use of bretylium tosylate as prophylaxis and treatment in hypothermic ventricular fibrillation in...

ORIGINAL CONTRIBUTION bretylium tosylate, for hypothermic VF; hypothermia, ventricular fibrillation, bretylium tosylate; ventricular fibrillation, hypothermic, bretylium tosylate

Use of Bretylium Tosylate as Prophylaxis and Treatment in Hypothermic Ventricular Fibrillation in the Canine Model

We conducted a study to determine ff bretylium tosylate (BT) is effective in the prophylaxis and treatment of hypothermic ventricular fibrillation (VF) in the setting of various maneuvers thought to induce this lethal arrhythmia. Twenty-two mongrel dogs were cooled to 24 C after being placed in a cold room. A t 24 C, a double-blinded placebo or BT solution was infused. The dogs then were removed from the cold. They underwent the following se- quential maneuvers: oral endotracheal extubation and intubation, central line and nasogastric tube placement, vigorous movement, and Swan-Ganz catheter insertion, ff VF ensued, arterial blood gases were drawn, and BT was given only if refractory to countershock and epinephrine. Of the dogs that were given placebo, six of I1 (55%) fibrillated with manipulation, as compared with one of 11 (9%) dogs pretreated with BT (P = .067). Three of the 1I dogs that received BT fibrillated within minutes of its infusion. In the placebo dogs that fibrillated, four required BT and two defibrillated with countershock alone or with epinephrine prior to achieving stable rhythms. ]Murphy K, Nowak RM, Tomlanovich MC: Use of bretylium tosylate as prophylaxis and treatment in hypothermic ventricular fibrillation in the canine model. Ann Emerg Med October 1986;15:1160-1166.]

INTRODUCTION The major cause of mortality in accidental hypothermia is ventricular

fibrillation (VF). 1 This lethal arrhythmia has been observed to follow endotracheal intubation,~, 3 electrical pacing,4, s movement, cardiac massage,6, z ac- tive external rewarming, and central line and nasogastric tube placement. 6 Controversy prevails regarding the real threat of performing these therapeutic maneuvers in the profoundly hypothermic patient. More aggressive rewarming methods (eg, warm humidified air by endotracheal intubation, warm cen- trally administered IV fluids) may even be postponed or abandoned because of the possibility of VF inherent in each technique.

Despite the often grave prognosis of patients with hypothermic VF, many authors have agreed that the use of most drags for its treatment is not warranted.2, s-15 Bretylium tosylate (BT), a bromobenzyl quaternary ammonium compound, is unique among antiarrhythmics in its efficacy in increasing the fibrillation threshold in hypothermic cats 16 as well as in the prophylaxis and treatment of hypothermic VF in dogs. lz These studies had limitations with regard to accidental hypothermia in that the BT was given during normothermia prior to cold induction, unphysiological when considering a drug to be given after recognition of the hypothermic state. A recent case report, however, cites spontaneous defibrillation in a profoundly hypothermic patient with the use of BTJ8 Our study was performed to evaluate whether pretreat- rnent BT in the dog during profound hypothermia would be effective in both prevention and treatment of VF in the setting of clinically relevant procedures.

MATERIALS AND METHODS Twenty-two conditioned adult mongrel dogs were cooled to 24 C with a

technique previously described.19 At 24 C, arterial blood gases were drawn, serum electrolytes were obtained, the time was recorded, and a 15-minute infusion of 18 mL (900 mg) (mean, 419.5 mg/kg) of a double-blind saline or BT was begun. At this time the dog was removed from the cold room and

Kathleen Murphy, MD* Richard M Nowak, MD, FACEP1- Michael C Tomlanovich, MD, FACEPt Detroit, Michigan

From the Department of Emergency Medicine, Tucson Medical Center, Tucson, Arizona;* and the Department of Emergency Medicine, Henry Ford Hospital, Detroit, Michigan.t

Received for publication August 20, 1985. Revision received February 17, 1986. Accepted for publication March 10, 1986.

Presented at the Scientific Assembly of the American College of Emergency Physicians in Dallas, Texas, October 1984.

Address for reprints: Richard M Nowak, MD, FACEE Department of Emergency Medicine, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202.

