American Journal of Emergency Medicine 31 (2013) 597-601

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American Journal of Emergency Medicine

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Review

The toxicology literature of 2011: issues impacting the emergency physician

Nathan P. Charlton MD ^a,b, Peter S. Morse MD ^a, Heather A. Borek MD ^b,

David T. Lawrence DO ^a,b, William J. Brady MD ^a,?

^a Department of Emergency Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA

^b Division of Medical Toxicology, Department of Emergency Medicine, University of Virginia School of Medicine, The Blueridge Poison Center, University of Virginia Medical Center, Charlottesville, VA 22908, USA

Carbon monoxide

Annane D, Chadda K, Gajdos P, et al. Hyperbaric oxygen therapy for acute domestic carbon monoxide poisoning: two randomized con- trolled trials. Intensive Care Med. 2011;37(3):486-492.

Carbon monoxide (CO) is a colorless and odorless gas that is formed during incomplete combustion of carbon products. Clinical effects can be nonspecific and range from malaise, headache, and nausea to more severe effects such as myocardial suppression, coma, and multisystem organ failure. Carbon monoxide is considered the leading cause of accidental poisoning deaths in the United States. Treatment of CO poisoning includes supplemental oxygen, but the use of hyperbaric oxygen (HBO) remains controversial. Prior research regarding the use of HBO in CO poisoning is confounding as patient populations differ as do specific HBO Treatment protocols. Hyperbaric oxygen is known to reduce the half-life of carboxyhemoglobin by 5-fold, but the benefit is unclear. A study in 2002 by Weaver et al [1] showed a decrease in delayed neurologic sequelae at 6 and 12 months in the hyperbaric group compared with the normobaric (NBO) group. However, other studies have shown no benefit and even potential harm with the use of HBO [2]. In an attempt to further define the role of HBO in the CO-poisoned patient, the authors of this study conducted 2 randomized controlled trials to evaluate HBO vs NBO for CO poisoning. The study was divided into 2 trials: Trial A included noncomatose patients, and trial B included comatose patients. Patients were randomized to groups as diagrammed below. Normobaric oxygen was given through a facemask or ventilator with a fraction of inspired oxygen of 100%. Hyperbaric oxygen sessions were of 2 hours’ duration in a multiplace chamber with a Plateau pressure of 2 atmospheres absolute. A total of 385 patients were enrolled in the

study: 179 patients in trial A and 206 patients in trial B.

lipid rescue therapy“>* Corresponding author.

E-mail address: [email protected] (W.J. Brady).

Patients received follow-up at 1 month, at which time they completed a questionnaire regarding physical symptoms as well as difficulties with Cognitive function. They were also assessed by a physician for abnormalities on physical and neurologic examination. The primary outcome measure was Complete recovery. The trial was stopped prematurely due to interim analysis showing a significantly lower recovery rate in comatose patients (trial B) who received 2 HBO sessions compared with the arm that received only 1 HBO session (42/105 vs 54/101, P = .007). In noncomatose patients (trial A), recovery rates were not significantly different in NBO vs HBO (45/86 NBO vs 46/93 HBO, P = .87), suggesting the inefficacy of HBO. Secondary outcome measures evaluated persistent neurologic se- quelae (PNS) and delayed neurologic sequelae (DNS); trial A showed no difference at 1 month of PNS or DNS between the 2 arms. Trial B showed significantly more patients with PNS at 1 month in the group that received 2 treatments with HBO (5% HBO x1 vs 21% HBO x2, P =

.003). There was no difference in DNS in the 2 arms of trial B.

For noncomatose patients, this study did not show any benefit of HBO over supplemental oxygen. For comatose patients, 1 treatment of HBO provided better outcome than 2 treatments; in this group, it is undetermined if HBO is better than supplemental oxygen alone. It is difficult to directly compare studies regarding HBO therapy for CO poisoning due to methodological differences of the studies (eg, differences in plateau pressure during HBO sessions, different primary outcome measures), this study adds to the perplexity as it used slightly different HBO parameters from other studies. However, the conclusions of this article further support the American College of Emergency Physicians Clinical Policy, stating that although HBO is a therapeutic option, there is not enough evidence to mandate its use in the CO-poisoned patient [3]. It also adheres to the conclusions of the 2011 Cochrane review stating “There is insufficient evidence to support the use of hyperbaric oxygen for treatment of patients with carbon monoxide poisoning [4].”

