Adverse effects of EMLA (lidocaine/prilocaine) cream and efficacy for the placement of jugular catheters in hospitalized cats

Abstract

EMLA is a lidocaine/prilocaine cream used for topical analgesia in human pediatric patients. The purpose of this study was to establish the safety of EMLA in clinically ill cats, to measure systemic absorption and to determine whether EMLA reduced the need for sedation for the placement of jugular catheters. Thirty-one cats were randomized to either a placebo or EMLA cream group. Cream was applied to a 10 cm² area over the jugular vein, with 1 h of occlusive dressing. Neither anesthetic was systemically absorbed in any cat, and no adverse clinical signs were observed. Struggling during catheter placement was less in the EMLA-treated cats compared to placebo, but did not reach significance (P=0.06). Jugular catheters were successfully placed in 60% of EMLA-treated cats and 38% of placebo cats; this difference was not statistically significant and may not justify the added steps of EMLA cream administration for this purpose. However, EMLA does appear to be safe in clinically ill cats, and may be useful for other applications such as for skin mass removal or repeated venepuncture.

Topical anesthetic creams and patches are used commonly in children and neonates to prevent pain associated with minor invasive procedures (Halimaa 2003). EMLA cream (Astra Pharmaceuticals) is a topical anesthetic that contains 2.5% lidocaine and 2.5% prilocaine as a eutectic mixture of local anesthetics. This mixture allows improved local absorption of each drug, without the use of organic solvents (Lener et al 1997); analgesia results from high local concentrations of lidocaine/prilocaine in the skin (Kopecky et al 2001). EMLA cream has proven efficacy as a local anesthetic for procedures such as venepuncture, intravenous catheter placement, and vaccinations in humans (Hallen and Uppfeldt 1982, Manner et al 1987, Rosdahl et al 1988, Vaghadia et al 1997, Halperin et al 2000). EMLA also reduces post-burn pruritus, and pain associated with spinal puncture, laser procedures and minor dermatological surgery (Gupta and Sibbald 1996, Egekvist and Bjerring 1997, Koscielniak-Nielsen et al 1998, Kopecky et al 2001). EMLA cream is well tolerated in most human patients, with only minor side effects of local blanching or erythema reported (Lener et al 1997). Rarely, excessive systemic absorption has led to methemoglobinemia or neurologic signs. These signs have been observed within 1–3 h of cream removal, in patients for whom EMLA has been applied to abraded skin (Hahn et al 2004), over a large surface area, or for more than 4–5 h (Lener et al 1997, Rincon et al 2000, Touma and Jackson 2001).

In healthy cats, EMLA cream was reported to reduce signs of discomfort during placement of peripheral catheters, but absorption and toxicity were not evaluated (Flecknell et al 1990). We previously reported that EMLA cream, when applied using a human pediatric dosing protocol (Chang et al 1994), was not associated with methemoglobinemia or clinical adverse effects in healthy cats (Gibbon et al 2003). However, the use of EMLA has not been evaluated in clinically ill, hospitalized cats.

Jugular catheters are the preferred means of venous access in many veterinary hospitals, but placement often requires the use of sedation, which can be associated with side effects such as hypotension in critically ill patients. The purpose of this study was to determine the efficacy of EMLA cream in allowing the placement of jugular catheters, without sedation, in hospitalized cats, and to determine whether EMLA was associated with adverse effects in clinically ill cats.

Clinically ill cats presenting to the critical care unit (CCU) with a need for IV catheter placement were eligible for the study. Cats with abraded or inflamed skin of the neck were not enrolled, because of enhanced absorption of EMLA cream through diseased skin (Juhlin et al 1989). Cats that were in shock, or that had clinical or historical evidence of anemia (packed cell volume <25%) were also excluded, because of repeated blood draws in the study design. All clients provided informed consent, and the study protocol was approved by the IACUC at the University of Wisconsin-Madison.

