Provider Update

Volume 18, Issue 4 

August/September 2001

HIPAA is on the Move

The Health Insurance Portability and Accountability Act (HIPAA) is moving full speed ahead. HIPAA regulations will have a significant impact on practically everyone in the healthcare industry including providers. Though somewhat similar toY2K, HIPAA is at a much larger scale and will impact all aspects of an organization. 

Medicaid has developed a HIPAA Core Team to work toward the goal of HIPAA compliance by the October 2002 deadline. The HIPAA core team is working closely with the Unisys HIPAA team. A gap analysis has been completed which has identified any gaps in our Medicaid Management Information Systems. Currently Louisiana uses over 1000 local procedure codes that have to be converted to national standard code sets. (See the Dec 2000/Jan 2001 Provider Update for the listing of acceptable standard code sets).

It is imperative that providers start now, if they have not already done so, to understand HIPAA and the impact it will have on their business. The first step all providers must take is to become familiar with the requirements of each rule and how it will affect them. 

Presently there are nine rules that make up HIPAA. Only two (2) rules have been finalized. 

The final rule concerning standards for electronic transactions was officially published in the Federal Register dated August 17, 2000 and will become effective on October 16, 2002. After that date, any electronic transmission utilized must be in the mandated format as indicated in the implementation guide. This Transactions and Code Set Rule includes claims, remittance, eligibility, enrollment, prior authorization, claim status, premium payment and claims attachment.

The final rule, for Privacy, was published in the Federal Register December 28, 2000 with a compliance date of April 14, 2003. This rule provides the first comprehensive federal protection for the privacy of health information. Under this final rule, Medicaid beneficiaries have significant new rights and protections against the misuse or disclosure of their health records. 

The Privacy Rule supplements the federal regulations by enhancing the right of the Medicaid beneficiary. The Privacy Rule adds to the current law in the following ways: 

� All Medicaid beneficiaries must be notified of their rights regarding disclosure of their health 
information and must be presented with comprehensible written information that describes 
those rights;

� Medicaid beneficiaries do have the right to choose non-disclosure of their health information 
without penalty; and

� Severe civil and/or criminal penalties will be assessed to health plans, providers and clearinghouses if
such data is used for purposes outside the context of the Privacy Rule and existing Medicaid statutes.

Under HIPAA, Congress requires health plans, health care clearinghouses, and those health care providers who conduct certain financial and administrative transactions electronically to comply with each set of final standards. It is vital that these covered entities develop materials to present to beneficiaries that clearly explain the rights each individual has regarding the disclosure of their health information. Additionally, all entities must provide training to their staff regarding the new procedure and designate a privacy officer who will handle all matters (including Medicaid data) regarding the Privacy Rule.

Currently, the Department of Health and Human Services (DHHS) is developing other administrative simplification standards. DHHS is continuing to work on the other proposed standards, but has published proposed rules for:

�Security, 
�National identifiers for health care providers, and
�National employer identifiers.

The final regulations will be published once the review process has been completed. 

The next step is to contact your software vendor to determine what modifications are necessary to ensure your system is compliant with HIPAA�s electronic transaction standards. Providers who prefer not to modify their systems may contract with clearinghouses that are HIPAA-compliant to transmit their transactions.

In the interests of making a smooth transition to HIPAA compliance, it is imperative that the lines of communication remain open between all entities. 

HIPAA is a work in progress since many of the rules are not finalized. Changes will be occurring frequently and flexibility will be the key. 

Medicaid will keep you informed through its usual lines of communication, which include the Provider Update, remittance advice messages, mailed notices and provider training. For other current HIPAA news you may want to visit the following HIPAA web sites:

http://www.hcfa.gov/medicaid/hipaa - General information on HIPAA and links to other HIPAA sites

http://www.aspe.hhs.gov/admnsimp - Text of Administrative Simplification law and regulations publishing dates

http://www.hcfa.gov/medicaid/hipaa/adminsim/hipaapls.htm - Previous and current issues of �Medicaid HIPAA Plus�

http://www.wpc-edi.com/addenda/  - 4010 transaction implementation guides

http://hipaadvisory.com/news/index.htm - Current news articles on HIPAA


Medicaid Primary Care Case Management

CommunityCARE is being expanded. Currently approximately eighty three percent (83%) of Medicaid recipients statewide are eligible to participate in CommunityCARE. The first new regions to be included in the program are Lake Charles Region V (Calcasieu Parish) and the Houma/Thibodaux area Region III (Assumption, Lafourche, St. James, St. John the Baptist, St. Mary and Terrebonne parishes). Eligible Medicaid recipients in Calcasieu parish will be enrolled in CommunityCARE effective August 1, 2001, and recipients in the Houma/Thibodaux region will be enrolled effective September 1, 2001. Medicaid recipients in other parishes will be enrolled in the program during the later months of 2001 and during 2002. 

