-23.4
- 1.4
- 19.5
- 1.1
-28.3
+ 19.2
+ 1.1
-9.1
+2.8
+ 1.0
-23.8
- 1.4
,~ Control (3) Epinephrine (6) NaHCO 3 (3) CaCI 2 (3)
PaO2
+ 19.1 + 9.4
Hydroxyethyl starch (3)
+ 10.0
50% g l u c o s e in water (3)
-27.1
+6.6
+0.4
Lidocaine (3)
- 15.7
+ 2.2
+ 0.1
+8.9
- 16.4
- 1.0
Epinephrine, N a H C O 3, atropine (3)
died. T o c a n t i n s and O ' N e i l l 6 found no evidence of fat emboli i n 40 patients treated w i t h intraosseous infusion of blood and other fluids and at autopsy of the patients who did not survive. N e i t h e r a u t o p s y s t u d y reported specific s t a i n s for fat. Wile and Shamberg s reported that pulmonary fat emboli occurred in a rabbit model receiving arsenotherapy by intraosseous i n f u s i o n . Five of s e v e n rabbits showed p u l m o n a r y fat emboli after r e c e i v i n g a r s e n i c t h r o u g h the bone marrow. Our s t u d y i n n o r m o t e n s i v e dogs found fat and bone marrow emboli i n the l u n g s i n all a n i m a l s a n d b o t h children i n w h i c h e m e r g e n c y drugs or s o l u t i o n s were a d m i n i s t e r e d by the intraosseous route. Despite the universal f i n d i n g of fat a n d b o n e marrow emboli in the lungs after in[traosseous i n f u s i o n , there were n o s i g n i f i c a n t a l t e r a t i o n s i n Pao2, PAo2-Pao2, or Q s / Q t d u r i n g t h e bur-hour study period. This suggests that a l t h o u g h fat and bone m a r r o w emboli are a c o m m o n occurrence after intraosseous infusions, they are not of i m m e d i a t e clinical importance and do n o t result i n a p u l m o n a r y fat embolism syndrome 28 or adult respiratory d i s t r e s s s y n d r o m e , w h i c h might interfere w i t h or c o m p l i c a t e resuscitation. However, the fat embolism syndrome can take as long as 48 to 72 hours to fully manifest. 29 i Pulmonary fat e m b o l i s m , a n d bone marrow emboli from intraosseous infusion m a y c o m p l i c a t e t h e p o s t resuscitation syndrome. P u l m o n a r y at and b o n e m a r r o w e m b o l i occur with any substance administered by the i n t r a o s s e o u s route, e v e n s m a l l 18:10October 1989
a m o u n t s of isotonic, n o r m a l saline. Bone marrow and fat emboli m a y be of acute clinical i m p o r t a n c e i n pat i e n t s w i t h intracardiac right-to-left s h u n t s because of the risk of cerebral e m b o l i and e m b o l i to other organs. We have also demonstrated that the p a t e n c y of the i n t r a o s s e o u s n e e d l e can be m a i n t a i n e d by a pressurized i n f u s i o n w i t h o u t further i n c r e a s i n g the risk of bone marrow and fat emboli. There are a n u m b e r of l i m i t a t i o n s and u n a n s w e r e d questions from our study. We specifically studied n o r m a l dogs in a nonarrest, n o n s h o c k model to avoid the c o n f o u n d i n g effects of shock and CPR producing bone marrow and fat emboli. Shock can cause b o n e m a r r o w n e c r o s i s , 9 a n d CPR w i t h external cardiac c o m p r e s s i o n s can cause rib and sternal fractures w i t h p u l m o n a r y fat and bone marrow emboli.l°, n Shock or cardiac arrest w i t h CPR would more closely m i m i c the situations in which intraosseous i n f u s i o n s are u s u a l l y used, and we are u n a b l e to answer whether shock a n d / o r CPR w o u l d i n c r e a s e or decrease the risk of bone marrow and fat emboli to the lungs. Shock or ext e r n a l cardiac c o m p r e s s i o n s m i g h t have an a d d i t i v e effect w i t h i n t r a osseous infusions, or the reduced perfusion m i g h t reduce the n u m b e r of emboli. Our prestudy review of the literature suggested that fat and bone marrow emboli to the lungs after intraosseous i n f u s i o n was a rare occurrence, and so we used n o r m a l saline • infusions as a control. In retrospect, a better control group would have been arrested or shocked a n i m a l s w i t h o u t Annals of
