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Original submitted manuscript 990542 – compare to final published version and reviews Copyright American College of Emergency Physicians Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonist Abstract Study objective: Although the addition of H2 blockers to H1 antagonists have been promoted for use in anaphylaxis, there have been no large studies establishing the advantage of this approach in treating acute allergic syndromes. In this study we tested the hypothesis that combined H1 and H2 blockage results in improved outcomes in patients treated for acute allergic syndromes compared to treatment with H1 blockade alone. Methods: In a randomized, double-blind, placebo controlled trial, 91 adult patients with acute allergic syndromes were treated with either diphenhydramine (50 mg) and saline (control group) or with diphenhydramine (50 mg) and ranitidine (50 mg)(active group). These patients were treated by parenteral administration. Patients were recruited from an emergency department at an urban academic medical center. The primary endpoints were resolution of urticaria, angioedema, or erythema at 2 hours time after protocol treatment. Areas of cutaneous involvement, heart rates, blood pressure, respiratory findings, and symptom scores were also assessed at baseline, I hours, and 2 hours. 1 Results: There were significantly more patients without urticaria at 2 hours time in patients in the active group compared to the control group. Both groups had similar proportions of urticaria at baseline. Logistic regression models to predict resolution of urticaria which accounted for baseline urticarial involvement showed odds ratios in favor of the active group treatment. Similar findings were observed when the absence of both urticaria and angioedema was considered as the dependent variable. There was not a significant difference between the 2 groups with regards to the absence of erythema or angioedema (irrespective of urticaria presence) at 2 hours. Blood pressure, and symptoms did not show differences between the 2 groups over time. Heart rates decreased during the first hour to a greater extent in the active treatment group compared to the placebo group. Consistent with this observation, multivariate analysis showed that, after adjusting for significant covariates, there was a significant effect of treatment over time on heart rates. Conclusion: These data show that adding H2 blockers to H1 antagonists results in additional improvement of certain clinical outcomes for patients presenting with acute allergic syndromes. This findings favor the recommendation for using combined H1 and H2 anti-histamines in acute allergic syndromes. 2 Introduction: Although pretreatment with combined H1 and H2 blockade has been shown to have advantages over H1 blockade alone in preventing allergic reactions (1-5) and in diminishing certain manifestations associated with parenteral histamine infusion(6), there have been only one small study (7) examining outcomes in treating patients with ongoing allergic reactions. Indeed, since allergic reactions may be associated with the elevation of mediators other than histamine, it is conceivable that merely blocking more histamine receptors with H2 antagonists would not result in clinical improvement due to a relatively smaller contribution of histamine to the manifestations in these patients. Mast cell or basophil release of histamine may result from specific IgE directed towards allergens. Alternatively non-IgE stimuli can stimulate histamine release resulting in identical clinical manifestations. Because mast cell or basophil release cannot be readily determined in the acute setting, most allergic reactions presenting to the emergency department are diagnosed on physical signs and symptoms in the setting of a consistent history. Histamine release can be varied in terms of the presenting physical signs. Cutaneous signs such as urticaria and angioedema predominate. However, flushing alone or the complete absence of cutaneous signs may occur (5). Given the heterogeneity and of these signs (some of which are highly nonspecific for histamine release), it is likely that allergic syndromes diagnosed on clinical grounds may misclassify patients in terms of actual histamine release associated manifestations. Anti-histamine administration has constituted one of the mainstays in treating acute allergic syndromes, and due to the relative safety of H1 antagonists, this approach to non-critically ill patients is reasonable. Patients who may not have histamine release may still benefit symptomatically from anti- 3 histaminic therapy. Some patients have more allergic symptoms, such as those with anaphylaxis, or they may have recurrence of presenting manifestations after initial H1 antagonist therapy. In these patients, the question of additional anti-allergic treatments is especially pertinent. The safety profile of H2 antagonists is excellent, and it is reasonable to consider the use of this agent not only in more severe cases but also for the purposes of expediting clinical improvement in the emergency department setting. However the additional benefit of H2 antagonists when given with H1 antagonists has never been examined in emergency settings in a large head to head controlled study. For this reason, we decided to determine whether combined H1 and H2 blockade treatment results in improved outcomes in patients presenting with acute allergic syndromes. We used a rather broad definition of allergic syndromes in order to approximate real life emergency department approaches to patients with various symptoms and signs. 