Lipid rescue therapy

Rothschild L, Bern S, Oswald S, Weinberg G. Intravenous lipid emulsion in clinical toxicology. Scand J Trauma Resusc Emerg Med. 2010;18:51-59.

It was found in the late 1970s that long-acting local anesthetics (bupivacaine, etidocaine) can produce sudden Cardiovascular collapse

0735-6757/$ - see front matter (C) 2013 http://dx.doi.org/10.1016/j.ajem.2012.10.011

as part of their toxicity [5]. It was not until approximately 20 years later that an antidote for this toxicity was discovered. Weinberg et al

[6] found that pretreatment with intralipid emulsion (ILE) increased the dose of bupivacaine needed to produce asystole in rats. They subsequently confirmed this finding in comparison with saline control and also showed that using ILE during resuscitation of bupivacaine- induced asystole improved mortality when compared with saline controls. Further studies have shown that ILE may show more favorable outcomes for resuscitation of local anesthetic-induced toxicity compared with standard resuscitation measures using epinephrine [7]. Intralipid emulsion is currently accepted as an antidote to Local anesthetic systemic toxicity, but its use is being explored as an antidote for other xenobiotic toxicities as well.

In their review article, Rothschild et al detail the historical emergence of ILE as an antidote as well as proposed mechanisms of action and a summary of its use for nonlocal Anesthetic agents. The 2 main proposed mechanisms include the “lipid sink” model and model of improved cardiac contractility due to enhanced fatty acid utilization. The “lipid sink” model suggests that by infusing lipid emulsion into the blood, the fat droplets form a Lipid compartment that acts to sequester the xenobiotic and pull it out of the tissues. Because local anesthetics are highly lipid soluble, the drugs move into the lipids rather than the heart or the brain. Numerous case reports have emerged since 2007 documenting use of ILE for resuscitation of toxicity related to xenobiotics other than local anesthetics.

Other recent articles also document the use of lipid emulsion in Poisoned patients. One case report details a 31-year-old woman who overdosed on propranolol and ethanol and presented with bradycar- dia, hypotension, hypoxia, seizures, hypoglycemia, and a prolonged QRS complex [8]. She was given treatment including glucagon, atropine, sodium bicarbonate, intravenous fluids, insulin and glucose therapy, and a dopamine infusion. The patient’s condition deteriorat- ed and she developed a Wide complex tachycardia. A 20% solution of ILE was administered resulting in transient improvement in hemo- dynamic parameters. She once again decompensated and was given an increased dose of ILE, which resulted in sustained clinical and Hemodynamic improvement such that the patient was able to be discharged to psychiatry the following day. The second case report details the treatment of a 51-year-old woman who presented after a bupropion overdose [9]. She developed refractory hypotension despite sodium bicarbonate and norepinephrine. Intralipid emulsion was initiated, which reportedly improved her hemodynamic status and allowed weaning of norepinephrine.

In a study by Harvey et al [10], propranolol toxic rabbits were randomized to resuscitation with either ILE or insulin and glucose therapy. Rate pressure product (RPP = HR x MAP) was used as the main measure of Cardiovascular performance. They found a trend toward greater RPP in the insulin-treated group, but this only reached statistical significance after 60 minutes. There was no statistically significant difference in MAP, heart rate, or survival between the 2 groups. This study suggests that ILE is not superior to high-dose insulin therapy in propranolol toxicity and may be inferior for a prolonged resuscitation. This study did not address the use of the 2 treatment modalities synergistically.

A study by French et al attempted to quantify the serum verapamil concentrations before and after the use of ILE [11]. serum samples were obtained from a 47-year-old man that intentionally overdosed on sustained release verapamil. After administration of ILE, the verapamil concentration in the serum (with the lipid portion removed) was essentially undetectable. The verapamil concentration rose again after ILE, which was thought to be due to continued gastrointestinal absorption. These findings support the “lipid sink” model of ILE in verapamil toxicity. Similarly to the criticism of other case reports, the authors point out that causation between ILE and clinical improvement cannot be proved due to the variety of other simultaneous treatment modalities being used.