15:10October 1986 Annals of Emergency Medicine 1160/51

BRETYLIUM TOSYLATE Murphy, Nowak & Tomlanovich

FIGURE 1. VF induced by Swan-Ganz catheterization in placebo dog (22 C).

FIGURE 2. Ventricular irritability in the form of premature ventricular con- tractions observed early during cold induction.

wheeled, with venti latory apparatus, out into the spacious laboratory cor- r idor . D u r i n g t h e i n f u s i o n and throughout the remainder of the experiment the dog was intubated endo- t racheal ly and vent i la ted artificially wi th an LP-3 portable vo lume ventilator (Ventilator Life Products, Inc, Boulder, Colorado). The oxygen supply was provided by a portable oxygen H- tank with connecting tubing from the tank to the ventilator by a flow meter and maintained at approximately 6 L O2/min. A continuous ECG was recorded by limb leads using a cardiac monitor. Cont inuous blood pressure recording was enabled by a Statham Gould P-23 ID strain gauge to a blood pressure amplifier. Cont inuous read- outs on paper of blood pressure, pulse, and hemodynamic wave forms were available through a Gould Brush 280 analogue strip chart polygraph record- er. A probe was placed 8 cm into the rectum for continuous temperature record ing us ing a YSI t h e r m o m e t e r probe.

Approximately ten minutes following the infusion of the unknown solution, five maneuvers were performed in sequence and blood pressure and ECG changes were recorded. This sequence of maneuvers was not inter- mpted except for the brief minute required to record hemodynamic param- eters and to assemble equipment and manpower. To begin, oral endotracheal ex tubat ion of the dog was followed i m m e d i a t e l y by r e in tuba t ion by a skilled animal technician. A central line was placed through the right external jugular vein with a 14-gauge 20- cm catheter. A #16 Levine nasogastric tube was passed to the distal esopha- gus at a length premeasured in a sacri-

ficed dog in this designated position. The dog then underwent four vigorous chest-roll movements with one back- and- for th m o v e m e n t of the thorax counting as one chest roll. Finally, a Swan-Ganz flow-directed catheter was i n t r o d u c e d t h r o u g h the e x t e r n a l jugular or femoral vein (depending on d i f f i cu l ty of procedure) and r ight atrial, right ventricular, pulmonary ar- tery diastolic, and pulmonary capil- lary wedge pressures were recorded.

If at any t ime during the sequence of the procedure the dog was in VF, the time was recorded, arterial blood gases were obta ined (corrected for temperature), 2o and 100% oxygen was begun. The dysrhythmia was recorded on paper and identified with which individual procedure it was coincident. The Swan-Ganz catheter, central line, or nasogastr ic tube was removed if fibrillation occurred during introduction; the endotracheal tube, however, remained in place. Closed-chest massage was inst igated achieving a diastolic pressure of approximately 40 mm, and the standard advanced cardiac life suppor t p ro tocol for wit- nessed VF was followed. 21 The arterial blood gases were available immediate- ly to assess the acid-base and oxygenation. BT 5 mg/kg was given only after the failure to convert with two 200-W c o u n t e r s h o c k s and 0.1 mg IV epi- nephr ine fol lowed by repeat countershock. The drugs usually were infused through the available central line. There was no absolute t ime period after wh ich resusci ta t ion efforts were terminated; however, it was not unusua l to pursue defibril lation attempts for as long as one hour. If the dog achieved a stable rhythm and arterial blood pressure, the remainder of the maneuvers were performed.

Following completion of all maneuvers or after failure to defibrillate, the t ime was recorded and a final arterial blood gas, ECG, and blood pressure were obtained. The dogs then were sacrificed using l0 mL T-61 Euthanasia so lu t ion (American Hoec hs t Corp,

Somerville, New Jersey) as needed un- til a flat line was noted on ECG.

The data were analyzed by analysis of variance or Student t test where apo plicable, and P < .05 was considered significant.