4 Methods: Adult patients (>18 years old) were considered for recruitment from the Emergency Department if they the following syndromes following an ingested food or ingested, inhaled, or injected drug or after contact with latex acute urticaria, acute angioedema, acute unexplained stridor, and acute pruritic rash. These manifestations should have been present for no greater than 12 hours from the time of alleged allergen exposure. Pregnant patients were excluded. Recruited patients were randomized to treatment with either diphenhvdramine 50 mg and ranitidine 50 mg (active treatment group) or diphenhydramine 50 mg and normal saline(control treatment group), in a convenience sample based on study physician scheduling(representing approximately 1/3 of all available attending physician time slots). Each treatment designation was placed in sealed, opaque envelopes stored in a locked cabinet. A staff member uninvolved with the patient’s care then drew into a syringe either 50 mg of raniditine solution or an equal volume of normal saline based on a random number assignment list. Immediately after an intravenous injection of 50 mg diphenhydramine was given, the unmarked syringe containing either saline or ranitidine was then given to the study physician, unaware of its contents. The physician then administered the contents by intravenous injection to the subject. Supplemental medications such as epinephrine, corticosteroids, bronchodilators, and additional doses of antihistamines as well as intravenous fluids were administered at the discretion of the study physicians. Patients also received supplemental oxygen and intravenous fluids at the discretion of the study physicians. Patients had heart rate, blood pressure, physical 5 findings, side effects, and symptoms assessed at baseline, 1 hour, and 2 hours relative to experimental treatment. Baseline temperatures were also recorded. Physical findings that were recorded included the presence and extent of urticaria and erthema, and the presence of angioedema, wheezing, stridor, abdominal distention or tenderness, and abdominal hyperactive bowel sounds. Historical features, physical findings (including heart rates, blood pressure and respiratory rates), and treatments were recorded on a study specific data input form. The extent of involvement with urticaria and erythema was assessed using a check off cartoon of body areas (similar to that used to assess burn area extent) printed on the data input sheet. Symptom scores were assessed at baseline, 1 hour, and 2 hours, using a preprinted form with none, mild, moderate, and severe check off categories. Since no prior studies existed to determine an estimate of effect size (in terms of resolution of urticaria and angioedema), an arbitrary sample size of 100 was used The primary variables of interest were resolution of urticaria, and angioedema at 2 hours time. Changes in heart rates, respiratory rates, blood pressure, and symptoms were also examined. The final disposition of the patient was also noted (admission, discharge, or leaving against medical advice). The study was approved by the Institutional Review Board and informed written consent was obtained from all patients. The resolution of urticaria, erythema, and angioedema was assessed using bivariate chi squared analysis and by multivariate logistic regression. Potential confounding factors and pertinent covariates were included in some multivariate models. 6 The changes in heart rates, blood pressure, respiratory rates, and symptoms were analyzed by repeated measured analysis of variance or covariance (8), with the time by group interaction being the analysis of primary interest (9). The Greenhouse-Geisser adjustment for non-sphericity was applied (10). Heart rates were normalized by logarithmic transformation for analysis. Analyses were performed using the JMPTM software package (Version 3.2)(SAS Institute, Cary NC). Certain statistical values are expressed with 95% confidence intervals. 