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Medications In The Hyperbaric Environment

Medications In The Hyperbaric Environment

Medications In The Hyperbaric Environment

A hyperbaric and hyperoxic environment creates numerous considerations for the use of drug therapies within it. Physiologic changes to the body from HBOT may lead to pharmacokinetic changes in drug disposition.  In addition, HBO acting as a drug can interact and enhance or lessen the physiologic effect of the drug. Most drugs will not interact unfavorably with oxygen. Unless specific contraindications or precautions have been addressed, it is generally safe to assume a medication can be used. Significant known exceptions and their evidence along with implications of hyperbaric oxygen will be discussed.[1]

Pharmacodynamic interactions result in modification of the pharmacologic effect of the drug after administration. These interactions will increase or decrease the effects of oxygen or the drug.[1]

DRUGS INCOMPATIBLE WITH HYPERBARIC OXYGEN DUE TO ENHANCED DRUG TOXICITY

Antineoplastic Drugs

Bleomycin Sulfate (Blenoxane®, Blenomax®)

  • Bleomycin is a polypeptide which fights against a number of tumors. The exact mechanisms of action of this drug are not clear; however, its cytotoxic effects are likely mediated through inhibition of cell cycle progression and the synthesis of DNA and protein.
  • The primary dose-limiting toxicity of Bleomycin is the development of pulmonary toxicity ranging from radiographic changes to pneumonitis and fatal pulmonary fibrosis. 
  • Controversy has surrounded the use of supplemental oxygen administration and perioperative patients who have received Bleomycin chemotherapy since 1978 due to oxygen-related risk to severe pulmonary complications.  [2]
  • Despite the theoretical risk, there are no articles specifically stating that HBO should be prohibited after bleomycin administration. As late as 2008, prior bleomycin remained an absolute contraindication to HBO therapy.  [2]
  • It is felt that as long as the patient has no signs of pulmonary compromise from fibrosis, and it has been over three months since he or she was treated with bleomycin, his or her exposure to bleomycin should not be a health factor.  [2]
  • If there is any question of pre-existing pulmonary disease, establish a baseline for pulmonary function with spirometry, diffusing capacity of the lungs for carbon monoxide (DLCO) and imaging and monitor for adverse changes during HBO therapy.  [2]
  • History of Bleomycin therapy may be considered as a relative contraindication to hyperbaric oxygen therapy.  [1]

Cisplatin (Cisplatin®, Platinol®)

  • Cisplatin has been used for a number of years in a variety of cancer treatment protocols.
  • The therapeutic benefit of this drug is realized through its ability to inhibit DNA synthesis affecting fibroblast production and collagen synthesis. 
  • Concomitant use of Cisplatin is a relative contraindication in patients who suffer from chronic, non-healing wounds and should not be considered for hyperbaric oxygen therapy due to diminished wound healing. 

  • In a life-threatening situation such as CAGE or gas gangrene, wound healing concerns are overridden by the emergency indication.  [1]

Doxorubicin (Adriamycin®, Doxil®, Rubex®)

    • Doxorubicin is an antineoplastic agent which interferes with DNA and protein synthesis.
    • This drug is widely distributed in the body but has particularly high concentrations in the heart, liver, and kidneys.
    • Adverse reactions such as cardiac dysrhythmias, acute left ventricular failure, and irreversible cardiomyopathies have been reported.
    • Extravasation of this drug typically results in significant tissue damage.
    • Given the lack of strong evidence and possibility of harm, HBO2 and doxorubicin should be avoided in combination. Some recommend at least 3 days go by between the last doxorubicin dose and the initiation of the course of HBO2.  [1]

    DRUGS DECREASING TOLERANCE TO OXYGEN TOXICITY

    Narcotic Analgesics

    • Narcotic analgesics may increase the risk of CNS oxygen toxicity.
    • In higher dosages, these drugs may cause respiratory depression resulting in carbon dioxide retention. This hypercapnea promotes CNS vasodilatation and increases oxygen delivery to the brain.  [1]