WHAT IS CommunityCARE?

CommunityCARE is a Medicaid managed care program operated in Louisiana under a Freedom of Choice waiver granted by the Health Care Financing Administration. It is a system of comprehensive health care based on a primary care case management (PCCM) model and currently operates in 20 rural parishes. CommunityCARE links Medicaid recipients with a physician, clinic, federally qualified health center, or rural health clinic that serves as the recipient�s primary care physician (PCP). The PCP is paid a monthly management fee in addition to the normal fee-for-service payment to manage the recipient�s health care. He/She acts as a �facilitator� and is responsible for preventive and acute care, health education, and referrals to specialists, inpatient hospitals, and other necessary health services. 

GOALS OF THE CommunityCARE PROGRAM

� Providing a �Medical Home� for Medicaid Recipients - The PCP provides basic primary care, and 
after-hours coverage. A CommunityCARE PCP is available or arranges for medical care coverage 24 
hours a day, 7 days a week, 365 days a year.
� Strengthening the Patient/Physician Relationship - As the PCP becomes familiar with the 
recipient�s health care needs, he/she is better able to diagnose and treat the medical needs than some
one who is unfamiliar with the recipient.
� Promoting the Educational/Preventive Aspects of Health Care -The PCP provides or oversees 
KIDMED preventive health care, immunizations and ongoing education to recipients.
� Promoting the Responsibility of the Recipient to Use Health Care Resources Appropriately - For 
basic medical care, the recipient must call his/her CommunityCARE PCP before going to any other 
physician, clinic, or hospital.
� Supporting Use of Quality Health Care Within the Recipient�s Community When Appropriate 
- The CommunityCARE Program was adopted to encourage recipients to obtain health care within 
their communities whenever possible.

REFERRALS

The CommunityCARE doctor will provide basic medical care and will refer the recipient to another medical care provider when specialty care is needed. For most medical care, recipients must contact their CommunityCARE doctor before going to another doctor, clinic, or hospital. Most Medicaid-covered services, including obstetrical services, require prior authorization and referral by the PCP. Services that do not require a referral by the PCP are:

� Chiropractic services upon KidMed referral
� Dental services for children (routine, in office)
� Dentures for adults
� EPSDT health services provided by schools or Early Learning Intervention Centers for �special 
needs� children
� Eye care services (routine, in office)
� Family planning services
� Home and community-based waiver services
� Mental health clinic services
� Mental health rehabilitation services
� Pharmacy services
� Transportation services
� Inpatient psychiatric services
� Psychiatrist�s services
� Targeted case management services
� Emergency services (post authorization required)

Any recipient seeking non-exempt medical services from a provider who is not listed as the CommunityCARE PCP on the recipient�s Medicaid file should be instructed to call his or her PCP. Recipients asking questions about referrals should be referred to the CommunityCARE contractor�s Client Service Representatives (CSRs) at 1 (800) 359-2122.

ELIGIBILITY FOR THE CommunityCARE PROGRAM

Most low income families with children, disabled adults, and children who are Medicaid recipients are required to participate in CommunityCARE except:
� Residents of nursing facilities (Skilled Nursing Facilities, Intermediate Care Facilities I and II), 
Intermediate Care Facilities for the Mentally Retarded (state schools and group homes), and 
psychiatric hospitals.
� Recipients who are 65 years or older
� Medicare (Part A & B) beneficiaries
� Medically needy recipients
� Foster children or children receiving adoption assistance
� Office of Youth Development clients
� Refugees
� Surveillance Utilization Review (SURS) Lock-in recipients
� Members of Health Management Organizations (HMO�s)
� Presumptively Eligible (PE) recipients

PCP SELECTION

Initial enrollment occurs when recipients first become eligible for Medicaid or when new parishes are designated as CommunityCARE parishes. New eligibles will choose their PCP or be auto-assigned within two months. During this time the recipient may use any Medicaid provider.