EmergencyMedicine
intraosseous infusions. The small n u m b e r of a n i m a l s studied w i t h each drug (three) is also a l i m i t a t i o n , alt h o u g h s t a t i s t i c a l a n a l y s i s of t h e 95% confidence limits suggests that 89% to 100% of i n t r a o s s e o u s infusions will result i n fat and bone marr o w e m b o l i to t h e l u n g s . Fat a n d b o n e m a r r o w e m b o l i to the l u n g s m u s t be specifically sought by specialized stains and directed a t t e n t i o n or they will be missed. The presence of b o n e m a r r o w a n d fat e m b o l i is such a universal finding that their absence suggests that the needle was n o t i n the bone m a r r o w d u r i n g adm i n i s t r a t i o n of drugs and fluids. CONCLUSION Fat and bone marrow emboli are a f r e q u e n t c o m p l i c a t i o n of i n t r a osseous infusions. T h e i r occurrence is not related to the drug or solution infused, and pressurized mainten a n c e infusion into the intraosseous n e e d l e does n o t i n c r e a s e the i n c i dence or a m o u n t of emboli. Despite the u n i v e r s a l occurrence of emboli, t h e y do n o t appear to be of a c u t e clinical i m p o r t a n c e and should n o t interfere w i t h the success of resusc i t a t i o n , except p o t e n t i a l l y i n pat i e n t s w i t h intracardiac right-to-left shunts.
REFERENCES
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cardiac resuscitation. A m Heart J 1975;89: 263-264. 12. Drinker CK, Drinker KR, Lund CC: The circulation in the mammalian bone marrow. Am J Physiol 1922;62:1-92. 13. Josefson A: A new method of treatment Intraossal injections. Acta Medica Scand 1934; 81:550-564. 14. Arbeiter HI, Greengard J: TibiaI bone marrow infusions in infancy. J Pediatr 1944;25:1-12. 15. Elston JT, Jaynes RV, Kaump DH, et al: Intraosseous infusions in infants. A m J Clin Pathol 1947;17:143-150. 16. Gimson JD: Bone-marrow transfusion in infants and children. Br Med J 1944;h748-749. 17. Gunz FW, Dean RFA: Tibial bone-marrow transfusions in infants. Br Med J 1945;1:220-221. 18. Meola P: Bone marrow infusions as a routine procedure in children. J Pediatr 1944;25:
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13-16. 19. Papper EM: The bone marrow route for injecting fluids and drugs into the general circulation. Anesthesiology 1942;3:307-313. 20. Tocantins LM, O'Neill JF: Complications of i n t r a o s s e o u s therapy. Ann Surg 1945;122: 266-277. 21. Tocantins LM, O'Neill JF, Jones HW: Infusions of blood and other fluids via the bone marrow. JAMA 1941;117:1229-1234. 22. Tocantins LM, O'Neill JF, Price AH: Infusions of blood and other fluids via the bone marrow in traumatic shock and other forms of peripheral circulatory failure. Ann Surg 1941; 114:1085-1092. 23. Shoot PM, B e rryhi l l RE, Benumof JL: Intraosseous infusion: Pressure-flow relationship and pharmacokinetics. J Trauma 1979; 19:772-774.
Annals of Emergency Medicine
24. Thompson BM, Rosetti V, Miller J, et al: Intraosseous administration of sodium bicarbonate: An effective means of pH normalization in the canine model. Ann Emerg Med 1984;13:405. 25. Spivey WH, Lathers CM, Malone D, et ah Comparison of intraosseous, central and peripheral routes of administration of sodium bicarbonate during CPR in pigs. Ann Emerg Med 1985;14:1135-1140. 26. Berg RA: E m e r g e n c y i n f u s i o n of catecholamines into bone marrow. Am J Dis Child 1984;138:810-811. 27. Hodge D: Intraosseous infusions: A review. Pediatr Emerg Care 1985;1:215-218. 28. Pollack R, Myers RAM: Early diagnosis of the fat embolism syndrome. J Trauma 1978;18: 121-123. 29. Peltier LF: The classic fat embolism: An appraisal of the problem. Clin Orthop 1984; 187:3-17.
