JOURNAL OF SURGICAL RESEARCH 14, 459464 (1973)

Hemorrhagic Studies with Severe Hemodilution in

Profound Hypothermia and Cardiac Arrest

HOWARD MORGAN, M.D., JOHN D. NOFZINGER, M.D.,

JAMES T. ROBERTSON, M.D. AND MARION DUGDALE, M.D.

INTRODUCTION

DURING THE EARLY 1960% profound hypothermia with cardiac arrest gained popularity in neurosurgery as an adjunct to the surgical treatment of intracranial aneu- rysms. The surgeon had the advantage of a wide operative exposure in a bloodless op- erative field. The techniques, physiology, and metabolic changes of profound hypo- thermia were described by several authori- ties [ 1, 3, 5, 7, 8, 11-141. During the late 1960’s, aneurysm surgery became more re- fined and these improvements along with the technical, metabolic and hemorrhagic problems encountered with profound hypo- thermia and cardiac arrest led to the general disuse of this procedure in neuro- surgery. Our interests in profound hypo- thermia with cardiac arrest as an adjunct to the surgical treatment of certain intra- cranial vascular lesions has continued, and we agree wit’h Sundt and coworkers who re- cently stated “. . . there are aneurysms presently considered inoperable that might be approached utilizing profound hypo- thermia . . . [and] . . . it is suggested that the approach, virtually abandoned a

From the University of Tennessee Medical Units, Departments of Neurosurgery and Hema- tology, 858 Madison Avenue, Room 231, Memphis, Tennessee 38103.

This paper was supported in part by grant 243365 1401 R05 USPHS NS06826.

The authors wish to thank Mrs. Marion John- son for her technical assistance and Drs. James Pate and J. T. Davis for their support.

Submitted for publication January 31, 1973.

decade ago, be reconsidered for selective cases” (9).

During the early part of the last decade, extensive experience was gained in our laboratory with profound hypothermia and cardiac arrest in over 700 dogs and in 10 patients. Using the closed chest technique to achieve rapid cooling and rewarming, the primary obstacle encountered was a hemorrhagic diathesis t.hat occurred fre- quently in patients and dogs at the craniot- omy site. Of course, in neurosurgery even a small ooze in a craniotomy wound may lead to disastrous consequences. The bleed- ing following hypothermic procedures ap- peared during the rewarming and in the early postoperative period. Hemorrhagic difficulties during profound hypothermia in the craniotomy wound were discussed by Drake [l] and Uihlein [lo] in 1964. This diathesis was studied extensively by Dug- dale and associates in our laboratory [2]. Clinically and experiment’ally, the bleeding was seen as a frequent but variable ooze from the craniotomy and sometimes other wounds as well and existed independent of heparinization and was elicited by both ex- tracorporeal perfusion and profound hypo- thermia, although much more so by the latter. This investigation, as well as patho- logical studies from experimental craniot- omy wounds, showed the bleeding problem was a result of a loss of platelets from the circulating blood, presumably due to se- questration and altered platelet activity, and activation of the fibrinolytic system, as

459

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460 JOURNAL OF SURGICAL RESEARCH, VOL. 14, NO. 5, MAY 1973

determined by the decreased euglobulin clot lysis time and increased activator. This diathesis was not completely controlled with the administration of epsilon amino- caproic acid (EACA), altering the fluid regime used during perfusion or the admin- istration of blood, Murphey and Nofzinger found that staging the procedure in dogs and patients lowered the incidence of bleed- ing from the craniotomy sit.e [2]. Their technique was t’o open the craniotomy elec- tively one week prior to actually operating on the aneurysm.

The present study was undertaken in an effort to circumvent the hemorrhagic prob- lems during profound hypothermia used in neurosurgery. The technique of severe hemodilution was modified from Dr. Myron B. Laver’s technique used at the Massa- chusetts General Hospital [4]. Dr. Laver has considerable laboratory and clinical ex- perience with severe hemodilution and hy- pothermia and recently used this technique with Dr. R. G. Ojemann on a neurosurgery case without bleeding difficulties.

