Probable case of anaphylaxis due to hydrocortisone in a septic shock patient

Introduction

Glucocorticoids, established therapeutic agents in the clinical management of septic shock, possess irreplaceable value in critical care medicine due to their multifaceted pharmacological properties, including anti-inflammatory, anti-allergic, and anti-shock effects. Paradoxically, while exerting anti-allergic therapeutic actions, these agents may also function as rare sensitizers capable of inducing anaphylactic shock. The earliest documented instance of glucocorticoid allergy was identified within a 1985 review, ¹ which chronicled over thirty cases of systemic glucocorticoid hypersensitivity reported by that period. Subsequent clinical reports have described glucocorticoid-induced immediate hypersensitivity reactions occurring worldwide,^2,3 and in 2005, the American Contact Dermatitis Society designated glucocorticoids its annual allergen of the year. ⁴ However, in the context of polypharmacy, particularly when accounting for individualized pathophysiological characteristics of patients, the clinical identification of glucocorticoid-induced allergic reactions becomes markedly more complex. To address these challenges and ensure methodological rigor, we used the CARE checklist ⁵ during the preparation of this case report (Supplemental Material). Accordingly, this clinical case report details a representative instance of sudden hemodynamic decompensation in a patient with septic shock following intravenous hydrocortisone administration. We prepared this report to establish diagnostic criteria for informing clinical decision-making in differentiating glucocorticoid-induced sensitization reactions from DLRs associated with concomitant medications. Furthermore, this case elucidates strategies for mitigating similar glucocorticoid-related ADRs.

Case report

The patient was a geriatric male presenting with “bilateral hip and sacrococcygeal ulcerative lesions persisting for 6 weeks.” One month preceding admission, he manifested an acute respiratory syndrome characterized by productive cough, wheezing, and febrile episodes (peak temperature 38.7°C), accompanied by hypotensive crisis (80/40 mmHg) in a long-term care facility, with no identifiable predisposing factors. Following unsuccessful management with intravenous fluid resuscitation, broad-spectrum antimicrobial therapy, and bronchodilator treatment, the patient underwent emergency transfer to our institution. Comprehensive diagnostic evaluation confirmed severe community-acquired pneumonia, prompting hospital admission. During hospitalization, the patient received multimodal therapeutic interventions including targeted antibiotic therapy, corticosteroid administration, mucolytic agents, electrolyte repletion, and enteral nutritional support, culminating in clinical stabilization and subsequent discharge. Notably, the patient developed progressive stage II pressure injuries in the sacrococcygeal region and bilateral trochanteric areas during prolonged immobilization. Current admission was necessitated by specialized wound management of these pressure injuries.

The patient’s medical history included essential hypertension with a 25-year duration, characterized by a peak recorded blood pressure of 180/100 mmHg. Current management with oral Sacubitril/Valsartan 100 mg once daily maintained adequate hemodynamic stability. Concurrent type 2 diabetes mellitus (10-year duration) demonstrated suboptimal glycemic control despite daily administration of oral Dapagliflozin 10 mg once daily. Neurological sequelae from a 2018 acute left middle cerebral artery infarction resulted in persistent right hemiparesis and Broca’s aphasia, rendering the patient fully bedbound with complete dependence for activities of daily living. Past surgical history was notable for appendectomy (1978). There was no documented history of drug hypersensitivity reactions or anaphylaxis. Immunization records were not formally documented. Relevant personal history revealed a four-decade tobacco use history (cessation achieved 7 years prior) and no alcohol consumption. Following hospital admission, the patient underwent standardized wound management and enteral nutritional supplementation. At 20:00 h on April 12, 2025, the patient manifested acute respiratory distress characterized by wheezing and oxygen desaturation to 85%. Clinical assessment revealed hemodynamic instability with vital signs as follows: blood pressure 88/41 mmHg, heart rate 105 bpm, and respiratory rate 27 cycles/min. Physical examination demonstrated labored open-mouth breathing accompanied by bilateral pulmonary rales and rhonchi. Given progressive cardiorespiratory instability, the patient was transferred to intensive care for advanced monitoring.