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The Safety of Intraosseous Infusions: Risks of Fat and Bone Marrow Emboli to the Lungs The technique of intraosseous infusion is a life-saving emergency alternative when IV access is impossible or will be critically delayed. Concerns about its safety remain, especially concerning the risk of bone marrow and fat emboli to the lungs. We examined autopsy pulmonary specimens on two children who had received intraosseous infusions during resuscitation attempts and found an average of 0.23 to 0.7i bone marrow and fat emboli per m m 2 of lung. We studied normotensive dogs with intraosseous infusions of emergency drugs and solutions into the distal femur. Three dogs were studied with each of the following emergency drugs or solutions: controls with normal saline (0.9% NaCI), epinephrine 0.01 mg/kg, NaHCO 3 1 mEq/kg, CaC1 10 mg/kg, atropine 0.01 mg/kg, hydroxyethyl starch 6% in normal saline 10 mL/kg, 50% dextrose in water 0.25 g/kg, =and lidocaine i mg/kg. Four hours after infusion, the animals were killed, and representative sections of the lung were examined with oil red-O and hematoxylin and eosin stains for the presence of fat and bone marrow ernboli. Fat and bone marrow emboli were found in all lung sections, varying from 0.11 to 4.48 emboli/mm 2 lung (mean, 0.91 emboli/mm 2 lung) for the emergency drugs and solutions and 0.06 to 0.53 emboli/mm 2 (mean, 0.29 e m b o l i / m m 2 lung) for the controls. Analysis of variance revealed no significant difference (P = .07) in mean number of fat and bone marrow ernboli per square millimeter of lung among the emergency drugs and :ompared with controls. The 95% confidence limits for estimating the proportion of the population to develop bone marrow and fat emboli after intraosseous infusions is 0.89 to 1.00. Despite the universal finding of fat and bone marrow emboli in patients and animals in which emergency drugs were administered by the intraosseous route, there were no significant alterations in Pao 2 or intrapulmonary shunt during the four-hour study period. This suggests that although fat and bone marrow emboli are acommon occurrence after intraosseous drug administration, they are not of any immediate clinical importance, do not result in a pulmonary fat embolism syndrome or adult respiratory distress syndrome that might :ornpiicate resuscitation, and should not preclude the use of the intraosseous route for resuscitation drugs when l v access is delayed or impossible. However, the pulmonary fat embolism syndrome m a y complicate postresuscitation care, and bone marrow and fat emboli m a y be of clinical importance in patients with intracardiac right-to-left shunts because of 1the risk of cerebral emboli and emboli to other vital organs. Orlowski JP, Julius CJ, Petras RE, Porembka DT, Gallagher JM: The safety of intraosseous infusions: Risks of fat and bone marrow emboli to the lungs. Ann Emerg Med October 1989;I8:1062-1067.]
James P Orlowski, MD*t Carmen J Julius, MDt Robert E Petras, MDt David T Porembka, DO*lJean M Gallagher, RN*t Cleveland, Ohio From the Pediatric and Surgical Intensive Care Unit,* The Department of Pathology,t and the Division of Anesthesiology, t The Cleveland Clinic Foundation, Cleveland, Ohio. Received for publication February 27, 1989. Revision received June 2, 1989. Accepted for publication June 23, 1989. Address for reprints: James P Orlowski, MD, Director, Pediatric Intensive Care, The Cleveland Clinic Foundation, One Clinic Center -- G61-70, Cleveland, Ohio 44195-5086.
INTRODUCTION Difficulty and delay in establishing IV access is not an u n c o m m o n emergency problem, especially in pediatric patients. 1 We have recently seen the rejuvenation of intraosseous infusions as a technique for emergency access to the circulation when IV access cannot be established or will be critically delayed. 2-4 Intraosseous infusion has distinct advantages over the alternative route, intratracheal drug administration. 2 Any drug or solution that can be administered intravenously can be given by the intraosseous route, including crystalloid and colloid solutions for volume resuscitation. Intra-
18:10October 1989
Annals of Emergency Medicine
1062/73
INTRAOSSEOUS INFUSION Orlowski et al
FIGURE 1. Quantification of bone marrow and fat emboli to the lungs after intraosseous infusions of normal saline and various resuscitation drugs and solutions. Numbers of emboli per square millimeter of lung are the average results of three studies with each drug or solution.
