Ceftriaxone Choledocholithiasis

(1)

EXPERIENCE

AND

REASON

133 REFERENCES

I.Kikuchi M. Lymphadenitis showing focal reticulum cell hyperplasia

with nuclear debris and phagocytosis. Nippon Ketsueki Gakkai Zasshi.

1972;35:379-380

2. Fujimoto Y, Kozima Y, Yamaguchi K. Cervical subacute necrotizing

lymphadenitis. A new clinicopathologic agent. Naika. 1972;20:

920-927

3. Dorfman RF, Berry GJ. Kikuchi’s histiocytic necrotizing lymphadenitis:

an analysis of 108 cases with emphasis on differential diagnosis. Semi,: Diagn Pathol. 1988;5:329-345

4. Dorfman RF. Histiocytic necroti.zing lymphadenitis of Kikuchi and

Fujimoto. Arc/i Pathol Lab Med. 1987;1l1:1026-1029

5. Turner RR, Martin J, Dorfman RF. Necrotizing lymphadenitis: a study of 30 cases. Am J Surg Pathol. 1983;7:115-123

6. Kuo T-T. Cutaneous manifestations of Kikuchi’s histiocytic necrotizing

lymphadenitis. Am ISurg Pathol. 1990;14:872-876

7. Feller AC, Lennert K, Stein H, Bruhn HD, Wuthe HH. Immunohistology and aetiology of histiocytic necrotizing lymphadenitis: report of three instructive cases. Histopathology. 1983;7:825-839

8. Kikuchi M, Yoshizumi T, Nakamura H. Necrotizing lymphadenitis: possible acute toxoplasmic infection. Virchows Arc!: A Pathol Anat

His-topathol. 1977;376:247-253

9. Fujimori T, Shioda K, Sussman EB, Miura M, Katayama I. Subacute

necrotizing lymphadenitis: a clinicopathologic study. Acta Patliol Jpn.

1981;31 :791-797

10. Garcia CE, Girdhar-Gopal HV, Dorfman DM. Kikuchi-Fujimoto disease

of the neck: update. Ann Otol Rhino! Laryngol. 1993;102:11-15

I I.Chan JKC, Wong KC, Ng CS. A fatal case of multicentric Kikuchi’s

histiocytic necrotizing lymphadenitis. Cancer. 1989;63:1856-1862

12. Hollingsworth HC, Peiper SC, Weiss LM, Raffeld M, Jaffe ES. An investigation of the viral pathogenesis of Kikuchi-Fujimoto disease.

Lack of evidence for Epstein-Barr virus or human herpesvirus type-6 as

the causative agents. Arch Pathol Lab Med. 1994;118:134-140

13. Takano Y, Saegusa M, Okudaira M. Pathologic analyses on non-overt necrotizing type Kikuchi and Fujimoto’s disease. Acta Pathol Jpn. 1993; 43:635-645

14. Imamura M, Ueno H, Matsuura A, et al. An ultrastructural study of

subacute necrotizing lymphadenitis. Am JPathol. 1982;107:292-299

15. Asano 5, Akiake Y, Jinnouchy H, et al. Necrotizing lymphadenitis: a

review of clinicopathological, immunohistochemical, and

ultrastruc-tural studies. Hematol Oncol. 1990;8:251-260

16. Tsang WYW, Chan JKC, Ng CS. Kikuchi’s Lymphadenitis. A

morpho-logic analysis of 75 cases with special reference to unusual features. Am ISurg Pathol. 1994;18:219-231

17. Chamulak GA, Brynes RK, Nathwani BN. Kikuchi-Fujimoto disease mimicking malignant lymphoma. Am ISurg Pathol. 1990;14: 514-523

18. Hansmann ML, Kikuchi M, Wacker HH, et al. Immunohistochemical

monitoring of plasmacytoid cells in lymph node sections of

Kikuchi-Fujimoto disease by a new pan-macrophage antibody Ki-Mi P. Human

Pathol. l992;23:676-680

19. Medeiros U, Kaynor B, Harris NL. Lupus lymphadenitis: report of a

case with immunohistologic studies on frozen sections. Human Pathol.

1989;20:295-299

20. Litwin MD, Kirkham B, Henderson DR. et al. Histiocytic necrotizing lymphadenitis in systemic lupus erythematosus. Ann Rheum Dis. 1992; 51:805-807

21. Satoh M, Nakamoto H, Okubo K, Ajmani AK. Histiocytic necrotizing

lymphadenitis in a sibling of a patient with systemic lupus erythema-tosus. Lupus. 1993;2:207-208. Letter.

