Open Journal Systems

CLINICAL CASES

Received: September 22^nd 2014

Accepted: February 12^th 2015

Anaphylactic shock associated with ceftriaxone, case report and literature review

Luis del Carpio-Orantes,^a Hugo Alberto Azuara-Trujillo^b

^aUnidad de Cuidados Intensivos, Hospital D’ María, Veracruz,
Veracruz, México

^bDepartamento de Alergología e Inmunología, Hospital General de Zona 2, Instituto Mexicano del Seguro Social, Hermosillo, Sonora, México

Communication with: Luis del Carpio-Orantes

Telephone: 923 1440, 931 3626, 932 2124

Email: neurona23@hotmail.com

This study presents a case of anaphylactic shock in a senile patient, who had a biphasic event associated with the administration of a beta-lactam cephalosporin (ceftriaxone), needing stay in the intensive care unit and support with vasoactive amines, which it is rare to see in this issue, already being in itself a difficult diagnosis and often undervalued by rejecting causes of shock in a senile patient other than cardiogenic or septic. Also, a case review is made based on epidemiological issues, clinical and paraclinical diagnosis, and current treatment implications based on current international guidelines and a review of the topic.

Keywords: Ceftriaxone, Anaphylaxis, Histamine, Epinephrine.

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Female patient, 88 years old, with a history of mixed heart disease, hypertension, compensated chronic heart failure, atrial fibrillation tachyarrhythmia, and COPD (Figures 1 and 2). Signs of frequent respiratory and urinary tract infection, treated with ceftriaxone 1 g intramuscular (IM) weekly for 6 months (by way of prophylaxis for recurrent infections, indicated as optional); she had also received a course of amikacin 500 mg IM daily for 7 days. No previously documented allergies.

Admitted to shock room after administration of dose of ceftriaxone 1 g IM (30 minutes post-application, apparently she changed from one brand to another and administered hydrocortisone 100 mg IM at home), presenting drowsiness, pallor, significant angioedema affecting eyelids, lips, and tongue region; without respiratory failure.

Drowsiness is identified with significant eyelid, labial, and lingual edema and generalized erythema; hypotension noted on her arrival, with blood pressure (BP) 60/40 mmHg, tachyarrhythmia with 105 bpm by atrial fibrillation rate monitoring, bilateral infrascapular crackling without spasms, saturation by pulse oximetry of 95%, without abdominal or distal compromise. Temperature of 36 °C.

Initial management simultaneously consisted of:

• Intravenous fluids
• 0.9% saline 1000 ml single dose bolus
• Starch 500 cc single dose bolus
• 1000 cc saline solution left for 12 h base
• Pharmacological management
• Adrenaline, 1 mg subcutaneous (SC) single dose
• Methylprednisolone 500 mg intravenous (IV) bolus, followed by 125 mg IV every 8 h
• Diphenhydramine 30 mg IV every 8 h
• Norepinephrine infusion at dose of 0.05 mcg/kg/min (0.3 mg/h)
• Cardiovascular management and thromboprophylaxis (digoxin, furosemide, enoxaparin) were added.

 

She was admitted to the intensive care unit for monitoring, with vital signs within normal (BP 120/50 mmHg, ABP 73 mmHg, HR 85 bpm, RR 18 rpm, 36 °C). Fortunately she did not require invasive airway management, meriting norepinephrine infusion for 24 hours as well as management with steroid and parenteral antihistamine for 5 days; during this period there was notable presence of intensified chronic heart failure and elevated procalcitonin and D-dimer, the first due to respiratory and urinary septic process and the second associated with heart failure as the thromboembolic element was ruled out, drawing attention to the excessive elevation of procalcitonin in the absence of severe pneumonia or data of true severe sepsis, probably associated with hypersensitivity reaction (Table I).

She was seen by cardiology, who performed echocardiography, finding LVEF 60% and segmental mobility preserved, without valvular dysfunction. She was also reviewed by pulmonology, who concluded an exacerbated chronic bronchitis (infectious exacerbation of chronic bronchitis, without criterion for community-acquired pneumonia).

