|Year : 2008 | Volume
| Issue : 4 | Page : 462
Intraoperative Anaphylaxis to Inj Ceftriaxone: Here We Go Again
Amit G Bhagwat1, Kirti N Saxena2
1 Senior Resident, Department of anesthesiology, Intensive Care and perioperative medicine, Maulana Azad Medical College & associated Lok Nayak Hospital, New Delhi, 110034, India
2 Professor, Department of anesthesiology, Intensive Care and perioperative medicine, Maulana Azad Medical College & associated Lok Nayak Hospital, New Delhi, 110034, India
|Date of Acceptance||30-Apr-2008|
|Date of Web Publication||19-Mar-2010|
Amit G Bhagwat
NU 17 A Pitam pura, New Delhi 110034, INDIA
Source of Support: None, Conflict of Interest: None
Anaphylactic reactions to intraoperative antibiotics are rare events and reactions after a negative intradermal skin testing are even rarer. We are reporting a case of grade V anaphylactic reaction to ceftriaxone, which occurred inspite of a negative skin testing preoperatively. Despite of the treatment along the established guidelines, patient suffered hypoxic brain damage ultimately having a fatal outcome 7 days later. This case highlights the limits of the screening test done preoperatively for antibiotic sensitivity and also the difficulty in resuscitating anaphylactic reactions when patient is on B blocker and under spinal anaesthesia.
Keywords: Anaphylaxis, Test dose, B-Blocker, Spinal anaesthesia
|How to cite this article:|
Bhagwat AG, Saxena KN. Intraoperative Anaphylaxis to Inj Ceftriaxone: Here We Go Again. Indian J Anaesth 2008;52:462
| Introduction|| |
Intraoperative antibiotic administration is a common practice. However, skin testing done prior to antibiotic administration may not detect all the sensitized cases  besides patients on B blocker and who had received spinal anaesthesia may show exaggerated response with difficulty in resuscitation of these patients.  We are describing one such case where patient had an anaphylactic reaction despite of a negative skin testing. Difficulty in resuscitating these patients due to concomitant administration of â blocker and spinal anaesthesia is highlighted.
| Case report|| |
A 52-yr-old, ASA II male was scheduled for stripping of varicose veins of left lower limb under spinal anaesthesia. He had a history of hypertension, which was controlled on oral atenolol 50 mg OD. He had no history of previous anaesthesia exposure& history of any known allergies were denied. Patient did not give any history of previous hospital admission for any illness.
As per the protocol in our institute, a day prior toscheduled surgery, patient was tested for sensitivity to ceftriaxone by intradermal skin testing against a isotonic saline control on other forearm, which yielded a negative sensitivity to ceftriaxone. He was premedicated with oral diazepam 10 mg HS and 10 mg 2 hrs before surgery and morning dose of oral atenolol 50 mg PO. On scheduled day, patient was taken inside the operation theatre and monitors were attached. His baseline readings were as follows: Pulse: 60/ min, BP: 146/94 mm of Hg, SpO2: 97 % on room air (ORA). After inserting an 18 G intravenous cannula, patient was preloaded with 500 ml of Ringer's lactate. Patient was positioned in left lateral position and was given spinal anaesthesia in L3 - L4 intervertebral space with 1.5 ml of 0.5 % bupivacaine (heavy). Patient was kept in lateral position for 10 min and then turned supine. Sensory block as is assessed by pinprick was till L1 on right side and T10 on left side.
While the patient was being cleaned and draped for surgery, on the request of surgeons, ceftriaxone 1 gm made up in 10 ml of NS was given as slow iv infusion as prophylaxis against postoperative infection. While the antibiotic was still being given, patient suddenly started complaining of severe pain in hand. This was followed by sudden onset of restlessness, chest pain and difficulty in breathing. Antibiotic administration was immediately stopped. His pulse rate dropped from 60 / min to 30 /min and BP dropped from 110 / 60 mm of Hg to 50 / 40 mm of Hg. Patient was immediately given 100% O2 using Bain's circuit while he was still breathing spontaneously. Immediately 1ml of epinephrine 1: 10000 was given intravenously suspecting anaphylaxis to ceftriaxone. Patient was reassured but he was becoming increasingly restless, drowsy, had frothing from mouth and become apneic and unconscious within next 10 sec. He further developed a maculopapular rash all over the body. Mechanical ventilation using bag and mask was tried, however it was not possible to ventilate the patient's lung and his trachea was immediately intubated with a cuffed orotracheal tube no. 8.0. However, ventilation was still difficult and the bag was still very "tight". Patient's SpO2 gradually dropped to 55%. On auscultation, there was minimal chest expansion and chest was absolutely silent signifying severe bronchospasm which had not responded to Inj epinephrine. A repeat epinephrine 1 ml of 1 in 10000 i.v was administered, without any effect, patient continued to have persistent bradycardia , hypotension , low SpO2 and non recordable EtCO2. Crystalloids were being given fast i.v through two 18 G intravenous canula and again a bolus of 1 ml of epinephrine 1: 10000 was given i.v followed by infusion of norepinephrine 3 mcg.min -1 , together with pheniramine maleate 25 mg, ranitidine 50 mg and hydrocortisone 2 gm iv. Five min had passed since patient became unconscious and continued to have persistent bradycardia, hypotension and severe bronchospasm with a SpO2 of 56%.When bronchospasm did not respond to epinephrine, aerosol of salbutamol 600 mcg and ipratropium bromide 80 mcg was given endotracheally.