22. Meyer 0, Kahn MF, Grossin M, et al. Parvovirus B19 infection can

induce histiocytic necrotizing lymphadenitis (Kikuchi’s disease) associ-ated with systemic lupus erythematosus. Lupus. 1991;1:37-41

23. Maeda T, Ashie T, Ishiyama N, Kikuiri K. A case of necrotizing

lymph-adenitis associated with aseptic meningitis. Jpn Soc Intern Med. 1987;76:

1073-1077

24. Yamsaki Y, Chiba 5, Misago M, et al. A case of subacute necrotizing lymphadenitis associated with aseptic meningitis. Jpn Soc Intern Med. 1986;75:687-690

Ceftnaxone

Choledocholithiasis

Ceftriaxone

is a broad-spectrum,

third-generation

cephalosponin.

The

formation

of biliary

sludge

and

cholelithiasis

after

ceftriaxone

administration

has

been

reported

and

is thought

by many

to be a benign

process.13

Despite

this,

cholecystectomy

has

been

performed

in

symptomatic

patients

who

have

re-ceived

ceftriaxone.3’4

This

complication

of ceftriaxone

therapy

is not

widely

appreciated

in the

gastroenter-ology

and

surgical

literature.

We

report

the

first

doc-umented

case

of ceftniaxone

choledocholithiasis.

CASE REPORT

A 9-year-old boy who 4weeks before admission was treated for

open head trauma was referred for evaluation of abdominal pain

and cholelithiasis. The patient sustained a comminuted, depressed

skull fracture of the left frontal area with underlying cerebral

laceration from being kicked in the head by a horse. No

preoper-ative plane abdominal radiographs or abdominal computed

tomo-graphic scans were obtained at that time. He was treated

surgi-cally by debridement and fracture elevation, followed by 48 hours

of fluid restriction (#{190}maintenance), lasix, and mannitol. His

treat-ment included a 7-day course of ceftriaxone at the recommended

dose of 100 mg/kg per day in two divided doses (3 g/d total). He

received no parenteral nutrition. The patient had an uneventful

perioperative course with complete neurologic recovery.

Five days after completing his course of ceftriaxone and

dis-charge from the referring hospital, episodic, crampy, epigastric

abdominal pain of increasing frequency and duration with

asso-ciated emesis developed. Plane abdominal radiographs revealed

no abnormalities. Ultrasound showed multiple echogenic foci

within the gallbladder. At admission the patient denied having

had anorexia, fever, chills, or diarrhea, but complained of upper

abdominal pain. Medical and surgical histories were

noncontrib-utory. A review of systems revealed no history of abdominal pain,

jaundice, nausea, or vomiting. There was no family history of

cholecystitis. A physical examination revealed normal vital signs

and a well-healed craniotomy incision, and an abdominal

exami-nation was remarkable for right-upper-quadrant and epigastric

tenderness, normal bowel sounds, and no peritoneal signs. A

rectal examination was unremarkable. Flat and upright abdominal

radiographs were unrevealing. Laboratory analysis showed a

white blood cell count of 8.4, hematocrit of 38, normal serum

electrolytes, alkaline phosphatase of 335 (0 to 35 /L), LDH of 124

(0 to 170 IU/L), bilirubin total of 06 (0.2 to 1.0 mg/dL), and

amylase of 98 (0 to 125 /L). A second ultrasound confirmed

cholelithiasis and additionally revealed a dilated common bile

duct (CBD) of 8.8 mm diameter and a CBD stone, which appeared

to be impacted at the ampulla (Figure).

At surgery, an open cholecystectomy was performed, and an

intraoperative cholangiogram confirmed a distal CBD stone and

partial obstruction of the CBD. CBD exploration with removal of

the CBD stone was uneventful, as was the patient’s postoperative

course. Analysis of the stone by polarization microscopy and

infrared spectroscopy (Laboratory for Stone Research, Newton,

MA) revealed it to be 100% ceftriaxone. The child has been well

without recurrence of symptoms in the 2 years since his last

surgery.

DISCUSSION

Ceftriaxone

is

a

semisynthetic,

third-generation

cephalosponin

with

a wide

spectrum

of antimicrobial

activity.