RESULTS At 24 C, 11 dogs received saline as

the placebo and 11 received BT. Of the 11 dogs given placebo, six (55%) fibrillated wi th manipula t ion , compared with only one of the 11 (9%) given BT (P = .0671). T h e r e m a i n i n g f ive placebo dogs did not fibrillate during any of the five maneuvers and were s table t h roughou t . Five of the six placebo dogs that fibrillated did so w i t h i n s e r t i o n of the S w a n - G a n z catheter (Figure 1). The remaining dog f i b r i l l a t ed w i t h i n s e r t i o n of the nasogastr ic tube. VF was not noted with endotracheal intubation, central l ine p lacement , or v igorous movement in the placebo dogs that fibrillated. The VF generally was seen after m u l t i p l e a t t e m p t s at S w a n - G a n z catheter insertion of often more than ten minutes, as this amount of time often was necessary to obtain record- ings of each characteristic wave form. In one dog, the procedure took approximately 36 minutes, after which the animal fibrillated. In another fibrillating placebo dog, bilateral attempts on each side of the neck were under- taken, wi th success occurr ing after catheterization of the femoral vein. Of the placebo dogs that fibrillated, all went on to successful resuscitation; four (66%) required BT to do so. The remaining two responded to countershock alone or countershock with epinephrine.

Three of the 22 dogs fibrillated at app rox ima te ly 23 C spon t aneous ly early on in the BT infusion four, six, and seven minutes into the 15-minute infusion. This was no t preceded by any procedure, movement, or manipulation. The remaining BT infusion was administered as rapidly as possi- ble as t reatment for the VE Two of

52/1161 Annals of Emergency Medicine 15:10 October 1986

these dogs were defibrillated easily after receiving one and two boluses of BT when the initial resuscitation pro- tocol was unsuccessful. They subse- quently went on to complete all invasive maneuvers including repeated Swan-Ganz catheter attempts with final stable rhythms.

The remaining dog that fibrillated during the BT infusion also completed the experiment with a stable final rhythm, but only after one hour of CPR including 13 countershocks and 1,800 mg BT because the dog fibrillated during each procedure. This dog fibrillated during the BT infusion, following intubat ion and central line placement, and intermittently during one hour of continuous insertion of the Swan-Ganz catheter. However, the dog regained a stable rhythm at termi- nation with a blood pressure of 70/40 rnm Hg and an idioventricular rhythm of 38. This dog, in comparison to the other two that fibrillated during the infusion, showed myocardia l irritability early in the experiment (Fig- ure 2) with ventricular premature beats at the onset and runs of ventricular tachycardia at 27 C that went untreated with cardioversion, lidocaine, or any other antiarrhythmic.

The remaining ten of the 11 dogs pretreated with BT did not fibrillate with any manipulation or procedure despite an overall mean of 24 minutes of Swan-Ganz catheter insertion attempts, with two subjected to more than one hour of this procedure.

When including both placebo- and BT-treated dogs, all nine that fibrillated during the experiment, whether during the infusion or following the maneuvers, seven (77%) achieved a stable rhythm following administration of BT. The remaining two (22%) responded to countershock alone or countershock with epinephrine.

A variable response to BT was noted with regard to the expected initial hypertensive response. Only two of the 11 dogs showed a hypertensive response following the BT infusion. No dog had a demonstrable precipitous hypotensive response after infusion; however, this was a qualitative observation because a progressive hypotension ensued from the hypothermia itself.

Although the K-thermia blanket and wet sheets were removed, the dogs continued to cool outside of the cold .room during the experiment. The mean temperature for all dogs was

FIGURES 3A, 3B, and 3C. Sinus bradycardia of three dogs as f inal rhythm at mean temperature of 21.5 C.

21.5 C at the end of the experiment. This degree of cooling varied with each dog because the length of time required to do all maneuvers was variable. At a final mean temperature of 21.5 C, 18 of the 22 dogs showed a sinus bradycardia of 44 beats per minute (Figures 3A to 3C). The remaining dominant rhythm in the other was idioventricular with a rate of 49 beats per minute. The mean blood pressure for all dogs at 21.5 C was 85/58 mm Hg.

The mean PaO2, PCO2, and pH, when corrected for temperature of the dogs that underwent VF during BT infusion, were 251 mm, 13 mm, and 7.70, respectively. The mean PaO 2 and pH of the placebo dogs that fibrillated with manipulation were 503 mm and 7.47, respectively. No dog in either group was hypoxic or acidotic. How- ever, five of these six dogs were hypo- carbic with a mean PCO 2 of 20 mm Hg. There was no waming dysrhythmia in the fibrillating placebo dogs. Osborn waves were noted in two of the six fibrillating placebo dogs (Figure 4). Prior to fibrillation, these dogs commonly exhibited a sinus bradycardia with an often bizarre QRS complex (Figure 5).

