Keep It Down In There: Stopping Prehospital Nausea and Vomiting

In recent years, paramedics have started using a class of medications called antiemetics to alleviate nausea and vomiting in the prehospital setting. Anecdotally, their use in the field has had good results, but there has been very little research on the topic, with only one study on their use in this setting.

MECHANISMS AND ETIOLOGIES OF VOMITING

Nausea or vomiting can occur by three mechanisms. First, vomiting can occur by the brain stem activating the brain's chemoreceptor trigger zone. This region contains serotonin (5-HT3), muscarinic cholinergic (M1), dopamine type 2 (D2), neurokinin type 1 (NK1), histamine (H1) and mu-opioid receptors. Stimulation of any receptor can result in activation of the zone, causing the patient to become nauseous and vomit. Second, stimulation of the chemoreceptor trigger zone can occur from irritation of the ear labyrinth, producing the same effect. Finally, stimulation of the gastrointestinal vagus nerve can activate the D2, NK1 or 5-HT3 receptors.¹

Some of the most common underlying causes of nausea or vomiting include gastroenteritis, bowel obstruction, pancreatitis, gallstones, head trauma and some medications. These medications are found in Table 1.

Table 1: Medications That Can Cause Nausea/Vomiting

• Opiates: morphine, hydromorphone, fentanyl
• NSAIDs: ibuprofen, naproxen, ketorolac
• Chemotherapeutic agents: cyclophosphamide, methotrexate, mercaptopurine
• Bisphosphonates: alendronate (Fosamax), ibandronate (Boniva), risedronate (Actonel)
• Anesthetic agents: nitrous oxide, sevoflurane, ketamine

PHENOTHIAZINES

Prehospital treatment of nausea and vomiting often involves phenothiazines, the largest of the five main classes of neuroleptic antipsychotic drugs. The two phenothiazines commonly used by paramedics are promethazine (Phenergan) and prochlorperazine (Compazine). Phenothiazines exert their antiemetic effect by blocking D2 receptors in the chemoreceptor trigger zone. Additionally, they antagonize histamine and muscarinic receptors, augmenting their antiemetic effect.

The onset of action for prochlorperazine is immediate when given intravenously (with a peak response in 2-4 hours), 60 minutes when given rectally and 30-40 minutes when given orally. The half-life is 7-9 hours. The onset of action for promethazine is approximately 3-5 minutes when given IV, 20 minutes when given intramuscularly and 60 minutes when given orally.

The side effects associated with phenothiazines are hypotension, sedation and extrapyramidal symptoms (EPS). EPS can manifest as involuntary lip smacking, akathisia and involuntary limb movements. Standard treatment of EPS, secondary to administration of phenothiazines, is diphenhydramine 25-50 mg IV. Concurrent administration of diphenhydramine with a phenothiazine is effective in preventing EPS. Both promethazine and prochlorperazine are compatible when mixed in the same syringe with diphenhydramine. Less common but more serious side effects associated with phenothiazines are QT interval prolongation, neuroleptic malignant syndrome, torsades de pointes and respiratory depression.¹

Neuroleptic malignant syndrome has been reported after just a single dose of a phenothiazine. It is characterized by muscle rigidity, hyperthermia, mental status changes and autonomic instability. Patients at risk for developing this syndrome are those concurrently using antipsychotics, lithium anticholinergic drugs and those with a history of a similar event. Respiratory depression is especially prevalent in children under 2. The FDA issued a black box warning concerning the administration of phenothiazines for nausea due to the risk of apnea in these patients. Patients with glaucoma should not receive either prochlorperazine or promethazine secondary to the anticholinergic side effects. Similarly, patients with bone marrow suppression should not receive this class of medications.

Promethazine is available for oral, intravenous and rectal dosage. Solutions of 25 or 50 mg/mL are most commonly available in the field. The preferred parenteral route of administration for promethazine is deep IM injection. IV administration has been associated with tissue necrosis and gangrene of the affected extremity. Promethazine should be injected no faster than 25 mg/min into a large vein (antecubital) through the port farthest from the vein. Have the patient immediately report any burning or discomfort. Prochlorperazine offers an advantage over promethazine because it can be given safely IV without worry of tissue necrosis. Prochlorperazine is also available in oral, intravenous and rectal formulations. Its typical dosing is 5-10 mg IV/IM/PO/PR. The maximum rate of IV administration for prochlorperazine is 5 mg a minute.

Overall, phenothiazines are effective medications for treating nausea and vomiting in the prehospital setting. Their low cost and multiple routes of administration make them popular options. But there are others.

BENZAMIDES

The prehospital benzamide is metoclopramide (Reglan). It blocks D2 receptors and has prokinetic properties that speed up esophageal motility and enhance gastric emptying. The onset of action for metoclopramide is approximately 1-3 minutes when given IV. The half-life is approximately 5-6 hours. Side effects are very similar to those of phenothiazines. They include EPS, anxiety, agitation, hypotension and tachycardia.

