1. Introduction
Jellyfish belong to the phylum Cnidarians. The phylum is subdivided into five classes (see
Figure 1: Staurozoa (Stauromedusae); Scyphozoa (true jellyfish); Hydrozoa (Portuguese Man O’ War, fire corals and hydroids); Cubozoa (box jellyfish); and Anthozoa (sea anemones and true corals) [
1]) and is composed of about 10,000 species, with 100 of them known to be dangerous to humans [
2,
3].
Jellyfish have a bell-shaped body (umbrella) of different sizes, with a varying number of tentacles, depending on the species. The tentacles reach from a few millimeters up to 40 m in length, depending on the species, with their color ranging from transparent to whitish, yellowish, purple or bluish [
2,
3].
The tentacles present specialized epidermic cells, called cnidocytes, that contain three categories of organelles, called cnidae (and also cnidocysts). Nematocysts, one of the three categories of cnidae, are hollowed capsules containing a tightly coiled and folder thread immersed in the cnidarians’ venom [
1,
2,
4]. Nematocyst thread tubules evert so that the venom is injected on the outside of the thread tube. Some thread tubes are also hollowed and can discharge venom through the end [
1,
2,
3]. Tentacles contain from a few thousand to several billion nematocysts [
1,
2].
Nematocysts are discharged onto the skin within a fraction of a second, making a jellyfish nematocyst discharge one of the most rapid mechanical events in nature [
5]. Nematocysts can function even when separated or if the organism is dead, although discharge rate decreases after death [
1,
6,
7].
Discharge of the jellyfish venom is triggered by mechanical stimuli (such as skin rubbing or tentacle traction) [
8], sudden increase in the osmotic pressure of the capsular fluid due to the removal of bound calcium ions [
9] and sudden relaxation of spring-like tensions in the nematocyst collagen framework [
5]. The above stimuli activate the uncoiling of the thread, which penetrates into the tissues, causing the nematocyst to discharge venom [
8,
10].
Although all cnidarians are capable of envenomation, most are harmless to humans, as some do not have nematocyst shafts of sufficient length to enable the thread to deposit toxins deep enough into the epidermis [
1,
11] or might produce toxins that do not cause significant harm to humans [
12]. Harmful cnidarians include vertebrate feeders or bigger jellyfish able to release large amounts of toxin [
1,
2].
Jellyfish are present in all oceans of the world [
2,
3], with their stings being commonly observed in warm tropical marine waters [
13,
14], as well as in more northern regions, such as the United Kingdom [
15], France [
16] and Norway [
17]. The geographic distribution of jellyfish seems to be undergoing an impact by global warming [
18,
19,
20].
Figure 1.
Cnidarians phylum: Main species byfamily and class.
Figure 1.
Cnidarians phylum: Main species byfamily and class.
It has been estimated there are 150 million jellyfish stings a year [
21], with some Pacific areas reporting up to 800 daily events at one single beach [
22,
23]. Therefore, beyond being a public health issue, jellyfish also constitute a threat to tourism [
24].
Skin contact with nematocysts resembles a prick, and the subsequent inflammation and nerve irritation produces pain, swelling and itching, potentially leading to skin necrosis in more severe stings (often from Australian chirodropid cubozoans) [
2,
25,
26]. The local effect of the venom is due to the penetration of the thread and the activity of various compounds, like phospholipase A2 [
7,
27], as well as exocytosis of mast cell granules (and, thus, possibly histamine release) [
28,
29]. Nematocysts can also cause potential systemic symptoms—as a result of the toxins entering the general circulation [
1]—including gastrointestinal (mainly
Physalia physalis and Pelagiidae spp.), muscular (
Physalia and cubozoans spp.), cardiac (
Physalia and cubozoans spp.), neurological (
Physalia and cubozoans spp.) and allergic manifestations (Pelagiidae and cubozoans spp.). Jellyfish toxins reportedly also include hemolytic and lethal fractions [
1,
30,
31]. The lethal fractions may contain cardiotoxins, able to produce ventricular arrhythmias and cardiac arrest, and neurotoxins [
1,
30,
31], which may cause respiratory failure and respiratory arrest [
32]. Intravascular hemolytic fractions can also precipitate acute renal failure [
1]. Cnidarians’ venom is also immunogenic, capable of generating antibody response [
1,
4,
24].
There has been a wealth of research done on the treatment of cnidarians’ stings, but confusion still exists as to what is the most effective first aid and clinical management [
32,
33,
34,
35]. Hence, there is an urgent need to consolidate a shared protocol for the management of these accidents.