DISCUSSION The risk attendant with performing

various maneuvers in the profoundly hypothermic state is controversial. Simply placing a cuff around the chest to record respiratory movements or removal of a rectal thermometer in the hypothermic dog has been reported to induce VF.~ Intraventricular catheters have been shown to raise the mean lethal temperature for VF in dogs. 23 Clinical experience in human beings has demonstrated VF to follow endotracheal intubation,2, 3 electrical pacing,4,s and nasogastric tube or esophageal probe placement.6,1~ In addition, VF has occurred during transport or in moving a patient from a stretcher.24, 25 These reports often are inconsistent and confusing to the practitioner because numerous others attest to the relative safety of these maneuvers. Led ingham used cen t ra l venous catheters in 44 patients with temperatures between 20 C and 34.3 C with no adverse affects, neither reflex

15:10 October 1986 Annals of Emergency Medicine 1162/53


cardiac slowing nor any induced arrhythmia. 12 Harari placed Swan-Ganz catheters and esophageal thermocou- ples in six patients with temperatures between 23 C and 29 C without ob- serving any ectopic activity. 26 Neither endotracheal intubationS, 27-3o nor central line placement28,al, 32 was with ill effect in many case reports in severe hypothermia. Despite the inconsis- tency of such reports, numerous ar- t ic les s t ress avoid ing such procedures 6, 14,15,28,33-35 and thus the medical community is hesitant to per- form these procedures as part of the assessment, stabilization, and rewarming effort in the hypothermic patient.

It generally has been agreed that most drugs or antiarrhythmics should be avo ided in severe h y p o t h e r - mia,2, sqs because of the relative re- sistance of the hypothermic heart to their effects, the danger of toxicity when rewarmed, 14 or the temperature- labile na ture of the drug itself.s Among the drugs that have been used for their antifibrillatory potential, magnesium exhibited efficacy in hypothermia during cardiopulmonary bypass. 36 Quinidine has prevented VF during induced profound hypothermia and during cardiac manipulation at 25 C to 30 C. 37-39 Procaine derivatives showed inconsistent and often poor results.38,4o, 41 Lidocaine has had mini- mal antiarrhythmic effect in hypothermia. 1

BT during normothermia increases fibrillation threshold and decreases defibrillation threshold,19, 42 making it unique among conventional antiarrhythmics. It completely suppressed VF during cooling, hemorrhage, and rewarming in 11 pretreated dogs at 24 C. lr In the same study, it was 50% successful in resuscitating the hypothermic, untreated, fibrillating dog. It has been shown to increase the fibrillation threshold in cats. 16 Bre- tylium has been shown to cause a spontaneous chemical defibrillation in normothermia experimentally 43 and clinically. 44 Bacaner reported that BT pretreatment completely protected eight consecutive neurosurgical patients from VF under conditions of hypothermia. 4s Dronen, too, has noted the unique potential in hypothermia. 46 Bretylium has been recom- mended as the singular drug useful in severe hypothermic VE 47

Despite these reports, one recent study showed bretylium to have no significant effect in causing or facili-

tating defibrillation in hypothermic fibrillating dogs. The BT was intro- duced after VF was achieved either spontaneously or by induction, and prophylaxis prior to VF was not ad- dressed. 4s Again, our major emphasis was to study BT as prophylaxis for hypothermic VF in the setting of various clinical maneuvers, as well as t'o address its use in the treatment of this arrhythmia.

The use of BT approached, but did not achieve, statistical significance in comparing the incidence of VF in the placebo- and drug-treated groups (P = .0671). The fact that five of the 11 placebo dogs did not fibrillate with any maneuver attests to a high degree of variability in each dog. Others have commented on biological variation with no fixed lethal temperature for VF in the same species. 49 Perhaps these nonfibrillating dogs represent a part of this heterogeneous group. In addition, the mean lethal temperature for VF in the dog is said to be less than 24 C.SO, sl

Five of the six placebo dogs fibrillated op.ly with repeated prolonged attempts at Swan-Ganz catheterization. Invasive maneuvers pe r se in the face of optimal acid-base status and oxygenation in a controlled environment may not be as dangerous as previously thought. Although definite individual variation exists between species in hypothermia, this would support pre- vious data in hypothermic human beings in which both central lines and Swan-Ganz catheters showed no ill effects. 26 The lack of any consistent clinical or experimental data to define the risk with each individual procedure was alluded to earlier. The fact that only one dog fibrillated following nasogastric tube placement lends cre- dence to this unpred ic tab le dys- rhythmic tendency.