All cats were evaluated with a complete history, physical examination, body weight, complete blood count, serum biochemistry panel and urinalysis. Because of the expected heterogeneity of a hospitalized population, the severity of illness for each cat was scored by one clinician blinded to treatment group (KW), using a simple scale of mild, moderate, or severe, based upon clinical signs, laboratory test results and clinical outcome (Peterson et al 2001). In addition, CCU nurses scored each cat's temperament as depressed, friendly, frightened, or fractious, prior to any intervention. These measures helped to ensure that cats with similar severity of illness and temperament were represented within each treatment group. Cats were randomized into two groups. The EMLA group received 1.0 g (1.0 cc drawn into a syringe) of EMLA cream applied to a 2×5 cm area of lightly shaved skin overlying the jugular vein, covered by a 6×7 cm occlusive bandage (Tegaderm, 3M Corporation). The Placebo group received a similar-appearing carrier cream without anesthetic properties (100% hydrophilic ointment, USP), applied in an identical manner. Nurses applying either cream wore gloves and were blinded to treatment group. After 60 min of application, the bandage was removed and the EMLA cream was removed with 70% isopropyl alcohol. A final close shave and a routine sterile scrub of the jugular area were then performed and a double lumen 19 gauge (5 Fr), 8-inch (13 cm) jugular catheter (Pediatric Two-Lumen Central Venous Cathether: Arrow International, Reading, PA, USA) was placed on the treated side. All study catheters were placed by one of three experienced CCU nurses.

During venepuncture for catheter placement, each cat was scored by the nurse for signs of discomfort, using the following scoring system adapted from the Modified Behavioral Pain Scale, which uses movement, facial expression and crying in evaluating pain in human pediatric patients (Halperin et al 2000):

• Struggling: None=0, Mild=1 (tenses body), Moderate=2 (struggles), Severe=3 (escapes restraint).

• Aggression: None=0, Mild=1 (hisses), Moderate=2 (attempts to scratch), Severe=3 (attempts to bite).

• Vocalization: None=0, Mild=1 (meow), Moderate=2 (growl), Severe=3 (loud cries).

If a cat scored 2 or greater in any category, attempted venepuncture was discontinued and the cat was sedated with midazolam (0.1 mg/kg IM) and butorphanol (0.4 mg/kg IM) before completing jugular catheter placement. Efficacy of the EMLA cream was evaluated in two ways: discomfort scores compared to placebo and the ability to place the jugular catheter without sedation.

Adverse effects were evaluated as previously described: evidence of local irritation (blanching or erythema), systemic lidocaine/prilocaine absorption, methemoglobinemia and clinical evidence of gastrointestinal upset, neurologic abnormalities or cardiovascular problems (Gibbon et al 2003). For evaluation of systemic absorption, blood samples (0.5 ml each in EDTA) were obtained at baseline and at two or more time points over the 6 h after EMLA or placebo cream application, for determination of serum lidocaine/prilocaine concentrations using high performance liquid chromatography (Gibbon et al 2003). In addition, whole blood in EDTA (0.1 ml) was drawn for methemoglobin analysis by co-oximetry (Watcha et al 1989, Rausch-Madison and Mohsenifar 1997) at the same time points. Cats were monitored with continual observation, and hourly recording of heart rate, respiratory rate, mucus membrane color, and demeanor, for 6 h after cream application. Groups were compared by unpaired t test or χ ², as appropriate, with P<0.05 considered significant. Data are reported as mean±SD.

Thirty-one cats completed the study, 15 in the EMLA group and 16 in the placebo group. Underlying disease diagnoses in the enrolled cats included acute and chronic renal failure, diabetic ketoacidosis, urinary tract obstruction, pancreatitis, liver disease, gastroenteritis and abdominal neoplasia. Groups did not differ in age, gender, body weight, temperament or severity of clinical illness prior to treatment (Table 1). Following EMLA or placebo cream administration, no signs of local irritation were observed in any cat, nor were adverse clinical signs attributable to lidocaine/prilocaine intoxication (vomiting, salivation, diarrhea, tremors or twitching, pallor, cyanosis, tachycardia or dyspnea) noted. Methemoglobin levels could not be determined in most cats because of a co-oximeter malfunction; blood from those few cats (n=5) that were analyzed had methemoglobin levels (<1%) well within the normal range for cats (Gibbon et al 2003). All cats in the EMLA and placebo groups had two to four blood samples analyzed for lidocaine/prilocaine concentrations between 1 and 6 h after EMLA application. Specifically, of the EMLA cats, 15 cats had baseline samples, nine cats had samples analyzed at 1 h, 10 cats at 2 h, three cats at 3 h, four cats at 4 h, three cats at 5 h, and four cats at 6 h after EMLA application. Of the placebo cats, 16 cats had baseline samples, nine cats had samples analyzed at 1 h, 11 cats at 2 h, four cats at 3 h, two cats at 4 h, three cats at 5 h, and five cats at 6 h after EMLA application. Plasma lidocaine/prilocaine concentrations were undetectable (<0.3 μg/ml) at all time points in both EMLA and placebo groups.