The recipient selects a PCP and must remain with that PCP for twelve months unless he or she meet the criteria listed below under � PCP Changes.� 

Recipients will receive a plastic Medicaid identification card and a letter giving them program information and their PCP�s name and telephone number. Whenever a new PCP is chosen or assigned, the recipient�s identification card will be updated electronically on the REVS and MEVS eligibility verification system to reflect the current PCP.

Auto assignments are carefully made to ensure that families are not split between PCPs. Whenever possible recipients are assigned to PCPs in their geographic area. Recipients who selected a PCP 
during a previous period of eligibility will be reassigned to the previous PCP to assure continuity of care. 

PCP CHANGES

CommunityCARE recipients may request that their PCP be changed for cause at any time. They may change PCPs without cause at any time during the first 90 days of an enrollment with a PCP and at least every 12 months thereafter.Questions regarding CommunityCARE can be addressed by calling 
(225) 342-1304.

Clarification of Keloid Surgery
RA Message 6/12/01 and 6/19/01 - FIMS # 6298

The 1998 Provider Training packet states on page 93 that providers will not be reimbursed for the removal of keloids if removal is/was for cosmetic reasons. The initial diagnostic visit is excluded from this policy and reimbursement for the initial diagnostic visit will be made.

Increase for CPT Code 46740
RA Message 7/3/01 and 7/10/01 - FIMS # 6345

Effective with date of service on and after June 1, 2001, the fee for CPT code 46740 (Repair of high imperforate anus with rectourethral or rectovaginal fistula; perineal or sacroperineal approach) was increased to $1,086.87.

Add-On Procedure Codes and 51 Modifier
RA Message 6/19/01 and 6/26/01 - FIMS # 6326

It has come to our attention that many providers have been using add-on procedure codes as primary procedure codes. These codes cannot be used in this way.

Effective immediately, add-on codes must be modified with a 51 modifier. They cannot be billed as primary procedures. If an add-on code is paid as a primary procedure because it wasn�t modified with a 51, the code which appears to represent the primary procedure will be denied with error edit 563 (adjust add-on code with 51 modifier) and will not be paid until the add-on code has been adjusted with the 51 modifier.

New Code Payable for CNP�s
RA Message 6/12/01 and 6/19/01 - FIMS # 6320

Effective with dates of service on or after April 1, 2001, locally assigned code Z9921 (Lunell Monthly Contraceptive Injection) has been added to the list of codes payable to Certified Nurse Practitioners. If you have billed for Lunell since April 1, 2001 and been denied, please resubmit your claim.

Rate Change for Morphometric Analysis: Tumor
RA Message 6/12/01 and 6/19/01 - FIMS # 6315

Effective with date of service on or after February 1, 2001, CPT code 88358 (Morphometric Analysis: Tumor) was made payable at a rate of $139.19 for the full service and $119.83 for the professional service.

Resistance Testing in HIV Infected Patients
RA Message 6/5/01 and 6/12/01 - FIMS # 6293

This year's issuance of the CPT contains three codes which are to be used by providers to bill for resistance testing in HIV-infected patients. These three codes are:

87901 (Infectious agent genotype analysis by nucleic acid [DNA or RNA], HIV 1, reverse transcriptase and protease);

87903 (Infectious agent phenotype analysis by nucleic acid [DNA or RNA] with drug resistance tissue culture analysis, HIV 1; up to 10 drugs); and 

87904 (.......; each additional drug, up to 5 drugs).

Recently the AMA issued code 0023T (Predictive phenotype) to be used in conjunction with code 87901. These four codes are designed to facilitate billing in pairs. For example: For just the phenotype test, bill code 87901 by itself. The virtual phenotype test should be billed as 87901 and 0023T. The complete phenotype test in which 15 drugs are tested must be billed with both 87903 and 87904. 

These four codes will pend for review as the criteria for testing must be met before the claim can be paid. Consequently, these claims cannot be billed electronically, as they must be accompanied by the results of lab tests, history and other applicable documentation. 

