An improved lidocaine infusion protocol for cardiac surgical patients

An Improved Lidocaine

Infusion

Laurence

Landow,

Protocol for Cardiac Surgical Patients MD, and John Wilson, PhD

A new protocol for lidocaine administration was tested to determine whether it would provide higher free and total serum lidocaine concentrations during and after weaning from cardiopulmonary bypass (CPB), without leading to accumulation toxicity, than those resulting from a conventional protocol (1.5 mg/kg loading dose bolus + 2 mg/min infusion rate). Ten elective adult cardiac surgical patients were studied. Ten seconds prior to aortic cross-clamp release (0 min), each patient received a lidocaine bolus (1.5 mg/kg) and simultaneous lidocaine infusion (5 mg/min for 1 hour, followed by 2 mg/min for 23 hours). Weaning occurred 20 to 30 minutes after cross-clamp release. Lidocaine levels were

S

UPPRESSION of ventricular dysrhythmias (VD) is essential for successful weaning from cardiopulmonary bypass (CPB). Because the incidence of ventricular fibrillation has been shown to be decreased significantly following administration of a lidocaine bolus immediately prior to cross-clamp release,’ many clinicians start a prophylactic lidocaine infusion at the same time they administer the bolus and maintain it for the next 12 to 24 hours. Despite lidocaine administration, some patients exhibit recurrent (“lidocaine-resistant”) VD, one cause of which may be inadequate serum lidocaine concentrations. In a recent prospective investigation’ of cardiac surgical patients receiving a lidocaine bolus (1.5 mg/kg) accompanied by a 2 mg/min infusion, subtherapeutic mean total lidocaine levels ( < 2 &mL) were found during CPB weaning and for about 2 hours thereafter. Although mean free lidocaine concentrations were within the therapeutic range (0.6 to 2 &mL), 40% of patients had subtherapeutic levels at least once during the same period. In an effort to improve this pharmacokinetic profile, a 24-hour infusion protocol was derived from computer simulation models that used pharmacokinetic data from the initial study.’ Different combinations of loading doses (1 to 4 mg/kg) and infusion rates (1 to 7 mg/min) were tested. The combination found most likely to produce therapeutic free and total drug levels without resulting in accumulation toxicity consisted of a 1.5 mg/kg loading dose in combination with a two-stage infusion rate, ie, 5 mg/min for 1 hour, followed by 2 mgimin for 23 hours. The aim of this investigation was to determine whether data derived from the simulation model were valid in cardiac surgical patients otherwise free of systemic disease. It is important to note that patients with a history of VD were intentionally excluded because it was thought to be unethical to withhold administration of additional lidocaine in the face of recurrent VD during weaning from CPB, until it could be demonstrated that this newer protocol was safe and that it was a more efficient method of attaining therapeutic drug levels. MATERIALS

AND METHODS

Ten adult patients scheduled for elective coronary artery bypass grafting or cardiac valve replacement surgery requiring CPB were studied. All patients gave informed consent to participate in this protocol, which was approved by the University of Massachusetts

determined from arterial blood samples at 0, 10,20, 30, and 60 minutes, and at 2, 4. and 24 hours postcross-clamp release. Compared with the conventional protocol, the new protocol showed a significant increase in mean total lidocaine concentration (P I 0.02) at 30 and 60 minutes, and a significant increase in mean free lidocaine concentration (P I 0.005) at 20, 30, and 60 minutes. No patient had toxic levels at 24 hours. Results of this study suggest that in patients undergoing cardiac surgery, a “5 + 2” mg/min infusion protocol is safe and superior to a conventional protocol in achieving therapeutic serum levels of free and total lidocaine. Copyright o 1991 by W.B. Saunders Company