7 Results: Among 100 patients recruited for the study, one was inadvertently studied twice. Only the first study for this patient was used. Eight other patients withdrew after the study medication had been obtained but before administration was given. Nine patients received experimental treatment but upon chart review had allergic manifestations for greater than 12 hours (2 patients each at 15 hours and 48 hours, 1 each at 19, 40, 58, 69, and 120 hours) . These patients were included in the analysis on an intention-to-treat principle. The patients recruited over a 12 month period between May 1998 and April 1999. There was no predominance of weekend or particular shift recruitment. The baseline characteristics of these patients are shown in part in Table I. No significant baseline differences were observed between the 2 groups. No patients had fever (T>38.8 C). Two patients had pretreatment blood pressures less than 90/60 (both in the raniditine group). Respiratory and gastrointestinal signs were present in many patients (Tables I and III). Wheezing in 12 patients was observed in the absence of a history of asthma. Non-atopic comorbid conditions were reported by 6 and 10 patients in the placebo and ranitidine groups respectively. These included hypertension (3), hypercholesterolemia (3), HIV infection (2), diabetes mellitus (2), thyroid disorders (2), substance abuse (1), cardiac disease(3), gastroesophageal reflux (l), seizures(1), and psychiatric disorders (2). Three patients were taking oral birth control pills. Ten patients had taken prior antihistamines within 36 hours of the study (4 in the raniditine group and 6 in the placebo group). There was no predominance of any particular comorbiditv in 8 either of the 2 treatment groups. There was a high incidence of reported asthma and nonasthmatic atopic conditions in both groups (Table I). More than half of the patients (n=58) had a suspected food allergic reaction. Of these patients, shellfish was implicated in 14, and fish, fruit, and vegetables were implicated in 9 patients each. Nut or peanut allergic reactions were suspected in 5 patients. Allergic reactions due to drug administration was suspected in 28 patients. Of these, anti-infectives were suspected in 11, non-steroidal anti-inflammatory drugs in 8, and psychiatric/neurologic drugs in 4. The causative agent in 5 patients was uncertain as to whether food or medication related to the allergic syndrome. Additional treatments were given to the study patients as detailed in Table II. There was no difference in the proportion of patients who received intravenous fluids between the 2 groups (data not shown). There were significantly more patients in the placebo group who received extra antihistamines. Seven patients were admitted to the hospital (3-ranitidine, 4-placebo). No adverse effects from the protocol treatment were observed. The proportions of patients with urticaria at baseline were similar between the 2 groups. For those patients with baseline urticaria, the numbers of areas involved with urticaria was not significantly different between the 2 groups. The number of patients with urticaria decreased somewhat more in the ranitidine group at 1 hour. The proportion of patients without urticaria was significantly greater in the ranitidine group (91.7%) at 2 hours compared to the placebo group (73.8%)(p =0.2). Furthermore the number of areas 9 involved with urticaria at 2 hours was significantly less in the raniditine group compared to the placebo group (Wilcoxon sign rank test, p= 0.2). In multivariate modeling, the number of areas involved with urticaria at baseline and treatment with raniditine or saline were used as predictors of urticaria presence at 2 these patients, shellfish was implicated in 14, and fish, fruit, and vegetables were implicated in 9 patients each. Nut or peanut allergic reactions were suspected in 5 patients. Allergic reactions due to drug administration was suspected in 28 patients. Of these, anti-infectives were suspected in 11, non-steroidal anti-inflammatory drugs in 8, and psychiatric/neurologic drugs in 4. The causative agent in 5 patients was uncertain as to whether food or medication related to the allergic syndrome. Additional treatments were given to the study patients as detailed in Table II. There was no difference in the proportion of patients who received intravenous fluids between the 2 groups (data not shown). There were significantly more patients in the placebo group who received extra antihistamines. Seven patients were admitted to the hospital (3ranitidine, 4-placebo). No adverse effects from the protocol treatment were observed. The proportions of patients with urticaria at baseline were similar between the 2 groups. For those patients with baseline urticaria, the numbers of areas involved with urticaria was not significantly different between the 2 groups. The number of patients with urticaria decreased somewhat more in the ranitidine group at 1 hour. The proportion of patients without urticaria was significantly greater in the ranitidine group (91.7%) at 2 hours compared to the placebo group (73.8%) (p=0.2). Furthermore the number of areas 10 involved with urticaria at 2 hours was significantly less in the raniditine group compared to the placebo group (Wilcoxon sign rank test, pO.02). In multivariate modeling, the number of areas involved with urticaria at baseline and treatment