Irukandji syndrome is a painful, potentially lethal condition caused by certain jellyfish from the Cubozoa class (box jellyfish) species. Although the sting is usually mild, systemic symptoms resembling a catecholamine surge can result in approximately half an hour, including tachycardia, hypertension, severe pain, muscle cramping, and is often followed by hypotension, pulmonary edema, and potentially life-threatening cardiac complications.
The syndrome was named in 1952 by Hugo Flecker, after an Aboriginal tribe located near Cairns, North Queensland, Australia. Irukandji syndrome is most notably caused by the jellyfish species Carukia barnesi, named after the scientist Jack Barnes, who discovered the species as the causative organism of the condition. Interestingly, he established the causative relationship after envenoming himself, his son, and a local lifeguard, which subsequently required treatment for the ensuing condition in a hospital. As such, this particular species is commonly referred to as the “Irukandji jellyfish.”
Carukia barnesi is a small jellyfish (cnidarian) with an approximate 2 cm diameter and 4 tentacles. Its small size allows them to sting their victims even through sting-resistant enclosures. Although Irukandji syndrome is most notably attributed to this particular species, there are up to 25 species that are implicated to also cause this condition, most if not all from the same family of Carybdeida, including but not limited to Alatina mordens, Malo maxima, Carybdea alata, Carybdea xaymacana, and Carybdea rastonii.
Although C. barnesi and its related species are of the same class as the cubozoan Chironex fleckeri, commonly known as “the box jellyfish” or “the sea wasp,” one should not confuse these different groups of species, as they cause very different clinical syndromes with highly differing prognoses.
Irukandji syndrome was originally thought to occur along Australia's northern coastline from Fraser Island in Queensland, across the Northern Territory to Broome in north Western Australia. However, the incidence of similar syndromes has been reported worldwide, including Thailand, the Caribbean, and the United States in the states of Florida and Hawaii. Despite these reports, not all cases have identified causative species.
In Australia, the reported hospitalizations from stings range from 50-100 annually. Marine activities, including snorkeling, scuba diving, and swimming, are associated with stings. As such, not only is this costly to the healthcare system, but there are also enormous financial impacts on tourism, the fishing industry, and commercial diving. The incidence of stings follows a bimodal pattern, with regional variation. In the Northern Australian territories, peaks occur in May and October. In the western region, peaks tend to occur between October through December and March through June. The regional variations between these bimodal patterns are attributed to environmental factors, including wind patterns, and lifecycle activity of the jellyfish themselves rather than variation with human activity. It is thought that these variations might even imply different causative species amongst these regions, but the relationship is not yet clear. Other environmental factors that are associated with a higher incidence of stings include low wind, high temperatures, decreased rainfall, increased sunlight, and high tide.
Stings also appear to occur in brief, epidemic, outbreaks. For example, 36 stings occurred during Christmas day of 1985. These attacks also appear to be well localized, in as many as forty victims can be stung within a period of a few hours at a single beach, while a nearby beach might have no such events. It is not clear if this pattern of outbreaks represents swarming by the organisms or simply passive aggregation. It is this pattern of mass sting events that catch the attention of the public.
Both the bell, as well as tentacles, of C. barnesi, contain nematocysts that allow the species to sting, unlike most jellyfish species. It is not clear, however, whether the bell, tentacles or both, contain the toxic fraction that causes the Irukandji syndrome.
Regardless of the organ that delivers it, the venom of C. barnesi is proteinaceous and contains a neural sodium channel activator, which acts on the same sodium channels that are sensitive to tetrodotoxin, causing the release of catecholamines, particularly norepinephrine and epinephrine, and also direct vasoconstrictor effects. It is this effect that is believed to be responsible for the sympathomimetic-like manifestations of Irukandji syndrome, characterized by hypertension and tachycardia.
Acute cardiac failure can also occur and is thought to be mediated by two possible mechanisms:
Human cases of severe envenomation were associated with systemic hypertension, myocardial dysfunction, and elevated serum troponin levels.
Cnidarian venoms, in general, cause pain by activation of transient receptor potential vanilloid-1 (TRPV1), a non-selective cation channel expressed in nociceptive neurons. However, it is not clear if Irukandji causing jellyfish cause pain via the same mechanism, given the difference in the timeframe of symptom onset.
The offending organism is often unnoticed, but victims often feel the onset of stinging pain at the affected site within seconds of the inciting event. The initial local pain is usually not severe and wanes within 30 minutes. Within the first 20 minutes, papular erythematous skin lesions can occur, approximately 2 cm in diameter, the same size as the jellyfish itself, often described as “goose pimples,” which usually fade shortly after, but can also persist for days.