Intralipid emulsion has been shown to be an efficacious antidote for local anesthetic-induced toxicity, and it is starting to be used as an antidote for a variety of other xenobiotics as well, after other treatment modalities have failed. Although there are numerous case reports of its successful use, clinicians should remain cautious and discuss its use with the local poison center before administration as its indication, mechanism, and side effects have not been fully delineated.

Oral hypoglycemic poisoning

Levine M, Ruha AM, LoVecchio F, et al. Hypoglycemia After Accidental Pediatric Sulfonylurea Ingestions. Pediatric Emergency Care. 2011;27(9):846-849.

Lung DD, Olsen KR. Hypoglycemia in Pediatric Sulfonylurea Poisoning: An 8-Year Poison Center retrospective Study. Pediatrics. 2011;127:e1558-e1564.

As the prevalence of diabetes is increasing in the United States, unfortunately, so are pediatric exposures to sulfonylureas [12]. Although data show that poison centers manage most pediatric poison exposures at home, most of the time sulfonylurea exposure results in referral to the emergency department (ED). There were a total of 3998 sulfonylurea exposures reported to US Poison control centers in 2010, with 977 of these representing pediatric exposures [13]. Single-agent ingestions represented 1712 of these exposures and often involved children younger than 6 years [13]. Sulfonylureas stimulate the release of insulin, which may result in hypoglycemia. Significant hypoglycemia can occur in children with as little as 1 pill [12-17]. Children appear to be at greater risk for hypoglycemia than adults as they have fewer glycogen reserves, increased rates of glucose utilization, and impaired glycogenolysis and gluconeogenesis [12,16]. Hypoglycemia can occur before clinical symptoms appear, and many cases document the potential for delayed onset hypoglycemia [12,15]. Following sulfonylurea exposure, practice patterns for monitoring pediatric patients vary; however, a common management practice for sulfonylurea exposure is to observe asymptomatic children for 8 hours with frequent glucose monitoring, allowing free access to food, but restricting supplemental intravenous glucose [16,18-20]. This management practice has been challenged with the assertion that the caloric intake of supplemental food can exceed that of a continuous D5 infusion masking the poisoning; multiple reports recommend an observation period of greater than 8 hours and up to

24 hours [21].

To aid in understanding the onset of hypoglycemia and clinical effects of pediatric sulfonylurea poisoning, Lung and Olsen evaluated a retrospective cohort of children with sulfonylurea exposures reported to the California Poison Control System between January 1, 2002, and December 31, 2009. A retrospective search of the California Poison Control System database was conducted to identify patients younger than 6 years who developed hypoglycemia (defined as a blood glucose b 60 mg/dL) after sulfonylurea exposure. Sex, age, specific drug ingested, estimated dose, estimated time of ingestion, times of episodes of hypoglycemia, number of episodes of hypoglycemia, symptoms, treatments given before and after hypoglycemia, and disposition were recorded. Supplemental glucose, either in the form of oral food or dextrose or intravenous dextrose provided before recording hypoglycemia, was categorized as prophylactic.

Of the 1943 cases of sulfonylurea exposure reported during this period, 300 resulted in hypoglycemia and were included in the study group; 221 cases met inclusion criteria for time-of-onset analysis. Most hypoglycemic patients (251; 84%) were clinically asymptomatic. The most common symptom (41 patients; 14%) was altered mental status. Only 5 of the patients in the study experienced seizures, and all 5 presented to a health care facility in a delayed fashion, after the seizure occurred. Mean time to onset of hypoglycemia in patients not given any prophylaxis was 2.0 hours (n = 157; range, 0.5-7 hours). The mean time of onset to hypoglycemia in patients receiving

prophylactic supplemental food was 5.9 hours (n = 40), although the range was 1 to 18 hours. Patients receiving intravenous dextrose prophylaxis had a mean time of 5.7 hours to hypoglycemia (n = 11; range, 1.5-9 hours). There was no significant difference in time to onset of hypoglycemia in patients supplemented with food vs those supplemented with prophylactic intravenous glucose (P = .83). Of 40 patients (17.5%) who received prophylactic food, 7 had onset of hypoglycemia greater than 8 hours after sulfonylurea ingestion. In those patients experiencing hypoglycemia for greater than 8 hours, 74% (28/38) had their nadir during nighttime hours (10:00 PM to 07:00 AM).