      Thyroid Replacement (Synthroid®, Levoxyl®, Cytomel®)

      • Thyroid supplementation resulting in a hyperthyroid state increases both pulmonary and CNS oxygen toxicity. This is likely mediated through increased sympathetic tone.
      • Active Grave's disease predisposes to seizures as the patient is hyperthyroid. 
      • There is no danger of oxygen toxicity in a patient taking thyroid supplement to maintain a euthyroid (having normal thyroid gland function) state. [1]

      Glucocorticoids

      • Corticosteroids (Deltasone®, Decadron®, Solu-Medrol®, Solu-Cortef®)
        • Corticosteroids increase the risk of oxygen toxicity. 
        • Careful monitoring of the patient who is receiving large doses of steroids is necessary and prophylactic anticonvulsants may be necessary along with frequent air breaks. [1]

      Sympathomimetic Amines - Dopamine (Intropin®) - Dobutamine (Dobutrex®) - Epinephrine (Adrenalin)

      • Drugs that increase sympathetic stimulation may increase the suceptibility to oxygen toxicity by similar means to enhanced metabolic rate.
      • Epinephrine was noted to increase pulmonary and CNS oxygen toxicity as early as the 1950’s. The mechanisms of this enhanced toxicity are not well understood; however, this must be given due consideration in the critical care setting where adrenergic agents are commonly utilized. [1]

      Central Vasodilators

      • Acetazolamide (Diamox ®)
        • Has carbonic Anhydrase-inhibiting effects in humans leading to retention of carbon dioxide which promotes vasodilation and increases cerebral blood flow. This enhances oxygen delivery and decreases the time to oxygen toxicity. 
        • Has diuretic effects and is commonly used for prophylaxis against high altitude sickness.
        • Through its CNS vasodilatory effects and consequent enhanced CNS oxygen delivery, the risk for oxygen toxic seizures is increased.
        • HBO pressures should be limited to 2.0 ATA in this setting. Addition of air breaks should also be considered. [1]
      • Mafenide Acetate (Sulfamylon ®)
        • A sulfonamide antimicrobial creme that inhibits the growth of a variety of microbial organisms
        • Has carbonic anhydrase-inhibiting effects in humans leading to retention of carbon dioxide which promotes vasodilation and increases cerebral blood flow. This enhances oxygen delivery and decreases the time to oxygen toxicity. 
        • It is recommended that this cream be removed from any patient entering the hyperbaric chamber.
        • Silvadene (Silver Sulfonamide) is the more common, safer alternative in the hyperbaric chamber. [1]

      Opiod Analgesics

      • Will enhance the risk of oxygen toxicity via CO2 retention, leading to central vasodilation similar to carbonic anhydrase inhibitors
      • Depress respiration by reducing the reactivity of the medulla to CO2 leading to a rise in arterial PCO2 causing the blood vessels of the brain to dilate.  Due to the increased blood flow, the amount of dissolved oxygen rises in the brain tissue. This rise speeds the development of oxygen convulsions.
      • Clinicians should monitor patients closely, and if respirations are noted to be decreased, the patient should be reminded to take deep breaths to ventilate and reduce the CO2 levels. [1]

      Hyperthermia

      • Elevation in temperature and metabolism leads to an increased susceptibility to oxygen toxicity.

      DRUGS INCREASING TOLERANCE TO OXYGEN TOXICITY

      Vitamin E (Alpha Tocopherol)

      • Acts  as an antioxidant and scavenges free radicals formed by oxygen
      • Some hyperbaric clinicians recommend a pretreatment dosage of 400 units p.o. per 90-minutes of oxygen breathing. [1]

      Propranolol

      • A beta-adrenergic blocker that has good penetration into the central nervous system. 
      • While propranolol is not recommended as a seizure-preventing medication, those who are on it may be more resilient to demonstrating signs of toxicity. [1]