For respiratory infection, it was decided to initiate levofloxacin 750 mg IV/day, 6 hours after the event, again presenting lower angioedema count without evidence of hypotension, reverting to an extra dose of diphenhydramine (20 mg); she remained under vigilance, and determination of serum IgE was performed as well as specific degranulation of basophils; low-dose oral macrolide was tested with adequate tolerance, and she was discharged with clinical improvement without evidence of any allergic reaction.

The conclusion was reached of type I IgE-mediated hypersensitivity reaction to ceftriaxone, pointing out that the patient had already been in contact with the drug for 6 months, and despite this, the reaction was anaphylactic shock, so the great elevation in procalcitonin without clinical correlation with severe sepsis stood out, and D-dimer associated with heart failure, which was chronic and exacerbated by the same process of anaphylaxis. We believe that there were no criteria for septic or cardiogenic shock, since the first is associated with previous true severe sepsis and an initial process of inflammatory response, which was not evident in this patient; also, the echocardiogram ruled out severe ventricular dysfunction with acceptable LVEF, ruling out cardiogenic shock. 

The second reaction to levofloxacin administration is striking, initially also thought to be a secondary hypersensitivity reaction to the drug, however basophil degranulation for levofloxacin was negative, which suggests that the second antimicrobial administration coincided with a probable biphasic response, presenting allergic symptoms once again, 6 hours from the initial event.  

Discussion

Anaphylactic shock, or anaphylaxis itself, is a generalized injury associated with immediate IgE-mediated hypersensitivity response (type I) of sudden onset, in which there is severe hemodynamic and multi-organ compromise when appropriate treatment is not received, which can cause death.

Prevalence

Its prevalence is 2%, although this is variable, and it seems to increase as those affected are younger. In Denmark a prevalence is reported of 3.2 cases per 100,000 inhabitants per year, while in the United States it is 7.6 cases per 100,000 inhabitants, induced by food in 30-50% of cases. In Mexico there are no precise statistics.

At the Congress of the European Academy of Allergy and Clinical Immunology in June 2014, a poster was presented entitled: Drug-induced anaphylaxis in Latin America, with the participation of Latin American doctors, including Mexicans, concluding that the pharmacological group with greatest risk is NSAIDs, followed by beta-lactam and non-beta-lactam antibiotics. With a prevalence of anaphylaxis of 28.8% (and of these cases, 47% with severe anaphylaxis, 28% reporting shock associated, and 23% receiving epinephrine), respiratory and gastrointestinal symptoms are the most frequent.¹

Etiology

Among the etiologies, theoretically any agent capable of activating mastocytes or basophils can trigger anaphylaxis. It is almost always associated with drug allergies (mainly antibiotics, most notably penicillin and related drugs) and food allergies (up to 30-50% of cases, the most common being seeds, such as nuts and peanuts, shellfish and fish, milk, eggs), insect bites, and subcutaneous immunotherapy; events associated with exercise (related to food intake) and idiopathic anaphylaxis are rare.^3,4

Risk factors

Risk factors have been identified: asthma (including controlled), COPD, and pregnancy have high incidence, as well as cardiovascular diseases, allergic rhinitis, eczema, and mastocytosis. The consumption of certain drugs: antihistamines such as diphenhydramine, chlorpheniramine (paradoxically), and any cardiovascular medication such as ACE inhibitors and beta blockers (which can mask many cardiovascular symptoms), have been associated with fatal anaphylaxis.³

Pathophysiology

The pathophysiology highlights an IgE-mediated reaction in which an allergen activates the mastocytes and basophils by binding to the specific IgE and its high affinity receptor (FeRI) on the cell surface, making substances already formed and accumulated in the granules of said cells (mainly histamine, tryptase, heparin, chymase, and cytokines) initiate the process of cell degranulation, which releases them, histamine in the highest proportion, initiating their effect at the cardiopulmonary level, through H1 receptors causing itching, rhinorrhea, tachycardia, bronchospasm, and the simultaneous activation of H1 and H2 receptors causing headache, flushing, and hypotension. Furthermore, the binding of histamine to H1 receptors causes activation of endothelial cells, thereby transforming L-arginine into nitric oxide, with subsequent vasodilation, initiating shock. The release of other mediators occurs in turn, such as prostaglandin PGD2, which promotes vasodilatation and widespread bronchospasm. Cysteinyl leukotrienes act in the inflammatory response, leukotriene C4 stimulates formation of LTD4 and LTE4 leading to hypotension, bronchospasm, and mucus production during anaphylaxis. Other pathways activated secondarily are the kinin–kallikrein system, the coagulation cascade, and the fibrinolytic system, which eventually lead to multiple organ dysfunction and death, similar to what happens in other states of shock, such as septic. Tryptase is the only protein concentrated in mastocyte granules; its plasma concentrations are related to the clinical severity of anaphylaxis.^3,4