The

half-life

of elimination

of ceftriaxone

is

approximately

8 hours,

which

allows

a dosing

inter-Received for publication Aug 15, 1995; accepted Oct 3, 1995.

Reprint requests to (T.M.C.) Pediatric General and Thoracic Surgery, The

Children’s Hospital of Philadelphia, 34th St and Civic Center Blvd,

Phila-delphia, PA 19104-4399.

Acad-emy of Pediatrics.

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134 EXPERIENCE

AND

REASON

Figure.

Ultrasound shows a

di-lated common bile duct and an

im-pacted stone at the ampulla (arrow).

val

of

once

or

twice

daily.5

Although

the

primary

route

of

excretion

is

renal,

approximately

40%

of

administered

ceftriaxone

is

secreted

unchanged

in

the

bile.6

These

factors,

along

with

the

drug’s

excel-lent

cerebrospinal

fluid

penetration,

have

contrib-uted

to

ceftriaxone’s

popularity,

particularly

in

the

pediatric

population.

A potential

adverse

effect

of

ceftniaxone

adminis-tration

not

previously

reported

in

the

surgical

liter-ature

is

the

formation

of

gallbladder

sludge.7

The

term

“pseudolithiasis”

has

been

used

to describe

this

condition.8’9

Ceftriaxone

possesses

a high

calcium-binding

affinity,

and

there

is a linear

binding

ratio

between

calcium

and

ceftriaxone.’#{176}

In

rats,

ceftriax-one

produces

a vigorous

choleresis

with

passive

flow

of calcium,

which

exceeds

the

solubility

product

and

results

in precipitation.11

The

typical

dose

of 60 to 100

mg/kg

per

day

in children

is equivalent

to an

adult

dose

of 4 to 7 g/d.

The

biliary

ceftriaxone

saturation

index

at

this

dose

has

not

been

studied,

but

extrap-olation

from

known

data

places

the

entire

index

range

above

the

metastable

limit,

which

would

pre-dispose

to precipitation.1#{176}

The

clinical

outcome

of

ceftriaxone-associated

sludge

has

not

been

studied

rigorously.

Prompt

res-olution

of

sludge

has

been

demonstrated

with

dis-continuation

of

the

drug.9’2 A

recent

study

using

serial

ultrasonographic

examination

of

the

gallblad-den

demonstrated

that

biliary

sludge

developed

in

46%

of children

receiving

ceftniaxone

(100

mg/kg

per

day).13

Symptoms

that

could

be

attributed

to

the

biliary

tract

developed

in

19%

of

these

patients.

Symptoms

resolved

with

discontinuation

of

the

drug.13

Several

reports

describe

patients

with

ceftniaxone

pseudolithiasis

who

required

cholecystectomy

for

presumed

acute

cholecystitis.3

A

single

case

of

re-versible

biliary

tract

obstruction

with

pancreatitis

as-sociated

with

presumed

ceftniaxone

pseudolithiasis

has

been

reported.14

The

present

case

represents

the

first

documented

case

of ceftriaxone-induced

chole-docholithiasis.

Ceftriaxone

is

a

option

for

single-agent

antibiotic

therapy,

and

its use

necessitates

awareness

of

and

monitoring

for

its

biliary

complications.

In

children,

the

lower

dose

of 50 mg/kg

per

day

(in

children

weighing

less

than

40 kg

or

doses

not

exceeding

2 g/d

total)

may

be

more

ap-propriate

to

avoid

exceeding

the

saturation

index,

which

results

in

precipitation.

However,

it

is

un-known

whether

even

this

lower

dose

will

prevent

ceftriaxone

precipitation.

Ceftriaxone

should

be used

with

caution

in

patients

with

fluid

restrictions

and

those

at risk

for

biliary

stasis

or stone

formation,

such

as

liver

transplant

recipients,

patients

receiving

pro-longed

parenteral

alimentation,

and

those

with

he-molytic

disease.