with raniditine or saline were used as predictors of urticaria presence at 2 proportion of baseline angioedema cases in the placebo group (Table III). Laryngoedema present at baseline resolved by 2 hours in 4/4 raniditine patients and 2/5 placebo patients. There was a significant decrease in heart rates over time in both groups (Table III). A greater decrease in heart rates in the ranitidine group was noted from baseline to the first hour and 1 hour heart rates were lower in the active group compared to the placebo group. Analysis of covariance was used further examine heart rate changes associated with treatment. A significant correlation was observed between the extent of either baseline erythema and baseline heart rates (Spearman rho test, p<O.OO1). When baseline erythema extent and epinephrine use were used as covariates (both showing highly significant covariate effects, p<=0.007 there was a significant treatment by time effect on heart (p=0.05, baseline contrasted with subsequent values). Post-hoc analysis contrasting the 1 hour heart rates with or without adjustment for covariates showed a significant (p<0.05) difference between the 2 groups with lower values for the ranitidine group, consistent with an relatively more rapid initial decline in heart rates for the raniditine group. Patients reported a various symptoms within the first hour of their reaction. Itching (n=77) and swelling (n=61) predominated. Feeling flushed and throat tightness 11 were also commonly reported (49 and 40 patients respectively). Nausea, dizziness, head pressure, and palpitations were reported in 30,27, 22, and 20 patients respectively. A metallic taste, headache, tongue swelling and blurry vision were reported by 15,14,11 and 9 patients respectively. Symptom scores did not show differences over time between the 2 groups. 12 Discussion: This study demonstrates the additional benefit of adding H2 blockers to H1 antihistamine treatment in on-going allergic reactions. This finding is important since all but one previous study have shown only a pretreatment effect for H2 blockade in allergic reactions. Kaliner et al (6) had demonstrated blunting some of infused histamine’s effects on normal volunteers using combined H1 and H2 blockade. This isolated mediator model, probably does not truly simulate in-vivo immediate hypersensitivity reactions, where multiple mediators are probably released. Differential antihistaminic drug effects on skin test wheal production by histamine verus allergen attest to the potential dangers in extrapolating about drug effects with isolated mediator challenges (11). Also in the model of infused histamine, urticaria and angioedema did not occur (6). These are cutaneous hallmarks of immediate hypersensitivity reactions, which in our present study showed effects from combined H1 and H2 treatment. One question in our study, which was not answered, was whether or not H2 blockade is beneficial in anaphylaxis. Only 2 patients had hypotension. Twelve patients without asthma had wheezing. Clearly this subset of patients is too small to examine potential treatment effects. When patients with more severe manifestations such as upper airway embarrassment, wheezing in the absence of a history of asthma, and hypotension were grouped, there was no group effect in the models predicting the primary outcomes (data not shown). There did not appear to be any differences between patients in this group and other patients with regards to resolution of respiratory signs over time. Wheezing resolved in all but one patient by 2 hours and thus a treatment effect on bronchospasm resolution is difficult to ascertain. Thus although it appears that H2 blockers added to H1 13 antihistamines improve cutaneous manifestations and slowing of heart rates in acute allergic syndromes, their added benefit in reversing hypotension and bronchospasm associated with anaphylaxis remains unproven. We were quite interested in the difference in slowing of heart rates between the 2 groups as this is consistent with a possible effect on the cardiovascular system from ranitidine (12). It is conceivable that the resolution of cutaneous edema was accompanied by less vascular permeability and subsequent heart rate declines in the ranitidine. To our knowledge this study is the first prospective study to show differential changes in cardiovascular parameters associated with antihistamine treatment (combined versus H1 alone) in ongoing allergic reactions. As heart rates were not the primary outcomes, some of the 2 hour values were not recorded. This may have reduced the power of our study to find a treatment effect. Heart rates may be affected by factors other than histamine mediated vasodilatation and reflex tachycardia (13). Clearly, larger studies on more patients with these more serious manifestations need to be performed in order to test the hypothesis that there is a clinical effect of combined H1 and H2 blockade in anaphylaxis. In view of the safety and apparently rapid onset of effects, there would appear to be little reason to not use H2 blockers in patients with anaphylaxis, since the cutaneous manifestations in these patients, especially urticaria and associated angioedema, as well as heart rates respond. Our findings in acute allergic syndromes differ somewhat from the study of Runge et al (7), who found a post-hoc advantage of addng cimetidine to diphenhydramine for “clinical relief” of urticaria, as well as improved symptom scores alter 30 minutes of follow-up but no changes in heart rates. Their study examined only 12 patients who had combined H1 and H2 blockade as I of 3 treatments (H1 blockade, H2 blockade, or both). 