Long-term consequences of abdominal aortic and junctional tourniquet for hemorrhage control.

BACKGROUND: Specialized tourniquets have been deployed to the battlefield for the control of junctional/pelvic hemorrhage despite limited knowledge concerning their safety and duration of use. This study investigated long-term effects of abdominal application of the abdominal aortic and junctional tourniquet (AAJT) in a swine survival model. METHODS: Anesthetized spontaneously air-breathing swine were subjected to bilateral femoral artery injuries and subsequent 40% hemorrhage. Further hemorrhage was controlled by applying the AAJT on the lower abdomen for 0 h (n = 2, controls), 1 h (n = 6), 1.5 h (n = 6), or 2 h (n = 3). Before tourniquet release, arterial injuries were repaired, and mechanical ventilation and rapid crystalloid fluid were provided for at least 5 min. Additional fluid and 500 mL autologous blood were transfused after restoring blood flow. Animals were recovered and their mobility and health monitored up to 2 wk. RESULTS: AAJT application occluded the infrarenal abdominal aorta and stopped bilateral groin hemorrhage with rapid reversal of hemorrhagic shock and improved cranial blood pressure. All animals including controls recovered overnight but regaining hind leg function varied among AAJT-treated groups. In contrast to 1 h AAJT-treated swine that recovered full mobility in 1 wk, 2 h animals developed persistent hind leg paraplegia concurrent with urinary retention and ischemic necrosis of lumber muscles and had to be euthanized 3 d after surgery. Half of the 1.5-h group also had to be euthanized early due to paraplegia, whereas the other half recovered motor function within 2 wk. CONCLUSIONS: The results of this animal study indicated that ischemic reperfusion injuries associated with abdominal application of the AAJT were time-dependent. To avoid permanent injuries, AAJT application on the abdomen to control a groin hemorrhage could not be longer than 1 h. This was consistent with recent instructions for application of this tourniquet on the abdomen in patients.

Dehydropyrrolizidine Alkaloid Toxicity, Cytotoxicity, and Carcinogenicity.

Dehydropyrrolizidine alkaloid (DHPA)-producing plants have a worldwide distribution amongst flowering plants and commonly cause poisoning of livestock, wildlife, and humans. Previous work has produced considerable understanding of DHPA metabolism, toxicity, species susceptibility, conditions, and routes of exposure, and pathogenesis of acute poisoning. Intoxication is generally caused by contaminated grains, feed, flour, and breads that result in acute, high-dose, short-duration poisoning. Acute poisoning produces hepatic necrosis that is usually confirmed histologically, epidemiologically, and chemically. Less is known about chronic poisoning that may result when plant populations are sporadic, used as tisanes or herbal preparations, or when DHPAs contaminate milk, honey, pollen, or other animal-derived products. Such subclinical exposures may contribute to the development of chronic disease in humans or may be cumulative and probably slowly progress until liver failure. Recent work using rodent models suggest increased neoplastic incidence even with very low DHPA doses of short durations. These concerns have moved some governments to prohibit or limit human exposure to DHPAs. The purpose of this review is to summarize some recent DHPA research, including in vitro and in vivo DHPA toxicity and carcinogenicity reports, and the implications of these findings with respect to diagnosis and prognosis for human and animal health.

The comparative toxicity of a reduced, crude comfrey (Symphytum officinale) alkaloid extract and the pure, comfrey-derived pyrrolizidine alkaloids, lycopsamine and intermedine in chicks (Gallus gallus domesticus).

Comfrey (Symphytum officinale), a commonly used herb, contains dehydropyrrolizidine alkaloids that, as a group of bioactive metabolites, are potentially hepatotoxic, pneumotoxic, genotoxic and carcinogenic. Consequently, regulatory agencies and international health organizations have recommended comfrey be used for external use only. However, in many locations comfrey continues to be ingested as a tisane or as a leafy vegetable. The objective of this work was to compare the toxicity of a crude, reduced comfrey alkaloid extract to purified lycopsamine and intermedine that are major constituents of S. officinale. Male, California White chicks were orally exposed to daily doses of 0.04, 0.13, 0.26, 0.52 and 1.04 mmol lycopsamine, intermedine or reduced comfrey extract per kg bodyweight (BW) for 10 days. After another 7 days chicks were euthanized. Based on clinical signs of poisoning, serum biochemistry, and histopathological analysis the reduced comfrey extract was more toxic than lycopsamine and intermedine. This work suggests a greater than additive effect of the individual alkaloids and/or a more potent toxicity of the acetylated derivatives in the reduced comfrey extract. It also suggests that safety recommendations based on purified compounds may underestimate the potential toxicity of comfrey.

