In general, there are no direct data to suggest that plasma causes phenytoin to precipitate. When phenytoin and TPN are compared through dual and triple lumen catheters, the phenytoin does not crystallize when infused alone or with adequate separation (triple lumen). In vitro tests demonstrate that the solubility is tenuous at best and small changes can cause significant precipitation.
Cox JW, Sage GP, Wynalda MA, Ulrich RG, Larson PG, Su CC. Plasma compatibility of injectables: comparison of intravenous U-74006F, a 21-aminosteroid antioxidant, with Dilantin brand of parenteral phenytoin. J Pharm Sci. 1991 Apr;80(4):371-5. Drug Metabolism Research, Upjohn Company, Kalamazoo, MI 49001.
The 21-aminosteroid antioxidant U-74006F (1) is being developed as an iv injectable agent for the treatment of human CNS trauma and ischemia. Because of its poor water solubility, the plasma compatibility of the parenteral formulation of 1 was evaluated using three models: (I) static solubility, (II) aggregometric, and (III) dynamic flow. The flow model was designed to mimic an iv infusion into the human antecubital vein, which was assumed to have plasma flow of 10 mL/min. Dilantin (phenytoin), the positive control, produced a precipitate in all three models from a 10% (v/v) mixture with human plasma, which approximates the in vivo ratio when the drug is infused at the recommended rate of 1 mL/min. Approximately 39% of the phenytoin dose in the flow model was retained on a downstream 3-microns filter as crystals. In comparison, the parenteral formulation of 1 produced minimal precipitate in models I and II from 40% mixtures with plasma, but higher percentages produced unstable suspensions with time-dependent precipitation. The percentage of the dose of the parenteral formulation of 1 retained on the filter in the flow model was 0.5% or less at infusion rates as high as 10 mL/min and 3% at 19 mL/min. At the 10-mL/min infusion rate, the mass of 1 retained on the filter per minute was less than 1% of the mass of phenytoin retained at the 1-mL/min infusion rate for Dilantin. The acceptable plasma compatibility of the parenteral formulation of 1 appears to be related to the solubilizing effects of plasma protein binding and pH suppression by the citric acid vehicle.
Collins JL, Lutz RJ. In vitro study of simultaneous infusion of incompatible drugs in multilumen catheters. Heart Lung. 1991 May;20(3):271-7. Related Articles, Links
Multilumen catheters are commonly used to simultaneously administer incompatible drugs to critically ill patients. Though there are no known documented reports that this practice has been responsible for harmful events in patients, likewise there are no published data to verify the safety and efficacy of this practice. This study utilized an in vitro model flow system to examine the physicochemical phenomena that occur when two incompatible drugs (phenytoin and total parenteral nutrition) are simultaneously administered through multilumen catheters. Flow conditions and drug infusions in the venous model were designed to mimic the in vivo clinical situation to evaluate two central venous catheter types, a double- and a triple-lumen catheter. Video recordings were made of drug interactions, and assays of phenytoin concentration were performed on samples of the circulating fluid. White clouds of phenytoin precipitation were observed near the tip of the double-lumen catheter but not the triple-lumen catheter. Infusion through the double-lumen catheter resulted in an average of 6% loss of phenytoin to precipitate, which, on microscopic examination, appeared as spindle-shaped crystals 25 to 50 microns in length and 5 to 10 microns wide. In some cases, millimeter-size fragments of phenytoin precipitate were seen to dislodge from the tip of the double-lumen catheter. The adjacent orifices at the tip of the end hole of the double-lumen catheter appeared to permit interaction of the two effusing streams of the incompatible drugs, whereas the staggered orifices of the triple-lumen catheter reduce this interaction.(ABSTRACT TRUNCATED AT 250 WORDS)
Gerardo Reyes,1 Gurpreet S Mander,1 Tarek S Husayni,1 Rabi F Sulayman,1 and David G Jaimovich1 In-vivo evaluation of simultaneous administration of incompatible drugs in a central venous catheter with a decreased port to port distance Crit Care. 1999; 3(1): 51-53.
Multilumen catheters are commonly used in critically ill children. Their use, however, is associated with significant morbidity. We studied the simultaneous administration of incompatible drugs using a new triple-lumen catheter with decreased length and port to port distances. Ten domestic swine, 10-20 kg in weight, were divided into two groups of five. Total parenteral nutrition was administered through the distal port and phenytoin was administered as a bolus and as an infusion in each group. Samples were taken from two sites during the bolus and at 1, 5, and 15 min during phenytoin infusion. Histograms were generated for particle size and concentration. Samples were also examined under the microscope for particles. Histograms of particle size did not show any alteration of the histogram that would suggest particle size > 2 ?m in diameter in the study or control samples. No particles were identified by phase microscope, light microscope, or Wright stain smear. The use of a triple-lumen catheter with a distance of 0.4cm between the proximal port and the medial port and 1.3 cm between the medial port and the distal port, for the in vivo simultaneous administration of incompatible solutions does not result in precipitates large enough to cause adverse clinical effects.