The literature tends to support a "wait, warm, and see" approach to the irritable hypothermic heart. Rewarm- ing to 28 C to 30 C prior to using cardioversion or drugs has repeatedly been advocated. The sudden onset of VF prior to achieving these warmer temperatures, however, may herald a grave prognosis despite rewarming attempts, thus the basis for an antifibrillatory agent as prophylaxis.

All six placebo-treated dogs that fibrillated were defibrillated success- fully despite temperatttres lower than 23 C. Sixty-six percent (four of six) required BT. Similarly, Buckley reported

BT to be successful in only 50% of his placebo-treated dogs that fibrillated. 17 Again, it is often advised to avoid any drug in hypothermic VF and to in- stead begin more aggressive rewarming techniques; however, these data suggest that BT may indeed be useful when treating hypothermic VF.

The remaining two placebo dogs that fibrillated were responsive to either countershock alone or countershock with epinephrine, and did not require bretylium. Electrical fibrillation often is not useful either clinically 36 or experimentally in severe hypothermia.lZ, 52 Many authors suggest rewarming to 28 C to 30 C prior to electrical defibrillation2,11,1s, 2s, 28,35,53-56 because attempts are usually regarded to be unsuccessful below these temperatures. Despite this, we agree with those who advocate a trial of electrical countershock in the setting of hypothermic ME14, 34 In one h u m a n study, on ly one - th i rd of fibrillating hypothermic patients sur- vived. 12 The immediacy to treat VF, with its attendant dismal prognosis, would seem to include a trial of electrical countershock. Our observation of the success of this procedure was limited to two dogs.

Three of the 11 dogs receiving the BT infusion fibrillated before half the solution was administered. Hypother- mia itself has been shown to cause an increase in circulating epinephrine and norepinephrine from the adrenal medulla sr as a response to cold stress. However, this has been observed in early hypothermia and thought not to complicate profound hypothermia at 24 C as in our dogs. Acute administration of IV BT causes an initial proadrenergic response with release of norepinephrine. After about 15 minutes it produces adrenergic neuronal blockade with an increased sensitivity to circulating catecholamines and an aggrava t ion of ex is t ing a r rhy th - mias.SS-6o

In two complex clinical settings, short-term dosing of bretylium was thought to play an important role in initiating ventricular tachycardia and fibrillation. 6o In this experiment each dog that fibrillated at 24 C did so within minutes of the infusion and not at the usual antiadrenergic time interval (after 15 minutes) after IV infusion when one would expect an arrhythmia to occur. Others have em- phasized that the net effect of BT on arrhythmias at a particular time after

54/1163 Annals of Emergency Medicine 15:10 October 1986

administration may not be quite as predictable as previously thought. In- deed, the proadrenergic response may last for up to 90 minutes rather than 15 minutes, with a sustained rather than transient worsening of the cardiac rhythm. It probably depends on a complex interaction of adrenergic, antiadrenergic, and antiarrhythmic effects. Paradoxical VF is not thought to be rare with BT, and its incidence remains to be determined. 61 Thus, despite the paradoxical VF seen early during BT infusion, we believe this should not preclude its use as a prophylactic agent. All three dogs were defibrillated easily and went on to complete all maneuvers (including repeat Swan-Ganz insertions) at the very low temperatures, again attesting to the effects of BT

The single dog pretreated with BT that repeatedly fibrillated during all procedures yet promptly defibrillated was atypical. The ventricular ectopy observed in this dog at higher than lethal temperatures may have been pre- dictive of a more susceptible myocar- dium. Some say the most common sequence of events in hypothermic dogs is ventricular ectopic beats followed by VE62, 63 No other dog that underwent VF was noted to have warning premature ventricular beats. Sinus bradycardia was the predomi- nant rhythm prior to VF, with fibrillation occurring abruptly and without warning. This lack of change of rhythm before the onset of VF has been noted elsewhere. 15

