Article, Surgery

Unnecessary surgery for acute abdomen secondary to angiotensin-converting enzyme inhibitor use

Unlabelled imageAmerican Journal of Emergency Medicine (2012) 30, 1607-1612

Brief Report

Unnecessary surgery for acute abdomen secondary to angiotensin-converting enzyme inhibitor use?

Laura C.G. de Graaff MD, PhD?, Martijn van Essen MD, PhD, Eleonora M. Schipper MD, Henk Boom MD, PhD 1, Erik J.J. Duschek MD, PhD 1

Department of Internal Medicine, Reinier de Graaf Group of Hospitals, 2600GA Delft, The Netherlands

Received 28 October 2011; accepted 29 October 2011

Abstract Acute abdominal pain is the reason for 5% to 10% of all emergency department visits. In 1 in every 9 patients, operated on for an acute abdomen, laparotomy is negative. In a minority of patients, the acute abdomen is caused by side effects of medication. We present a case of unnecessary abdominal surgery in a patient with acute abdominal pain caused by intestinal angioedema (AE), which was eventually due to angiotensin-converting enzyme inhibitor (ACE-i) use. We hope that this case report increases awareness of this underdiagnosed side effect. Emergency department physicians, surgeons, internists, and family physicians should always consider ACE-i in the differential diagnosis of unexplained abdominal pain. Since early withdrawal of the medication causing intestinal AE can prevent further complications and, in some cases, needless surgery, we propose an altered version of the known diagnostic algorithm, in which ACE-i and nonsteroidal anti-inflammatory drugs-induced AE is excluded at an early stage.

(C) 2012

Introduction

Acute abdominal pain is the reason for 5% to 10% of all emergency department (ED) visits [1]. Depending on the severity of the clinical presentation, patients with an acute abdomen will eventually undergo laparotomy, showing acute appendicitis in 57.6%, peritonitis in 14.4%, Bowel obstruction in 7.9% in male, and ovarian cyst torsion in 24.5% in female patients. However, in 12.2% (1 in every 9 patients operated on for an acute abdomen), laparotomy is negative [2]. On a yearly basis,

? Author disclosure summary: LCGdG, MvE, EMS, HB, and EJJD have nothing to declare.

* Corresponding author. Tel.: +31 628880877; fax: +31 15 2603627.

E-mail address: [email protected] (L.C.G. de Graaff).

1 These authors share senior authorship.

this means unnecessary abdominal surgery for a significant number of patients. The acute abdomen accounts for 10% of malpractice claims [3].

To reduce the number of negative laparotomies, it is vital that the physician is familiar with the presentations of common diseases that cause abdominal pain [4,5]. Previous studies have shown that a considerable amount of diagnostic errors could be reduced by paying more attention to diagnosis before laparotomy [6,7].

In a minority of patients, the acute abdomen is not caused by a disease but by side effects of medication. We believe that, especially in those patients, unnecessary abdominal surgery is extremely regretful. We present a case of unnecessary abdominal surgery in a patient who presented with acute abdominal pain, which was eventually due to angiotensin-converting enzyme inhibitor (ACE-i) use.

0735-6757/$ - see front matter (C) 2012 doi:10.1016/j.ajem.2011.10.028

case presentation“>Case presentation

A 49-year-old Antillian woman presented to the ED of our hospital with acute abdominal pain and nausea. She did not have any complaints of diarrhea, dysuria, or fever. Her medical history revealed hypertension, epilepsy, and bronchitis, for which she used lisinopril, levetiracetam, and nitrazepam. She used an intrauterine device for birth control, and she had her last menstrual period 3 weeks before admission.

Physical examination revealed a blood pressure of 170/102, a pulse of 90 per minute, and body temperature of 37.2?C. There was abdominal rebound tenderness and abdominal distension. On admission, the C-reactive protein level was 34 mg/L (normal, b10 mg/L), and the erythrocyte sedimentation rate was 39 mm/h (normal, b20 mm/h). Furthermore, serum ?-glutamyl transpeptidase, lactate dehydrogenase, and creatine kinase were elevated: 58 U/L (normal, b40 U/L), 259 U/L (normal, b250 U/L), and 291 U/L (normal, b145 U/L), respectively. The aminotransferases and lactate were normal. Chest x-ray was unremarkable. Pregnancy test was negative, and the gynecologist excluded Pelvic inflammatory disease. Ab-

dominal x-ray showed distension of intestinal loops without signs of perforation or obstruction. abdominal computed tomographic scan revealed an edematous small bowel and ascites without signs of perforation or obstruction (Fig. 1).