C.S. Ted Tse, PharmD, MBA, and Raied Abdullah, MD. Dissolving Phenytoin Precipitate in Central Venous Access Device
TO THE EDITOR:
We describe a patient in whom sodium bicarbonate solution was used to restore patency of a central venous access device that was occluded by precipitate of phenytoin sodium injection. A 63-year-old man was admitted to our hospital for ventilator management complicated by distal esophagitis, deep venous thromboses requiring an inferior vena caval filter, recurrent aspiration pneumonia, line infections, respiratory failure requiring intubation, and seizures. A Groshong catheter (Bard Access Systems, Salt Lake City, Utah) was in the right subclavian vein. The patient had received antibiotics and vasopressor agents. At the time of the incident, medications were phenytoin by intravenous injection, 125 mg every 8 hours; norepinephrine by infusion, 8 mg in 250 mL of 5% dextrose in water; dopamine by infusion, 800 mg in 250 mL of 5% dextrose in water; vancomycin by injection, 1 g in 250 mL of normal saline every 36 hours; furosemide by injection, 20 mg every 8 hours; and total parenteral nutrition by continuous infusion.
After 30 doses of phenytoin sodium (USP, 250 mg/5 mL, Elkins-Sinn, Inc., Cherry Hill, New Jersey), the right subclavian Groshong port was found to be occluded. Urokinase, 5000 U (Abbokinase Open-Cath, Abbott Laboratories, Abbott Park, Illinois), was unsuccessfully given by injection to restore patency. The instillation of two 5-mL injections of sodium bicarbonate (8.4% sodium bicarbonate injection, USP, Abbott Laboratories) to the central line at 30-minute intervals resulted in good blood return in the line.
Injected phenytoin sodium crystallizes into insoluble phenytoin when admixed with solutions of 5% dextrose in water. A key factor in the precipitation of phenytoin is the pH of the solution. A solution of 5% dextrose in water, which is acidic (pH, 4.0), caused the phenytoin sodium injection, a basic solution (pH, 12.0), to precipitate. Instillation of sodium bicarbonate solution into the central line restored the pH to basic, with subsequent dissolution of the precipitate. Occlusion of the central line is common, and phenytoin precipitation may be overlooked as a source of occlusion. Admixing phenytoin sodium in 100 mL of normal saline and infusing it over 30 minutes may minimize the chance of precipitation. Only one report of a similar incident was found [1].
Injected sodium bicarbonate can clear phenytoin precipitate in central venous catheters. A syringe smaller than 5 mL should be avoided because it may generate high pressure and dislodge blood clots or phenytoin precipitate into the bloodstream. Clinical trials are needed to establish standardized procedures.
References: Akinwande KI, Keehn DM. Dissolution of phenytoin precipitate with sodium bicarbonate in an occluded central venous device. Ann Pharmacother. 1995; 29:707-9.
marc
-----Original Message-----
From: Lynn Hadaway [mailto:[EMAIL PROTECTED]]
Sent: Wednesday, February 08, 2006 8:57 AM
To: Kokotis, Kathy; Heather Nichols; [EMAIL PROTECTED]; [EMAIL PROTECTED]; Leigh Ann Bowe-geddes; [EMAIL PROTECTED]
Subject: [vascular] RE: Dilantin
Kathy, I am well aware of what is stated in Gaharts and Trissels. But
what I interpreted from your first message was not what those
references are stating.
Yes, phenytoin can precipitate in a syringe or bag when the pH
changes. However, I have never seen any information in any reference
anywhere stating that contact between any drug and blood inside the
vein will lead to a precipitate formation.
So yes, precipitate formed during the administration (tubing, bag,
syringe) will end up in the lungs. But I do not believe that one can
state that contact with the blood in the vein will cause
precipitation simply because the pH of the bloodstream is much lower
than the drug. Maybe Marc Stranz can offer his insights into this
issue or maybe I just misunderstood what you were trying to say. Lynn
At 4:12 PM -0700 2/7/06, Kokotis, Kathy wrote:
>Go down to the Pharmacy and ask them for their copy of Trissels
>handbook of injectable drugs. It is updated yearly and has the info
>I just gave you on solubility. Every pharmacy has a copy
>
>You will also find the info I gave you in Gahart Intravenous
>Medications by Mosby which is also updated yearly
>
>Hope that helps
>
>kathy
>
>________________________________
>
>From: Heather Nichols [mailto:[EMAIL PROTECTED]]
>Sent: Mon 2/6/2006 8:13 AM
>To: Kokotis, Kathy; [EMAIL PROTECTED]; [EMAIL PROTECTED];
>[EMAIL PROTECTED]; Leigh Ann Bowe-geddes;
>[EMAIL PROTECTED]
>Subject: RE: Dilantin
>
>
>Sounds like basic chemistry to me, but I to would like a reference
>to show this, as I have been making an ongoing case against Dilantin
>for some time now here at my facility.