In this study, the authors concluded that the common 8-hour observation period with free access to food is an unreliable monitoring period for sulfonylurea poisoning. This method would have resulted in missing 7 cases of hypoglycemia. The authors found that free access to food can delay the onset of hypoglycemia by up to 18 hours after ingestion. Although children who were fasted after exposure were found to experience hypoglycemia within 7 hours of ingestion, it would be unethical to withhold food for this long from children during daytime hours. As the nadir for blood glucose was often during the night, the authors suggest overnight observation (with an overnight fast) or up to a 24-hour monitoring period for pediatric sulfonylurea exposure. Although only 300 of the 1943 reported cases developed hypoglycemia, the authors suggest that these admissions would not result in significant resource utilization as large Tertiary care children’s hospitals admit an average of less than 2 patients per year with sulfonylurea exposure [22].

Levine et al designed a study to determine the incidence of hypoglycemia in accidental pediatric sulfonylurea exposures. A retrospective chart review was conducted of accidental pediatric sulfonylurea exposures from a period between July 1, 2009, and December 31, 2009, presenting to the author’s institution. All patients were admitted to the medical toxicology inpatient service. Patients were excluded if the ingestion was a suicide attempt. Age, sex, specific drug ingested, time to presentation to health care facility, observation time in a health care facility, symptoms, presenting blood glucose level, and lowest blood glucose level were recorded. Hypoglycemia was defined as a serum or capillary glucose level of less than or equal to 50 mg/dL.

After exclusion of 8 nonaccidental poisonings, the study popula- tion included 93 patients. The median age was 1.83 years. The median presenting blood glucose was 80 mg/dL. Overall, 41 patients (44%) developed hypoglycemia, within a mean time of 5 hours postexposure (interquartile range, 3-9 hours). Of the 21 presentations that were known ingestions, 16 (76%) developed hypoglycemia. Of the 93 patients, 36 were found with a sulfonylurea in their mouth; 10 of these patients (27.7%) developed hypoglycemia. Of the 93 patients, 33 were found playing with sulfonylureas, but it was unknown if an ingestion actually occurred. Hypoglycemia occurred in 13 (39%) of these patients. Of the primary products ingested, glipizide was more likely than glyburide to result in hypoglycemia with an odds ratio of

3.89 (95% confidence interval [CI], 1.51-9.98). Of the 93 patients, 4 (4.3%) developed hypoglycemia greater than 8 hours after ingestion. No patient developed hypoglycemia greater than 13 hours after the time of ingestion. In the study, 11 of the patients initially presented with altered mental status or seizure. The median presenting blood glucose for those with altered mental status was 33 mg/dL, whereas for those presenting with seizure, it was 11 mg/dL. Time from ingestion to presentation of this group was not available in the article. Despite having a more stringent criteria for hypoglycemia (50 vs 60 mg/dL), this study documents a higher rates of hypoglycemia than 2 prior studies evaluating pediatric sulfonylurea exposure (30% and 27%, respectively) [21,23]. The authors chose the 50 mg/dL cut off as they felt this more accurately represented the true definition of pediatric hypoglycemia and was a more significant value in predicting symptomatic hypoglycemia. Although the mean time from ingestion

to developing hypoglycemia was 5 hours, 4% of the patients developed hypoglycemia at greater than 8 hours.

As a result of these 2 studies, it appears that all pediatric patients with accidental sulfonylurea exposure should be admitted for observation. The observation time for asymptomatic, euglycemic children should be at least 18 hours, including an overnight fast. Children may be allowed to eat during normal waking hours. As the nadir of blood glucose often occurs at night, blood glucose levels should be conducted more frequently (ie, every 1 hour) during this time. Children should only be supplemented with intravenous dextrose if hypoglycemia occurs [24].

Crotalidae envenomation

Ruha AM, Curry SC, Albrecht C, et al. Late hematologic toxicity following treatment of rattlesnake envenomation with Crotalidae polyvalent immune Fab antivenom. Toxicon. 2011;57:53-59.