International Aids Society and Kaiser Foundation criteria for resistance testing will be used in determining if a claim can be paid. If these criteria are met, the Louisiana Medicaid Program will pay for one billing of code 87901 by itself; one billing of codes 87901 and 0023T, and one billing of codes 87903 and 87904 per calendar year per recipient. 

As stated earlier, codes 87901 and 0023T billed together represent the virtual phenotype and codes 87903 and 87904 billed together equal the complete phenotype. The genotype test is billed using code 87901 by itself.

Listed below is the number of times each code will be reimbursed in a calendar year per patient (provided he/she meets the criteria) and its fee. This policy is effective with date of service January 1, 2001.




Electronic claims and hard copy claims billed without the appropriate attachments will be denied with error edit 481 - Send documentation to justify specific lab test.

Retrospective Reviews of Length of Stays

Effective with date of service June 20, 2001, a hospital may request a retrospective review for inpatient hospital services only in two situations:

� Retroactive recipient eligibility - Providers have up to one year from the date that the 
recipient was added to the eligibility file to request a retrospective review.
� A dually eligible recipient has exhausted his/her Medicare Part A benefits - Providers have 
up to sixty (60) days from the date of the Medicare Part A Explanation of Benefits (EOB) 
verifying that the benefits have been exhausted to request a retrospective review.

The two-year requirements for timely filing are applicable for retrospective reviews.

Medicare Part B Changes to Daily Payment Cycle

As of July 2, 2001, Medicare has changed its payment cycle from a weekly to a daily payment cycle. This means that you will receive your Medicare payments faster and will be alerted to any denied claims sooner.

All finalized claims will be held to the payment floor (14 days for electronic and 27 days for paper) before being released for payment in a daily cycle. Medicare believes that this will allow for a continuous flow of claims payments.

If you have any questions regarding this change, please contact your Medicare Customer Services Department.

Designation Change for KIDMED Providers

The designation of Board Certified Social Worker (BCSW) has now been changed in Louisiana to Licensed Clinical Social Worker (LCSW). Please make the necessary changes to the KIDMED Social Worker Consult code descriptions found in your KIDMED Provider Manual on pages VIII-6&7.

2001 Provider Training Workshop Schedule

2001 Unisys Provider Workshops

Following is the schedule for the 2001 Unisys Provider Workshops. The annual Unisys Provider Workshops focus on presenting vital policy and billing information to our Medicaid provider community. With that in mind, our intent is to create a neutral atmosphere for delivery of the educational materials to the providers in attendance. The Department of Health and Hospitals has asked Unisys Provider Relations to address questions relating to recent policy and procedure changes. 

Our training format separates basic information from specific program information. The Basic Medicaid Information workshops will cover general Medicaid policy such as standards for participation, recipient eligibility and ID cards, CommunityCARE, third party liability, how to obtain assistance from Unisys, etc. This information will be presented ONLY in the Basic sessions and will not be repeated in specific program workshops, with the exception of CommunityCARE. 

All Basic workshop sessions will be identical in content. Providers may choose to attend any of the basic sessions in addition to their specific program, or they may choose to attend only the specific program session for their provider type.

In each specific program workshop, Unisys staff will discuss (for that specific Medicaid program) recent policy or procedure changes and will address frequent claim denial causes and solutions. Basic information such as eligibility, third party liability, etc. WILL NOT be presented in the specific program workshops.

CommunityCARE policy and procedures will be discussed in all of the workshops with the exception of Long Term Care, Waiver, PreCert, Eligibility, Ambulance, NEMT, EPSDT and Case Management.

An Eligibility workshop geared toward the LaCHIP eligibility category and EPSDT services availability and access is being offered again this year. Anyone who services EPSDT recipients is encouraged to attend.

Hospital training and Precertification training are being held as separate sessions this year. Personnel from the Utilization Review Department of each hospital and those involved in precertification for inpatient admissions, including hospital case managers who do precertification, should attend the Precertification workshop, which will contain information specifically for precertification. The Hospital workshop will focus on hospital policy in general and on billing policies and procedures.

Pharmacy training will not be held with these workshops this year. Pharmacy providers will be notified of other arrangements for training as that information becomes available. Pharmacy providers who also provide services through the DME program may wish to attend the DME workshop, however.

Mental Health Rehabilitation and Hemodialysis Facility training will not be held this year. Providers of
these services will be notified of other arrangements for training as that information becomes available.