Severe systemic symptoms usually occur within the first 30 minutes of a sting, but this can range anywhere from 5-120 minutes. These systemic symptoms are the hallmark of the original description of the classic Irukandji syndrome. They include back pain, diffuse muscle cramping, nausea, vomiting, profuse diaphoresis, headache, anxiety, agitation, nausea, vomiting, and piloerection. Abdominal pain usually occurs in association with muscle cramping. Due to the hyperadrenergic nature of the toxin causing the syndrome, hypertension and tachycardia are often seen. One case series identified the mean peak systolic blood pressure to be 153 mm Hg. However, blood pressures as high as 300/180 mm Hg have been reported.
The syndrome is classically associated with a sense of “impending doom.” In general, most cases will improve within 6 to 24 hours, but can sometimes recur. In severe cases, cardiac failure with pulmonary edema can occur by the proposed mechanisms outlined previously and can lead to respiratory failure. Two reported deaths by intracranial hemorrhage, secondary to severe hypertension, have also been observed.
Interestingly, most cases of Irukandji syndrome and stinging occurs within net enclosures designed to prevent jellyfish stings. This is likely due to the fact that the responsible organism is capable of fitting through the openings of the enclosure, which typically measures 2 cm. Tourists, who are not aware of this phenomenon, are particularly susceptible. A history of tourism or foreign travel should, therefore, raise one’s suspicion of this condition. Additionally, stings tend to occur in clustered sporadic outbreaks, so it is not uncommon to see multiple patients presenting to the emergency department of the hospital for symptoms consistent with Irukandji syndrome in one day, even if previous cases in the hospital have been remote.
A thorough history and physical is essential to the evaluation of this condition and to help in distinguishing it from mimics. Although microscopic identification of nematocyst cnidocytes from skin scrapings has been successfully performed in studies, most institutions will likely lack the personnel capable of identifying these structures, and widely available commercial testing in this manner has not been established. There is no commercially available specific laboratory test to confirm the presence of Irukandji syndrome or the sting of Irukandji-causing jellyfish. As such, the diagnosis is made clinically.
Testing should be performed to help identify alternative causes of patients’ symptoms and to identify complications associated with Irukandji syndrome. Prior to the initiation of any diagnostic testing, however, it is crucial to assess and stabilize a patient’s airway, breathing, and circulation.
Electrocardiographic (ECG) changes have been shown to occur with Irukandji syndrome including atrial and ventricular ectopy, atrioventricular conduction defects, ST-segment elevation, T-wave abnormalities, and cases of non-sustained ventricular tachycardia. As such, it is important to obtain an ECG to screen for dysrhythmias
Cardiac enzymes should be sent to identify myocardial damage, which is not uncommon with the disease process and could represent severe pulmonary edema, demand ischemia, or associated cardiomyopathy.
A chemistry panel, including a renal function panel, can help identify cases of renal failure that have been shown to occur. A serum lipase can help make the diagnosis of pancreatitis associated with the syndrome.
A chest X-ray is useful to visualize the degree of pulmonary edema or to help differentiate the etiology of chest pain or dyspnea in an undifferentiated patient.
Drug screens can sometimes be helpful when there is not a clear history in an undifferentiated patient showing signs consistent with the sympathomimetic syndrome. However, urine drug screen results should never be relied upon to guide treatment as a negative test result does not rule out any presentation, and a positive test result does not exclude other pathology. Also, urine drug screens often display false-positive results due to cross-reactivity with other agents, as well as false-negative results due to various factors, such as the timing of metabolism and misinterpretation of results.
If a patient is showing signs of headache, altered mental status, or acute encephalopathy, computed tomography (CT) imaging of the brain should be considered, as both cerebral edema and intracranial hemorrhage have been associated with Irukandji syndrome.
In summary, it is recommended to obtain the following tests in the evaluation of a patient in whom you are considering the diagnosis of Irukandji syndrome:
No direct antivenom for the venom of C. barnesi or other Irukandji-causative species currently exists. As such, treatment is largely supportive. Similar to the management of other cnidarian envenomations, treatment should be primarily directed towards:
There is a paucity of evidence regarding the optimal management of Irukandji syndrome, and studies with conflicting results have been published in the scientific literature. Although there are multiple consensus guidelines for the management of cnidarian envenomations in general, the applicability of these management strategies on the various cnidarian species, a group extremely heterogeneous in both physiology and toxin effects, is questionable. The only consensus guidelines specifically directed towards the management of Irukandji syndrome comes from the Queensland Government Irukandji Taskforce, Pereira, et al. 2007.