MATERIALS AND METHODS

Seventeen adult mongrel dogs, unselected as to sex, were used in this study weighing between approximately 20 and 30 kg. Anes- thesia was induced by intravenous pento- thal 1 ml 25% solution per 5 lb body weight plus 0.4 mg of atropine. The animal was intubated and put on the automatic res- pirator using penthrane plus 95% 02 and 5% co,.

A right parietal craniotomy was done and the dura was opened with a small area of brain exposed. A temperature probe was inserted into the brain to a depth of ap- proximately 1.5 cm. Large bore catheters were placed in both femoral veins for venous drainage during perfusion; one leading to the atrium and one leading to the bifurcation of the vena cava. These were heparinized as well as a stainless-steel arterial catheter secured in the left femoral artery for inflow during perfusion. Central venous pressure (CVP) and intravenous lines were connected as shown in Fig. 1, as

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MORCTAN ET AL.: PR0F0UhTI) HYPOTHERMIA AND CARDIAC ARREST 461

well as an arterial line for blood pressure monitoring and blood withdrawal.

The dog was bled through the right femoral artery into ACD bags and the blood stored at room temperature. During this time the central venous pressure and the syst’emic blood pressure were monitored carefully and lactated Ringer’s solution with albumin (approximately 12.5 g al- bumin per 1000 cc lactated Ringer’s) was administered intravenously to maintain the blood volume. Hemodilution was continued until t’he hematocrit was approximately 20%.

After initial hemodilution was completed, the dog was put on the extracorporeal, closed-chest system and hypothermia was begun. The hematocrit was further reduced to approximately 10%. It usually required approximat#ely 30 min to cool the dog to the desired temperatures of 10% esopha- geal and brain at which time the pump and respirator were stopped. The animal was exsanguinated by draining the venous blood into the venous reservoir and oxygenator by gravity. The cardiac arrest was main- tained for 30 min.

After completion of the circulatory ar- rest, the blood in the pump was recirculated and was retooled and re-oxygenated. The dog’s blood volume was reconstituted by pumping in the blood from the venous reservoir. The heat exchanger was reversed and the rewarming cycle was started. The dog usually required external defibrillation at approximately 25% esophageal. The dog was placed back on the respirator wit,hout penthrane when there was sign of cardiac activity, and remained on the respirator unt’il he ventilated well on his own. Re- warming was continued until the dog’s brain temperature was in the range of 35”C, at which time the perfusion was stopped. The flow rates used in cooling and rewarming were in the range of 70-80 ml/kg of body weight/min. Both cooling and rewarming required about 30 min.

After the perfusion was stopped, the heparin was reversed using a dose of

protamine 1.4:1. During the early part of the rewarming period, furosemide 20 mg was administered intravenously.

After the conclusion of the rewarming perfusion, the dog’s own stored blood was given back. Care was taken at this time not to overload the heart by monitoring care- fully the CVP. The blood was given back over a 30-60-min period during which time the dog began to wake up and was extubated.

Blood studies were drawn serially during the procedure: (1) before hemodilution, (2~ after hemodilution, (3) at the begin- ning of cooling, (4) at the end of cooling when cardiorespiratory arrest was insti- tuted, (5) 1 min after the pump was re- started, (6) at the end of rewarming, (7) at the cessation of perfusion, and (8) after giving the dog back his own stored blood. These st#udies included hematocrit, fibrino- gen, phase platelet count and total serum protein. Activator, a measure of the fibrino- lytic system, was done at the beginning and at the termination of the procedure. Thrombin times were done at the conclu- sion of the procedure to check the heparin reversal.

The surviving dogs were sacrificed from 1 wk to 3 mo after the procedure. During this time all surviving dogs appeared neu- rologically normal.