LUNG EMBOLI
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5
FIGURE 2. Fat emboli in a pulmonary arteriole (original magnification, x 320). O~
tracheal drug administration is limited to epinephrine, atropine, lidocaine, and naloxone. Intraosseous infusions were commonplace in the 1930s and 1940s but fell out of use with the advent of improved IV needles and catheters. The only reports examining the risks of pulmonary emboli from intraosseous infusions are from older medical literature and are contradictory. A large clinical series of approximately 1,000 infusions in 495 patients reported no evidence of pulmonary emboli clinically or at autopsy in a limited number of patients; 5 other clinical studies had the same results.6, 7 However, a study in a rabbit model found pulmonary fat emboli in five of seven rabbits given arsenic by the intraosseous route. 8 Our study was designed to assess the risks of fat and bone marrow emboli to the lungs resulting from intraosseous infusions of common emergency drugs and solutions. We describe the frequency, amount, and sequelae of pulmonary fat and bone marrow emboli as a result of intraosseous infusions.
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MATERIALS A N D METHODS Thirty dogs weighing 18.4 to 26.8 kg were studied after intraosseous infusion of emergency drugs and solutions into the distal femur. Drugs administered by the intraosseous route w e r e e p i n e p h r i n e 0.01 m g / k g , N a H C O 3 1 mEq/kg, atropine 0.01 mg/kg, CaC12 10 mg/kg, lidocaine 1 mg/kg, 6% hydroxyethyl starch in normal saline 10 mL/kg, and 50% dextrose in water 0.25 g/kg. Three dogs were studied with each drug; control studies with intraosseous infusion of normal salin'6 (0.9% NaC1) were also conducted with three dogs. Additional studies with combination resuscitation drugs, epinephrine intraosseously in shock animals, and maintenance of the patency of the in74/1063
traosseous needle by pressurized infusion were also conducted. These studies were approved by the Animal Care and Research Projects Committees of the Cleveland Clinic Foundation. The animals were anesthetized with sodium pentobarbital (30 mg/ kg) and studied in the anesthetized, n o r m o t e n s i v e state. The a n i m a l s were not studied in the arrest, CPR, or shock states because shock is known to cause bone marrow riecrosis 9 and external cardiac compressions can cause rib and sternal fractures as well as pulmonary fat and bone marrow emboli.lo, 11 Although shock or cardiac arrest with CPR Annals of Emergency Medicine
would more clearly mimic the situations in which intraosseous infusions would be used, either of these states would potentially cause the complications we were looking for as a direct result of intraosseous infusions and could confound the results. We used 14-gauge reusable bone m a r r o w aspirate needles and 14gauge Jamshidi/Kormed disposable bone m a r r o w needles (American Pharmaceutical Laboratories, Glendale, California). After intraosseous administration of the drug by manual bolus push followed by a 5-mL normal saline flush, the animals were followed for four hours with sequential measurements of blood levels of 18:10 October 1989
FIGURE 3. Fat and bone m a r r o w emboli in t w o p u l m o n a r y arterioles (hem a t o x y l i n and eosin stain at original magnification, x 320). FIGURE 4. Fat and bone m a r r o w emboli in a p u l m o n a r y arteriole (original magnification, x 320).