If in the acute field setting, shortly after a suspected sting, victims should be rescued/removed from the water to prevent further stings. Basic life support measures should be performed, if necessary. As most stings from Irukandji-causative species will result in severe symptoms, emergency medical services should always be alerted, and the patient transported to a hospital. Respiratory failure can ensue, prompting the need for oxygen, non-invasive positive pressure ventilation, or even endotracheal intubation.
Preventing Nematocyst Discharge
The prevention of further nematocyst discharge into victims, either by inactivation, removal, or a combination, is likely beneficial for pain control, minimizing local tissue toxicity, and decreasing systemic toxicity. Various modalities have been proposed in the literature.
Acetic acid: Acetic acid, usually in the form of household vinegar (5% acetic acid), has been traditionally recommended for the use of cnidarian stings, usually in the pre-hospital setting. It is believed that it acts by deactivating undischarged nematocysts in the skin. Several studies have demonstrated that acetic acid can inactivate undischarged nematocysts of several species, including C. fleckeri, Carybdea rastonii, and species implicated in causing Irukandji syndrome including Tamoya spp. In fact, acetic acid is recommended by the Australian Resuscitation Council for jellyfish stings in tropical Australia, with specific instructions to "liberally douse/spray the sting area with vinegar (4%-6% acetic acid for 30 seconds,)" and has traditionally been used as first aid for the treatment of stings from C. barnesi and many other jellyfish species.
Although in the United States, vinegar is recommended as a first-aid treatment for all jellyfish envenomations by the American Heart Association (AHA) and the American Red Cross, medical toxicologists caring for such patients generally recommend acetic acid application for "jellyfish" stings occurring in the Indo-Pacific region, as acetic acid application to jellyfish stings occurring in the United States could enhance nematocyst discharge, thus worsening the condition. Since Irukandje syndrome typically occurs in the area of the Indo-Pacific, geographical guidelines emphasize the use of acetic acid, as there some evidence to specifically support its use specifically in stings from C. barnesi. However, no randomized control trials currently exist that support its use for cases of Irukandji syndrome.
If vinegar or another acetic acid solution is not available, nematocysts can be washed away with seawater. Care should be used not to expose the nematocysts in the skin to freshwater, as this might lead to a massive discharge of nematocysts. Other methods of removal include the application of gentle pressure using a credit card or similarly shaped object. Care should be used to avoid using too much pressure as it can cause the nematocysts to release their toxin. A slurry composed of sodium bicarbonate (baking soda) and seawater in a ratio of 50% baking soda and 50% seawater can be applied to the sting site to prevent further nematocyst discharge before removal, depending on the species. If no tools are available to assist in removal, it is recommended to use gloves if manipulating with the hands.
Alleviating Local Venom Effects
Heat: Applications of heat, in the forms of hot water, hot packs, or warm showers has been proposed as a possible treatment to relieve pain associated with jellyfish stings. Although no trials have been conducted for the stings of C. barnesi, at least two trials in the literature have investigated the effect of heat application on the pain caused by the related carybdeid species C. alata. One trial demonstrated the superior efficacy of hot water (40 – 41 degrees C) compared to either meat tenderizer or vinegar on paired control volunteers who were stung on each of their arms.
The other compared the use of hot packs that reached a maximum temperature of 118 degrees F (approximately 43.3 degrees C) to cold packs with minimum temperatures of 42 degrees F (approximately 5.5 degrees C) in swimmers accidentally stung on the beach, which demonstrated greater efficacy in pain control from the use of heat compared to cold pack applications. A more recent systematic review evaluating multiple studies and multiple treatment modalities for jellyfish stings also demonstrated similar increased efficacy of hot water immersion in controlling pain, but in victims stung by Physalia spp. However, as warm water usually takes the form of freshwater, which could potentially cause nematocyst discharge, care should be taken not to apply this treatment until after the nematocysts are removed or inactivated.
Lidocaine: Topical lidocaine in concentrations ranging from 1%-15%, has been shown to both decrease pain and inhibit nematocyst discharge in a study involving stings from the Chironex fleckeri, Chiropsalmus quadrumanus, and the Atlantic sea nettle, Chrysaora quinquecirrha. However, this study was limited by a small sample size of two subjects, consisting only of the authors themselves, leaving it susceptible to bias. A more recent study demonstrated that in vitro, lidocaine could inhibit the discharge of nematocysts from the jellyfish species Pelagia noctiluca. Though an entirely different class from the cubozoans that cause Irukandji syndrome, its effect in this species indicates potential promise in carybdeids. However, as similar studies performed on stings from Irukandji-causative species are currently lacking, the data cannot be extrapolated to recommend the routine use of lidocaine for pain caused by these species.
