Abstract

Hypoglycemia can be a common complicating factor in a number of clinical conditions in neonate, juvenile, and adult animals. Glucose production is related to the absorption of ingested carbohydrates, gluconeogenesis from non glycogen stores, and mobilization of glucose from glycogen stores (Allen, 1983). There are a number of clinical scenarios that can impact glucose levels at various stages of glucose production. These may include a decrease in energy intake relative to energy outflow (negative nitrogen balance), an increase in energy utilization relative to intake or body energy stores, and abnormal glucose utilization from pancreatic disease or external insulin excess.

While hypoglycemia etiologies are often shared across animal age classes, some etiologies are more commonly seen in one age class over another. In neonates, failure to nurse, maternal incompetence, maternal rejection, maternal death, environmental complications such as rain or hypothermia, and septicemia can all contribute toward a hypoglycemic state. Complicating factors for juveniles under maternal care may be similar, though the effects of maternal compromise may be delayed if juveniles have access to other external energy sources. Conversely, the impact of the loss of external food sources may be delayed by continued nursing support. Adult onset hypoglycemia may also result from malnutrition, septicemia, shock, or pancreatic disease, such as insulinoma. Other potential causes may include pancreatic neoplasia, non-pancreatic neoplasia (hepatocellular carcinoma, hepatoma, hemangiosarcoma, and leiomyosarcoma), hepatopathy, hypoadrenocorticism, and renal failure (Reine et al., 2006).

Traditional veterinary education focuses on a number of treatment options for hypoglycemia often emphasizing the intravenous administration of carbohydrates and other energy sources. While this therapeutic option is often easily accomplished in domestic or terrestrial animals; aquatic animals present some additional diagnostic and therapeutic challenges when medically managing hypoglycemia. These may include limitations with the aquatic environment such as low ambient air and water temperature, IV access and maintenance, and intractability to handling. Ultimately, for successful treatment of hypoglycemia, alleviation of the initial crisis, as well as the underlying cause of the problem, must be addressed.

Presentation

Signs of hypoglycemia are relatively non-specific and need to be differentiated from those caused by other clinical conditions, such as hypocalcemia and encephalitis. Neurological signs may vary but include generalized weakness, muscle twitching, ataxia, blindness, seizures, and behavioral abnormalities. Hypoglycemia can be associated with poor body condition or obvious emaciation, but can also occur in cases with more subtle weight loss.

Young animals that appear less robust than normally expected for their age class may be at risk of a hypoglycemic event. The onset of signs in these cases may be subtle, and the clinician should consider the potential for hypoglycemia in any neonate or juvenile that is failing to gain weight or showing signs of poor food intake and/or weight loss. Neonates and juveniles with a loss of food intake and a gradual loss of body mass may show clinical signs varying from general inactivity, to weakness and depression, and seizures. In some animals, however, severe hypoglycemia or chronic recurrent hypoglycemia may be associated with chronic malnutrition and emaciation in the absence of seizures. Such cases of chronic hypoglycemia require close monitoring because of the potential of reoccurrence after initial rescue therapy if the underlying condition is not corrected.

There may be behavioral differences in response to environmental change in some aquatic species that affect the clinician's initial response at presentation. Young sea turtles and manatees often do not show a significant increase in the level of their activity when held out of the water. Turtles may need to be placed into shallow water as part of their behavioral evaluation to differentiate their low normal activity from hypoglycemic depression. Similarly neonatal manatees must be closely observed to fully appreciate the difference in behavior when first kept out of water. In these species, the clinician must rely more on glucose findings in order to avoid delays in diagnosis since seizuring is not common even with very low glucose levels.

The onset of cold weather may also play a role in the development of hypoglycemia in a number of species. Juvenile waterfowl that have not achieved full body weight and laid down metabolic reserves in the form of body fat are often victims of the first cold period. In these cases, energy is lost in attempts to adjust to cold water and ambient air temperatures, ultimately resulting in a negative nitrogen balance for the young birds. Hatchling birds may also develop hypoglycemia 5 to 7 days after hatching if nutritional intake is not adequate to energetically compensate for environmental challenges.