Safety concerns of herbal products and traditional Chinese herbal medicines: dehydropyrrolizidine alkaloids and aristolochic acid.

In many countries, including the United States, herbal supplements, tisanes and vegetable products, including traditional Chinese medicines, are largely unregulated and their content is not registered, monitored or verified. Consequently, potent plant toxins including dehydropyrrolizidine alkaloids and other potential carcinogens can contaminate these products. As herbal and food supplement producers are left to their own means to determine the safety and purity of their products prior to marketing, disturbingly often good marketing practices currently in place are ignored and content is largely undocumented. Historical examples of poisoning and health issues relating to plant material containing dehydopyrrolizidine alkaloids and aristolochic acids were used as examples to demonstrate the risk and potential toxicity of herbal products, food supplements, or traditional medicines. More work is needed to educate consumers of the potential risk and require the industry to be more responsible to verify the content and insure the safety of their products.

An in vitro comparison of the cytotoxic potential of selected dehydropyrrolizidine alkaloids and some N-oxides.

Plants producing dehydropyrrolizidine alkaloids (DHPAs) are found throughout the world and they are dangerous to human and animal health. Several DHPAs are carcinogenic but only riddelliine has been classified as a potential human carcinogen by the National Toxicology Program. As DHPA-related carcinogenicity is probably linked to cytotoxicity, a model of CRL-2118 chicken hepatocyte cytotoxicity was developed to compare equimolar DHPA exposures between 19 and 300 µM. Alkaloid-related cytotoxicity was estimated using cytomorphology, cell viability reflected by mitochondrial function and cellular degeneration reflected by media lactate dehydrogenase activity. Lasiocarpine induced cytotoxicity and decreased cell viability in a concentration dependent manner at 24 h. At similar concentrations and exposures of 48 and 72 h, seneciphylline, senecionine, monocrotaline and riddelliine were cytotoxic. None of the DHPA-N-oxides were significantly cytotoxic at these concentrations. Using graphic analyses the median cytotoxic concentration (DHPA concentration that produced ½ the maximum response) were estimated. The estimated descending order of cytotoxicity was lasiocarpine, seneciphylline, senecionine, heliotrine, riddelliine, monocrotaline, riddelliine-N-oxide, lycopsamine, intermedine, lasiocarpine-N-oxide and senecionine-N-oxide. This comparison identifies DHPAs that were more cytotoxic than carcinogenic riddelliine. Additional studies to better characterize the carcinogenic potential of these alkaloids are essential to better determine the risk they each may pose for human and animal health.

Heterozygous p53 knockout mouse model for dehydropyrrolizidine alkaloid-induced carcinogenesis.

Dehydropyrrolizidine alkaloids (DHPA) are a large, structurally diverse group of plant-derived protoxins that are potentially carcinogenic. With worldwide significance, these alkaloids can contaminate or be naturally present in the human food supply. To develop a small animal model that may be used to compare the carcinogenic potential of the various DHPAs, male heterozygous p53 knockout mice were administered a short-term treatment of riddelliine 5, 15 or 45 mg kg(-1) bodyweight day(-1) by oral gavage for 14 days, or dosed a long-term treatment of riddelliine 1 mg kg(-1) bodyweight day(-1) in pelleted feed for 12 months. Exposure to riddelliine increased the odds of tumor development in a dose-responsive manner (odds ratio 2.05 and Wald 95% confidence limits between 1.2 and 3.4). The most common neoplastic process was hepatic hemangiosarcoma, which is consistent with published lifetime rodent riddelliine carcinogenesis studies. Angiectasis (peliosis hepatis) and other previously unreported lesions were also identified. The results of this research demonstrate the utility of the heterozygous p53 knockout mouse model for further investigation of comparative carcinogenesis of structurally and toxicologically different DHPAs and their N-oxides.