Histamine2 receptor blocker in the treatment of protamine related anaphylactoid reactions: two case reports

Two case reports are described of acute anaphylactoid reactions following the administration of protamine to reverse the anticoagulation effect of heparin in patients undergoing coronary artery bypass graft surgery. The administration of cimetidine seemed to reverse the anaphylactoid reaction after conventional treatment with epinephrine, H1 receptor blocker, and steroids had failed. We recommend that H2 receptor blockade be included with other drugs in the treatment of anaphylactoid reactions following protamine, and possibly after anaphylactoid reactions associated with other substances.     

Role of cytokines in anaphylactoid reaction with marked eosinophilia in a hemodialysis patient

Hemodialysis is rarely terminated by events associated with anticoagulants. A 69-year-old woman on hemodialysis due to chronic renal failure (CRF) developed an anaphylactoid reaction with hypereosinophilia. On the basis of clinical and laboratory findings, we concluded that the causes of this anaphylactoid reaction were low-molecular-weight heparin and heparin. Our patient also showed high levels of soluble interleukin-2 receptor (sIL-2R) and eosinophil cationic protein (ECP), which decreased after the cessation of hemo-dialysis. To date, there has been no report of high levels of cytokines induced by hemodialysis-associated anaphylactoid reaction. In this report, we discuss the mechanism underlying drug-induced anaphylactoid reaction, particularly that involving eosinophilia and cytokines.     

Extracorporal therapy with AN69 membranes in combination with ACE inhibition causing severe anaphylactoid reactions: still a current problem?

The negatively charged membrane AN69 is known to evoke anaphylactoid reactions both without and with concomitant ACE inhibition. Underlying reasons are mainly the induction of bradykinin release due to the negatively charged membrane and the reduced degradation of bradykinin due to ACE inhibition. This complication has been reported repeatedly, but anaphylactoid reactions still occur in clinical practice. We recently had to treat two patients who suffered anaphylactoid reactions during extracorporal therapy with an AN69 membrane and simultaneous ACE inhibition. The first incident occurred in a patient on hemodialysis, the second was in a patient on continuous venovenous hemofiltration. An anaphylactoid reaction induced by an AN69 membrane during continuous, extracorporal treatment in combination with ACE inhibition has not been reported so far. Our report intends to serve as a reminder that the potentially lethal combination of AN69 membranes with ACE inhibitor treatment should be avoided.     

Complications caused by protamine. 2. Therapy and prevention

Treatment of reactions. The treatment of reactions to protamine is still symptomatic. Hypotension resulting from systemic vasodilation (anaphylactoid reaction) is treated by volume infusion, and alpha-stimulating catecholamines may be necessary. The combination of increased right ventricular afterload and systemic hypotension (anaphylactic/anaphylactoid reaction) requires primarily the improvement of coronary perfusion pressure and, thus, of O2 delivery to the right ventricular myocardium. To this end, catecholamines with alpha-stimulating action should be administered. Nitroglycerin is indicated when pulmonary hypertension persists in the presence of essentially normal systemic pressure. In the acute situation, steroids and antihistamines have no beneficial effect. Prevention of protamine reactions. For prevention of systemic hypotension by vasodilatation, protamine should be infused very slowly and not during hypovolemia. General prophylaxis using H1/H2 antagonists is not justified. Reliable preoperative identification of patients who would suffer an anaphylactic/anaphylactoid reaction to protamine, for example by skin tests or by measuring specific anti-protamine IgE or IgG antibodies, is not possible. This prevents individual prophylaxis in risk patients. In view of the low incidence of severe protamine reactions and the lack of better alternatives to the heparin/protamine regimen, general prevention is not indicated. For patients who are potentially at risk (insulin-dependent diabetics, prior protamine exposure), the side-effects of preventive measures must be weighed against their benefits. Only known sensitivity to protamine justifies certain preventive actions. In vascular surgery prostacyclin can be used instead of heparin/protamine or can be withheld (fading out of heparin action). Administration of steroids and/or antihistamines should be avoided. In cardiac surgery the use of hexadimethrine (if available) or total avoidance of protamine is paramount. Corticosteroids may be considered. Aortic administration of protamine and anticoagulation with ancrod are not recommended. The most promising compounds for rpharmacologic prevention of anaphylactic/anaphylactoid reactions in the future are thromboxane receptor antagonists.     

