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PHARMACOLOGY: Anti-Emetics
EMS systems are evolving from entities that only exist to initiate emergency treatment of obviously life-threatening traumatic and nontraumatic conditions to those which can perform triage, identify risk factors for and sentinel signs and symptoms of potentially serious medical conditions, apply point-of-care and diagnostic testing and begin the first stages of emergency department treatment. As EMS systems mature, so does the realization that the EMS contact interval represents the first opportunity for these healthcare providers to positively affect the outcome of a subset of the ED patient population that calls 9-1-1 because they not only perceive that they have an emergency condition, but that an intervention can be made quickly to treat it.
Such treatment for symptoms like nausea and vomiting would not have been considered the role of a paramedic even 15 years ago. These 9-1-1 patient contacts frequently began and ended with an apology for being unable to offer any treatment for the patient retching in the back of the ambulance. Today it is not only possible, but quite simple to provide prompt symptomatic relief to patients who have nausea and/or vomiting prior to their arrival in an ED.
It is essential to recognize that not all vomiting is viral-related; there are often potentially serious medical conditions that generate these symptoms, especially in the geriatric population and those with a history of or predisposition to cardiovascular or endocrine disease. While a complete discussion of the origins of nausea and vomiting is beyond the scope and intention of this article, EMS providers who treat this patient subset must be as equally quick to ask themselves why this is happening as they are to administer an intravenous or intramuscular injection.
PREHOSPITAL ANTI-EMETICS
There are four pharmaceuticals commonly used in EDs across the United States to treat nausea and vomiting. Three of the four are commonly available in EMS systems, although promethazine has been losing favor (see below). We have not included droperidol because its use rapidly declined after an FDA black box warning over five years ago. We have also chosen not to include pediatric dosages or pediatric-specific drug information, since children under 14 do not typically require medication with these agents in the acute care setting. Most EMS protocols also restrict delivery of anti-emetics to the adult population.
As always, paramedics must use the medication provided by their agency and through their protocol set. In almost all scenarios, only the parenteral form of the medication will be available for prehospital use; however, you may encounter these drugs in patient's homes, since several of these agents are also available in oral or suppository form, which patients may be taking by prescription. We have listed the most common brand name next to each pharmaceutical agent for recognition purposes, although generic equivalents are available for all.
Promethazine (Phenergan)
Promethazine is one of the phenothiazines, which were originally designed as anti-psychotics. It is primarily used as an anti-emetic, although it also contains antihistamine and sedative properties. Its mechanism of action is antagonism of central and peripheral H1 receptors.
Promethazine is available in 12.5, 25 and 50 mg tablet form, 6.25 mg/5 ml syrup and 25 mg suppositories. Solution for injection is manufactured in concentrations of 25 mg/ml and 50 mg/ml, each in 1 ml vials. The standard adult dose is 12.5–25 mg IV, IM, PO or PR administered every four hours as needed. The maximum dose (at any one point in time) for nausea and vomiting is 50 mg given intravenously (IV), intramuscularly (IM), by mouth (PO) or by rectum (PR).
Adverse drug effects include extra-pyramidal side effects (EPS) such as tremor, slurred speech, akathisia (restlessness) and dystonia (involuntary muscle contractions). For more information on the treatment of acute dystonic reactions, see the FAQs on page 60. Promethazine may cause sedation and respiratory depression when combined with alcohol, barbiturates, other phenothiazines, sedatives and narcotics. It may also cause excessive anticholinergic side effects when combined with antihistamines, other phenothiazines and certain tricyclic antidepressants.
Promethazine is contraindicated in people who are taking any of the MAO inhibitor class of drugs, due to the potential for development of hypertensive side effects. It should also be avoided in patients who already exhibit a decreased level of consciousness. Promethazine is considered a Category C (unknown if safe) medication in terms of its use in pregnancy. Studies in animals suggest no adverse effects on the fetus, but caution should be exercised in the third trimester, as the drug may lower the seizure threshold in the mother.
This most important concern about promethazine and its use in 2007 is that this medication has recently been found to have caused several high-profile cases of local tissue necrosis when given parenterally, particularly intravenously. This concern stems from inadvertent intra-arterial administration, which has occurred both in the ED and EMS settings recently. In several instances, patients have lost digits or part of their upper extremity.