Several authors have summarized the literature on the jellyfish phenomenon and the evidence concerning the various treatment approaches. Our aim was to integrate the knowledge reported by the most authoritative reviews and most recent research papers.
4. Discussion
Treatment of jellyfish envenomation is primarily directed at [
52]:
Alleviating the local effects of venom (pain and tissue damage);
Preventing further discharge of nematocysts;
Controlling systemic reactions, including shock.
The most important step after envenomation is basic life support (ABCs), with the aim of maintaining respiration and blood circulation [
2,
98], and tentacle removal, since as long as tentacles adhere to the skin, nematocysts continue to discharge venom [
2,
100]. Tentacle removal should, however, be delayed until the patient is stable [
41].
It is still debated which is the most appropriate method for tentacle removal, as the procedures may stimulate further nematocyst discharge [
52]. Flushing the stung skin area with sea water is recommended [
2,
44,
50,
100], as well as the use of tweezers to remove tentacles [
112]. Tentacles may also be removed with bare hands, but it is best to immediately rinse off the rescuer’s fingers carefully afterwards to prevent secondary stings [
42].
As toxins vary among jellyfish species [
1,
2,
116], different remedies are necessary to control pain, additional venom liberation and local reactions. The ideal treatment would be readily available, cheap, effective for inactivating toxins of various jellyfish species and would prevent further discharge of venom [
52]. Although there are differences between species, there seems to be evidence and consensus on oral/topical analgesics, baking soda, hot water, ice packs and (for cubozoans and non-Australian
Physalia) topical vinegar. In tropical Australia, where the risk of life-threatening cubozoans is substantial, the Australian Resuscitation Council (ARC) recommends vinegar application followed by tentacle removal and ice pack application if the jellyfish responsible cannot be clearly identified as harmless. Sea water should be used if vinegar is not available. Out of the tropics, where non-life-threatening jellyfish species predominate, the priority is pain relief, and the first aid approach should be sea water rinsing followed by either hot water (42 °C for 20 min) for confirmed
Physalia stings or ice packs for stings of unknown origin [
98]. All measures that could cause massive discharge of nematocysts should be carefully avoided.
Ice seems to slow the diffusion of the venom, thus acting as a painkiller, whereas the mechanism of pain relief due to heat is still debated. It is unlikely that it could be attributed to the denaturation of the venom. Cnidarians’ toxins denature rapidly above 50 °C [
117], but this condition probably does not occur on human skin, where temperatures would be lower and the inactivation time longer. Cnidarians’ venom may have already circulated away from the sting site at the time of initiating treatment. Furthermore, denaturing the venom is unlikely to affect the pain in an already existing injury. Some authors argue that heat may modulate the pain receptors, thus leading to a reduction in pain sensation [
118].
High dosages of intravenous ascorbate were reported to decrease the pain 10 min after administration to a male stung in both legs by a medusa while he was net fishing at a Malaysian beach. The responsible jellyfish was not identified, but since the local symptoms initially increased after application of vinegar, it seems plausible that the species involved could have been a scyphozoan. Vitamin C is considered effective against various toxins [
119].
PIB for jellyfish envenomation remains controversial and is considered potentially dangerous [
114], with some Northern Australian territories not recommending it as first aid treatment [
120]. A significant amount of venom might remain in not yet discharged nematocysts adhered to the patient’s skin, and PIB pressure may stimulate venom extrusion from them [
81,
114]. Moreover, PIB may even interfere with the ability of vinegar to prevent additional discharge of venom from unexploded nematocysts [
114]. Some experts argue that the likely increased liberation of venom generated by PIB could be offset by the containment of the venom in the limbs and decreased systemic absorption of toxin due to bandaging [
115]. This compartmentalization of the venom within the sting area in
C. fleckeri stings appears limited, however, as the health effects of the toxin develop within minutes, suggesting involvement of the circulatory system rather than the lymphatics [
114]. Although massive and fatal
C. fleckeri envenomation might have intravascular venom injection from venom covered tubules penetrating blood vessels, as well as slower lymphatic drainage, the benefit of PIB in counteracting the movement of venom from the sting site via the lymphatics and small blood vessels has still to be further tested [
1]. Furthermore, the only real benefit of PIB seems to be immobilization and subsequent decrease in blood and venom flow; however, this can also be accomplished by other means without compression bandages [
114]. Thus, despite being advocated by experts and authorities [
115,
121], the ARC does not recommend the use of PIB [
98,
114].