After administration of salbutamol and ipratropium bromide, bronchospasm started getting relieved and saturation gradually rose to 90 % at FiO 2 of 1. However patient was still having bradycardia (P= 30 / min) and hypotension (BP =50 / 30 mm of Hg), despite giving epinephrine and crystalloids (3 litres). Seven min had passed since patient became unconscious and it was now decided to give vasopressin. Vasopressin 5 U was given i.v and second bolus of vasopressin 5 U was given two minute later to which BP responded and rose to 89 / 50 and stabilized. Pulse increased to 134 / min.
Patient was then sedated, paralysed (with midazolam 2mg.hr -1 and vecuronium 6 mg i.v stat respectively) and transferred to ICU for overnight elective ventilation. Patient was prescribed dexamethasone 6mg iv 8 hrly and ranitidine 50mg iv 8 hrly. Blood samples for serial tryptase levels were taken at 2, 4 and 24 hrs after ICU admission and was found to be raised (sample at 2 hrs after ICU admission - 134 nmol/l , at 4 hrs of ICU admission 180nmol/l and at 24 hrs of ICU admission 10 nmol/l, normal value < 13.5 nmol/l).
Patient was weaned off the ventilator and extubated next morning, however he was not responding to verbal command and responding to only deep painful stimuli and had to be reintubated. MRI done on second day revealed cerebral hypoxic damage. The temporal association of onset of symptoms to administration of ceftriaxone and increased level of serial serum tryptase had confirmed that reaction was an anaphylactic reaction and triggering agent was ceftriaxone. After that patient had downhill course and subsequently succumbed to ARDS and septicemia on 7 th day of ICU stay.
| Discussion|| |
Anaphylaxis is a severe, life threatening, generalized or systemic hypersensitivity reaction .If the anaphylaxis is caused by an allergic mechanism, it is termed allergic anaphylaxis and if not, non allergic anaphylaxis (anaphylactoid - old nomenclature). 
We are reporting a case of intraoperative anaphylaxis to ceftriaxone, which occurred despite of the negative intradermal skin testing to ceftriaxone one day preoperatively.
This highlights the shortcomings of intradermal testing. Although intradermal skin testing is a highly sensitive test but it is also associated with higher false positives, which are clinically irrelevant.  Besides, expertise of the person in performing the testing also matter as dilution of the drug taken for performing the test and setting up of the both positive and negative control are important issues and failure to do so might leads to ominous results.  In our case positive control with histamine chloride (10 mg.ml -1 ) was not put up by the attending nurse. Common errors while performing intradermal testing are (1). Test sites are too close together and false positive results can be observed. (2) Volume injected too large. (3). High concentration leading to false positive results. (4). "Splash" reactions caused by air injection. (5). Subcutaneous injections leading to a false negative test (no bleb formation). (6) Intracutaneous bleeding site read as an adequate test. (7) Too many tests performed at the same time may induce systemic reactions.  Besides skin testing might give false negative result with concomitant administration of blocker can lead to an exaggerated response to the test dose itself. 
The incidence of anaphylactic reaction during anaesthesia has been reported as 1:6000 to 1:20000 anaesthetic.  The various agents implicated are muscle relaxants(61.6%), latex(16.6%), antibiotics (8.3%), hypnotics(5.1%), colloids(3.1%), opioids(2.7%) and others(2.6%) (aprotinin, ethylene oxide, local anaesthetic). , Of all the antibiotics, reactions occur most commonly to penicillins(1/1000). Though earlier it was thought that penicillin cross reacts with â - Lactam antibiotics, it seems that risk of anaphylaxis was overestimated and therefore cephalosporins may be considered for patients with penicillin allergy, however only after negative skin testing, with the awareness of the fact that test dose itself may sensitise the patient to antibiotic and the preservative present are a important cause of anaphylaxis. , In our case the vial of the ceftriaxone used was preservative free. It might be possible that test dose given one day prior to surgery may itself have sensitised the patient to ceftriaxone leading to anaphylactic reaction to full dose on the day of the surgery. 