The Institute for Safe Medication Practices (ISMP, www.ismp.org), a national clearinghouse for information related to pharmaceutical use by U.S. healthcare providers recommends several precautions to prevent tissue damage: limit the initial dose to 6.25–12.5 mg, limit the concentration to 25 mg/ml or further dilute it with 10–20 ml of normal saline, administer through a large-bore vein (not in the hand or wrist), administer through a distal IV port (i.e., not directly into the vein), administer slowly (over 15–20 minutes), and instruct the patient to report any pain or burning. Furthermore, they suggest that the two best choices to avoid potential patient complications are to give the drug as an IM injection (avoid IV use) or choose another anti-emetic and avoid promethazine altogether.
Given the degree of concern about promethazine, coupled with release of the generic version of ondansetron, a popular anti-emetic that had been very expensive until the patent expired on the brand name Zofran in December 2006, many EMS systems have changed their formularies to prohibit the use of this agent. Any EMS provider who is mandated by protocol to use promethazine and all EMS medical directors who have decision-making authority in systems that still utilize this medication should read an August 2006 newsletter article about these issues at ISMP's website: www.ismp.org/Newsletters/acutecare/articles/20060810.asp.
Prochlorperazine (Compazine)
Prochlorperazine is a centrally acting anti-emetic that selectively blocks dopamine-2 receptors in the brain. Tablets are available in 5 and 10 mg; suppositories are available in 2.5 mg, 5 mg and 25 mg. Solution for injection is manufactured as a 5 mg/ml concentration and is available in 2 ml and 10 ml vials. The standard adult dose is 5–10 mg given IV, IM, PO or PR, which can be repeated every 6–8 hours as needed. The maximum dose is 40 mg/day by any route.
Prochlorperazine can cause extra pyramidal effects similar to promethazine: sedation, hypotension and cardiac dysrhythmias including QT prolongation. It may also lower the seizure threshold in patients with seizure disorders. Also similar to promethazine is local tissue damage that may occur during extravasation of the drug through a blown IV site. Thus, IM administration may be the safest route.
Numerous drug-drug interactions also exist with prochlorperazine, especially for drugs that are metabolized in the liver. It should be avoided in patients with narrow angle closure glaucoma, severe liver or cardiac disease, and decreased level of consciousness. Prochlorperazine is also a Category C drug in terms of its unknown effects on the fetus. Human studies do not exist, but animal studies suggest there is no risk during pregnancy.
Metoclopramide (Reglan)
Metoclopramide blocks dopamine receptors in the brain and promotes gastric motility and intestinal transit time without increasing gastric, pancreatic or biliary secretions. For these reasons, it is a favored anti-emetic for longstanding diabetic patients who have delayed gastric emptying, which is a frequent cause of abdominal pain and vomiting. Metoclopramide is available as 5 and 10 mg tablets and a 5mg/5ml concentration as a syrup formulation. For parenteral administration, it is manufactured as a 5 mg/ml concentration available in 2, 10 and 30 ml vials. Typical adult dosage is 5–10 mg given PO, IV or IM every 6–8 hours. Metoclopramide is the least likely agent of the four presented in this article to be present in EMS system formularies.
There are rare reports of neuroleptic malignant syndrome, a syndrome of hyperthermia, muscle rigidity and a variety of other symptoms in patients taking neuroleptic drugs, in conjunction with metoclopramide (and with prochlorperazine) use. Extrapyramidal reactions, such as akathisia, are most likely to occur in adolescents after high IV doses, but may be avoided if patients are pretreated with diphenhydramine. Increasing intestinal motility can also cause or exacerbate diarrhea.
Use with caution in patients with renal impairment, hypertension, CHF or cirrhosis, since transient increases in aldosterone may cause fluid retention or volume overload. Patients with renal impairment may require dosage adjustment. It may be prudent to wait for lab results before administering metoclopramide. Also avoid using metoclopramide in patients taking MAO inhibitors, those who may have intestinal obstruction, pheochromocytoma, history of seizure disorder or drugs that can cause extrapyramidal reactions.