the drug and arterial blood gases. After four hours, the animals were killed with an overdose of pentobarbital and potassium chloride, and the lungs and section of femur in which the intraosseous infusion had occurred were resected and fixed in formalin. One representative section of the right upper, right lower, left upper, and left lower lobes of the lung were routinely processed, embedded in paraffin, cut, and stained with hematoxylin and eosin (H + E). One additional random lung section was taken from each dog and stained by the oil red-0 method. Representative sections of bone surrounding the needle puncture site were placed in de!8:10October 1989
calcification solution, trimmed and routinely processed, embedded in paraffin, cut, and stained with H + E. Bone marrow and fat emboli were quantitated in the following manner. Each vascular lumen containing bone marrow or fat elements was counted. Quantitative counts were taken of the H + E-stained Sections to determine the total number of bone marrow and fat emboli per slide. Slides stained by the oil red-0 m e t h o d served to verify that areas appearing as fat emboli in H + E sections did contain fat. The total area of lung tissue per slide was measured using a digitizing pad, microcomputer, and image analysis software (R & M BioAnnals of Emergency Medicine
metrics, Nashville, Tennessee). The number of bone marrow and fat emboli per square millimeter of tissue was t h e n c a l c u l a t e d . Values expressed from both right and left lungs represent the average number of emboli per square millimeter in the total sampled lung tissue. Slides from each section of bone (one per dog studied) were examined for cortical and trabecular bone necrosis or bone marrow or marrow fat necrosis. Arterial blood gases over the four h o u r s of s t u d y w i t h the a n i m a l breathing 100% oxygen were used to c a l c u l a t e c h a n g e in Pao2, PAo 2 - Pao2, and i n t r a p u l m o n a r y shunt (Qs/Qt) as measures of clinically significant pulmonary fat embolism syndrome or adult respiratory distress syndrome. Two children who w e r e resuscitated using intraosseous infusions and CPR, but s u b s e q u e n t l y died within four hours and had autopsies, also were studied with stains and quantification of bone marrow and fat emboli in a similar manner to the dog study. Results were analyzed statistically by analysis of variance for comparing the n u m b e r of emboli among the emergency drugs and solutions and with controls and by the binomial distribution to define the 95% confidence limits for the occurrence of emboli after intraosseous infusions.
RESULTS Fat and bone marrow emboli to the lungs were found in all animals and both pediatric patients. Fat and bone marrow emboli varied from 0.11 to 4.48 emboli/mm 2 lung (mean, 0.91 e m b o l i / m m 2 lung). This compared with control values of 0.06 to 0.53 e m b o l i / m m 2 l u n g ( m e a n , 0.29 emboli/mm 2 lung). As shown (Figure 1), the combination therapy of epinephrine and sodium bicarbonate was associated with an a m o u n t of emboli to the lungs that was not only greater than other amounts but was also greater than the sum of ef1064/75
INTRAOSSEOUS INFUSION Orlowski et al
FIGURE 5. Effect of pressurized and nonpressurized m a i n t e n a n c e infusions into the intraosseous needle on the occurrence of pulmonary fat and bone m a r r o w emboli. Pressurized m a i n t e n a n c e infusions did not ii~crease the risk of emboli. fects of the drugs separately. Of the single-drug therapies, calcium chloride and lidocaine were associated with the m o s t emboli. Amazingly, sodium bicarbonate alone was associated w i t h the fewest emboli. Epinephrine intraosseously resulted in the same number of emboli whether the animal was normotensive or in shock. Even the c o n t r o l a n i m a l s w h o s e only i n t r a o s s e o u s infusion was isotonic normal saline developed bone marrow and fat emboli to the lungs. Analysis of variance indicated no significant difference (P = .07) in mean number of emboli per square millimeter of lung among the emergency drugs or solutions and compared with controls. Examples of the fat and b o n e m a r r o w e m b o l i are shown (Figures 2 through 4). We also examined the effects of pressurizing the m a i n t e n a n c e infusion into the intraosseous needle to maintain the patency of the needle throughout the four hours of study. W i t h o u t pressurization, the intraosseous needle tends to occlude and needs to be flushed manually occasionally during use. A pressurized m a i n t e n a n c e infusion did not increase the incidence of emboli in either lidocaine or epinephrine drug