It is the currently accepted practice to treat North American pit viper envenomation with Crotalidae Polyvalent Immune Fab antiven- om (Fab AV) if the patient experiences significant local swelling and/ or has hematological abnormalities including coagulopathy, hypofi- brinogenemia, and thrombocytopenia. Treatment with Fab AV is effective in improving the clinical symptoms and correcting labora- tory abnormalities. However, there are well-documented reports of symptom recurrence as well as recurrence of coagulopathy or thrombocytopenia on Laboratory analysis [25-28]. Recurrence varies in severity; mild cases have needed admission for observation and supportive care. Other cases have warranted retreatment with Fab AV, and the most severe have demonstrated significant bleeding that required further dosing with Fab Av and the transfusion of blood products. The proposed mechanism of this recurrence is pharmaco- kinetic differences between circulating venom antigens and Fab AV. Possible considerations for these differences in pharmacokinetics include delayed absorption of venom, dissociation of venom from antivenom, and more rapid clearance of Fab AV compared with venom components [25,29].

Following the treatment of venomous pit viper bites with Fab AV, there continues to be no consensus on how long patients should be followed or how frequently laboratory values should be checked. The purpose of this study was to indentify incidence and time of onset of new or recurrent hypofibrinogenemia, coagulopathy, or thrombocy- topenia following treatment with Fab AV to define parameters on how often and for how long patients should be monitored.

The authors performed a retrospective study analyzing the charts of 66 patients treated with Fab AV following rattlesnake envenom- ation and who had follow-up evaluation at least 48 hours after completing treatment.

The authors found that, at the time of first follow-up appointment (at least 48 hours after last dose of Fab AV), 21 patients (32%) had coagulopathy, hypofibrinogenemia, or thrombocytopenia. In 18 patients, this represented recurrence, whereas in 3 patients, this represented a new abnormality that was not present on initial hospitalization. Of the 23 patients with more than 1 follow-up visit, 15 patients had normal values at the First visit. Of these 15 patients, 5 (8% of the study population, 33% of this subgroup) were found to have abnormalities at a second visit 7 to 12 days following treatment. Five patients (8%) developed severe late hematologic toxicity, defined as both fibrinogen less than 35 mg/dL and prothrombin time greater than 100 seconds or platelets less than 50000/mm³. Only one of these patient required admission to the hospital and was retreated with Fab AV for severe thrombocytopenia (platelets 15 K/mm³). There were no patients seen in follow-up with active bleeding.

The results of this retrospective study supported a growing number of case reports, which described late recurrent hematological abnormalities occurring at 5 to 7 days following Fab AV treatment [28,30]. As there was new onset coagulopathy and thrombocytopenia

high-dose insulin therapy”>found after discharge in patients that had no abnormalities during initial hospitalization and treatment, initial coagulopathy cannot be used a marker for which patients will need follow-up. The authors suggest that all patients should have an initial follow-up appointment 2 to 3 days following treatment and a second appointment at 5 to 7 days to assure late toxicity has not developed. In addition, all patients should be warned about late onset hematologic toxicity.

Digoxin poisoning

Levine M, Nikkanen H, Pallin DJ. The effects of intravenous calcium in patients with digoxin toxicity. Journal of Emergency Medicine. 2001;40(1):41-46.

Digoxin is a cardiac glycoside frequently used for the treatment of congestive heart failure and atrial fibrillation. Digoxin works by inhibiting the sodium-potassium ATPase; this increases intracellular sodium and leads to increased intracellular calcium, which ultimately causes positive inotropic action. In overdose, the inhibition of sodium- potassium ATPase often leads to hyperkalemia. In the typical ED patient, calcium is an important part of the treatment of hyperkale- mia. It is used to stabilize the myocardium and prevent dysrhythmias. However, based on case reports and animal studies, calcium has been traditionally discouraged in the setting of digoxin toxicity for the treatment of hyperkalemia.

Animal studies suggest that calcium increases digoxin toxicity, but it is argued that this evidence is not clinically relevant due to the high calcium concentrations used in these studies [31-35]. Theories postulate that calcium can precipitate an irreversible noncontractile state caused by failure of diastolic relaxation or, alternatively, that calcium excess could lead to ventricular dysrhythmias through delayed after-depolarizations [36]. Literature reveals 5 case reports where patients being treated with cardiac glycosides experienced fatal dysrhythmia temporally related to receiving calcium. However, each case is complicated, and it is difficult to draw any cause and effect type conclusions [31,37,38].

