Allergic Reactions: Stages According to Ring and Messmer

Allergic reactions are time-critical emergencies where accurate severity assessment directly determines the therapeutic strategy. The Ring and Messmer classification has established itself as the standard grading system in German-speaking countries and provides you as a clinician or nurse with a structured tool to rapidly assign symptoms to a severity grade and consistently escalate treatment. From an isolated skin finding to cardiac arrest – each stage requires specific interventions that you must master to minimize morbidity and mortality.

Pathophysiological Fundamentals

Allergic reactions in the strict sense (type I reaction according to Gell and Coombs) are based on IgE-mediated degranulation of mast cells and basophilic granulocytes. Upon re-exposure to the allergen, preformed mediators are released within seconds to minutes – primarily histamine, tryptase, and heparin – along with de novo synthesis of leukotrienes, prostaglandins, and platelet-activating factor (PAF).

The clinical consequences result from the effects of these mediators:

• Histamine: Vasodilation, increased permeability, bronchospasm, stimulation of nociceptors (pruritus)
• Leukotrienes (especially LTC4, LTD4): Prolonged bronchospasm, mucosal edema
• PAF: Platelet activation, massive blood pressure drop through vasodilation and capillary leak
• Prostaglandin D2: Vasodilation, bronchospasm

It is important to distinguish between immunologically mediated (IgE-mediated or complement-mediated) and non-immunologically triggered reactions (formerly "anaphylactoid" reactions). The Ring and Messmer classification is deliberately clinically descriptive and applicable regardless of the underlying mechanism – this is what makes it so valuable in acute situations.

The Ring and Messmer Classification

The classification published by Ring and Messmer distinguishes four severity grades of anaphylactic reactions. It is based on the organ systems involved and the degree of hemodynamic compromise. In clinical practice, this classification has prevailed over other grading systems (e.g., the three-tier WAO classification) in German-speaking countries.

Stage I – Skin and Mucosal Reaction

Clinical Presentation:

• Flush, erythema, generalized urticaria
• Pruritus (generalized or localized)
• Angioedema (Quincke's edema), predominantly affecting lips, eyelids, hands
• Rhinoconjunctivitis: sneezing, rhinorrhea, conjunctival injection

In stage I, only the skin and mucous membranes are affected. There are no respiratory or cardiovascular symptoms. The general condition is usually good, and the patient is hemodynamically stable.

Typical pitfall: Generalized urticaria without dyspnea or circulatory compromise is not uncommonly dismissed as trivial. However, it can progress to stage III or IV within minutes. Every generalized skin reaction following allergen exposure therefore requires continuous monitoring and availability of emergency medications.

Stage II – Mild Systemic Reaction

Clinical Presentation:

• All symptoms of stage I, plus:
• Mild respiratory symptoms: onset of dyspnea, mild bronchospasm, stridor
• Mild cardiovascular involvement: tachycardia, mild hypotension (systolic > 90 mmHg)
• Gastrointestinal symptoms: nausea, vomiting, abdominal cramps, diarrhea
• Agitation, anxiety

In stage II, the reaction manifests systemically for the first time. Vital functions are impaired but still compensated. It is crucial that you recognize stage II as a potentially unstable condition that can progress to severe anaphylaxis at any time.

Stage III – Severe Systemic Reaction (Anaphylaxis)

Clinical Presentation:

• Severe bronchospasm with respiratory failure
• Laryngeal edema with inspiratory stridor progressing to airway obstruction
• Shock: pronounced hypotension (systolic < 90 mmHg), tachycardia > 120/min
• Altered consciousness to loss of consciousness
• Cyanosis
• Fecal and/or urinary incontinence possible

Stage III represents an immediately life-threatening situation. The massive capillary leak can lead to distributive shock with a relative volume deficit of up to 35% of circulating blood volume within minutes. Bronchospasm can be so severe that conventional ventilation is barely possible.