studies compared with nonpressurized m a i n t e n a n c e infusion (Figure 5). The examination of the section of femur into which the bone marrow needle was placed and the drug administered revealed that the greatest degree of bone marrow necrosis and hemorrhage occurred w i t h the sodium bicarbonate infusions either alone or in c o m b i n a t i o n w i t h epinephrine. The second greatest bone marrow damage occurred with 50% dextrose in w a t e r and; third, epin e p h r i n e and lidocaine. The bone marrow was normal j n some of the epinephrine, DsoW, and lidocaine infusions and in the calcium chloride and hydroxyethyl starch infusions. Ventilation-perfusion abnormalities associated with intraosseous infusions were assessed by analyzing 76H065
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a r t e r i a l b l o o d gases. As s h o w n ( T a b l e ) , t h e c h a n g e s in Pao2, PAo 2 - Pao2, and Qs/Qt were insignificant. The greatest detriment in ventilation-perfusion abnormalities resulted from NaHCO8 intraosseous infusion and resulted in an average decrease in Pao 2 of 28 m m Hg (less than 10% change), a 19 m m Hg increase in P A o 2 - P a o 2 and a 1% increase in Qs/Qt. The 95% confidence limits based on the binomial distribution revealed that one can be reasonably confident that a high proportion (0.89 to 1.00) of intraosseous infusions will result in fat and bone marrow emboli to the lungs. DISCUSSION
I n t r a o s s e o u s infusion is a technique for obtaining access to the circulation. Unlike peripheral veins, intramedullary blood vessels do not collapse in shock. Intraosseous infusion is a c t u a l l y an IV i n f u s i o n t h r o u g h blood vessels w i t h i n the bone marrow, which are held open by a rigid, noncollapsible ,bony wall. It was first described m o r e t h a n 50 years ago,12,la and most of the experimental and clinical experience with the technique was described during the 1940s. 1¢-22 These studies showed the technique of intraosseous infusion to be safe, easy, and effective. As IV catheters and needles were developed and improved during the 1950s and 1960s, intraosseous infusion was largely forgotten. With the present Annals of Emergency Medicine
resurgence of interest in the technique, animal and clinical studies have again d e m o n s t r a t e d its effectiveness. 23 While the IV route is still the route i of choice for administering drugs and l fluids, vascular access m a y be diffi-] cult or impossible to establish rap-J idly in children in circulatory col-] lapse or cardiac arrest. 1 For these c h i l d r e n and s o m e adults, intraosseous infusion is a practical and ef-i fective initial alternative. It is an ef-i fective route for the administration] of sodium bicarbonate,24, 25 calcium, I and glucose, none of which can be given by the endotracheal route. In: addition, infusions of crystalloid, colloid, blood, dopamine, 26 epinephrine, and dobutamine 26 can be given intraosseously while attempts at IV cannulation are under way. 2z Because the t e c h n i q u e of intraosseous infusion is recommended for life-threatening emergencies where vascular access is critical, there are few relative contraindications One~ of the unanswered questions about I its safety is the risk of bone marrow] and fat emboli to the lungs. The risks[ of these complications might the0.} retically be greatest with hypertonic, lipophilic, or lipolytic substances. / The only studies to address these] complications were performed in the I 1940s and produced contradictory re. I sults. Heinild et al s reported no evi-] dence of fat emboli in approximately l 1,000 pediatric infusions using post-T m o r t e m examination of patients who 18:10 October 1989
TABLE. V e n t i l a t i o n - p e r f u s i o n a b n o r m a l i t i e s occurring w i t h i n f o u r h o u r s o f intraosseous infusions
A PAO2-PaO2
A Qs/Qt (%)
-23.4
- 1.4
- 19.5
- 1.1
-28.3
+ 19.2
+ 1.1
-9.1
+2.8
+ 1.0
-23.8
- 1.4
,~ Control (3) Epinephrine (6) NaHCO 3 (3) CaCI 2 (3)
PaO2
+ 19.1 + 9.4
Hydroxyethyl starch (3)
+ 10.0
50% g l u c o s e in water (3)
-27.1
+6.6
+0.4
Lidocaine (3)
- 15.7
+ 2.2
+ 0.1
+8.9
- 16.4
- 1.0
Epinephrine, N a H C O 3, atropine (3)