The guidelines for treatment of anaphylaxis are now well established and epinephrine and fluid resuscitation remain the mainstay of the management.  The risk factor which increases the severity of reaction are preoperative B blocker administration, epidural anaesthesia and history of asthma. , In our case patient was on oral atenolol 50 mg OD (for hypertension) and had taken the drug 2 h before as premedication, beside patient was also given spinal anaesthesia. Spinal anaesthesia might have resulted in a more catastrophic presentation. â blocker might have reduced the efficiency of endogenous and exogenous catecholamine response and hence making the reaction more severe and the patient's resuscitation more difficult. This is in accordance to the French survey report of 2001, in which 8/477 were found to have long-term administration of â blockers, 7 of these suffered grade II reaction and 1 developed grade IV reaction with cardiac arrest. 
Intraoperative administration of antibiotic for the prophylaxis against postoperative infection is only effective when given within 1 h prior to incision  . It should be administered preoperatively in the preoperative area or on the OT table prior to induction of anaesthesia. Administration after establishing the anaesthesia and after the skin incision should be avoided as it results in multiplicity of agents administered; creating confusion about culprit agent causing the adverse reaction, beside effects of other anaesthetic agents make the reaction more severe and resuscitation more difficult.
In our case, there were two distinct reasons for the sudden cardiovascular collapse.
1) Spinal anaesthesia -This was a contributing factor to cardiovascular collapse due to the sympathetic blockade in the lower half of the body.
2) β-blockers- β-blockers block the response of the body to endogenous catecholamines leadingto an exaggerated response to allergens. but responded to vasopressin which acts on different receptors.
Serial serum tryptase is the immediate investigation to be done as soon as possible. 
Tryptase, a stable protease stored-in mast cell granules, is liberated into blood if mast cell activation occurs and stays at increased concentrations in plasma for 6 h.  After degranulation, it is thought to reach its peak level in the plasma after approximately 1 h. Serum samples should therefore be taken as soon as practicable after the start of the reaction, after 1 h and 6-24 h later.  A serum sample is required and this should be refrigerated, not frozen, if it can be analysed within 48 h. A value more than 13.5 nmol.l -1 is considered significant. According to epidemiological study of 1999-2001 from France, the positive predictive value of tryptase for the diagnosis of anaphylaxis is 92.6%; the negative predictive value is 54.3%. 
In our case patient suffered hypoxic damage to brain because of severe hypotension and bronchospasm, which did not respond to repeated doses of epinephrine, the reason for which could be â - blocked status of our patient. Hypotension was treated using vasopressin and bronchospasm responded to salbutamol and ipratropium bromide. The predominant reasons for acute cardiovascular collapse in anaphylaxis are vasodilatation and leakage of plasma from capillaries due to increased permeability mediated by prostanoids, leukotrienes, and kinins.  The primary therapy of anaphylaxis remains epinephrine (and not vasopressin), a catecholamine with both alpha and beta agonist effect.  Epinephrine inhibits further vasodilating mediator release from basophils and mast cells, reduces bronchoconstriction, increases vascular tone, and improves cardiac output. , Vasopressin which is a potent vasoconstrictor has no role in inhibition of mediator release from mast cells or bronchoconstriction making it a second choice drug (for hypotension) after epinephrine fails. 
Our patient inspite of our best effort succumbed to anaphylaxis. However, it was nearly impossible to predict these kinds of reactions on the basis of history and skin testing as both false positive and false negative test may occur because of the improper technique or material. False negative skin test can be caused by (i) Extracts of poor initial potency; (ii) Drugs modulating the allergic reaction; (iii) Diseases attenuating the skin response; (iv) A decreased reactivity of the skin in the infants and elderly patients; and (v) Improper technique (no or weak puncture).  Improper technique might be the reason for false negative skin test in our patient.
Hence, there always going to be some cases, labeled falsely as non-sensitive to the antibiotic in question. We recommend the following to deal with such cases.
- Whatever may be the report of the sensitivity test, initial 1 ml of drug should be first given as a test dose and only after that, the rest of the antibiotic is to be given as a slow IV infusion.
- Antibiotic as prophylaxis against postoperative infection is only effective when given within 1 h of skin incision, so that antibiotic should be given in preoperative ward or on the OT table before induction of anaesthesia. Any kind of antibiotic after incision or after initiation of anaesthesia should be avoided.
- Drugs like corticosteroids, NSAIDS,&β-agonist might interfere with drug sensitivity testing giving false negative result.
- Awareness of the fact that β- blocker and neuraxial anaesthesia might make patient more resistant to the effect of epinephrine and hence use of other potent vasoconstrictor like vasopressin more sooner that later.
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