The critically ill patient received endotracheal intubation with concomitant mechanical ventilation to maintain airway patency and ensure adequate oxygenation. This intervention was supplemented with continuous sedation and analgesia administered via sufentanil and midazolam infusions. Hemodynamic stabilization was achieved through targeted vasopressor therapy, administering norepinephrine, vasopressin, and methylene blue, alongside antimicrobial treatment consisting of tigecycline (Chiatai Tianqing Pharmaceutical Group, batch 240814115, 50 mg/dose) and cefoperazone-sulbactam sodium (Pfizer, batch 8190645, 1.5 g/dose). Owing to persistent refractory hemodynamic instability unresponsive to initial interventions, hydrocortisone (China National Pharmaceutical Group Rongsheng Co., Ltd., batch 2409201, 20 ml:100 mg) 200 mg in 100 mL of 0.9% sodium chloride solution, was administered for septic shock management on April 15, in accordance with the 2021 international guidelines for the management of sepsis and septic shock. ⁶ Notably, within 30 min post-hydrocortisone administration (initiated at 11:30), the patient exhibited progressive cardiovascular collapse, manifested by: (1) tachycardia progression (92→128 bpm); (2) hypotensive crisis (50–61/24–45 mmHg); (3) respiratory compensation (19→31 rpm); (4) peripheral circulatory failure (cold extremities with diaphoresis); and (5) normothermic maintenance (36.5°C–36.8°C). Following the onset of hemodynamic instability during hydrocortisone infusion administration, a potential ADR was clinically suspected. The hydrocortisone intravenous infusion was promptly discontinued, with concomitant upward titration of norepinephrine and methylene blue dosages to maintain hemodynamic stability. Concurrent administration of amiodarone was initiated for ventricular rate control, supplemented by supportive measures including volume resuscitation. This therapeutic regimen aimed to address both cardiovascular instability and underlying metabolic disturbances through pharmacologic intervention and essential supportive care. After symptomatic treatment, subsequent hemodynamic monitoring revealed stabilization in the patient’s vital signs: blood pressure ranging from 106–135/44–68 mmHg, heart rate maintained between 70 and 96 bpm, and respiratory rate within 18–22 breaths per minute. Regrettably, the blue discoloration of the patient’s skin induced by methylene blue injection compromised the observation of clinical signs during ADR episodes. This impediment precluded accurate assessment of facial color changes and potentially delayed the timely identification of the aforementioned ADR. Nevertheless, close monitoring of the ADR was maintained by the clinical team, and effective countermeasures were implemented, thereby ensuring the patient’s safety.

Discussion

Glucocorticoids compensate for the absolute or relative insufficiency of adrenal cortisol during stress through exogenous supplementation, activating the genomic effects of cytoplasmic glucocorticoid receptors. This mechanism specifically inhibits the nuclear translocation of pro-inflammatory transcription factors, such as NF-κB, significantly reducing the synthesis and release of pro-inflammatory cytokines, including interleukin-6 and tumor necrosis factor-α. Concurrently, by upregulating α-adrenergic receptor expression, glucocorticoids enhance the physiological responsiveness of vascular endothelial cells to circulating catecholamines. These dual mechanisms synergistically stabilize hemodynamic status, manifested as an increase in mean arterial pressure and a reduction in vasopressor dependence, thereby effectively reversing the pathological progression of shock.^7,8 Given their well-documented pharmacological effects, glucocorticoids have become an integral component of comprehensive septic shock management protocols. The 2021 guidelines for the diagnosis and treatment of septic shock explicitly recommend adjunctive intravenous glucocorticoid therapy for anti-shock treatment when high-dose vasopressors are required to maintain blood pressure. Hydrocortisone is the preferred agent, with a recommended dosage of 200 mg/day, administered as a 50 mg intravenous bolus every 6 h or via continuous infusion. The optimal timing for initiation is within at least 4 h after norepinephrine or epinephrine reaches ⩾0.25 μg/(kg·min). ⁶ In this instance, the maximum norepinephrine dosage administered reached 0.5 μg/(kg·min), yet mean arterial pressure remained below 65 mmHg, thereby meeting the criteria for glucocorticoid therapy. However, the initiation of hydrocortisone was notably delayed, commencing only on the third day of conventional anti-shock treatment. Whether the delayed administration negatively impacted the therapeutic efficacy of hydrocortisone remains unclear.