died. T o c a n t i n s and O ' N e i l l 6 found no evidence of fat emboli i n 40 patients treated w i t h intraosseous infusion of blood and other fluids and at autopsy of the patients who did not survive. N e i t h e r a u t o p s y s t u d y reported specific s t a i n s for fat. Wile and Shamberg s reported that pulmonary fat emboli occurred in a rabbit model receiving arsenotherapy by intraosseous i n f u s i o n . Five of s e v e n rabbits showed p u l m o n a r y fat emboli after r e c e i v i n g a r s e n i c t h r o u g h the bone marrow. Our s t u d y i n n o r m o t e n s i v e dogs found fat and bone marrow emboli i n the l u n g s i n all a n i m a l s a n d b o t h children i n w h i c h e m e r g e n c y drugs or s o l u t i o n s were a d m i n i s t e r e d by the intraosseous route. Despite the universal f i n d i n g of fat a n d b o n e marrow emboli in the lungs after in[traosseous i n f u s i o n , there were n o s i g n i f i c a n t a l t e r a t i o n s i n Pao2, PAo2-Pao2, or Q s / Q t d u r i n g t h e bur-hour study period. This suggests that a l t h o u g h fat and bone m a r r o w emboli are a c o m m o n occurrence after intraosseous infusions, they are not of i m m e d i a t e clinical importance and do n o t result i n a p u l m o n a r y fat embolism syndrome 28 or adult respiratory d i s t r e s s s y n d r o m e , w h i c h might interfere w i t h or c o m p l i c a t e resuscitation. However, the fat embolism syndrome can take as long as 48 to 72 hours to fully manifest. 29 i Pulmonary fat e m b o l i s m , a n d bone marrow emboli from intraosseous infusion m a y c o m p l i c a t e t h e p o s t resuscitation syndrome. P u l m o n a r y at and b o n e m a r r o w e m b o l i occur with any substance administered by the i n t r a o s s e o u s route, e v e n s m a l l 18:10October 1989
a m o u n t s of isotonic, n o r m a l saline. Bone marrow and fat emboli m a y be of acute clinical i m p o r t a n c e i n pat i e n t s w i t h intracardiac right-to-left s h u n t s because of the risk of cerebral e m b o l i and e m b o l i to other organs. We have also demonstrated that the p a t e n c y of the i n t r a o s s e o u s n e e d l e can be m a i n t a i n e d by a pressurized i n f u s i o n w i t h o u t further i n c r e a s i n g the risk of bone marrow and fat emboli. There are a n u m b e r of l i m i t a t i o n s and u n a n s w e r e d questions from our study. We specifically studied n o r m a l dogs in a nonarrest, n o n s h o c k model to avoid the c o n f o u n d i n g effects of shock and CPR producing bone marrow and fat emboli. Shock can cause b o n e m a r r o w n e c r o s i s , 9 a n d CPR w i t h external cardiac c o m p r e s s i o n s can cause rib and sternal fractures w i t h p u l m o n a r y fat and bone marrow emboli.l°, n Shock or cardiac arrest w i t h CPR would more closely m i m i c the situations in which intraosseous i n f u s i o n s are u s u a l l y used, and we are u n a b l e to answer whether shock a n d / o r CPR w o u l d i n c r e a s e or decrease the risk of bone marrow and fat emboli to the lungs. Shock or ext e r n a l cardiac c o m p r e s s i o n s m i g h t have an a d d i t i v e effect w i t h i n t r a osseous infusions, or the reduced perfusion m i g h t reduce the n u m b e r of emboli. Our prestudy review of the literature suggested that fat and bone marrow emboli to the lungs after intraosseous i n f u s i o n was a rare occurrence, and so we used n o r m a l saline • infusions as a control. In retrospect, a better control group would have been arrested or shocked a n i m a l s w i t h o u t Annals of
EmergencyMedicine
intraosseous infusions. The small n u m b e r of a n i m a l s studied w i t h each drug (three) is also a l i m i t a t i o n , alt h o u g h s t a t i s t i c a l a n a l y s i s of t h e 95% confidence limits suggests that 89% to 100% of i n t r a o s s e o u s infusions will result i n fat and bone marr o w e m b o l i to t h e l u n g s . Fat a n d b o n e m a r r o w e m b o l i to the l u n g s m u s t be specifically sought by specialized stains and directed a t t e n t i o n or they will be missed. The presence of b o n e m a r r o w a n d fat e m b o l i is such a universal finding that their absence suggests that the needle was n o t i n the bone m a r r o w d u r i n g adm i n i s t r a t i o n of drugs and fluids. CONCLUSION Fat and bone marrow emboli are a f r e q u e n t c o m p l i c a t i o n of i n t r a osseous infusions. T h e i r occurrence is not related to the drug or solution infused, and pressurized mainten a n c e infusion into the intraosseous n e e d l e does n o t i n c r e a s e the i n c i dence or a m o u n t of emboli. Despite the u n i v e r s a l occurrence of emboli, t h e y do n o t appear to be of a c u t e clinical i m p o r t a n c e and should n o t interfere w i t h the success of resusc i t a t i o n , except p o t e n t i a l l y i n pat i e n t s w i t h intracardiac right-to-left shunts.
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Annals of Emergency Medicine
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