Metoclopramide is a Category B medication in pregnancy. This means either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).
Ondansetron (Zofran)
Ondansetron is a selective serotonin 5-HT3 receptor antagonist. Standard and quick-dissolve versions are available as 4 and 8 mg tablets; a strawberry-flavored solution contains 4 mg/5 ml. The solution for injection is manufactured generically as a 4 mg/2 ml single dose vial or 40 mg/20 ml multidose vial. Adult dosage is 4–8 mg given PO, IV or IM three times a day as needed.
There are few adverse drug reactions with ondansetron, and the only absolute contraindication to its use is hypersensitivity. Most of the adverse effects have been attributed to chemotherapeutic agents the patients were taking when originally enrolled in drug trials; however, although there are no documented adverse drug interactions, patients taking medications like theophylline, phenytoin or warfarin should have their levels followed, since ondansetron is also metabolized by several cytochrome P450 enzymes. Some patients experience transient blurred vision after infusion. In patients with severe liver disease, the dose should not exceed 8 mg in 24 hours. There is also a theoretical risk of QT prolongation when combined with certain medications. Ondansetron is a Category B drug in pregnancy.
FAQs Regarding Prehospital Treatment of Nausea and Vomiting
What literature support exists for anti-emetic use in the prehospital environment?
There is very little research in peer-reviewed emergency medicine literature concerning paramedic administration of anti-emetics. That is not to say there is anything dangerous or taboo about this practice. Most of what we do in EMS has not been appropriately researched for a variety of reasons, including the fact that out-of-hospital research is notoriously difficult to conduct, especially the prospective studies that are considered to be most worthwhile and of scientific merit. Administration of anti-emetics to a population of patients who need them is considered to be a standard emergency medicine practice that has few complications from a single dose, both from the technical aspect (i.e., injection of a medication) and the clinical aspect (i.e., decision to administer the medication). Thus, it is unlikely that we will ever see many studies about whether out-of-hospital delivery is appropriate.
We found one published abstract and no published articles concerning prehospital anti-emetic use. In 2005, the Department of Emergency Medicine at Christiana Care Medical Center in Delaware, known for outstanding EMS research both in terms of quality and quantity, presented results of a retrospective study conducted from 2003–2004 about the use of promethazine in the state of Delaware. Seventy-one percent of the almost 300 patients who were administered the medication by paramedics reported relief of symptoms prior to arrival in the ED.
Is prehospital treatment of nausea/vomiting recommended for pediatric patients?
The answer is "no" for several reasons. First, more often than not in kids, the condition is related to viral illness, which resolves quickly. Second, several of the medications traditionally used to treat this condition can cause drowsiness. Parents are taught that this is a danger sign in children because it represents altered mental status due to progression of illness. Therefore, we do not like to administer medications that cause this condition, with the exception of low-dose narcotic pain medications for non-infectious disease situations. Third, calculation of drug dosages for children is complicated and introduces the possibility of medical error. Fourth, there are very few studies evaluating the safety and efficacy of these medications in the pediatric population.
Am I masking a condition that will cause the ED physician to miss a diagnosis?
No. There is no disease process that will be missed because the emergency physician does not personally witness an episode of vomiting in the ED. This is a myth that seems to be perpetuated by both residency-trained emergency physicians and those who work in EDs without primary EM training. Additionally, none of the anti-emetics discussed here contain analgesic properties (so they don't mask pain) and the drowsiness side effects are minimal, if present at all. Certainly, the patient should still be able to provide a history upon arrival in the ED. It is possible that the effects of drowsiness can be magnified by co-administration of parenteral narcotics, but it is unlikely that the clinical effect will be severe.
Is a second dose of anti-emetic ever indicated during transport?
There is no indication to provide (nor will the standard EMS protocol permit) a second dose of anti-emetic in the field during routine EMS operations.
Are anti-emetics safe in pregnancy?