Diagnosis

The diagnosis must be clinical, and it is almost always associated with an allergen (food or drugs) that triggers the immune and inflammatory response, with subsequent clinical signs, which can begin in seconds or hours, most commonly in the first hour of allergen exposure, which initially affects the skin and mucous membranes (angioedema, generalized maculopapular dermatitis), extending to the respiratory system (being the principal organ of shock, with severe bronchospasm, sometimes irreversible) and hemodynamic alterations leading to a state of shock, the cardinal data being cardiovascular complications, hypotension (secondary to extravasation of fluids) and vasodilatation, which produce a state of mixed shock (hypovolemic and distributive) where blood volume may decrease by 35% in the first ten minutes. The decrease in cardiac output is due to poor venous return and myocardial ischemia; in this factor, hypoxemia is concomitant with severe anaphylaxis.^2,3,4

Precise diagnostic criteria are listed, all on a clinical basis:

• Acute onset, sudden signs, affecting skin and mucous membranes (80-90% of patients) in addition to any of the following:
  • Pulmonary compromise (dyspnea, wheezing or bronchospasm, stridor, hypoxemia)
  • Hypotension and/or compromise of target organs related to hypotension (syncope, oliguria, etc.)
• Two or more of the following, occurring after contact with an allergen:
  • Involvement of skin and/or mucous membranes in the form of rash, generalized urticaria, angioedema
  • Pulmonary compromise
  • Hypotension and associated symptoms (syncope, hypotonia, incontinence)
  • Gastrointestinal symptoms (nausea, vomiting, stomach cramps, abdominal cramps)
• Hypotension after allergen exposure:
  • Pediatric population: hypotension by age group and/or 30% decrease in baseline systolic blood pressure (SBP)  
  • Adults: SBP < 90 mmHg or decrease of 30% from baseline SBP

 

Anaphylactic reactions are almost always monophasic, however 20% of patients, especially adults, present biphasic cycles, which are characterized by an initial profile of anaphylactic shock, which remits and is presented again 1 to 8 hours (12 hours for some authors) after the first exhibition, for which reason hospital surveillance remains important in those who have presented anaphylactic shock.

For confirmatory tests, it is possible to measure some substances that show significant elevation in acute conditions and are almost always related to the acute setting, for conclusive diagnosis:

 

• Total tryptase, with the sample obtained between 15 minutes and the first 3 hours after onset of acute illness. It should be noted that tryptase levels also increase with myocardial infarction, amniotic fluid embolism, polytrauma, etc. Very high serum levels (greater than 11.4 ng/mL) are associated with mastocytosis or clonal disorders of mastocytes (preferably measuring alpha and beta tryptase, the latter related to degranulation of basophils).
• Serum and urinary histamine, obtaining the sample between the first 15 minutes to 1 hour after acute signs beginning, have greater sensitivity and specificity to support the clinical diagnosis. It should be noted that this can be elevated in scombroidosis (consumption of red meat fish rich in histamine).
• There are other unusual or experimental substances such as platelet activating factor, mastocyte carboxypeptidase A3, mature b-tryptase, chymase, etc.
• Serum IgE and basophil degranulation have low sensitivity and specificity, and are useful to determine the non-specific allergic component and some specific drug allergies, respectively.

Treatment

Once shock is identified, early treatment is paramount, given that once multiple organ injury is triggered, the prognosis is bleak.