Large trials on topical inhibitors as effective measures to prevent jellyfish stings are ongoing and look promising [
21]. A skin inhibitor cream (Safe Sea
®, by Nidaria Technology, Zemah, Jordan Valley, Israel) is already commercially available in many countries worldwide to provide practical and cheap protection for swimmers against jellyfish stings. This preparation was recently formulated as a waterproof sunscreen containing octyl methoxycinnamate and zinc oxide, allowing both jellyfish inactivation and sunburn protection with a single application. Safe Sea
® is effective in preventing nematocysts from firing, but is not helpful after the stinger has fired [
21]. This product was applied on the forearm (and conventional sunscreen on the other) of healthy volunteers exposed to tentacles of
C. quadrumanus and
C. fluorescens in one RCT and to tentacles of
C.
capillata in another more recent Norwegian RCT. Safe Sea
® was also tested in a field RCT conducted in Florida and Belize (areas where
C.
quinquecirrha,
C.
quadrumanus,
Lunuche ungulate and
Physalia are common). In all the above trials, Safe Sea
® did not eliminate the stings, but significantly reduced their frequency and severity [
21,
122,
123]. Safe Sea
® is likely to be effective against a vast range of jellyfish species [
21]. It would therefore be interesting to test it also with more dangerous species, such as
C.
fleckeri,
C.
barnesi and
P.
physalis.
In terms of preventive medicine, divers and swimmers in risky areas should wear personal protective equipment (PPE). PPE is, in fact, almost totally effective against all jellyfish stings and is routinely recommended in Australia for all people (tourists, locals and recreational divers) [
24]. Full-Body Lycra
® suits have been used by divers since the early 1980s and seem to be the best choice for routine-use protective clothing against
C. barnesi [
24]. However, the recreational public when swimming in risky areas seems reluctant to use PPE, as it was estimated that less than 5% of Queensland beach users wear any type of stinger protection [
24]. Those who cannot refrain from diving/swimming in risky areas due to their occupation should wear protective gear. As these suits often leave the face, hands and feet exposed, snorkelers and pearl divers in Western Australia modify them to cover the whole body and avoid severe and/or life-threatening jellyfish stings [
21,
124].
Stinger nets are also used in Australia to keep jellyfish out of highly used swimming areas; however, these barriers (which normally have 2.5 cm holes) are more likely to be effective against larger species, such as
C. fleckeri, as smaller jellyfish like
C. barnesi are able to get through the nets [
21,
24,
125].
Adequate signage should be placed at beaches to notify tourists about the jellyfish risk; water should not be entered during risky months. Tropical species, such as the chirodropids, occur predominantly (but not exclusively) during the summer months in the boreal and austral hemispheres, being found almost year round at the equator [
2,
61,
75].
The vulnerable population (especially tourists and children) should be targeted through health education on how to avoid envenomations, how to behave in the event jellyfish are seen in the water (although most chirodropids are never seen and for them PPE is essential) and in the event of stings (first aid guidelines). Although sometimes impractical, free ice packs, as well as vinegar, should be made available at distribution points. Vinegar is very cheap, simple to use and does not have an expiration date; hence, it is also easy to keep on a boat, in the trunk of a car or at the beach. Bathers should be instructed on first aid measures.
Epidemiological data on jellyfish risk should be routinely collected to better inform and educate those categories at risk on the appropriate treatment modalities. Published literature on stings has been both limited and conflicting, treatment guidelines still lack consensus and it is often difficult to identify the jellyfish species involved (especially in the case of cubozoans) [
2,
126].
5. Conclusions
Efficacy of treatment relies mostly on studies without controls, studies based on physiology and basic science, case reports and expert opinions. To date, only eight RCTs [
21,
23,
43,
47,
102,
104,
122,
123] and one non-randomized controlled trial [
51] investigating jellyfish treatment/prevention have employed adequate controls. Further research is needed to develop a recognized protocol for the management of jellyfish stings, although observing a rigorous and sound methodology seems problematic (difficulties in recruiting patients, randomization, outcome assessment,
etc.). It is essential in future trials to exactly identify the jellyfishes under study, as many different species may be present even in the same waters: the larger the study, the more varieties may be involved.
Despite the above limitations, there seems to be evidence and consensus on the efficacy of oral/topical analgesics, baking soda, hot water, ice packs and (only for cubozoans and non-Australian Physalia) topical vinegar. A skin inhibitor cream is effective in preventing nematocysts from firing, significantly reducing the frequency and severity of stings.
Dissemination of appropriate treatment modalities should be deployed to better inform and educate those at risk. Adequate signage should be placed at beaches to notify tourists of the jellyfish risk. Swimmers in risky areas should wear protective equipment.