Anaphylactoid reactions to contrast media which occurred during cholecystectomy and subsequent disseminated intravascular coagulation--a case report]

A 67-year-old woman without any history of allergic episode developed severe hypotension (40 mmHg) without skin rash one minute after the administration of amidotrizoic acid for intraoperative cholangiography during thoracic epidural and light general anesthesia. Although ephedrine, methoxamine, dopamine and norepinephrine were administered, severe hypotension persisted for three hours and epinephrine was only effective. Marked elevations of serum levels of histamine, leukotriene D4 and leukotriene E4 were noted after the episode, suggesting the occurrence of the anaphylactoid reaction to amidotrizoic acid and the activation of the immunological complement system. After the recovery from the anaphylactoid reaction, the patient developed disseminated intravascular coagulation (DIC) and severe bleeding around the wound for which reoperation was needed. It is necessary to consider some prophylactic treatments against DIC when severe anaphylactoid reaction occurred.     

Anaphylactoid Reaction to Dextran—A Report of 133 Cases

From 1968 to 1975, the Swedish Adverse Drug Reaction Committee received 113 reports on anaphylactoid reaction to dextran 70, and 20 reports on the same reaction to dextran 40. For 1975, this would equal a reported incidence of anaphylactoid reaction to dextran 70 of 1:2,500. The median age of patients reacting to dextran 70 was 63 years. Median age increased with increasing severity of the anaphylactoid reaction: from 48 years in patients who died. Symptoms were noticed within 10 min of the start of the infusion, or before 100 ml had been infused in 96 patients (85%) with an anaphylactoid reaction to dextran 70. There was a tendency for severe reactions to be observed earlier than milder ones. Symptoms also tended to be observed earlier in conscious than in unconscious patients. Reactions reported to have occurred in unconscious patients tended to be more severe than those in conscious patients. Patients with anaphylactoid reaction to dextran 40 did not differ from those with reactions to dextran 70 with regard to age, severity of the reaction or time before onset of symptoms. There was one death in this group.     

Anaphylactoid Reaction to Etomidate: Report of a Case

We report an anaphylactoid reaction to etomidate twice in a 60-year-old male with coronary artery disease and peripheral vascular disease. Following the first anaphylactoid reaction, the patient developed myocardial infarction. In addition, the patient’s blood was moderately positive for latex antibodies, which made the differential diagnosis difficult. We concluded that the patient had anaphylactoid reaction to etomidate due to the temporal relationship to induction with the drug. The patient did not manifest similar reaction to other induction drugs used for other surgeries. The patient recovered from both incidents of anaphylactoid reaction to etomidate following intravenous administration of epinephrine and fluids.     

Anaphylactoid reactions to Dextran 40 and 70: reports to the United States Food and Drug Administration, 1969 to 2004

BACKGROUND: Clinical dextrans, such as Dextran 40 and Dextran 70, are associated with anaphylactoid reactions caused by dextran-reactive immunoglobulin G antibodies. When infused immediately before clinical dextrans, dextran 1 significantly reduces the incidence of severe anaphylactoid reactions. The objective of the study was to describe the frequency and characteristics of reports submitted to the United States Food and Drug Administration (FDA) for anaphylaxis or anaphylactoid events after clinical dextran administration. METHODS: We searched the FDA's Adverse Event Reporting System for reports associated with a clinical dextran and describing anaphylaxis/anaphylactoid reactions. Our case definition for a probable anaphylaxis/anaphylactoid event required signs or symptoms from at least two body systems, with at least one sign or symptom being hypotension, vasodilation, or respiratory difficulty, and onset within 60 minutes. Other reports were considered possible cases if the reporter specifically described the reaction as anaphylaxis or an anaphylactoid reaction. Premier RxMarket Advisor provided estimates of total US hospitalizations with clinical dextran or dextran 1 administration from 2000 to 2004, based on discharge billing data from a sample of US hospitals. The IMS National Sales Perspective provided estimates of total doses of dextrans sold in the United States from 1999 to 2004, based on volumes of dextrans sold in a sample of retail and nonretail outlets. RESULTS: The FDA received 366 clinical dextran adverse event reports from 1969 to 2004, of which 90 (24.6%) were anaphylaxis/anaphylactoid events. The ratio of hospitalizations where clinical dextran was administered to hospitalizations where dextran 1 was administered was 28.4:1. The expected ratio would be 1:1 if all clinical dextran patients had received dextran 1 pretreatment. The ratio of clinical dextran doses sold to dextran 1 doses sold in the United States was 38.6:1. CONCLUSIONS: A high proportion of adverse event reports for clinical dextrans described anaphylaxis or anaphylactoid reactions. Hospital discharge and product sales data suggest that dextran 1 has not been used consistently before clinical dextran administration in recent years. To reduce the risk of anaphylactoid reactions, physicians should consider routine administration of dextran 1 before the infusion of a clinical dextran.     