      Tromethamine (THAM)

      • A buffering agent that will generate bicarbonate from carbonic acid instead of carbon dioxide. [1]

      Chlorpromazine (Thorazine®, Largactil®) and Promethazine (Phenargan®)

      • This medication showed a protective effect against CNS oxygen-induced seizures.
      • Have similar mechanisms to sympatholytic properties of drugs
      • Phenothiazines that have minimal effect on CNS vasomotor tone (those containing a piperazine side chain) should also have a similar benefit. [1]

      CONSIDERATIONS FOR COMMONLY USED DRUGS

      Anticonvulsants

      • The use of anticonvulsants may be either prophylactic or for the treatment of seizures which do not stop when oxygen inhalation is terminated. 
        • If anticonvulsants are used prophylactically to suppress convulsions, it is critically important that the usual oxygen/pressure time limits be observed.  
      • In the patient who is febrile, toxic from gas gangrene, taking steroids, or has an idiopathic-low seizure threshold, prophylactic administration of a suitable anticonvulsant may be indicated. [1]                             

        Phenobarbital (Luminal®)

        • Phenobarbital is efficacious in the prevention of CNS oxygen-induced seizures; however, respiratory depression must be considered which could lead to elevated levels of CO2, thereby increasing the risk of CNS oxygen-induced seizures. [1]

        Benzodiazepines (Ativan®, Valium®, Librium®) Phenytoin / Phosphenytoin (Dilantin®)

        • Benzodiazepines are effective as anticonvulsants and are generally well tolerated in the hyperbaric patient.
        • Benzodiazepines are useful in treating patients with significant confinement anxiety and patients may require larger doses than would be expected.
        • Monitoring of respiratory an mental status is recommended for patients who receive benzodiazepines prophylactically or emergently. [1]

        Phenytoin

        • Phenytoin has been widely used in epilepsy, but its efficacy in preventing oxygen convulsions is not well established
        • Clinical experience dictates that its effect in stopping oxygen seizures can be substantial in the acute situation.  [1]

        Disulfiram (Antabuse®)

        • Inhibits ethanol oxidation to acetic acid and halts metabolism in the acetaldehyde stage.
        • Causes flushing, nausea, and vomiting and is intended to deter the user from ingesting alcohol.
        • The risk of using Disulfiram in the chamber is that it blocks the production of superoxide dismutase (SOD), a major protective enzyme against oxygen toxicity.
        • Initially, animal studies showed promising results with the use of Disulfiram for the prevention of both pulmonary and central nervous system oxygen toxicity.
        • This protective effect proved to be dramatic even with oxygen exposures as high as 6 atmospheres absolute (ATA). 
        • Theoretically, Disulfiram may be protective for single hyperbaric treatments but may enhance toxicity with multiple treatments.
        • It is no longer considered a contraindication to HBOT. [1]

        Insulin

        • The effects of HBO2 on insulin activity are clearly potentiated. Blood glucose levels have consistently been shown to fall in diabetic patients who are undergoing HBOT with average drops in blood glucose levels between 21-51 milligrams per deciliter. 
        • Insulin requirements in diabetics may change rapidly, precipitating unexpected hypoglycemia. 
        • HBO2 patients should be closely monitored for signs of hypoglycemia. Blood glucose levels must be checked prior to and immediately post HBO treatment.  
        • Glucose supplementation with orange juice is suggested for pre-treatment blood glucose levels ranging 100-120 mg/dl. It is advised to hold HBO for pretreatment blood glucose levels less than 100 mg/dl. [1]

        Pseudoephedrine (Sudafed®)

        • A front line decongestant for ear barotrauma
        • At pressure depths of 3.0 ATA, studies showed an increase in anxiety scores, a decrease in verbal fluency scores, and an increase in mean heart rate. [3]
        • Be aware that this medication can increase patient anxiety.  [3]

        Dimenhydrinate (Dramamine®)