Many pregnant women experience some degree of nausea and vomiting during early pregnancy. This symptom can also represent the early presentation of gallbladder disease and appendicitis. Some women develop excessive vomiting, known as hyperemesis gravidarum, and become rapidly dehydrated. ED therapy lasts many hours and may require admission to the hospital. Anti-emetics including Category C drugs (unknown safety profile in pregnancy) are given along with crystalloid replacement in the ED. Paramedics must follow protocol guidance in this scenario. If no guidance exists, encourage your regional EMS administrators to have specific instructions regarding this patient subset added to the protocols.
When the dosage recommendations state "5–10 mg IV," which one is correct?
This is a common problem encountered when teaching medicine, and the EMS scenario is no exception. There is a famous proverb that reads, "Medicine is a science, but its practice is an art." Most medications have a range in which they will be effective. Certain patients, including the elderly and those with various pre-existing conditions, may do better with smaller doses of particular medications. In the EMS setting, protocols are best designed so the exact answer is provided in terms of medication dosing, route and frequency. This is the best mechanism to prevent errors. Consult your medical director or system administrator if there is any confusion about dosing of anti-emetics (or any other drug) for out-of-hospital use.
If the patient does not specifically ask for an anti-emetic, should I give it?
This is another common issue in EMS practice and one of our pet peeves. Patients are generally not considered experts in emergency medicine and EMS practice—you are! Most civilians have no idea what the scope of practice is for a paramedic or what medical interventions and therapies can be delivered on an ambulance. Thus, failure of the patient to ask for a particular medication cannot be taken as an indication that it is not needed or desired. Treating healthcare providers should explain the nature of the patient's symptoms to the best of their ability and then offer the modalities that are available for symptom mitigation. In short, when your patient is nauseous or vomiting, evaluate and treat life- threatening medical conditions first. As early as possible, offer the option for a symptom-relieving medication that is available and within your local protocols to deliver.
Why would I give an anti-emetic IM when I could give it IV?
Our recommendation is to always give these medications intravenously, if possible. If the patient is ill enough that 9-1-1 was called and emergency medical intervention is indicated, the patient typically requires IV fluids and potentially lab work and other diagnostic studies. The only indication to avoid the IV route becomes lack of IV access. None of these agents should cause any significant hemodynamic effects that would necessitate fluid resuscitation or withholding of the drug should IV access be unobtainable.
Would intraosseous (IO) access ever be warranted to deliver an anti-emetic?
If an IO line will be placed only to deliver an anti-emetic and not because the patient had failure of IV access in the setting of critical illness, the answer is "no."
What do I do if the patient develops a dystonic reaction?
Dystonia is sustained, often painful muscular spasms, producing twisting abnormal postures that may be confused with partial seizures. Approximately 3%-10% of patients exposed to neuroleptics will experience an acute dystonic reaction, which can occur shortly after the medication is metabolized. Prochlorperazine represents the largest threat for development of dystonia of the four medications discussed in this article. Acute dystonias usually present with one or more of the following symptoms:
- Buccolingual: protruding or pulling sensation of tongue
- Torticollic: twisted neck, or facial muscle spasm
- Oculogyric: roving or deviated gaze
- Tortipelvic: abdominal rigidity and pain
- Opisthotonic: spasm of the entire body.
Treatment of an acute dystonic reaction is easily accomplished by administration of 50 mg of diphenhydramine either IV or IM. This medication, commonly known as Benadryl, should be available on virtually every ALS vehicle in the country. If a protocol does not exist for the treatment of a dystonic reaction in your EMS system, contact base command, describe the situation and request permission to initiate treatment.
SUMMARY
Although there is a paucity of literature on anti-emetic administration in the prehospital setting, paramedic delivery of an appropriate agent according to protocol can decrease the time to treatment for hundreds of thousands of emergency department patients annually who access 9-1-1 and present with nausea and vomiting.
David Jaslow, MD, MPH, EMT-P, is the director of the Division of EMS and Disaster Medicine within the Department of Emergency Medicine, and Anne Klimke, MD, EMT-B, is currently in her third year of a five-year dual emergency medicine residency and EMS/Disaster Medicine fellowship program at Albert Einstein Medical Center in Philadelphia. Both physicians provide medical oversight to the Bryn Athyn Fire Company in suburban Philadelphia.