The patient exhibited the classical shock triad (hypotension, tachycardia, and peripheral circulatory failure) during hydrocortisone infusion, coinciding with multiple concurrent therapeutic interventions, including sufentanil, midazolam, enteral nutrition via nasogastric tube (TPF-D emulsion), and polypharmacy comprising cefoperazone-sulbactam, tigecycline, aminophylline, atorvastatin, mosapride, and rivaroxaban. While a temporal correlation exists between hydrocortisone administration and the onset of ADRs, the patient presented with hypotension upon ICU admission and received a clinical diagnosis of septic shock. Notably, the shock state persisted despite adequate fluid resuscitation and anti-infective therapy. Consequently, no definitive causal relationship could be established between the ADR occurrence and specific drug administration, nor could it be determined whether the event constituted a manifestation of the disease’s natural progression. The complexity of assessing ADR causality was further heightened by the patient’s extensive polypharmacy. The Naranjo causality assessment ⁹ yielded a score of four, indicating a “possible” association (Table 1). In addition, the ADR observed in this patient precipitated a decline in blood pressure to hypotensive shock levels, compromising respiratory and cardiovascular function (Table 2). This event necessitated intravenous pharmacological intervention and emergency resuscitation. In accordance with Hartwig’s Severity Assessment Scale, ¹⁰ this ADR was categorized as severe (level 5). For preventability analysis, we also consider definite, probable, and possible ADRs. The Modified Schumock and Thornton criteria ¹¹ for preventability analysis are detailed in Table 3, and this ADR was assessed as “probably preventable.”

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Table 1.

Questions comprising the Naranjo algorithm employed in causality evaluation of ADRs. ⁹

Questions	Yes	No	Do not know score	Score*
1. Are there previous conclusive reports on this reaction?	+1
2. Did the adverse event appear after the suspected drug was administered?	+2
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1
4. Did the adverse reaction reappear when the drug was readministered?			0
5. Are there alternative causes (other than the drug) that could, on their own, have caused the reaction?	−1
6. Did the reaction reappear when a placebo was given?			0
7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?			0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?			0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?		0
10. Was the adverse event confirmed by any objective evidence?	+1			Total score 4

*

The ADR was assigned to a probability category from the total score as follows: definite ⩾9, probable 5 to 8, possible 1 to 4, doubtful ⩽0.

ADR, adverse drug reaction.

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Table 2.

Hartwig’s scale depicting assessment criteria and corresponding severity levels for ADRs severity assessment. ¹⁰ .

Level	Criteria
Mild (level 1)	The ADR requires no change in the treatment with the successful drug Mild
Mild (level 2)	The ADR requires the suspected drug be withheld, discontinued, or otherwise changed. No antidote or other treatments required, and there is no increase in length of stay
Moderate (level 3)	The ADR requires the suspected drug be withheld, discontinued, or otherwise changed, and/or an antidote or other treatments required, with no increase in length of stay
Moderate (level 4)	Any level 3 ADRs that increase the length of stay by at least 1 day or were the reason for admission
Severe (level 5)	Any level 4 ADRs that require intensive medical care
Severe (level 6)	The ADRs causing a permanent harm to the patient
Severe (level 7)	The ADRs directly or indirectly leading to the death of the patient

ADR, adverse drug reaction.

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Table 3.

Modified Schoumock and Thornton scale listing questions utilized in the assessment of preventability categories for ADRs. ¹¹ .

Definitely preventable
Was there a history of drug allergy or previous reaction to the drug?
Was the drug involved inappropriate for the patient clinical condition?
Was the dose, route, or frequency of administration inappropriate for the patient’s age, weight, or disease status?Probably preventableWere therapeutic drug monitoring or other necessary laboratory tests not performed?
Was a drug interaction involved in ADRs?
Was poor compliance involved in ADRs?
Was preventive measure not prescribed/administered to the patients?
Not preventable
If all above criteria not fulfilled

ADR, adverse drug reaction.

Current literature demonstrates that ADRs to glucocorticoids predominantly manifest as immediate hypersensitivity responses and immune-mediated reactions, characterized by mucocutaneous manifestations (rash, urticaria, pruritus), respiratory complications (dyspnea, laryngeal edema, bronchospasm), and hemodynamic disturbances (anaphylactic shock). Pharmacoepidemiologic studies reveal that hydrocortisone and methylprednisolone exhibit the most significant associations with these reactions. Patient cohorts with asthma and organ transplant recipients demonstrate elevated ADR risks, while intravenous administration exhibits a substantially higher ADR incidence compared to oral or intramuscular routes.^2,3,12–15 The potential mechanisms underlying the ADR in this case may involve the following aspects:

In summary, the occurrence of the aforementioned ADR in this patient may be related to the structural characteristics of hydrocortisone injection itself, the use of excipients, the combined use of cefoperazone sodium and sulbactam sodium, failure to dilute according to the concentration specified in the drug instructions, and the patient’s pathophysiological state, all of which collectively contributed to the occurrence of this ADR. Notably, in addition to hydrocortisone injection, allergic reactions to other glucocorticoids have been documented in the literature and case reports.^{15,21,25–27} The underlying mechanisms demonstrate both shared characteristics and individual variations, suggesting possible incomplete cross-allergenicity among different glucocorticoids. ²⁸

However, there exists no documented evidence addressing the primary diagnostic challenge of differentiating hypersensitivity reactions induced by hydrocortisone injection from DLRs, particularly in circumstances where hydrocortisone injections are co-administered with pharmacological agents known to induce DLRs—a critical distinction for informing appropriate clinical management.