Medical Center Committee on the Protection of Human Subjects in Research. Patients included for data analysis had left ventricular ejection fractions estimated to be greater than 50% at angiography and were without significant renal, pulmonary, or hepatic dysfunction as determined by routine biochemical testing. All patients were premeditated with morphine, 0.1 mg/kg, intramuscularly, and lorazepam, 2 mg, orally, the morning of surgery. Preoperative cardiac medications taken by the patient at admission were ordered on the morning of surgery for all patients. Prior to anesthetic induction with fentanyl or sufentanil and pancuronium or vecuronium, all patients had radial and pulmonary artery catheters inserted under local lidocaine anesthesia. All patients underwent continuous visual electrocardiographic (ECG) monitoring of leads II and V, for the entire intraoperative study period by one of the investigators (L.L.), and of lead II by the nurse responsible for the patient in the intensive care unit. Total CPB time and aortic cross-clamp time were recorded. CPB was conducted in the standard fashion with one of four oxygenators (Maxima SK 1380 [Medtronics Corp, Anaheim, CA], BOS CM 50 [Bentley Carp, Irvine, CA], M-2000 [Shiley Corp, Irvine, CA], or Terumo 5.4 [Terumo Corp, Tokyo, Japan]) with integral heat exchanger and an extracorporeal pump. The mean pump prime volume was 2 L and consisted of heparin, 4,000 IU, and Ringer’s lactate (pH = 6.5). Heparin, 300 W/kg, was injected before insertion of the aortic and vena caval cannulae. The aorta was cross-clamped and hyperkalemic Buckberg-type cardioplegic solutions were infused. CPB involved moderate hypothermia (27”C), pump flow rates of 1.7 L/minim*, mean arterial pressures of 55 to 65 mm Hg, and hemodilution to a hematocrit of 20% to 25%. Rewarming was started as the last distal anastomosis was being completed, after which the aortic cross-clamp was removed to resume total cardiac perfusion. Once core temperature had increased to 38°C and sufficient surgical hemostasis had been achieved, the patient was weaned off CPB. Vasodilators and inotropes were administered as indicated to maintain cardiac index greater than 2.2 L/min/m*. Ten seconds prior to aortic cross-clamp release, each patient received a 1.5 mg/kg lidocaine bolus into the venous reservoir of the CPB system and an infusion of 5 mg/min for 1 hour through the sidearm of the pulmonary artery catheter introducer via a controlled volumetric infusion pump (Imed Corp, San Diego, CA).

From the Departments of Anesthesiology and Pharmacy, Universiv of Massachusetts Medical Center, Worcester, MA. Address reprint requests to Laurence Landow, MD, 1600 Massachusetts Ave #304, Cambridge, MA 02138. Copyright 0 1991 by W.B. Saunders Company 1053-0770/91/0503-0003003.QOl0

210

LANDOW AND WILSON

After 60 minutes, the infusion rate was decreased to 2 mg/min and maintained for 23 hours before termination. Five milliliters of arterial blood were obtained just prior to lidocaine administration (0 min) and at 10, 20, 30, and 60 minutes and 2, 4, and 24 hours following the lidocaine bolus. If the patient was on CPB, samples were obtained from the arterial-venous sampling port; if off CPB, the sample was taken from the radial arterial catheter after approximately 10 mL of dead-space blood had been removed. Samples were refrigerated and centrifuged the next morning in the hospital laboratory and the plasma fraction was frozen at -12°C until assayed. These specimens were handdelivered by one of the authors to Astra Pharmaceutical Company (Westboro, MA), where free and total lidocaine serum levels were determined by gas chromatography using a nitrogen-phosphorus detector. Results of free and total serum concentrations were analyzed to determine mean 2 standard deviation. The one-sided hypothesis was that the “5 + 2” infusion rate used in this study would produce higher serum lidocaine levels than a conventional infusion rate of 2 mg/min. Comparison of mean levels for both free and total lidocaine concentrations was made between the new and conventional protocols at identical time points (10 to 240 minutes) by means of a one-tailed t test with Bonferroni adjustment. APvalue <0.05 was regarded as significant. Comparison of the two protocols for (1) percent of patients within the therapeutic range for the entire testing period, and (2) percent of samples within the therapeutic range, for both free and total lidocaine concentrations between 10 and 240 minutes, was made using the x2 test. APvalue I 0.05 was regarded as significant.

Table 1. Total Lidocaine Levels Conventional Protocol

Therapeutic

samples (%)

Patients in the therapeutic

range (%)

N&V Protocoi

30

60x

0

30*

?? P < 0.005 between protocols.

Moreover, although mean free lidocaine concentrations were within the therapeutic window of 0.6 to 2.0 ugimL from 20 to 240 minutes, in both studies (Fig 2) 98% (1 83%) of individual samples in the new protocol were in the therapeutic range (P I 0.005) and 89% (v 60%) of patients in the new protocol were consistently in the therapeutic range (P = NS) for the same time period (Tables 2 and 4). At 24 hours, 7 of 10 patients had therapeutic total lidocaine concentrations (Table 3) whereas all but one had therapeutic free lidocaine concentrations (Table 2). Unlisted values in Tables 2 and 3 represent samples that were broken in transport, drawn at incorrect times, or had inadequate labeling. It is believed that case 7 had atypical free and total lidocaine levels at 0 minutes due to inadvertent contamination at the time of collection. Other unlisted values at 0 minutes represent levels too low to be detected.

RESULTS

DISCUSSION

This study is similar to the previous lidocaine study’ in that (1) no VD were noted during the study period, and (2) weaning from CPB occurred at approximately the same time (20 to 30 minutes) after aortic cross-clamp release. For the study period extending from 20 to 240 minutes, the new protocol, in contrast to the conventional protocol, produced (1) mean total lidocaine concentrations consistently within the therapeutic range of 2 to 5 ug/mL (v a subtherapeutic trough from 20 to 120 minutes; Fig 1); (2) 60% (v 30%) of samples in the therapeutic range (P I 0.005; Tables 1 and 2); and (3) 30% (v 0%) of patients consistently in the therapeutic range (P I 0.005; Tables 1 and 3).