Anaphylaxis during anaesthesia: diagnosis and treatment

Anaphylactic and anaphylactoid reactions during anaesthesia are rare, but potentially life-threatening allergic events. The worst manifestations are cardiovascular collapse, bronchospasm and laryngeal oedema. Anaphylactic and anaphylactoid reactions are clinically indistinguishable. The most incriminated agents are neuromuscular blocking drugs and latex. Treatment consists of instant interruption of contact with possible antigens, 100% oxygen, intubation, adrenaline and volume expansion. The incidence of cross-reactivity between neuromuscular blocking drugs is high. Further investigation of a suspected anaphylactic reaction is mandatory to find the responsible drug and to make future anaesthesia safe. Diagnosis is made with intraoperative tests (serum histamine and mast cell tryptase) and postoperative tests (skin tests and RASTs for specific IgE antibodies).     

Anaphylactic and anaphylactoid reactions

Anaphylactic and anaphylactoid reactions are an important area of anaesthesia and critical care medicine. Clinically they may be indistinguishable, and the immediate management for both conditions is identical. Immediate recognition and appropriate management are vital to prevent death. The aims of testing are to confirm an anaphylactic or anaphylactoid reaction, to identify the causative agent and to test for cross-reactivity with other related agents. Testing is complex and should be supervised by a clinical immunologist.     

Acute respiratory distress during Caesarean section under spinal anaesthesia A probable case of anaphylactoid reaction to Syntocinon

A case of life-threatening respiratory distress during a Caesarean section under spinal anaesthesia is reported. Possible causes of the event including anaphylactoid reactions and the methods of their diagnosis are discussed. The most likely cause of the episode was felt to be an anaphylactoid reaction to Syntocinon.     

Ethylene Oxide (ETO) as a Major Cause of Anaphylactoid Reactions in Dialysis (A review)

Ethylene oxide (ETO), an alkylating compound of high chemical reactivity, is widely used for gas sterilization, but recently serious ETO side reactions have been recognized. With chronic ETO exposure, increased spontaneous abortion, sister chromatid exchange, and leukemia are observed. After medical use of ETO outside nephrology, contact dermatitis, cardiopulmonary shock (during cardiopulmonary surgery), allergic local reactions to ETO sterilized lenses, and anaphylactoid reactions to ETO sterilized catheters have been described. In numerous dialysis patients widespread hypersensitivity to ETO has been documented by skin prick test and ETO radioallergosorbent test (RAST). Furthermore an anaphylactoid "first-use reaction" was described in dialyzed patients, most of whom were using hollow-fiber dialyzers. After long discussions whether complement activation versus hypersensitivity is the cause of such acute anaphylactoid reactions, more recent studies using either ETO RAST or basophil degranulation tests implicate ETO hypersensitivity as their major cause. The high prevalence of sensitization to ETO and the frequency, unpredictability, and potential danger of anaphylactoid reactions to ETO lead to the conclusion that ETO sterilization of dialyzers should be discontinued, since alternative modalities of sterilization are currently available.     

Safety of intra-articular hyaluronates for pain associated with osteoarthritis of the knee

Sodium hyaluronate (Hyalgan, and Supartz) and hylan G-F 20 (Synvisc) are hyaluronans (HA) injected intra-articularly for pain relief in osteoarthritis of the knee. Each product has demonstrated a very favorable safety profile in clinical trials and practice. The most common adverse event associated with their use is mild injection site pain and swelling. Rare incidences of pseudogout and anaphylactoid reactions have been reported to be associated with their use. Occasionally, pseudosepsis, also known as a severe acute inflammatory reaction (SAIR) syndrome, has been reported to be associated with these products. Clinical and postmarketing data indicate that HA therapy is a safe treatment for osteoarthritis of the knee.     

Réaction anaphylactoide singulière après chlorure de succinyl-choline chez un enfant de 21 mois

An anaphylactoid reaction occurring after the intravenous administration of succinylcholine in a 21-month-old child is reported. The clinical manifestations and signs were limited to the upper airways and eyelids. The child was not known to be allergic or atopic. The IgE level was normal. The search for specific anti-choline IgE antibodies was negative. The skin tests were strongly positive for succinylcholine. The physiopathological and immunoallergic differences between anaphylaxis and anaphylactoid reaction are briefly discussed.     

Anaphylactoid reactions after cisatracurium administration in six patients.