Due to space limitations in all workshops, only personnel involved in billing should be in attendance (with the exception of the Precertification workshop). Attendees should arrive 15 - 20 minutes early to register. 

Remember,

� Each person MUST have his or her provider name and Medicaid provider ID number in order to register and attend, and 

� Providers are required to have a valid Medicaid provider ID number for each specific program workshop attended.


Medicaid programs for discussion at the workshops include:

1. Basic Medicaid Information: All providers may attend. Basic Medicaid information will be presented, including standards for participation, recipient eligibility and ID cards, CommunityCARE, third party liability, remittance advice review, how to obtain assistance from Unisys, Provider Relations information, common generic denial reasons and methods of correction, etc. This information will not be repeated in any of the 
specific program workshops listed below, with the exception of CommunityCARE.

2. Eligibility: All providers may attend. 

3. Professional: Physicians, Labs, Optometrists, Ambulatory Surgery Centers, Optical Suppliers, Nurse Practitioners, Audiologists, CRNAs, and Mental Health Clinics. Only the areas listed will be discussed in the Professional session.

4. Hospital: Acute, Rehabilitation, Long Term, Free-standing Psych, and Distinct Part Psych hospitals. Hospital policy and billing issues will be presented.

5. Precertification: Hospital Utilization Review or other personnel involved in obtaining precertification. Precertification workshops will include policy and procedures specific to precertification (not billing). THIS SESSION IS FOR HOSPITAL CASE MANAGERS.

6. Long Term Care: Nursing and ICF/MR Facilities and Hospice Services. This program will be held in all locations except Covington and Houma

7. Home Health Agencies and Free-standing Rehabilitation Centers: Home Health providers who are also DME providers should attend both the Home Health and DME sessions. This program will be held in all locations except Covington and Houma.

8. Durable Medical Equipment (DME) Suppliers. DME providers and pharmacies providing services through the DME program may wish to attend this workshop. This program will be held in all locations except Covington and Houma.

9. Dental: EPSDT, and Adult, and Oral Surgery dental training will ONLY be offered in New Orleans (concurrent with the 52nd Annual New Orleans Dental Association (NODA) Conference), and in Alexandria. Please note that you do not have to be registered with the NODA Conference to attend the dental provider training. 

10. Ambulance Transportation: Ambulance providers only�does not include non-emergency non-ambulance transportation. This session will only be held in New Orleans, Shreveport/Bossier City, and Lafayette.

11. Non-emergency Medical Transportation: Non-emergency non-ambulance providers only�does not include ambulance transportation. This session will only be held in New Orleans, Shreveport/Bossier City and Lafayette.

12. EPSDT: EPSDT Health Services (school boards and Early Intervention Centers ONLY).

13. Federally Qualified Health Centers and Rural Health Clinics This session will be held in every location except for Covington, Houma, Alexandria and Lake Charles.

14. KIDMED � This session will be held everywhere except for Covington and Houma. 

15. Case Management: Contract case management providers and targeted case management providers. Waiver providers may also attend this session for informational purposes. This session will be held in Baton Rouge, New Orleans, and Alexandria ONLY. THIS SESSION IS NOT FOR HOSPITAL CASE MANAGERS.

16. Waiver: MR/DD and Elderly and Disabled Adult waiver providers, EPSDT PCS providers and Children�s Choice providers should attend. Case management providers (this does not include hospital case managers) may also attend this session for informational purposes. This session will be held in Baton Rouge, New Orleans, Alexandria, and Lafayette ONLY.

Please refer to the following list for dates (Day 1 and Day 2) and times at each workshop location. Note that there may be more than one session held at the same time. There is no pre-registration required. Please direct any questions concerning the workshops to Unisys Provider Relations at 800-473-2783 or (504) 924-5040. Meeting sites should be contacted for directions or sleeping accommodations ONLY! DO NOT contact the meeting sites with questions related to the workshops!

Schedule of Locations and Dates

Unisys Provider Relations Field Analysts Here to Help You

The following is a listing of the Unisys Provider Field Analysts and the parishes each is responsible for. Please call your representative for any questions you may have regarding your Medicaid training and billing needs.