The objective of this retrospective study was to compare the frequency of life-threatening dysrhythmia and mortality in digoxin toxic patients who received calcium vs those who did not. Fatal dysrhythmias were defined as ventricular fibrillation, sustained ventricular tachycardia, Mobitz II second degree block, complete heart block, or asystole. The authors reviewed charts of 161 adult patients with a diagnosis of digoxin toxicity over a period of 17.5 years.

The authors found 23 patients with documented digoxin toxicity who received calcium. In these patients, no life-threatening dys- rhythmias occurred within 4 hours of calcium administration. There was also no statistical difference in mortality in patients who received calcium vs those who did not (22% vs 20%, P = .78). In the patients who were treated with calcium, there was a nonsignificant trend toward decreased mortality (odds ratio, 0.76; 95% CI, 0.24-2.5).

A multivariate logistic regression was used to control for age, blood urea nitrogen, creatinine, peak digoxin concentration, and peak potassium concentration. Peak potassium concentration was the only variable associated with increased mortality. With each 1 mEq/ L rise in serum potassium, there was an increased mortality odds ratio of 1.5 (95% CI, 1.0-2.3). Among the patients with marked hyperka- lemia (N 5.5 mEq/L), there was an odds ratio for mortality of 2.0. (P =

.07; 95% CI, 0.93-4.5).

This is a small retrospective study; however, the authors concluded that there was no evidence of fatal dysrhythmia or increased mortality in patients with digoxin toxicity who received intravenous calcium. Other limitations to this study in this study were that patients were all adults and were primarily having Chronic digoxin toxicity, only 1 patient presented with an acute overdose. In addition, although patients had elevated digoxin levels, clinical signs of digoxin toxicity were not reported. Despite the limitations of the

article, it may alleviate some apprehension about administering calcium to the undifferentiated hyperkalemic patient who may be taking digoxin.

High-dose insulin therapy

Holger JS, Stellpflung SJ, Cole JB, et al. High dose insulin: a consecutive case series in toxin-induced cardiogenic shock. Clinical Toxicology. 2011;49(7):653-658.

There are multiple agents that, when taken in overdose, can induce cardiogenic shock. Although high-dose insulin therapy has become more mainstay treatment for Calcium-channel blockers, many other xenobiotics can produce cardiogenic shock that may be amenable to high-dose insulin therapy [39,40]. Accordingly, high-dose Insulin infusion has become a popular Treatment modality. However, if used at too low of a dose or later in course of resuscitation, the authors suggest that it may not be effective. In this article, the authors detail a case series where high-dose insulin infusion, up to 10 U/kg per hour, was used to manage patients with toxin-induced cardiogenic shock.

This article is an observational consecutive case series of patients treated by the medical toxicology service at the authors’ institution between February 2007 and March 2010. Patients presenting with toxin-induced cardiogenic shock were all treated with the institutions standard protocol, which includes a regular insulin bolus of 1 U/kg follow by an infusion of regular insulin at 1 U/kg per hour titrated up to a maximum of 10 U/kg per hours depending on Clinical response. Intravenous dextrose is used to maintain a blood glucose greater than 200 mg/dL.

During the study period, 12 patients were treated using this protocol. The mean maximum infusion rate was 8.35 U/kg per hour. The most frequent toxins involved were ?-blockers; however, calcium-channel blockers, amitriptyline, and polydrug ingestions were also included. Patients who had been on vasopressor therapy had this tapered off while on high-dose insulin.

Eleven of the twelve patients survived. One fatality occurred in a patient whose insulin infusion was discontinued and norepinephrine reinitiated, which was a protocol violation. Half of the patients experienced hypoglycemic events, all received intravenous dextrose. However, there were no adverse sequelae due to hypoglycemia. Eight patients developed hypokalemia (b 3.0 mmol/L), and 6 received potassium infusion. No adverse arrhythmias were noted.

In this article, a series of patients with toxin-induced cardiogenic shock was successfully treated with high-dose insulin therapy. In the authors’ experience, a high-dose insulin protocol using doses up to 10 U/kg per hour is safe and effective at reversing toxin-induced cardiogenic shock. The authors propose that insulin’s inotropic as well as vasodilatory properties combine to increase cardiac output. This limits the use of vasopressors that may have harmful side effects. Because of the incidence of hypoglycemia, frequent blood glucose levels should be checked with intravenous dextrose supplementation as necessary.

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