Neonatal cetaceans and pinnipeds that do not consume adequate amounts of milk may initially increase their nursing attempts as their hunger drive increases. Changes in nursing activity or reduced observations of milk from the mother could indicate deteriorating nutritional intake of young animals, and increased potential for hypoglycemia to occur. Visually these individuals will lose weight, so monitoring body weight may be helpful in assessing this parameter. Observers can be stationed to monitor for nursing activity and the presence of milk. Low activity and poor response to environmental change may also be clues of impending hypoglycemia.

Diagnosis

Rapid on-site diagnosis of hypoglycemia can initially be accomplished with a range of commercially available products. Glucose strips with colorimetric indicators, while once common, have generally been replaced by glucometers, often used for diabetic support. This technology relies on very small volumes of whole blood and offers quick diagnostic results, particularly for facilities lacking the capability of on on-site laboratory determination of glucose levels. Even establishments with laboratory capability should have these available for rapid determination or after hours use. It is generally recommended to run glucose determination tests early in the diagnostic work-up, since animals with severe hypoglycemia may succumb during an extended diagnostic workup. This approach should also take priority over other tests if blood samples are limited and the index of suspicion for hypoglycemia is high. Full blood samples should follow closely to better determine the initial causes of the hypoglycemia.

Serum glucose levels may vary slightly between aquatic species though the range is similar to other animals. Birds, cetaceans, sea turtles and pinnipeds usually range from 80 to 120 mg/dl. Manatees may range from 60 to 100 mg /dl. This difference may be partially attributable to dietary composition and less reliance on glucose as a primary energy source. In spite of these range differences, the clinician should not accept glucose blood values in the lower end of the range as normal, in animals that are thin or emaciated. The clinician should also view the lower glucose levels as suspect in situations where animals are exposed to stressors that would normally raise glucose levels such as handling or transport.

Glucose monitoring should be continued until the individual is serologically stable and other energy sources are administered. As long as the glucose serum level is unknown or low, or the patient continues to show signs of weakness or need of therapeutic support, glucose should be monitored. Individuals with severe hypoglycemia should be rechecked after each readjustment in carbohydrate therapy, which may entail multiple times per day initially and often twice a day after initial stabilization. For many species the diagnosis is made by accessing the vascular system. However in cases where an animal's size or anatomy makes intravascular access difficult, the clinician may have to rely on clinical response to glucose administration for confirmation of suspected hypoglycemia.

Therapy

Therapeutic approaches for hypoglycemia vary greatly among clinicians and aquatic patients. A number of factors may come into play that include interest in internal and emergency medicine of neonates and juveniles, and dedication to the extra time and effort needed to successfully treat the complicated hypoglycemic patient. Since the proper therapeutic approach often involves non-veterinary personnel it is imperative that the nursing staff or caretakers are also well versed in recognition of the hypoglycemic state and the therapy necessary to properly address the different presentations.

Hypoglycemia therapy may initially involve a rescue phase where adequate carbohydrates are administered to halt glucose destabilization and reverse low serum glucose levels. The amount needed for this phase is variable but can be quickly adjusted based on adequate monitoring. It is rare that a single dose treatment of dextrose or other carbohydrates is adequate to stabilize a hypoglycemic patient. The therapeutic approach will usually involve multiple treatments or chronic administration of carbohydrates as well as the introduction of other energy sources to successfully stabilize hypoglycemia. Glucose replacement and supplementation is a temporary method of stabilization for the central nervous system but has some limitations. Glucose alone is not an adequate substitute for other tissue energy requirements which are better met with lipid and protein utilization.