HCFA Name Change

In June of this year the Health Care Fianancing Administration (HCFA) name changed to Centers for Medicare and Medicaid Services (CMS). For more information regarding this change go to the following website:

http://www.hhs.gov/news/press/2001pres/20010614a.html

Clarification of Adult Denture Program - Partial Denture Policy
RA Message 6/19/01, 6/26/01, and 7/3/01 - FIMS # 6336

This notice is to provide clarification of existing Adult Denture Program partial denture policy which can be found on pages 5-12 and 5-13 of the Medicaid Dental Services Manual. 

Removable acrylic partial dentures will only be provided as a program benefit in the following select instances:

� The partial denture must oppose a full denture; and

� The recipient must be missing at least two anterior teeth, or missing at least four posterior teeth 
on either side of the arch for which the partial denture is requested; and

� The potential abutment teeth should be caries free or properly restored and, within reason, 
periodontally sound to last for seven years. 

One partial denture and one reline per arch are allowed in a seven-year period. The delivery of a partial denture prevents an authorization of a complete denture for that arch for seven years. The program does not provide or fund two partials in the same oral cavity. Should you have any questions regarding this policy, you may contact the LSU School of Dentistry by calling 
(504) 619-8589.

Question Corner

Beginning with this issue we will be instituting the Question Corner. This regular feature will contain a few of the questions providers most frequently ask. In each edition of the Provider Update a specific program will be highlighted. Program managers and the Unisys Provider Relations Unit will supply the questions and answers. We hope this feature will provide useful information. The Question Corner will appear just before the LADUR article.

CommunityCARE
1. How are recipients assigned to a CommunityCARE PCP?
The program is mandatory for most Medicaid recipients. They are given the opportunity to choose a PCP from the providers in their area who have enrolled in the program. If they do not choose a PCP, one is assigned to them.

2. What kinds of providers can enroll as CommunityCARE PCP�s?
Physicians (including family practitioners, general practitioners, pediatricians, internists, and ob-gyn), physician groups or clinics, Rural Health Clinics, and Federally Qualified Health Clinics are eligible for enrollment as CommunityCARE providers. Practitioners must be able to offer the full range of primary care services for CommunityCARE recipients.

3. How can I obtain more information about CommunityCARE, or enrollment materials?
You may contact Unisys Provider Relations at 1- 800 - 473-2783. Also be sure to read the article in this issue of the Provider Update which has additional information about CommunityCARE.

4. I see Medicaid recipients in my practice now. How will my practice be affected when my parish is brought into CommunityCARE?
If you are not enrolled as a CommunityCARE PCP, you must acquire a referral from the CommunityCARE PCP in order to bill Medicaid for services rendered to a CommunityCARE recipient. 

5. When will my parish be brought into CommunityCARE?
Calcasieu Parish will be included in CommunityCARE effective August 1, 2001. Assumption, Lafourche, St. James, St. John the Baptist, St. Mary, and Terrebonne parishes will be included in the program effective September 1, 2001. Other parishes will be phased into the program during the remainder of 2001 and during 2002.

6. What is the policy concerning emergency room usage under CommunityCARE?
Emergency services do not require prior authorization but do require post authorization. If possible, the recipient should attempt to contact the PCP before seeking emergency room services. If this is not possible, the PCP should be notified as soon as possible after a recipient seeks emergency room services.

If a recipient goes to the emergency room, the CommunityCARE doctor will decide whether the illness or injury meets the definition of an emergency medical condition according to the following �prudent layperson� standard: 

�A medical condition manifesting itself by acute symptoms of sufficient severity (including severe pain) such that a prudent layperson who possesses an average knowledge of health and medicine, could reasonably expect the absence of immediate medical attention to result in placing the health of the individual (or with respect to a pregnant woman, the health of the woman or her unborn child) in serious jeopardy, serious impairment of bodily functions or serious dysfunction of any bodily organ or part.�

Medicaid will not pay for emergency room treatment of illnesses or injuries that do not meet the prudent layperson standard and can be treated in a doctor�s office. If a recipient goes to the emergency room for routine medical treatment without an approval by the PCP, the recipient will be asked to pay for the services rendered in the emergency room.