        • A commonly used antihistamine to control motion sickness
        • At pressures of 3. ATA, studies showed an adverse effect on mental flexibility and memory but did not show an effect on heart rate.  [3]

        ANTIARRHYTHMIC AGENTS

        Amiodarone

        • An antiarrhythmic agent commonly used to treat supraventricular and ventricular arrhythmias.
        • Tends to accumulate in several organs including the lungs.
        • Pulmonary toxicity usually manifests as an acute or subacute pneumonitis, typically with diffuse infiltrates on chest x-ray and high-resolution CT.   [4]
        • Results with HBOT and amiodarone are potentially worsening outcome of pulmonary oxygen toxicity with potentially permanent disability. However, there are no reports in the literature except in abstract form. The ultimate result of Amiodoarone in the face of HBOT is unknown. 

        TRANSDERMAL DELIVERY SYSTEMS

        • Transdermal medications are becoming more commonplace. While there have been no definitive studies, medication delivery through these systems is likely unaffected however consideration should be given to HBO’s vasoconstrictive effect and the potential for temporarily altered absorption in a hyperbaric environment.
        • Common types of medication patches include: nitrogylcerin, Clonidine, Narcotic (duragesic), Exelon (dementia), Estrogen, Testosterone, Oxytrol (incontinence), Scopolamine, Lidocaine, and Flector patch (diclofenac). 
        • The potential risk of fire exists with the addition of adhesives and other hydrocarbon vehicles within the respective systems.
        • Therapeutic warming wraps and patches consist of finely divided powdered iron, sodium chloride, and charcoal enclosed in a gas permeable pouch. The pouch is stored inside an airtight wrapper until ready to use. When the wrapper is opened, air diffuses through the pouch initiating an exothermic oxidation reaction between the iron and oxygen producing iron oxide and heat. Sodium chloride acts as a catalyst to speed up the rate of reaction. Charcoal is present to disperse the heat. The rate of warming is controlled by the amount of iron and oxygen to react.  [5]
        • As a general rule, it is felt prudent to remove the patches and use an acceptable alternative medication or mode of delivery.
        • The final decision as to whether the medication patch may enter the chamber is between the HBO Safety Officer and the Medical Director. 

        IMPLANTABLE MEDICATION DELIVERY SYSTEMS

        • A number of medication pumps are available to deliver medications on a continuous basis.
        • The specific medication utilized must be considered in each case.
        • The delivery device must be approved for use under hyperbaric conditions.
        • Product specifications should be obtained from the manufacturer to determine if the device may be used.


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        NOTE: This is a controlled document. This document is not a substitute for proper training, experience, and exercising of professional judgment. While every effort has been made to ensure the accuracy of the contents, neither the authors nor the Wound Reference, Inc. give any guarantee as to the accuracy of the information contained in them nor accept any liability, with respect to loss, damage, injury or expense arising from any such errors or omissions in the contents of the work.

        REFERENCES

        1. Harry T. Whelan, Eric Kindwall et al. Hyperbaric Medicine Practice 4th Edition Best Publishing Company. 2017;volume fourth():.
        2. K. Torp, M. Carraway, M. Ott, B. Stolp, R. Moon, C. Piantadosi, J. Freiberger et al. Safe Administration of Hyperbaric Oxygen after Bleomycin: A Case Series of 15 Patients. UHM 2012 .;volume 39(No. 5):873-879.
        3. Taylor DM, O'Toole KS, Auble TE, Ryan CM, Sherman DR et al. The psychometric and cardiac effects of pseudoephedrine in the hyperbaric environment. Pharmacotherapy. 2000;volume 20(9):1045-50.
        4. Wolkove N, Baltzan M et al. Amiodarone pulmonary toxicity. Canadian respiratory journal. 2009;volume 16(2):43-8.
        5. G. Raleigh, R. Rivard, S. Fabus et al. Air Activated Chemical Warming Devices: Effects of Oxygen and Pressure UHM 2005.;volume 36(No. 6):445-449.
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