Oral Route

Oral supplementation is most applicable with mild to moderate hypoglycemia where the patient is still capable of ingesting carbohydrate formulas without the potential for regurgitation or aspiration. It can be used in severely hypoglycemic patients if there are no other easily accessible routes of administration available. Oral administration can be achieved with voluntary intake, assisted drinking, or orogastric or nasogastric tubing. Oral glucose supplements ranging from 10 to 15% solution may initially be administered in severely affected individuals. In less severe cases of hypoglycemia, treatment with lower oral glucose concentrations may help reduce the likelihood of osmotic diarrhea or other gastrointestinal upset. Combining dextrose with electrolyte solutions may also be beneficial. Solutions with low glucose levels (less than 10%) may not be adequate for stabilization of severe hypoglycemia, particularly as a sole source of therapy. Where volume may be an issue, such as in neonatal manatees or sea turtles the initial dose may be based on body weight as well. In general, 1.2 ml glucose (50%) per kilogram body weight can be administered as a rescue dose orally. This is given every 3 hours or more often, if symptoms reoccur or glucose values remain low. It is diluted in adequate water or electrolytes to reach a level of 10 to 12% dextrose when possible. In cases where animals are not tolerant of such volumes, smaller amounts of the glucose solution can be administered more often. With orogastric tubing of glucose solutions, it is generally recommended that any stomach fluid be evacuated from the stomach before administering any additional fluid volume.

Some small animals and birds can sometimes be encouraged to drink by placing small amounts of fluid on the tongue or gingiva. Drops of a dextrose solution placed in a small gap of a bird's bill may be wicked into the mouth by capillary action. The administrator must observe for swallowing movement before multiple attempts to avoid potential aspiration of hyperosmotic fluid. A 5 to 10% solution of dextrose can be added to drinking water for birds and small mammals during the initial phase of hypoglycemia treatment if they are still drinking voluntarily. Other compounds such as syrups have been used as an oral rescue supplement in dogs and cats. Some clinicians are fearful of using more concentrated oral glucose solutions because of the potential for creating osmotic diarrhea. This concern should be secondary to the animals' survival since this issue can be managed clinically by checking fecal glucose levels and adjusting the glucose supplementation accordingly. The clinician should also recognize that initially the hypoglycemic patient's deficit will allow a greater intake of dextrose. As the patient responds and other energy sources are included the excess glucose will be excreted in the feces.

Numerous commercial products are also available that contain high amounts of carbohydrates as well as other energy sources. These can assist in the acute rescue phase but also contribute quickly to the wider energy support needed with fats and proteins. The clinician should be aware of the potential for gastrointestinal upset with some of these products, but that effect can be decreased by a slower introduction into the diet. Neonatal manatees have been managed by the authors with low residue diets, commercially produced for humans. Nutramigen Lipil® and Enfamil® can be used as a carbohydrate source that includes easy-to-digest protein and fats. Once beyond the rescue phase of hypoglycemia treatment, these products can be combined with other dietary components, thereby diluting the carbohydrate content which is less critical at that stage of therapy. Variations of these products include those lacking lactose and those with reduced cow milk protein. Vital HN® has been used as a similar compound in sea turtles. It may be used initially as the sole source of oral hydration or mixed with ground fish to supplement carbohydrate needs. Medium chain triglycerides (mct) and canola oil can be introduced to help decrease the need for carbohydrate supplementation in neonatal manatees, while still providing energy support. Where there is a suspicion of intestinal disease, canola oil should be initially avoided and/or introduced slowly to the diet to reduce the likelihood of intestinal upset. Menhaden oil and mct oil have been used in sea turtles to help to decrease the use of carbohydrates as well. These should also be introduced judiciously to avoid intestinal upset.

Subcutaneous Route

The use of subcutaneous glucose supplements is usually limited to concentrations less than 2.5% to avoid tissue complications. This level is not adequate to stabilize severely hypoglycemic individuals, but it can be used as an ancillary support in early stages of treatment. Half strength saline with 2.5% dextrose is available commercially and osmotically preferable to adding dextrose to full strength electrolyte solutions. Where sodium levels are decreased or fluid therapy is for extended periods other routes should be utilized.