Louisiana Drug Utilization Review (LADUR) Education

Acetaminophen Toxicity

Mark Ryan, RPh, CSPI, Director Louisiana Drug and Poison Information Center
The University of Louisiana at Monroe College of Pharmacy

Issues:

� Acetaminophen toxicity, both from intentional and accidental overdose affects large numbers of patients each year

� Many clinicians are unfamiliar with the treatment of acetaminophen toxicity

� Patients and caregivers need additional education to reduce the risk of acetaminophen toxicity

Introduction:
Acetaminophen (N-acetyl-p-aminophenol [APAP]) is the most widely used analgesic and antipyretic on the market today. Acetaminophen was made available without a prescription in 1955 and is now found either as a single agent or in combination products in over 200 preparations. Cases reported to the Toxic Exposure Surveillance System of the American Association of Poison Control Centers document over 108,000 calls to poison centers in the United States in 1999 that were the result of acetaminophen overdose1. There were 177 deaths in 1999 in which acetaminophen was implicated.

Pharmacology:
Acetaminophen is rapidly absorbed after ingestion, with peak levels occurring at 30 to 60 minutes after ingestion of a therapeutic dose of an uncoated tablet.2 There are also several extended release formulations on the market today. These products have a slightly decreased area under the curve and maximal concentration versus a standard release formulation. 

Metabolism of acetaminophen occurs almost entirely in the liver. Sulfation and glucuronidation account for greater than 90% of metabolism. The non-toxic byproducts are excreted in the urine. Less than 5% is excreted unchanged in the urine. The remaining 5% is metabolized by the cytochrome P-450 MFO system to a highly reactive substance capable of causing damage to hepatic cells. This reactive electrophile is N-acetyl-p-benzoquinoneimine (NAPQI). In most cases when a therapeutic dose is taken, NAPQI is detoxified by hepatic stores of glutathione and the resultant mercaptide conjugate is excreted in the urine. In cases of overdose and in therapeutic misadventure, normal metabolic pathways are saturated, glutathione stores are depleted, and NAPQI is available to covalently bond to hepatic cells, resulting in damage and cell death.

Pathophysiology:
When hepatic stores of glutathione are depleted by 70%, NAPQI binds to hepatic macromolecules that contain cysteine.3 Covalent binding of NAPQI causes damage which is primarily observed as necrosis in the centrilobular region of the liver. The mechanisms by which NAPQI causes damage to hepatic cells are not fully understood.

Risk factors:
Adults who ingest greater than 7.5 g in a 24 hour period are at risk for developing acetaminophen toxicity. Adults who ingest > 150 mg/kg in an acute ingestion are at risk. Children seem to be more resistant to the toxic effects of acetaminophen and the potential risk level in an acute ingestion is 200 mg/kg. Evidence suggests that fasting patients are at a greater risk for hepatotoxicity after both acute ingestions and chronic ingestions above the 4 g/day maximum recommended dose.4 Bulimic patients and those with cachexia have demonstrated reduced hepatic stores of glutathione and thus are at a greater risk. Also at risk are patients who have any type of hepatic insufficiency. Patients who are on medications that induce the P450 MFO system, such as INH or phenytoin, are in a high risk group. Patients who ingest alcohol, especially chronically, tend to have reduced glutathione stores and are also at risk for developing hepatotoxicity when taking acetaminophen.5 

Clinical Presentation:
It is quite common for a patient who has overdosed on acetaminophen to present initially with no symptoms. Because of this possible absence of overt evidence to aid in a differential diagnosis, early detection of a potential acetaminophen overdose is imperative. Early signs of toxicity include nausea and vomiting, malaise, pallor, and diaphoresis. Signs indicative of liver injury, including right upper quadrant pain, persistent nausea and vomiting, and generalized abdominal pain may only become evident 24 to 48 hours after ingestion. Elevations in serum transaminases may begin to rise as early as 8 hours after ingestion but typically rise from 24 to 36 hours post ingestion.6 The full extent of hepatic insult and injury may be realized 3 to 4 days after ingestion. Hepatotoxicity may range from mild symptoms with an elevation in serum transaminases (ALT > 1000 IU/L [normal: < 40 IU/L]) to fulminant hepatic failure where serum transaminases are typically much more elevated (> 10,000 IU/L). While most patients with even extreme elevations in transaminases will recover completely, death may occur during the period 5 to 7 days post ingestion. 