Results of this in vivo investigation confirm the validity of the computerized pharmacokinetic model. For the 220. minute period starting with weaning from CPB, increasing the lidocaine infusion rate for the first hour from 2 to 5 mg/min, (1) eliminated the subtherapeutic trough for total lidocaine; (2) significantly increased the percentage of samples with free lidocaine concentration in the therapeutic range; and (3) did not cause accumulation toxicity at 24 hours. This work is similar to the previous lidocaine pharmacokinetic investigation’ in which no VD were noted during the same 220-minute window. One explanation for this observation is that despite inadequate total lidocaine levels (in the first study), mean free lidocaine concentrations were within the therapeutic range in both studies. Three features of this study deserve comment. First, the sample size was small. Second, the study was not controlled; however, it was the authors’ feeling that because the characteristics of the two study populations were similar (elective cardiac surgery patients of both sexes with ejection fractions >50%, no history of VD, and otherwise free of systemic disease) and the surgical team (anesthesiologists, surgeons, and perfusionists) was identical, internal controls would have duplicated measurements made in the previous study. Third, the study did not determine whether the incidence of VD was diminished by use of this protocol. As noted, the aim was to determine whether this new protocol was efficient and safe. The question of dysrhythmia suppression will be addressed in a follow-up study. The monitoring of total plasma drug concentrations is firmly established in clinical practice. However, there is growing concern that this may be misleading in situations in

3.0

r

z E

~-0

Conventional

H

Improved

Protocol

Protocol

L = D10.02

01

0

l/2

1

2

3 Time (hours)

4

5

6

Fig 1. Total lidocaine levels. Dotted line represents minimum therapeutic concentration (2 pg/mL). Note absence of subtherapeutic trough with new protocol.

ANlMPROVEDLlDOCAlNElNFUSlON

PROTOCOL

211

Table2. Free LidocaineLevels(kg/mL) Time (min) Case No.

0

-

2 3

10

20

30

60

120

1.6

1.3

1.4

1.3

1.0

1.0

1.1

1.2

1.4

1.0

1.3

1.0

1.0

1.1

0.7

0.7

0.2

0.4

0.7

0.6

240

0.7

24 h

0.4 0.7

4

0.2

1.5

1.4

1.2

1.1

5

0.1 -

2.4

2.2

2.2

2.4

1.0

1.0

2.8

1.6

1.6

1.4

0.7

0.7

2.4 -

1.3

1.4

1.8

1.6

1.7

1.3

8 9

-

1.8

1.4

1.8

1.1

1.1

1.6

1.4

10

-

0.9

1.0

1.1

1.2

1.0

1.0

0.8

6 7

-

-

Mean

0.90

1.62

1.38

1.48

1.40

0.94

1.01

0.79

SD

1.30

0.63

0.37

0.40

0.41

0.29

0.42

0.39

which plasma drug binding varies, because recent reports suggest that a drug’s efficacy and side effects generally relate better to the free (unbound) concentration than to the total concentration.3 Although it has been recognized for some time that important alterations can occur in plasma lidocaine binding and that this variability is due almost entirely to changes in the acute phase reactant, cu,-acid glycoprotein (AAG),4 only recently have these changes been documented in patients placed on CPB.’ In cardiac surgical patients, dilution of plasma proteins by CPB pump prime5 is the most likely reason why free fraction (free drug concentration divided by total drug concentration) increases from a normal value of 30% to 40% to about 50%. Free fraction gradually returns to baseline approximately 6 hours after weaning from CPB as plasma volume returns to baseline, secondary to redistribution and elimination of excess fluid.2 A major problem in interpreting free levels of lidocaine while the patient is on CPB is a potential interaction with heparin.’ In vitro, heparin affects plasma lidocaine levels indirectly by activating lipoprotein lipase, an enzyme that increases plasma nonesterified fatty acids (NEFAs).~ NEFAs are able to displace bound drug from protein binding sites causing an acute increase in free fraction. This results in increased distribution of the drug outside the plasma space, a decrease in total and bound plasma concentrations, and a higher volume of distribution.7 How-