>Thanks Kathy
>
>Heather Nichols RN BSN CRNI
>Infusion Services
>University of Louisville Trauma Institute
>530 S. Jackson St.
>Lou. Ky. 40202
>(502)562-3530
>
>>>> "Lynn Hadaway" <[EMAIL PROTECTED]> 02/06/06 9:42 AM >>>
>
>Kathy, I must ask for your reference for this information. Please
>provide it or tell us where you are getting this concept. Thanks, Lynn
>
>At 7:09 PM -0700 2/5/06, Kokotis, Kathy wrote:
>>Dilantin is in some ways not even compatible with normal saline or
>>your bloodstream
>>
>>Normal saline pH 5.5
>>Bloodstream pH 7.35
>>dilantin pH 12-14 but if it falls below 10 it precipitates. Both
>>blood and normal saline make the pH fall below 10 so therefore you
>>will find crystals of dilantin in the lungs if it does not
>>preceipitate sooner. Are we not lucky the lungs are a great filter
>>of life
>>
>>Kathy
>>
>>________________________________
>>
>>From: [EMAIL PROTECTED] on behalf of Leigh Ann Bowe-geddes
>>Sent: Sat 2/4/2006 6:34 AM
>>To: [EMAIL PROTECTED]; [EMAIL PROTECTED]; [EMAIL PROTECTED]
>>Subject: Re: Dilantin
>>
>>
>>Nancy:
>>Dilantin is very prone to precipitation. It is not compatible with
>>anything except NS. Flushing is very important, but there is another
>>issue. The lumen through which the dilantin is infused should be
>>dedicated to dilantin and NS only. Some of the drug may cling to the
>>internal lumen, and if anything other than NS is infused between
>>dilantin doses, you get dilantin crystals in the line.
>>There are some other issues with dilantin. It is very important to
>>flush well, and to administer the medication properly. It is not
>>stable if the pH is allowed to drop, and the normal pH of dilantin
>>is very high, somewhere in the 12-13 range.
>>Leigh Ann
>>
>>Leigh Ann Bowe-Geddes, RN, CRNI
>>IV Therapy Specialist
>>Infusion Services Department
>>University of Louisville Hospital
>>Louisville, KY
>>502-562-3530
>>
>>>>> "Nancy Sullivan" <[EMAIL PROTECTED]> 02/03/06 8:26 PM >>>
>>
>>I know you ladies and gentlmen have probably discussed this many
>>times, but I'm new to these message baords and have a questions.
>>
>>My hospital has a policy that states: "DO NOT INFUSE DILANTIN THRU
>>PICC LINES." I have been working at this hospital for 3 years and it
> >does seem like every time a nurse puts dilantin into a
>>picc--occlusion and loss of the line. I have been told that it is a
>>flushing problem and lack of education. We use groshong and per q
>>cath piccs. SO PLEASE EDUCATE ME IN THIS MATTER, BECAUSE I WOULD
>>LOVE TO EDUCATE THE REST OF THE STAFF.
>>Thanks in advance
>>Nancy Sullivan RN
>>
>>
>>________________________________
>>
>>Yahoo! Mail
>><http://us.rd.yahoo.com/mail_us/taglines/virusmail/*http://mail.yahoo.com>
>>- Helps protect you from nasty viruses.
>>
>>
>>-----------------------------------------------------
>>Confidentiality Disclaimer
>>
>>This message, including any attachments, is confidential, intended
>>only for the named recipient(s) and may contain information that is
>>privileged or exempt from disclosure under applicable law, including
>>PHI (Protected Health Information) covered under the Health
>>Insurance Portability and Accountability Act (HIPAA) of 1996. If
>>you receive this message in error, or are not the named
>>recipient(s), please notify the sender or contact the University of
>>Louisville Health Care I.S. helpdesk at 502.562.3637 to report an
>>inadvertently received message.
>
>
>--
>Lynn Hadaway, M.Ed., RNC, CRNI
>Lynn Hadaway Associates, Inc.
>126 Main Street, PO Box 10
>Milner, GA 30257
>http://www.hadawayassociates.com
>office 770-358-7861
>
>
>
>
>-----------------------------------------------------
>Confidentiality Disclaimer
>
>This message, including any attachments, is confidential, intended
>only for the named recipient(s) and may contain information that is
>privileged or exempt from disclosure under applicable law, including
>PHI (Protected Health Information) covered under the Health
>Insurance Portability and Accountability Act (HIPAA) of 1996. If
>you receive this message in error, or are not the named
>recipient(s), please notify the sender or contact the University of
>Louisville Health Care I.S. helpdesk at 502.562.3637 to report an
>inadvertently received message.
--
Lynn Hadaway, M.Ed., RNC, CRNI
Lynn Hadaway Associates, Inc.
126 Main Street, PO Box 10
Milner, GA 30257
http://www.hadawayassociates.com
office 770-358-7861
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