Stage IV – Cardiac Arrest

Clinical Presentation:

• Respiratory and cardiac arrest
• Asystole, pulseless electrical activity (PEA), or ventricular fibrillation

Stage IV is the most extreme form of anaphylaxis. Without immediate resuscitation measures and high-dose epinephrine therapy, the outcome is fatal. In the context of AHA guidelines, this represents a cardiac arrest with a reversible cause – anaphylaxis is therefore one of the treatable etiologies within the framework of H's and T's.

Stage-Appropriate Therapy

The treatment of anaphylactic reactions follows a clear escalation scheme. As a general principle: Every anaphylactic reaction requires immediate discontinuation of the allergen source (if identifiable), positioning based on the predominant symptoms, and continuous monitoring.

General Initial Measures (All Stages)

• Stop allergen exposure (e.g., discontinue infusion, remove insect stinger)
• Call for help – consider anesthesia/emergency physician early
• Monitoring: ECG, SpO2, non-invasive blood pressure measurement; aim for invasive pressure monitoring at stage ≥ III
• Large-bore IV access (at least 2× ≥ 18 G at stage ≥ II)
• Positioning: Upright position for dyspnea, Trendelenburg position for hypotension, recovery position for unconscious patients with preserved spontaneous breathing

Therapy Stage I

• H1 antihistamine: Dimetindene (Fenistil®) 0.1 mg/kg IV (max. 8 mg) or clemastine 2–4 mg IV
• H2 antihistamine: Ranitidine 50 mg IV (the combination of H1 and H2 blockade potentiates the antihistaminergic effect)
• Glucocorticoids: Prednisolone 1–2 mg/kg IV or methylprednisolone 1–2 mg/kg IV (onset of action not until 30–60 minutes – serves to prevent protracted and biphasic reactions)
• Observation: At least 6–8 hours, as biphasic reactions can occur in up to 20% of cases

Therapy Stage II

All measures from stage I, plus:

• Nebulized epinephrine: For laryngeal edema/stridor, epinephrine 3–5 mg undiluted via nebulizer
• Bronchodilation: Salbutamol 2–4 puffs via metered-dose inhaler or 2.5–5 mg via nebulizer for bronchospasm
• Volume therapy: Crystalloid solution (balanced electrolyte solution) 500–1000 ml as a bolus for hypotension
• Epinephrine IM: With clinical progression or inadequate response, administer epinephrine 0.3–0.5 mg intramuscularly into the lateral thigh (vastus lateralis) early. The IM route is the preferred route of administration when IV access is not available

Clinical Decision Point: The threshold for epinephrine administration should be low in stage II. Waiting for further deterioration is a common and potentially fatal error. The AHA guidelines clearly emphasize: Epinephrine is the first-line medication for anaphylaxis, not antihistamines or glucocorticoids.

Therapy Stage III

All measures from stages I and II, plus:

• Epinephrine IV: 0.01–0.05 mg (10–50 µg) slowly titrated intravenously. Practical approach: 1 mg epinephrine in 100 ml normal saline (concentration 10 µg/ml), then administer 1–5 ml increments based on response. Alternatively: 0.1 mg boluses (1 ml of a 1:10,000 dilution)
• Epinephrine infusion: For persistent hypotension, 0.05–1 µg/kg/min as a continuous infusion
• Aggressive volume resuscitation: Crystalloids 20–40 ml/kg, repeated as necessary. For refractory shock, consider colloid solutions (caution: hydroxyethyl starch can itself trigger anaphylactic reactions)
• Airway management: Early endotracheal intubation for laryngeal edema before swelling makes conventional intubation impossible. Consider a surgical airway (emergency cricothyrotomy) if laryngoscopic intubation fails
• Oxygen: High-flow (15 L/min via reservoir mask, target SpO2 > 94%)
• Vasopressors for epinephrine-refractory cases: Norepinephrine 0.1–1 µg/kg/min or vasopressin 1–2 IU as a bolus, then 0.01–0.04 IU/min
• Glucagon: For patients on beta-blocker therapy who do not respond to epinephrine: glucagon 1–5 mg IV as a bolus, then 5–15 µg/min as an infusion. Glucagon acts via a catecholamine-independent mechanism with positive inotropic and chronotropic effects