Opioid analgesia: The severe pain associated with Irukandji syndrome will likely require opioid analgesia to manage, usually intravenously. Fentanyl has been proposed as the recommended opiate for use in Irukandji syndrome due to its decreased likelihood of causing cardiovascular collapse and hypotension.
Controlling Systemic Effects
Nitroglycerin: Nitroglycerin, a potent and titratable vasodilator, is the first-line treatment for hypertension associated with Irukandji syndrome as recommended by the Queensland Government Irukandji Taskforce. Its effect on both venous and arterial dilation, decreasing both systemic pre-load and afterload confers benefits in patients with life-threatening pulmonary edema. It already has established use and benefits in decreasing rates of intubation for acute decompensated heart failure from etiologies other than Irukandji syndrome. Known outside the United States as glyceryl trinitrate, it was first proposed as a pre-hospital treatment for hypertension associated with Irukandji by Fenner and Morris in 2003. In their case series of three patients with clinically confirmed Irukandji syndrome, the medication was delivered sublingually every 5 minutes, leading to improvement in severe hypertension. In the hospital, if hypertension persists, nitroglycerin can be started as an infusion and titrated to effect on blood pressure, per hospital protocol. As with other applications of nitrates, its use is contraindicated in patients taking phosphodiesterase inhibitors (i.e., sildenafil, tadalafil, and vardenafil).
Phentolamine: Due to its alpha-adrenergic antagonism effects, phentolamine has been proposed as a possible treatment for hypertension associated with Irukandji syndrome in doses of 5 to 10 mg boluses, or as an infusion. Due to the potential for delayed cardiac failure, hypotension, and pulmonary edema in severe cases, phentolamine, which is reversible and with a shorter half-life, is recommended over phenoxybenzamine, a more long-acting irreversible alternative. However, a titratable vasodilator, such as nitroglycerin, should preferably be used first, particularly in patients with concurrent heart failure, unless contraindicated,, and phentolamine initiated for cases refractory to nitrates, as directed by the guidelines set forth by the Queensland Irukandji Taskforce.
Benzodiazepines: Benzodiazepines have long been established as the mainstay of treatment in hyperadrenergic states, such as sympathomimetic toxicity. It is recommended as an adjunctive treatment for pain and hypertension in Irukandji syndrome by the Queensland Irukandji Taskforce. The combination of appropriate analgesia and benzodiazepines will usually resolve hypertension associated with Irukandji syndrome.
Magnesium sulfate (MgSO4): Magnesium has been an established therapy in multiple hyperadrenergic conditions including but not limited to pheochromocytomas and pre-eclampsia. It is also used to treat and prevent cardiac arrhythmias. It is believed that magnesium can decrease the release of catecholamines, as well as decrease systemic vascular resistance in hyperadrenergic states. As such, magnesium has been implicated as a potential treatment for Irukandji syndrome and was first introduced in 2003 as a potential treatment in hypertension associated with Irukandji syndrome (Corkeron 2003). However, the evidence in existence regarding the efficacy of magnesium is conflicting. A systematic review in 2017 regarding the efficacy of magnesium in reducing symptoms associated with Irukandji syndrome included one small randomized control trial and 8 case series.
The one randomized control trial, which included 39 patients throughout 2003-2007, evaluating the efficacy of magnesium infusion in conjunction with fentanyl patient-controlled analgesia, did not show any significant reduction in opioid medication usage compared to fentanyl with the addition of a placebo. As such, the use of magnesium sulfate infusion did not appear to have any clear benefit for pain control. Of the 8 case series, 7 reported some benefit of magnesium for pain relief and/or blood pressure reduction. More recently in 2019, Rathbone et al., including two of the three authors who wrote the previous systematic review, performed a retrospective review examining 112 patient cases of Irukandji syndrome that received care by the Queensland Ambulance Service, did find statistically significantly lower pain scores in patients treated with the combination of magnesium and morphine compared to morphine alone. This study, although a retrospective review, did have a larger sample size compared to the previous randomized control trial and showed results consistent with the multiple case series. As such, there is insufficient data to recommend or exclude the use of magnesium sulfate in the treatment of Irukandji syndrome. As such, its use can be considered in severe cases, with a recommended starting dose by the Queensland Irukandji Taskforce Guidelines of 0.15 mmol/kg (37.5 mg/kg) over 15 minutes.