IMPLICATIONS: We report six cases of anaphylactoid reaction after the administration of the muscle relaxant cisatracurium. They include two first-time documented anaphylactoid reactions after a precurarising dose. These incidents challenge existing views of a substantially reduced anaphylactoid potential of cisatracurium relative to other muscle relaxants.     

Life-threatening anaphylactoid reaction following etomidate

In a patient scheduled for coronary artery bypass grafting induction of anaesthesia resulted in a life-threatening anaphylactoid reaction with development of an erythema of the neck. Severity and duration of hypotension and tachycardia were such as to require intensive management and postponement of surgery. Skin tests ruled out any other cause except etomidate. Hence for definite surgery exactly the same induction manoeuvre was chosen, but etomidate was omitted. Anaesthesia and surgery proceeded completely uneventfully. There can be no doubt that this anaphylactoid reaction (grade III according to the classification proposed by Lorenz and Doenicke) was caused by etomidate.     

Management of acute anaphylactoid reactions

It must be emphasized that successful treatment of a severe anaphylactoid reaction requires rapid diagnosis and initiation of the resuscitation ABC. Intravenous volume infusion and epinephrine are the mainstays of treatment, and antihistamines are useful. Bronchospasm and persistent hypotension will require specific measures, and the overall intensity of treatment needs to be frequently and critically assessed. Identification of the offending drug and appropriate patient follow-up are essential sequelae of successful resuscitation.     

Anaphylaxis following administration of intravenous methylprednisolone sodium succinate in a renal transplant recipient

Methylprednisolone sodium succinate (MPS) is widely used in the management of renal transplantation. Of interest is the rare occurrence of anaphylaxis and anaphylactoid reaction to MPS. We report on a patient who developed anaphylaxis following the intravenous administration of MPS during a renal transplant operation. Intracutaneous testing was carried out with MPS and a strong positive reaction was observed. Histamine and tryptase concentrations were high after the anaphylactic reaction. Including the present case, there have been 13 reports of anaphylactic or anaphylactoid reactions to MPS, occurring in renal transplant recipients. Clinicians should be aware of the potential risk of MPS administration. If transplant patients undergo skin testing against MPS prior to transplant, they may benefit from an alternative medication with other corticosteroids. To use MPS without severe adverse reactions, lower administration rates and dosages are very important.     

ANAPHYLACTOID RESPONSE TO THIOPENTONE

A case is reported of anaphylactoid response to thiopentone,used for the induction of anaesthesia for cystoscopy in a 56-year-oldwoman. The dose precipitating this reaction was only 50 mg andthe patient had no previous history of any allergic tendency.A full recovery was made, though gastrointestinal disturbancespersisted for several days. The treatment, differential diagnosis,investigations and recommendations for subsequent anaestheticmanagement are discussed. ^*Now at Edgware General Hospital, Edgware,Middlesex. 1     

Complications caused by protamine. 1: Pharmacology and pathophysiology

Protamine is a strongly alkaline polypeptide with a molecular weight of about 4500. Protamine solutions contain paraben compounds as antimicrobial agents. Rapid neutralization of heparin by protamine may cause an anaphylactoid reaction characterized by a non-immunogenic histamine release and by unknown mediators mechanisms. This response is associated with systemic peripheral vasodilation resulting in slight to moderate hypotension. Weak negative inotropic effects by mechanisms different from the reduction of ionized calcium concentrations may also contribute to systemic hypotension. Apart from these mostly slight reactions, severe reactions may occur with life-threatening systemic hypotension, bronchospasm and, in rare cases, death. They are caused by anaphylactic/anaphylactoid reactions resulting in catastrophic pulmonary vasoconstriction which induces right and eventually global ventricular failure. Sensitization to protamine (anaphylactic) and anaphylactoid reactions are the underlying mechanisms. The majority of anaphylactic/anaphylactoid reactions are associated with complement activation and the release of anaphylatoxins C3a and C5a. These activate the cyclo-oxygenase pathway of the arachidonic acid metabolism in yet unidentified cells, probably within the lung. As a result, thromboxane and prostaglandins are released. Thromboxane is the pivotal mediator responsible for the pulmonary vasoconstriction and, presumably, also for the bronchospasm during protamine reactions. The pronounced activation of polymorphonuclear leukocytes and the decrease in platelet counts may reflect a mere epiphenomenon. The degree of right ventricular afterload increase at which systemic hypotension requiring immediate therapy would occur depends mainly on the contractile state of the heart. Potential risk patients for severe protamine reactions are depot insulin-dependent diabetics and patients with prior exposure to protamine.