The risk of EPS with metoclopramide is related to the rate of administration, so it is prudent to administer the medication slowly. Other risk factors include female sex, diabetes, advanced age and higher cumulative doses. If EPS occurs, treat it in the same manner as phenothiazine-associated EPS. Metoclopramide and diphenhydramine are compatible when combined in the same syringe for IV administration. Contraindications include patients with known obstruction, gastrointestinal bleeding, epilepsy and pheochromocytoma.

Be cautious with metoclopramide in patients who cannot tolerate increases in fluid burden, such as those with congestive heart failure and cirrhosis, because it has been reported to cause a spurious increase in aldosterone. Catecholamine release has also been reported with metoclopramide, so use it with caution in patients with baseline hypertension. Metoclopramide can also exacerbate Parkinson's symptoms. The most common prehospital starting dose is 10 mg, but some studies have suggested doses up to 50 mg may be more appropriate. Reduce dosages for patients with renal failure secondary to the accumulation of active metabolites.

ANTIHISTAMINES

Diphenhydramine is commonly given in the prehospital setting for allergic reactions, but it also contains antiemetic properties. Although its mechanism is not fully clear, it is felt to suppress vestibular neuronal firing in the middle ear. However, its sedation and anticholinergic properties may also play roles. The typical side effects of anticholinergics are sedation, dry mouth, dizziness, urinary retention, hypertension, tachycardia and blurred vision. Administer diphenhydramine with caution in patients on concurrent MAOI therapy or with glaucoma or a history of prostatic hyperplasia. When diphenhydramine is given to children, paradoxical excitation may occur. The standard dose for nausea and vomiting is 25-50 mg IV/PO/IM. Diphenhydramine is a good alternative for patients with contraindications to the other antiemetics or as adjunctive treatment.

5-HT3 RECEPTOR (SEROTONIN) ANTAGONISTS

Until recently ondansetron was reserved for patients with nausea and vomiting who did not respond to other, less expensive options. Now the development of a generic product has drastically decreased the cost of the medication, paving the way for its use as a first-line treatment for nausea and vomiting.^2,3

Ondansetron acts as an antagonist of the brain's 5-HT3 receptors. Since the mechanism of action differs from the aforementioned antiemetics', it can be used in combination with them without the risk of additive side effects. The onset of action is approximately 3-5 minutes IV and 30-60 minutes orally. The half-life is approximately 5.5 hours, allowing for 6- to 8-hour dosing. Ondansetron is extensively metabolized by the liver; due to this, the maximum daily dose for patients with hepatic impairment is 8 mg. The typical starting dose is 4 mg; however, significantly higher doses are used for patients on chemotherapy. Safety data in pediatric and pregnant populations are an advantage for using ondansetron.

COSTS

EMS purchasers may have been reluctant to stock name-brand Zofran (ondansetron) based on its relatively high cost. However, since the expiration of GlaxoSmithKline's patent in December 2006, the release of generic ondansetron in single-dose vials offers a cost-effective alternative. This, along with its fewer side effects, seems to make it a better choice.² A 4-mL single-dose vial of generic ondansetron can be ordered for $0.52 per unit. Previous studies regarding the efficacy of ondansetron on inpatient postoperative nausea and vomiting indicated that some patients required multiple or rescue doses to achieve relief. Metoclopramide (Reglan) wholesales for $0.32 per 10-mg single-dose vial. Prochlorperazine (Compazine) wholesales for $9.56 per the same size vial--almost 30 times as expensive.

CONCLUSION

Antiemetics play an increasingly important role in the prehospital setting. No matter what the cause of a patient's vomiting or nausea, alleviating it will result in patients who are more comfortable and easier to treat.

REFERENCES

Jaslow D, Klimke A. Prehospital pharmacology: Antiemetics. EMS Magazine 36(11): 56-61, 2007.

Chang P, Okamoto M, Chen J, Frame D. Cost-effectiveness analysis of ondansetron and prochlorperazine for the prevention of postoperative nausea and vomiting. J Managed Care Pharma 11(4): 317-321, 2005.

Warden CR, Moreno R, Daya M. Prospective evaluation of ondansetron for undifferentiated nausea and vomiting in the prehospital setting. Preh Emerg Care 12: 87-91, 2008.

Mark A. Merlin, DO, EMT-P, FACEP, is an assistant professor and EMS medical director in the Department of Emergency Medicine at the University of Medicine and Dentistry of New Jersey's Robert Wood Johnson Medical School, as well as medical director for the New Jersey EMS Task Force and EMS/Disaster Medicine Fellowship.

Dan Frazier, MICP, is a paramedic for Robert Wood Johnson University Hospital.

Brant Maslowski, MICP, is a paramedic for Robert Wood Johnson University Hospital

Patrick Bridgeman, PharmD, is an emergency-medicine pharmacologist at Robert Wood Johnson University Hospital.