Prognosis: 
While rare, there are cases each year in which liver transplantation occurs as a result of acetaminophen-induced hepatotoxicity. If therapy is indicated and the patients AST is normal at the time of antidote administration, then that patient will almost certainly survive and will not be a candidate for a liver transplant.7 Patients who present with a pH of < 7.30 or with a combination of creatinine > 3.3 mg/dL, PT > 100 seconds, and grade III or IV encephalopathy are in great danger of dying without liver transplantation.8 Any patient who meets these criteria should be evaluated for liver transplantation. Patients who survive stage IV will return to normal liver function and will require no long term care or monitoring.

Treatment:
Controversies continue to abound with respect to the best form of gastrointestinal decontamination to be used in poisoned patients. These same controversies apply to the patient who has overdosed on acetaminophen. Due to the time factor in initiating and performing gastric lavage, it is usually not recommended in cases of acetaminophen overdose due to the very rapid gastrointestinal absorption of acetaminophen. If the ingestion has occurred in the past hour, activated charcoal would be a reasonable therapy option. Many clinicians have been hesitant to administer activated charcoal in the setting of an acetaminophen overdose for fear the acetaminophen would bind to the antidote and limit or prevent it from being effective. These fears have been shown to be unfounded for several reasons. First, if charcoal is to be administered, it is most effective if given within the first hour and certainly no later than 4 hours past ingestion since acetaminophen absorption can be considered complete by that time in a single entity overdose. In a mixed overdose activated charcoal (AC) may be useful several hours past the 4 hour mark. Second, hepatic glutathione stores are adequate to detoxify any NAPQI formed for about 8 hours after ingestion.9 A rational therapy option that is used frequently is to separate the activated charcoal and the N-acetylcysteine (NAC) by 1-2 hours if it can be done safely. NAC is absorbed quickly in the upper GI tract and is not likely to interact with the actions of activated charcoal if the two are not given at the same time. 

The major area of concern lies in cases of mixed ingestions where it would be necessary to administer activated charcoal and NAC at the same time. While there is clear evidence that activated charcoal does bind NAC,10,11 there is no evidence that this is a clinically significant event.12 No formal studies have been performed to evaluate this issue but enough information is available so that current practice is to administer activated charcoal and NAC simultaneously if needed or to space the two out by 1 hour if possible.

The antidote, N-acetylcysteine, has been found to be very effective in preventing toxicity by limiting the amount of NAPQI that is formed and also by aiding in detoxifying any NAPQI which has formed. NAC is supplied in 10 and 20% solutions for injection. It is administered orally in most situations today in a concentration of 5%. When emesis, a frequent side effect of therapy occurs, antiemetics are administered. Metoclopramide, dosed in a range of 0.1 to 1.0 mg/kg seems to be the most effective. At the higher doses of metoclopramide, diphenhydramine is also given to decrease the dystonic effects that will likely occur. Aside from a very offensive sulfur odor, NAC displays very few side effects. Nausea and vomiting are the most common. Diarrhea occurs infrequently, and there are rare cases of skin rash reported.13In cases where oral NAC cannot be tolerated, the medication can be administered via a nasogastric tube. Giving small aliquots of NAC will often decrease or eliminate the gastrointestinal side effects. In the rare cases where this route of administration also fails, intravenous NAC is considered. While not yet approved for IV use in the U.S., NAC has been used safely in Europe in this manner for many years. A protocol for IV administration can be obtained by contacting the Louisiana Drug and Poison Information Center. 

The 72 hour oral NAC protocol is as follows: a loading dose of 140 mg/kg is administered, and 4 hours after the loading dose the maintenance doses are started. The maintenance doses, 70 mg/kg each, are given every 4 hours for a total of 17 doses. If vomiting occurs within 1 hour of administering a dose, the entire dose is repeated. It is very important that once a patient is deemed to be at risk by plotting their time versus serum concentration on the Rumack-Matthews nomogram that NAC therapy be initiated and continued until the entire regimen is completed.

Conclusion:
Since the first cases of acetaminophen toxicity were noticed in Britain in the late 1960�s, our level of understanding regarding the cause and management of acetaminophen toxicity has continued to increase. While we can manage the toxic effects, education of patients to the dangers of overmedicating or often unwittingly mixing medications that contain acetaminophen falls squarely in the lap of the healthcare professionals who treat these patients. While the acute, intentional overdose patients will continue to be seen, properly educating patients about the dangers of acetaminophen can reduce the tremendous numbers of chronic ingestions relating to the misuse of acetaminophen.

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