FRANK M. ROBERTSON, MD

TIMOTHY M. CROMBLEHOLME, MD, FAAP

Division of Pediatric Surgery

SARAH E. BARLOW, MD

MENNO VERHAVE, MD

Division of Pediatric Gastroenterology

Tufts University School of Medicine and

the Floating Hospital

New England Medical Center

Boston, MA 02111

DANIEL BROWN, MD

Department of Pediatrics

Portsmouth Regional Hospital

Portsmouth, NH 03801

REFERENCES

1.Meyboom RHB, Kuiper H, Jansen A. Ceftriaxone and reversible

chole-lithiasis. Br Med J.1977;297:858-859

2. Jacobs RF. Ceftriaxone-associated cholecystitis. Pediatr I,ife’ct Dis J.1988;

7:434-436

3. Roche Laboratories. Roce’p/iin. Report of Cast’s of Positiz’c’ Gallbladder

Sono-‘rai,is in Patients Receiz’i,o’ Roce’pl:in. Revised Scit’,itific Update. Nutley, NJ:

Hoffman-La Roche, Inc; 1993

4. Lopez AJ, O’Keefe P, Morrissey M, et al. Ceftriaxone-induced

at Viet Nam:AAP Sponsored on September 1, 2020

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EXPERIENCE

AND

REASON

135

thiasis. A::;: 1,iter,i Med. 1991;115:712-714

5. Patel IH, Kaplan SA. Pharmacokinetic profile of ceftriaxone in man. Am

IMed. 1984;77(4C):17-25

6. Park MZ, Lee SP, Schy AL. Ceftriaxone-associated gallbladder sludge. Gastroenterology. 1 991 ;100:l 665-1670

7. Lee SP, Lipsky BA, Teefey SA. Gallbladder sludge and antibiotics.

Pediatr Infect Dis J.1990;9:422-423

8. Pigrau C, Pahissa A, Gropper S. et al. Ceftriaxone-associated biliary pseudolithiasis in adults. Lancet. 1989;2:165-166

9. Heim-Duthoy K, Caperton EM, Pollock R, et al. Apparent biliary pseudolithiasis during ceftriaxone therapy. A,itiniicroh Agents

C/ic-n:ot/ier. 1990;34:1 146-1149

10. Shiffman ML, Keith FB, Moore EW. Pathogenesis of ceftriaxone-associated biliary sludge. Gastroenterology. 1990;99:1 772-1778 11. Xia Y, Lambert KJ, Schteingart CD, et al. Concentrative biliary secretion

of ceftriaxone. Gastroenterolory. 1990;99:454-465

12. Schaad UB, Tschappeler H, Lentze MJ. Transient formation of precipi-tation in the gallbladder associated with ceftriaxone therapy. Pediatr

Infect Dis 1.1986;5:708-710

13. Schaad UB, Suter S. Borradori AG, et al. A comparison of ceftriaxone and cefuroxime for the treatment of bacterial meningitis in children.

N EngI IMed. 1990;322:143-147

14. Zinberg 1’Chernaik R, Coman E, et al. Reversible symptomatic biliary

obstruction associated with ceftriaxone pseudolithiasis. An: I

Gastroen-terol. 1991;86:1251-1254

stress

has

become

an

essential

component

of modern

pediatric,

anesthetic,

and

surgical

practiceP8

Opioids

and

benzodiazepines

are

the

most

widely

used

drugs

to

treat

pain

and

sedate

children.9

Intra-venous

and

epidural

patient-controlled

analgesia,

continuous

opioid

and

benzodiazepine

infusions,

and

around

the

clock

(versus

on

demand,

“pm”)

analgesic

and

sedative

administration

are

increas-ingly

used

in the

management

of acute

pain,

whether

surgical

(eg,

postoperative

or

posttraumatic

pain)

or

medical

(eg,

sickle

cell

vaso-occlusive

crisis,

cancer

pain).

10-12

Unfortunately,

the

use

of opioids

and

sedatives

for

more

than

5 to 10 days

has

created

iatrogenic

opioid

and

benzodiazepine

tolerance

and

dependence.13

This

is particularly

common

when

fentanyl,

a very

potent

opioid

agonist,

is administered

by

continuous

infusion

over

a relatively

short

period

(5

days)

of

time.’’5

There

are

very

few

guidelines

or

protocols

to treat

or

prevent

withdrawal

symptoms

in

pediat-nc

patients.14’16

We

report

our

management

experi-ence

with

this

new

iatrogenic

problem.

CASE

1

The

Management

of Opioid

and

Benzodiazepine

Dependence

in

Infants,

Children,

and

Adolescents

ABBREVIATIONS. IVPCA, intravenous patient-controlled

analge-sia; PCA, patient-controlled analgesia; IV, intravenous; ECMO,

extracorporeal membrane oxygenation; G proteins, guanine

flu-cleotide-binding proteins; NMDA, N-methyl-o-aspartate; cDNA,

complementary deoxyribonucleic acid; GTPase, guanosine

tniphosphate; cAMP, cyclic adenosine monophosphate; GABA,

gamma-aminobutyric acid.