ever, it must be emphasized that this effect has only been shown to exist in vitro and may be artifactual due to continued lipase activity on endogenous substrate found in the blood sample.*zYIn any event, addition of protamine at the termination of CPB should reverse most, if not all, of the heparin-induced elevation of free lidocaine.” Presently, most hospital laboratories do not measure free lidocaine concentrations. Not surprisingly, there is even less prospective pharmacodynamic information concerning free drug concentrations than about total drug concentrations, and much of this is anecdotal.“~” For the purposes of these studies, a therapeutic window for free lidocaine (0.6 to 2.0 ug/mL) was calculated by taking the total lidocaine therapeutic window used by the hospital laboratory (2 to 5 &mL) and multiplying it by the normal free lidocaine fraction (30%). In both studies, mean free lidocaine concentration was within therapeutic limits, but the standard deviation was significantly smaller and the mean level significantly higher in this study than in the previous one. There are multiple possible causes of VD during weaning from CPB, including (1) ischemia (eg, due to inadequate myocardial protection,13 inadequate revascularization, left ventricular distentionI particulate embolization,‘5 coronary artery spasm); (2) electrolyte abnormalities (eg, hypomagnesemia, hypokalemia), and (3) acid-base disturbances. Therapy includes electrical and/or pharmacological intervention together with correction of the underlying cause(s),

Table3. TotalLidocaineLevels(pg/mL) Time (min) Case

No.

0

10

20

30

60

120

240

24 h

1.4

1.9

1.9

0.8

1

0.1

2.6

1.5

1.4

1.7

1.5

2

0.1

1.7

1.3

1.2

1.6

1.7

3

0.1

2.3

1.7

1.8

2.2

1.9

4

0.4

3.2

2.9

2.7

2.9

1.9

2.7

3.4

5

0.2

3.1

3.4

3.6

4.2

-

3.0

3.3

6

0.1

5.4

2.7

2.8

3.0

2.5

2.1

4.1

7

5.3

2.9

3.1

3.9

3.3

2.5

3.5

4.9

a

0.2

2.8

2.8

2.6

2.3

1.9

2.5

4.0

9

1.1

0.1

2.1

1.7

2.7

1.8

2.0

2.8

4.3

10

0.1

1.6

1.9

1.9

2.0

2.1

2.0

2.4

Mean

0.67

2.77

2.30

2.46

2.50

2.00

2.43

3.02

SD

1.63

1.08

0.76

0.89

0.83

0.33

0.64

1.41

212

LANDOW AND WILSON

Table 4. Free Lidocaine Levels

.... .

.

. .. . .

&-A Conventional -

Improved

. . . ..

Conventional Protocol

Protocol

Protocol

Therapeutic

- = p
samples 1%)

Patients in the therapeutic

range

(%)

N&V Protocol

83

98”

60

89t

?? P 2 0.005 between protocols. tP = NS.

A o’,

0

I

I

l/2

1

I 2

3 Time (hours)

4

5

6

Fig 2. Free lidocaine levels. Dotted lines represent serum concentrations of therapeutic free lidocaine (0.6 to 2.0 kg/mL). Note higher mean free lidocaine concentration with new protocol.

if possible. Although internal defibrillation or cardioversion is rapid, it has been shown to cause subendocardial injury,16 and repeated attempts increase the amount of this injury.’ Among antidysrhythmic drugs, lidocaine is the drug of first choice because it is easily and quickly administered, and relatively devoid of undesirable cardiovascular effects at blood levels within the therapeutic range.17 Because free lidocaine levels are not routinely measured and subtherapeutic levels are a distinct possiblity in patients being weaned from CPB, it is tempting to speculate that a substantial percentage of recurrent VD are (mis)labeled “lidocaine resistant.” In clinical practice, pharmacological treatment of such dysrhythmias can be problematic and potentially harmful. The most common approach is to administer additional boluses of lidocaine. This can lead to unpredictable and even toxic drug levels depending on the time that has elapsed between the initial and subsequent

doses of lidocaine. An alternative approach is to add procainamide to the regimen. Unfortunately, this drug is notorious for causing and/or aggravating hypotension and myocardial depression,@ severely limiting its usefulness in the hemodynamically unstable patient. Moreover, procainamide belongs to the Ia class of drugs that are well known for their proarrhythmic effect (ie, creating or aggravating VD).” This insidious side effect is accentuated by concomitant abnormalities common in cardiac surgical patients, such as electrolyte disturbances, (particularly hypokalemia and hypomagnesemia),” as well as the infusion of catecholamines and calcium channel agonists.” Alternative secondline agents, such as propranolol,‘” bretylium,‘* and esmolol.22 although possibly less proarrhythmic, have significant negative cardiovascular side effects that make them as undesirable and difficult to titrate as procainamide. Few would question that the safest method of providing therapeutic lidocaine concentrations in the cardiac surgical patient is to use a standardized protocol. The present results suggest that the patient being weaned from CPB is more likely to have therapeutic free and total lidocaine concentrations if this new protocol is followed. Prospective randomized trials comparing the new and conventional protocols in patients at high risk for VD are indicated to determine whether there is significant improvement in outcome. ACKNOWLEDGMENT The authors

thank Stephen

Baker, PhD, for statistical

support.

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AN IMPROVED LIDOCAINE INFUSION PROTOCOL

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