Table 1.

Baseline clinical parameters in 31 hospitalized cats randomized to EMLA (eutectic mixture of local anesthetics) cream topical anesthesia or placebo did not differ significantly between groups

Clinical variable	EMLA group (n=15)	Placebo group (n=16)
Age (years)	10.4±4.0	9.3±5.9
Gender
MN	11	11
FS	4	4
MI		1
Body weight (kg)	4.3±1.1	4.1±1.2
Attitude
Depressed	5	4
Fearful	2	6
Fractious	2	2
Friendly	6	4
Disease severity
Mild	0	0
Moderate	7	9
Severe	8	7

MN=male neutered; FS=female spayed; MI=male intact.

Mean scores for struggling during venepuncture were lower in the EMLA group (1.6±0.8) compared to the placebo group (2.2±0.8), with a trend towards statistical significance (P=0.06; Table 2). Sixty percent of cats in the EMLA group (nine out of 15) had jugular catheters placed without sedation, compared to 38% of cats in the placebo group (six out of 16; P=0.21). Our targeted sample size (n=30 cats) was designed to provide a 99% chance of detecting a 50% difference between groups in the need for catheter placement, with α=0.05. We would have needed more than 30 cats in each group to show that the observed 22% difference in sedation rates, if a true difference, was significant. However, in designing the study, we felt that anything less than a 50% reduction in the need for sedation was probably not clinically useful, given the extra time and effort required to use EMLA.

Table 2.

Efficacy outcomes in 31 hospitalized cats randomized to EMLA cream topical anesthesia or placebo

Outcome parameter	EMLA group (n=15)	Placebo group (n=16)	P value
Struggling score	1.6±0.8	2.2±0.8	0.06
Aggression score	0.9±1.1	1.2±1.0	0.51
Vocalization score	1.1±1.1	1.1±0.8	0.98
Total discomfort score	3.7±2.2	4.5±2.3	0.31
Jugular catheter placement without sedation	n=9 (60%)	n=6 (38%)	0.21

Although the use of EMLA did not eliminate the need for sedation for jugular catheter placement, we cannot conclude that EMLA cream is without analgesic effects in cats. We chose to test EMLA cream in this setting because jugular catheters provide many advantages over peripheral catheters, such as administration of parenteral nutrition, measurement of central venous pressure and the ability to repeatedly draw blood samples without additional venepuncture. Cats generally require sedation for jugular catheter placement, which may be undesirable in some hospitalized patients; we therefore chose this setting because effective local analgesia would have great clinical utility. However, cats require relatively prolonged restraint for jugular catheter placement, and the cats in this study may have struggled or vocalized for reasons other than pain, such as fear, fractious temperament or positioning discomfort. CCU technicians noted that some EMLA-treated cats did not react to the initial venepuncture, but then struggled during subsequent threading of the catheter down the jugular vein into the thoracic inlet (which was not in the field of EMLA cream application), which then precluded complete placement without sedation.

From the results of this study, we can conclude that EMLA is without significant adverse effects when used as described in clinically ill cats, and that it may provide local analgesia that is sufficient to allow catheter placement in some cats without sedation. However, other factors may override the benefit of local analgesia in eliminating the need for sedation in this setting. Further evaluation of EMLA cream for other procedures requiring less prolonged restraint, such as direct blood pressure measurements, repeated venepuncture when performing glucose curves, blood donation, or superficial skin mass removal, are warranted.