Treatments Not Recommended
Urine: Despite popular belief, urine should not be used in the acute treatment of any cnidarian stings and can actually cause nematocyst discharge, which can increase a patient's venom load as well as worsen their clinical condition.
Box jellyfish antivenom: The antivenom for the similar yet more deadly cubozoan C. fleckeri has been proposed as a possible treatment for Irukandji syndrome. However, studies have not demonstrated any efficacy of this antivenom for Irukandji syndrome. Its use is not recommended.
Beta-blockers: Although potent as anti-hypertensive agents, beta-blockers should be avoided in the management of Irukandji syndrome due to the potential for causing significant hypotension, or by theoretically causing unopposed alpha stimulation during the potential catecholamine excess in Irukandji syndrome, which could potentiate coronary vasoconstriction and ischemia.
As the clinical signs and symptoms of Irukandji syndrome can present similarly to many other disease processes, the patient’s history is critical in making the diagnosis, as well as distinguishing it from alternatives. A location where Irukandji-causative cnidarian species are endemic should increase one’s clinical suspicion for Irukandji syndrome compared to other cnidarian envenomations. Other disease processes that could potentially cause similar symptoms are listed below:
Although extremely painful, commonly requiring opioid analgesia and inpatient hospital management, Irukandji syndrome is usually non-fatal, particularly if supportive treatment is initiated promptly. Not all stings from jellyfish species with the potential to cause Irukandji syndrome, including C. barnesi, necessarily cause the clinical syndrome with each sting occurrence, and most patients who present to the emergency department after a sting can be discharged home within 24 hours of presentation.
In severe cases, respiratory failure requiring mechanical ventilation can occur, requiring intensive care unit admission.
The first two reported deaths in association with Irukandji syndrome were both secondary to intracranial hemorrhage. It is believed that these occurred as a sequela of severe hypertension. It is important to note that in one of the cases, the patient was taking the anticoagulation drug warfarin and had a supratherapeutic INR of 4.9, likely predisposing to bleeding.
Though rare, cases of pancreatitis, priapism, and acute renal failure have been documented in the literature.
Although most cases will have a resolution of pain within 24 hours, some individuals may experience recurrence of pain after 24 hours, prompting repeat visits to the hospital for treatment. In one documented case, the pain was noted to recur up to one year later.
Whenever possible, it is recommended to consult a local toxicology service or the local Poison Control Center to aid in the management of Irukandji syndrome or other cnidarian envenomations.
Patient education is paramount in the prevention of Irukandji syndrome. Although people native to the regions endemic to Irukandji-causative species are often well aware of the dangers and necessary safety precautions, foreign travelers often fall victim to stings and therefore have a higher incidence of Irukandji syndrome. Travelers need to know that “stinger-resistant” enclosure nets, often used to prevent stings from other jellyfish species, will not prevent stings from species that cause Irukandji syndrome, due to the organisms’ small size. The most effective form of protection while swimming is a full-body lycra “stinger suit.”
Although these suits can decrease the incidence of Irukandji syndrome by decreasing the total body surface area at risk for stings, it will not eliminate their occurrence, as it only requires one sting at an exposed area to cause the full-blown clinical syndrome. As such, the absolute best form of prevention would be to avoid swimming/submersion in waters endemic to suspected species altogether.
Once the patient is stabilized, and nematocysts are removed, it is important to perform basic wound care. Tetanus prophylaxis should be updated if necessary. The routine use of antibiotics is not recommended unless there are clear signs of secondary infection.
Currently, there is a paucity of evidence for the optimal management of Irukandji syndrome, both from an individual patient standpoint, as well as a population. More research is required and will likely require collaboration between multiple specialties, including, but not limited to, marine biologists, ecologists, medical practitioners, toxicologists, and social scientists.
An early warning system to detect Irukandji-causative species is currently in development by Commonwealth Scientific and Industrial Research Organisation (CSIRO), the Australian Government’s federal research agency, employing methods such as advance cameras, traditional net sampling, and statistical models using historical environmental data from the Australian Venomous Jellyfish Database (AVJD) to help predict when stings are at greatest risk of occurring. (Condie et al. 2018)
At the local level, properly developed and implemented emergency medical service protocols in regions where Irukandji syndrome is likely to occur can allow for prompt treatment for patients in the pre-hospital setting. Patients with Irukandji syndrome are best managed by an interprofessional team approach.
Advances in scientific evidence, detection modalities, and regional protocols will likely decrease disease incidence, improve patient outcomes, and lessen the socio-economic impact.
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