As

physicians

and

nurses,

we

have

a fundamental

obligation

to manage

pain

and

relieve

patient

suffer-ing

as

a crucial

element

of our

professional

commit-ment

to

patient

care)’2

These

are

not

merely

lofty

ideals;

effective

pain

management

produces

a

myr-iad

patient

benefits

including

reduced

morbidity

and

mortality,

early

mobilization,

and

shortened

hospital

stay.3

Historically,

children

were

undertmeated

for

pain

and

for

painful

procedures

because

of

the

common

wisdom

that

children

neither

responded

to,

nor

me-membemed,

painful

experiences

to

the

same

degree

that

adults

did.

This

is simply

untrue.

We

now

know

that

even

neonates

experience

pain

and

that

all

chil-dren,

even

the

critically

ill,

respond

to noxious

stim-uli

with

biochemical

and

physiologic

stress

me-sponses

that

if

untreated

can

lead

to

increased

patient

morbidity

and

mortality.4’5

Effective

pain

therapy

to block

the

myriad

physiologic

responses

to

Received for publication Dec 8, 1994; accepted Aug 29, 1995.

Reprint requests to (MY.) Dept of Anesthesiology, Johns Hopkins Hospital, Halsted 842, 600 N Wolfe St. Baltimore, MD 21287.

Acad-emy of Pediatrics.

The patient, an 8-year-old, 25-kg, previously healthy white

male, was the victim of a lawn mower accident. The child

sus-tamed extensive lower extremity injuries requiring multiple

sun-gical corrective procedures (debridement, skin grafting) and

mul-tiple daily dressing changes. Analgesia was achieved with

morphine provided by a patient-controlled infusion pump

(intra-venous patient-controlled analgesia [IVPCA]). Initially the

pa-tient-controlled analgesia (PCA) pump was programmed to

pro-vide a basal infusion rate of 20 gig/kg/h and patient-initiated

boluses of 20 pg/kg/dose. Five patient-initiated doses were

al-lowed per hour and the lock-out period between doses was

pro-grammed at 8 minutes. Additionally, the child required

midazo-lam (0.1-0.2 mg/kg) and fentanyl (2-5 .tg/kg) for dressing

changes that occurred 2 to 4 times a day. After the first week of

hospitalization supplemental fentanyl for dressing changes was

discontinued and the nursing staff was instructed to increase the

morphine boluses to 75 jg/kg/bolus during dressing changes.

The PCA pump lock-out period was also decreased to 5 minutes

during dressing changes. Seven weeks after the injury, the child’s

wound had improved significantly. The wound had been skin

grafted and dressing changes were less traumatic. Discharge to

home was anticipated within the ensuing 10 days. Over the

fol-lowing week the child’s IVPCA settings were reduced by 10% a

day. No signs of opioid withdrawal were encountered. When the

basal rate of morphine was 10 jig/kg/h (0.25 mg/h), intravenous

(IV) morphine was discontinued and oral morphine was started.

IV morphine was converted to oral morphine in a ratio of 1:4 (10

.tg/kg/h IV morphine 40 tg/kg/h oral morphine). The total

daily oral morphine dose of 24 mg (40 j.g/kg/h X 25 kg x 24 h)

was administered in four divided doses (6 mg) every 6 hours. The

child was discharged home. Over the next 9 days his morphine

dose was reduced gradually using the tapering schedule listed in

Table I. He never experienced any signs of opioid withdrawal.

One week after completing his tapering schedule for opioids,

he returned for another surgical procedure. He received our

rou-tine postoperative analgesic regimen, namely, morphine IVPCA at

20 xg/kg for both the basal and bolus rate. Four days after the

surgical procedure he was easily converted from parenteral

opi-oids to oral nonopioid analgesics.

CASE 2

The patient, a previously healthy, 5-kg, 4-month-old infant was

admitted to the Pediatric Intensive Care Unit with congestive

heart failure due to an anomalous left coronary artery. The child

underwent a successful emergency reimplantation of the coronary

artery but could not be weaned off the cardiac bypass machine

because of poor left ventricular function. Extracorporeal

mem-brane oxygenation (ECMO) was initiated and maintained for 5

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1996;98;133

Pediatrics

Daniel Brown

Frank M. Robertson, Timothy M. Crombleholme, Sarah E. Barlow, Menno Verhave and