Many factors are believed to be re- sponsible for the high incidence of hypothermic VF. Hypoxia, acidosis, and abrupt alkalosis6, 64 are among them. The mean PaO 2 of 503 in the fibrillating placebo dogs certainly was more than adequate. The mean PCO 2 of 20 mm with a mean pH of 7.47 was a gradual rather than precipitous mild alkalosis. A progressive respiratory alkalosis is known to occur in severe hypothermia due to decreased CO2

production.65, 66 Also contributory to this alkalosis was our technical in- ability to decrease ventilatory rate with cooling, due to intrinsic equipment limitations.

The tendency of the animal to con- tinue to cool in excess of 2.5 C despite removal from the cold surroundings has been noted in o ther experi- ments, s2 In two studies after dogs were removed from immersion in an iced bath, the rectal temperature fell an additional 2 ° to 4 ° C, rate unspec- ified "due to a flow of heat from the warmer core. "67 This fact has significance in the prehospital phase in which difficult extrications and prolonged transport times actually may be attendant with worsening of the hypothermic state to a critical temperature for VF. 6 With the frequent jostling inside the vehicle, a variable oxygen delivery, a precarious acid-base status, and the subsequent drop in core temperature, BT may be worthy as a prophylactic measure in the field and should be studied further.

The usual reservation in the past precluding use of BT is hypotension,68, 69 al though this is usual ly orthostatic and not marked. 66 This possibility should not deter the use of bretylium, however. Hypotension in itself is very characteristic of profound hypothermia per se. We observed no precipitous or unexpected hypotension that was inappropriate to the degree of hypothermia achieved in the placebo- and bretytium-treated groups.

In severe hypothermia, perfusion to the liver is diminished with a resul- tant decreased ability to metabolize or detoxify drugs.9, 65 Bretylium is not m e t a b o l i z e d in the l iver and is entirely renally excreted.70, 71 In addition, there is a decreased glomerular filtration rate and renal blood flow in hypothermia and, thus, the danger of toxicity on rewarming. 6s To date, the therapeutic or toxic levels of BT have not been determined and standard dosages of BT probably are conser-

Annals of Emergency Medicine

FIGURE 4. Osborn wave seen at 29 C.

FIGURE 5. Sinus bradycardia w i t h bizarre QRS complex seen in placebo dogs prior to VF.

vative. 72 We used a mean dosage of 40.5 mg/kg infused over 15 minutes in our canine model. In addition, one dog received an 1,800-rag (60 mg/kg) total dosage during long re susc i t a t ion efforts with a final stable rhythm. More than 30 mg/kg has been given in human beings inadvertently with no dysrhythmia observed. 7o The high dose used in our experiment for prophylaxis (40.5 mg/kg) may have its op- ponents because it was infused over a relatively short time (15 minutes) into a relatively small (24-kg) organism with a beating, nonarrested heart. For prophylaxis, recommendat ions include the standard dosages of BT infused over a much longer period of time as optimum dosages, again, have not been determined. Finally, bretylium, unlike many other drugs, is quite stable/n vitro over a broad temperature range (personal communica- tion, Joan Para, Medical Services De- partment, American Critical Care), a quality that makes it part icularly useful in hypothermia.

C O N C L U S I O N In general, the incidence of VF with

various maneuvers in severe hypothermia may be low when the cooling rate, oxygenation, and acid-base status are controlled. However, VF remains a threat, no tably in the prehospi tal phase when these factors often are not ensured and the patient may cool to even more fibrillatory temperatures. BT may be an effective agent in the prophylaxis of VF in a profoundly hypothermic patient in the field as well as in the hospital. Although the prophylactic use of BT in the two groups did not reach generally considered statistical significance (P < .05), the strong trend (P = .067) for its use

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is seen. Recommendations include in- fus ion over m u c h longer periods in more standard dosages, even though opt imal dosage and toxici ty of the drug in hypothermia remains to be as- cer ta ined . BT, in addi t ion , may be efficacious in the treatment of hypothermic VE Further controlled clinical studies of the use of prophylactic BT in h u m a n beings under conditions of hypothermia are warranted.

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