In the differential diagnosis between hydrocortisone injection-induced hypersensitivity reactions and DLRs, particular attention must be paid to the following distinguishing characteristics: clinically, while both conditions demonstrate overlapping manifestations, including cutaneous erythema, respiratory distress, hypotension, and tachycardia, critical differentiation lies in dermatological presentation. The key distinguishing points between the two are: patients with DLRs typically do not present with typical rashes or urticaria, and gastrointestinal symptoms (such as nausea and vomiting) are more prominent; whereas in allergic reactions, over 90% of cases manifest cutaneous symptoms such as angioedema, urticaria, and pruritus. ²⁹ This clinical divergence originates from distinct pathophysiological mechanisms: immunoglobulin E (IgE)-mediated type I hypersensitivity underlies drug reactions, whereas disulfiram-like phenomena arise from acetaldehyde accumulation secondary to aldehyde dehydrogenase inhibition, representing a non-immunogenic metabolic disorder. This mechanistic distinction provides theoretical justification for employing in vitro diagnostic modalities, including cutaneous provocation testing and patch testing. ²⁸ Temporally, corticosteroid-related immediate hypersensitivity reactions predominantly manifest within minutes following parenteral administration or inhalation exposure, with topical applications potentially inducing contact urticaria within 20 min. Delayed hypersensitivity reactions to topical corticosteroids typically emerge after hours to days, presenting as eczematous dermatitis requiring confirmatory patch testing. Contrastingly, DLRs demonstrate characteristic temporal patterns, with most cases developing symptoms within 5–60 min post-ethanol exposure, though rare delayed presentations may occur up to 24 h following ingestion. Etiologically, hydrocortisone hypersensitivity represents aberrant immunoreactivity to active pharmaceutical ingredients or excipients, whereas DLRs diagnosis necessitates the satisfaction of two essential criteria: (1) recent pharmacological exposure (⩽7 days) to agents with aldehyde dehydrogenase inhibitory properties; (2) confirmed ethanol contact preceding symptom onset, encompassing dietary ethanol consumption, pharmaceutical ethanol-containing preparations, or cutaneous ethanol-based antiseptic applications. This case meets the core diagnostic criteria for a DLR (recent history of cefoperazone sodium and sulbactam sodium use and ethanol exposure), but also exhibits the typical temporal characteristics of a glucocorticoid allergic reaction, complicating the differential diagnosis between the DLR and the ADR induced by hydrocortisone injection. To clarify the distinction, glucocorticoid skin prick testing or patch testing can be performed to rule out an allergic reaction, while dynamically monitoring the patient’s ethanol exposure history and medication records; if the clinical presentation is predominantly characterized by disulfiram-like features such as flushing, palpitations, and vomiting, and lacks positive immunological test evidence, the diagnosis of a DLR is supported. However, in this case, allergy testing was not performed due to the low incidence of allergic reactions (approximately 0.3%–0.5%^21,22) and the patient’s subsequent death, which precluded follow-up and thereby failed to satisfy laboratory confirmation criteria for an allergic reaction to hydrocortisone injection. Following the discontinuation of hydrocortisone injection and the continuation of cefoperazone-sulbactam therapy, the patient attained hemodynamic stability within 6 h after targeted medical intervention. Furthermore, the patient had previously been treated with cefoperazone-sulbactam as an anti-infective agent before the current hospitalization and reported no history of allergies. Based on the temporal sequence of drug exposure, clinical manifestations, and therapeutic response, this case strongly supports the diagnosis of anaphylactic shock induced by hydrocortisone injection. While as a single-case report with inherent sample size limitations, the external validity of these findings requires further multicenter validation.

Conclusion

This case illustrates that glucocorticoids, although employed in the management of allergic reactions, may themselves induce anaphylactic shock. To enhance the prediction and prevention of such adverse events, we recommend the integration of systematic risk assessment protocols into clinical practice, particularly for high-risk patients—such as patients with immunologically active conditions (e.g., sepsis) or those receiving complex medication regimens. Where appropriate, pre-administration skin testing or in vitro allergenicity screening should be considered to identify susceptible individuals. Strict adherence to established preparation protocols—including appropriate dilution and administration techniques—coupled with enhanced pharmacovigilance measures, can further mitigate the incidence of these reactions.

Supplemental Material