Intracoelomic or Peritoneal Route

While not a common route for many species, intracoelomic administration of glucose has been extensively used in sea turtles in cases of severe hypoglycemia. Many hypoglycemic stranded sea turtles present comatose and emaciated, with serum glucoses ranging from 4 to 20 mg/dl and hematocrits as low as 4%. In these cases, concurrent gastrointestinal ileus can greatly limit effectiveness of oral glucose therapy. At some facilities, lack of trained personnel also makes intravenous monitoring of turtles challenging. Intracoelomic administration of 5% glucose can be used as an alternative route of administration where intravenous, oral or interosseus routes are not possible or available for extended periods. The volume is determined by the relative level of hypoglycemia and generally ranges from 10 to 18 ml of 5% dextrose per kilogram of body weight. The clinician should expect a clinical improvement within 20 to 30 minutes of initial administration. If blood glucose levels do not improve in that time an intravenous bolus of 10% glucose can be given to provide some glucose source until the animal can better absorb the coelomic fluids. Once initial hypoglycemia is corrected, it is recommended that glucose levels be checked twice daily to monitor that fluid therapy is adequately maintaining levels. As the patient stabilizes, this approach can be reduced to once daily, and eventually discontinued. The coelomic approach has also been used with very small birds when no other route is feasible. Caution must be taken, however, since intracoelomic fluid therapy can result in air sac complications. As with any initial approach the patient should begin receiving oral supplementation of energy sources as soon as possible.

Intraosseous Route

The intraosseous technique has also been used commonly in sea turtles but requires some skill in placement of the needles and constant monitoring to avoid fluid administration problems. As with intravenous administration, intraosseous needle placement and monitoring can be labor intensive which is a consideration with limited personnel. For some species it is also not as applicable because of constant patient movement.

Intravenous Route

Usually considered the primary therapy of severe hypoglycemia, intravenous administration of dextrose is often more challenging in aquatic species due to limited vascular access. Intravenous therapy can be applied in many cases when animals are less responsive or physically restrained out of the aquatic environment. A number of aquatic species, however, are too active in the water environment (cetaceans, manatees) and do not lend themselves to sustained periods out of water for long-term intravenous therapy. Others, such as otters and pinnipeds, are prone to chewing fluid administration lines. In spite of such limitations this technique can be used for short or intermittent periods, particularly in the initial rescue phase for hypoglycemia or in comatose or less mobile individuals. The amount of dextrose administered intravenously is partially dependent on the degree of the hypoglycemia. Severely hypoglycemic individuals may require a 10 to 12% solution (one ml/kilogram) for rescue therapy. Extravasation of these hypertonic solutions can result in tissue damage, so appropriate needle or catheter placement in the vessel is important. Monitoring of serum glucose will help determine subsequent therapy adjustments. Once animals are beginning to stabilize, lower percentage glucose fluids can be utilized during therapy. Once an animal can accept oral energy sources, this will greatly aid in further glucose stabilization.

Maintaining adequate glucose levels after initial rescue of a hypoglycemic patient is critical to avoid recurrence and the potential for irreversible central nervous system damage. Survival of the patient is heavily influenced by the recognition of the degree of hypoglycemia and the rapidity and persistence of intervention by the clinician. Despite the challenges of aquatic animal patients, diagnostic and treatment options exist for addressing hypoglycemia successfully. Ultimately, as in terrestrial animals, correction of the underlying cause of hypoglycemia will offer the best opportunity for resolution of the problem.

Products Listed

 Nutramigen, Enfamil, Mead Johnson and Co., Evansville IN, 47721 www.enfamil.com

 Vital HN, Ross Products, Columbus, OH, 43215 www.ross.com

References

1.  Allen T. Canine Hypoglycemia. 1983. Current Veterinary Therapy VIII, W.B. Saunders Co., Philadelphia, PA, 845-850

2.  Reine N, Bonczynski J. Pancreatic Beta Cell Neoplasia, 2006 Saunders Manual of Small Animal Practice, Third ed., Saunders Elsiever, St. Louis, MO, 390-392.