RESULTS

All of the seventeen dogs survived the severe hemodilution procedure. One dog went into heart failure during the hemo- dilution, but was put on t,he extracorporeal perfusion and underwent. hypothermia. However, he died during rewarming. In this dog and in one other dog who died approxi- mately 12 hr after perfusion, death was at- tributed to fluid overload. No albumin was used in these dogs, which required a much greater volume of lactated Ringer’s solu- tion. Another dog died of aspiration of gas- tric contents following removal of the endo- tracheal tube. Two dogs died the evening

462 JOURNAL OF SURGICAL RESEARCH, VOL. 14, NO. 5, MAY 1973

Dog # Before After Blood Back

1 186 99 2 --- Dog Died --- 3 126 53 4 423 131 5 109 41 6 107 58 7 200 105 8 147 105 9 110 122

10 129 TLWe 11 77 129 12 253 180 13 59 53 14 178 99 15 --- Dog Died -L- 16 182 126 17 91 13

Fig. 2. Activator levels (mm’) before and after completion of hypothermic perfusion with severe hemodilution.

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following the perfusion, apparently due to pulmonary difficulties.

None of the 17 dogs showed any signs of significant bleeding or oozing from their craniotomy, exposed brain or other wounds. The activator levels in 13 of the 15 dogs in which it was measured actually de- creased during the perfusion (Fig. 2) in comparison to a marked increase in the ac- tivator which had been observed in hypo- thermic perfusion in the past [2].

Figure 3 illustrates the progressive changes in hematocrit or packed cell vol- ume (PCV). After giving the dog back his stored blood the hematocrit was still lower

than at the beginning of the hemodilution. This was attributed partially to some blood loss during the surgical procedures and par- tially to the hemodilution effect of the re- maining excess fluid. The fibrinogen (Fig. 4) and total protein (Fig. 5) values demon- strated a similar effect. Four dogs in which no albumin was used had a markedly lower protein during perfusion than did those

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MORGAN ET AL.: PROFOUND HYPOTHERMIA AND CARDIAC ARREST 463

dogs which did receive albumin with the lactated Ringer’s solution. The platelet count (Fig. 6) showed a profound decrease during hypothermic perfusion, even more of a drop than could be explained by hemo- dilution alone. However, after rewarming and after administration of the dog’s stored blood t,he platelet count increased markedly.

At the conclusion of the procedure, the dogs usually had an excess fluid of 2000-3000 ml and showed a corresponding weight gain. However, all of the dogs were putting out large volumes of urine by this time. All the excess fluid was lost by 12 hr after completion of the procedure and most of it was lost by 6 hr. Thrombin times drawn after administration of protamine showed adequate reversal of heparin.

CLINICAL EXPERIENCE

Using a similar closed-chest perfusion technique described above with severe hemodilution during profound hypothermia with cardiac arrest, one patient at the Uni- versity of Tennessee Medical Units re- cently underwent surgical treatment of a large basilar artery aneurysm and a small internal carotid artery aneurysm. The hemodilution and perfusion procedures went smoothly. There was no unusual bleeding from the craniotomy wound; the fibrinolytic system was not significantly ac- tivated and the platelet count was 128,000 at the conclusion of the procedure. How- ever, the patient suffered a severe post- operative deficit (right hemoplegia, dys- phasia, and left third nerve paralysis) which was attributed to trauma to mid- brain at surgery and angiographically proven severe postoperative vasospasm.

CONCLUSION

Severe hemodilution (hematocrit ap- proximately 10%) may be beneficial in preventing the hemorrhagic diathesis that frequently accompanied profound hypo- thermia procedures in neurosurgery in the past. Severe hemodilution appears to lessen

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the activation of the fibrinolytic system and a sizable part, of the patient’s own blood components (including platelets) are given back after rewarming, having es- caped the trauma of perfusion and hypo- thermia. Although most intracranial aneu- rysms can be surgically treated without hypothermia and cardiac arrest, we believe this procedure is of benefit in certain diffi- cult cases and severe hemodilution may help prevent the previously recognized, often disastrous hemorrhagic problems en- countered in the cranitomy wound.

REFERENCES

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closed-chest technique of profound hypo- thermia in neurosurgery. Anesthesiology 25: 131, 1964. 11.

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VOL. 14, NO. ;j, MAY 1973

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