Therapy Stage IV

• Immediate CPR according to current AHA guidelines (C-A-B sequence)
• Epinephrine: 1 mg IV every 3–5 minutes (standard resuscitation dose)
• Massive volume resuscitation: Aggressively administer fluids in parallel with CPR
• Defibrillation: For ventricular fibrillation or pulseless ventricular tachycardia according to standard ALS algorithm
• Treat reversible cause: Anaphylaxis as the cause of cardiac arrest must be communicated to the entire team so that specific therapy (epinephrine, volume) is not delayed
• Prolonged resuscitation: In anaphylaxis-induced cardiac arrest, the prognosis is generally good if the cause is treated promptly. A longer resuscitation duration than for other causes is justifiable

Special Considerations and Clinical Pitfalls

Biphasic Reactions

In up to 20% of cases, symptoms recur after initial response to therapy – typically 4–12 hours after the initial event, and in rare cases up to 72 hours later. Glucocorticoids are specifically used for prophylaxis of biphasic reactions, although the evidence for this is limited. Every patient with anaphylaxis ≥ stage II should be monitored for at least 12–24 hours.

Beta-Blockers and ACE Inhibitors

Patients on beta-blocker therapy may respond paradoxically or with diminished effect to epinephrine. Competitive blockade of β-receptors limits the bronchodilatory and positive inotropic effects. Glucagon is the reserve medication of choice in this situation. ACE inhibitors increase the risk of severe anaphylactic reactions because they inhibit bradykinin degradation.

Perioperative Anaphylaxis

In the operating room setting, diagnosis is more challenging because skin symptoms may be hidden under surgical drapes, and hypotension and bronchospasm have a broad differential diagnosis. Common triggers include neuromuscular blocking agents (especially succinylcholine, rocuronium), antibiotics, latex, and dyes. Serum tryptase measurement (sampling: 30–120 minutes after symptom onset, second sample at 24 hours as a baseline value) is mandatory for retrospective diagnostic confirmation.

Differential Diagnoses

Not every acute circulatory reaction is anaphylaxis. Important differential diagnoses include:

• Vasovagal syncope: Bradycardia (not tachycardia!), no urticaria, rapid response to supine positioning
• Hereditary angioedema (HAE): No urticaria, no pruritus, does not respond to epinephrine/antihistamines
• Bronchial asthma: Isolated bronchospasm without skin symptoms or circulatory involvement
• Mastocytosis: Recurrent anaphylaxis-like episodes, elevated baseline tryptase
• Pheochromocytoma crisis: Hypertension rather than hypotension
• Panic attack: Tachycardia and dyspnea without objectifiable findings

Summary: Stage-Appropriate Management at a Glance

Stage	Key Symptoms	Key Therapy
I	Urticaria, flush, angioedema	Antihistamines (H1+H2), glucocorticoids
II	+ Dyspnea, tachycardia, GI symptoms	Epinephrine IM, bronchodilators, volume
III	Shock, severe bronchospasm, altered consciousness	Epinephrine IV titrated, aggressive volume resuscitation, airway management
IV	Cardiac arrest	CPR, epinephrine 1 mg IV every 3–5 min, defibrillation for shockable rhythm

The key message: Epinephrine saves lives. Antihistamines and glucocorticoids are adjunctive therapy – they do not replace epinephrine. Underdosing or delayed administration of epinephrine is the most common therapy-related error in fatal anaphylaxis cases.

Practical Training

Stage-appropriate therapy of anaphylactic reactions requires not only theoretical knowledge but above all practical routine: rapid recognition of severity grades, safe preparation and dosing of epinephrine, and structured team communication under time pressure. In the emergency training courses at Simulation Tirol, you train exactly these scenarios in realistic simulations – including escalation from mild skin findings to cardiac arrest. This is how you build the confidence and competence that makes the difference in a real emergency.