14 Their methodology was suboptimal in 3 important areas. First, there was no statistical adjustment for multiple comparisons (which given 3 treatment groups and 3 pairwise comparisons, would have increased the p-values obtained). Secondly baseline manifestations (which differed significantly between the treatment groups) were not taken into account in analyzing outcomes. Thirdly an arbitrary definition of “clinical relief” was used as the main endpoint. Unlike our study, the clear endpoint of resolution of urticaria with or without angioedema was not studied. Our larger study using ranitidine as the H2 blocker in 48 patients found a significant difference in resolution of urticaria (an unambiguous outcome) which remained alter adjustment of baseline urticaria extent, but not in symptoms. This may in part have been due to a longer time-frame of observation. It is conceivable that earlier symptom benefits from combination therapy were eliminated with longer follow-up due to more cumulative symptom resolution in both groups. The fact that there was more resolution of urticaria in the ranitidine group has potential implications in terms of resource utilization in emergency departments. With the quicker resolution of urticaria with or without angioedema, there is a possibility that patients could be discharged sooner from the ED. The patients in our study had additional treatments including steroids, epinephrine, albuterol, and extra doses on antihistamines. The placebo group had significantly more additional diphenhydramine treatments. This could have potentially confounded the effect on urticaria resolution if this had been occurred instead in the ranitidine group. We feel it is likely that more diphenhydramine was given in the placebo group because the study physicians felt these patients were doing as well. Despite this additional antihistamine treatment, the placebo group had less resolution of urticaria with 15 or without angioedema. Unlike the situation with asthma (14), we did not find a significant effect of parenteral corticosteroids in the resolution of allergic cutaneous manifestations. Unexpectedly, we also did not observe a covariate effect for epinephrine administration with respect to urticaria resolution. This may have been due to that fact that clinicians gave both steroids and epinephrine in sicker patients, who are less likely to respond. The patients in this study did not have a history of chronic urticaria. Two patients of several patients who were seen by one of the study physicians after the protocol treatment, did report recurrences of urticaria. Thus it is possible that a few of the patients presented with their initial episode of a chronic process. In chronic urticaria, the response to combined H1 and H2 blockade has been modest at best (15-18). To our knowledge no large studies have been performed to examine for a benefit in this treatment approach. Moreover the endpoints for treatment responses in chronic urticaria often relate not to individual outbreaks of urticaria but to frequency of urticaria and degree of itch over a longer period of time such as 1-4 weeks. It is likely that these chronic urticaria patients have a different pathway of cutaneous mast cell release that perhaps may not involve systemic histamine release as is seen often in more severe acute allergic syndromes. It thus may not be advisable for clinicians to extrapolate from the treatment effects observed in this study to assuming potential benefits in patients with chronic urticaria. 16 References: 1. Schoning 5, Lorenz W. Prevention of allergoid (cutaneous anaphylactoid) reactions to polygeline (Haemaccel) in orthopaedic patients by premedication with H1and H2-receptor antagonists. Dev Biol Stand 1980;48:241-9. 2. Lorenz W, Doenicke A, Schoning B, Mamorski J, Weber D, Hinterlang S. Schwarz B, Neugebauer E. H1 + H2-receptor antagonists for premedication in anaesthesia and surgery: a critical view based on randomized clinical trials with Haemaccel and various antiallergic drugs. Agents Actions 1980;1O( Pt 2):114-24 3. Tryba M, Zevounou F, Zenz M. [Prevention of anaphylactoid reactions using intramuscular promethazine and cimetidine. Studies of a histamine infusion model] [Article in German] Anaesthesist 1984;33(5):218-23 4. Ring J, Rothenberger KH, Clauss W. 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