All treatment guidelines note adrenaline (epinephrine) as the drug of first choice, primarily intramuscularly, with the recommendation to apply it to the outer thigh for better absorption (recommendation class A). The dose is 0.01 mg/kg in a 1:1000 solution (1 mg/ml), the maximum dose being 0.5 mg in adults and 0.3 mg in children, which can be repeated every 5 to 15 minutes, with significant improvement usually after two doses.^3,4 

Overall, fluid resuscitation therapy is recommended with isotonic saline (0.9%) in rapid bolus of 1 to 2 liters, or a rate of 5 to 10 ml/kg in adults, and 10 ml/kg in children during the first 5-10 minutes of signs. Oxygen therapy is also recommended, as are monitoring of neurological status and, if required, advanced airway management and brain-heart-lung resuscitation. 

When the administration of IM/SC epinephrine does not reverse the signs of anaphylactic shock, it is imperative to use other vasoactive substances aimed at abating the systemic vasodilation caused, these medications being high-risk and for careful management, so they should always be done in a hospital environment and ideally in an intensive care unit (recommendations class A-B):^5,6

• Epinephrine infusion at variable doses (dose 1:10,000 at a ratio of 1 to 10 mcg/min) in case of failure of initial intramuscular doses and after fluid resuscitation.
• Norepinephrine, often in continuous infusion with variable doses (0.1-0.4 mcg/kg/min, with a maximum dose of 0.6 mcg/kg/min).
• Vasopressin (persistent or vasoplegic shock), intravenous bolus of 40 IU, or continuous infusion with variable doses (0.01 to 0.04 IU/min).
• Second-line drugs, with evidence of recommendation class C, which can be initiated concomitantly for better resolution of anaphylactic shock, include:⁷
• Atropine in intravenous bolus, in case of bradycardia favoring hemodynamic decompensation.
• Corticosteroids (inflammation and bronchospasm), ideally methylprednisolone 125 mg intravenously every 6 hours in adults or 1-2 mg/kg/day in children. Hydrocortisone 200 mg/day for adults, 100 mg/day for children.
• Antihistamines, H1 inhibitors (urticaria), diphenhydramine 25 to 50 mg intravenous in a single bolus or every 8 hours, depending on reaction. In children a dose of 1-2 mg/kg. Chlorpheniramine 10 mg intravenous bolus in adults, in children 2.5-5 mg.
• B2 agonists (bronchospasm), nebulized salbutamol or albuterol with 0.5 ml of a 0.5% solution, or two inhalations with a medium dose inhaler up to 3 doses. In patients taking beta-blockers (which are more susceptible to more severe and refractory signs), the use of isoproterenol at high doses is recommended (up to 80 times the normal dose) to reverse the blockage of beta receptors.
• H2 inhibitors, ranitidine 50 mg IV bolus every 6-8 hours in adults, 1 mg/kg/dose in children.
  

References

1. Jares, EJ., Sanchez-Borges, M., Gomez, M., et-al. Multinational experience with hypersensitivity drug reactions in Latin America. Annals of Allergy, Asthma & Immunology. Volume 113, Issue 3, Pages 282–289, September 2014.
2. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, Khan DA, Lang DM, Park H-S, Pichler W, Sanchez-Borges M, Shiohara T, Thong BY-H. International Consensus on drug allergy. Allergy 2014; 69: 420-437.
3. Simons FER, Ardusso LRF, Bil_o MB, El-Gamal YM, Ledford DK, et al. The Update 2012: ‘‘World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis’’. Curr Opin Allergy Clin Immunol 2012, 12:389-399.
4. Simons FER, Ardusso LRF, Bil_o MB, El-Gamal YM, Ledford DK, et al. The ‘‘World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis’’. World Allergy Organization Journal 2011;2(3):13-36 on February 24, 2011.
5. Kim, Harold & Fischer, David. Anaphylaxis. Allergy, Asthma & Clinical Immunology 2011, 7(Suppl 1):S6
6. Simons FER. Anaphylaxis: Recent advances in assessment and treatment. J Allergy Clin Immunol 2009;124:625-36.
7. Mendoza Magaña, MJE., Rosas Vargas, MA., Guillen Escalon, JE. Et-al. Anafilaxia y Choque Anafilactico. Revista Alergia México 2007;54(2):34-40.

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