Because of the acute abdomen, intestinal ischemia was suspected, and an explorative laparotomy was performed. Apart from edematous small bowel and a large quantity of free intra-abdominal serous liquid, no anomalies were found. The intestine was vital, and there were no signs of perforation. Ascites culture was sterile. Complement profile and urine porfyrine profile turned out to be normal. Three days after surgery, the patient still had severe abdominal pain despite broad spectrum antibiotics, anal- getics, and laxatives. She was transferred from surgery to the internal medicine department, where a detailed medication history was taken. This revealed that lisinopril had been started only 3 days before the abdominal pain began. Because ACE-i-induced angioedema (AE) was suspected, lisinopril use was replaced by amlodipine. After 3 days, the abdominal pain had completely disappeared, and patient was released from hospital several

days later.

Fig. 1 Abdominal computed tomographic scan showing an edematous small bowel and ascites without signs of perforation or obstruction.

Discussion

We present a case of unnecessary abdominal surgery in a patient who presented with acute abdominal pain, caused by AE due to ACE-i use.

Angioedema is a self-limiting, nonPitting edema that occurs in the mucous membranes or skin. Most frequently, it occurs on the lips, tongue, face, and acra [8]. When the pharynx and larynx are involved, patients can present with severe respiratory distress.

Occasionally, the bowel can be involved [9], and in the absence of other symptoms, these patients may present as having an “acute abdomen,” like our patient.

JL Milton [10] first described AE in 1876, and Quincke

[11] was the first to give the name angioneurotic edema to the disease.

In our patient, AE was induced by lisinopril use. Angiotensin-converting enzyme inhibitor and other drugs, such as Nonsteroidal anti-inflammatory drugs , are well known to cause AE [12,13].

Angiotensin-converting enzyme, also called kininase II, normally inactivates a number of peptide mediators includ- ing bradykinin. Bradykinin, a member of the kinin family of polypeptides, is released from high-molecular-weight kini- nogen by the kallikreins (peptidases involved in inflamma- tion, blood pressure regulation, coagulation, and pain) [14]. Bradykinin is a potent vasoactive peptide. Inhibiting its inactivation by the use of ACE-i could induce AE due to its increased availability [15-17]. Although a partial C1 esterase

inhibitor deficiency might be a predisposing factor for ACE- i-related AE [18], ACE-i can induce AE in previously healthy individuals, like our patient who was only known with epilepsy and hypertension.

Apart from hypertension, ACE-is are widely used in the treatment of heart failure, myocardial infarction, renal failure, and diabetic nephropathy. Over the last several years, the use of ACE-i has increased to more than 40 million people worldwide, which may explain the increasing prevalence of AE [19].

For patients who once had AE, the use of ACE-i should be strictly prohibited, and Alternative medication should be prescribed. Like ACE-i, Angiotensin II receptor blockers block the renin-angiotensin system. Since their introduction in 1995, angiotensin II receptor blockers were initially thought not to cause AE because they do not inhibit breakdown of bradykinins. However, there is now evidence showing an association with AE [20], and therefore, they may not be safe for patients with prior ACE-i-induced AE. Apart from ACE-i, NSAIDs are well known to cause AE. The current theory about the pathogenesis of AE due to NSAIDs assumes that the inhibition of cyclooxygenase 1 by NSAIDs leads to a shunting of arachidonic acid metabolism toward the 5-lipoxygenase pathway, which results in an increased synthesis and release of cysteinyl leukotrienes, Inflammatory mediators that increase vascular permeability

[13] (Fig. 2).

Although ACE-i and NSAIDs are the most important cause of drug-induced AE, it has been reported as a side

Fig. 2 Mechanisms and pathways involved in the etiology of AE. Encircled numbers refer to mechanisms and pathways described in Table 1. Amp P indicates aminopeptidase P; C1 inh, C1 esterase inhibitor; BK, bradykinin; HMWK, high-molecular-weight kininogen; COX-1, cyclooxygenase 1.

effect of other drugs such as statins; proton pump inhibitors; Selective serotonin reuptake inhibitors and other antidepres- sants; and, more recently, tacrolimus [21,22].

The incidence of AE caused by any ACE-i treatment varies from 0.1% to 1% [18], and the frequency of AE associated with lisinopril is reported to be 0.1% [20]. The incidence of ACE-i-related AE is about 3 times higher in blacks than in white subjects, 4-fold higher among patients with a history of drug rash, 2-fold higher in patients with seasonal allergies, and 1.5-fold higher in patients older than 65 years [20]. Most attacks of AE occur within the first week of therapy, but there are reports of AE as long as 2 years after start of therapy [18].

Apart from AE caused by medication, there are many other forms of AE, such as hereditary and acquired C1 esterase inhibitor deficiency-related AE (hereditary AE [HAE] and acquired AE [AAE], respectively), acute allergic AE (to food, toxins, inhaled allergens, or drugs), nonallergic drug reactions, and idiopathic AE (Table 1; Fig. 2). Angioedema caused by C1 esterase inhibitor deficiency is characterized by uncontrolled complement activation, result- ing in AE. It can be either hereditary or acquired. Hereditary AE is an autosomal dominant condition affecting the C1 INH gene encoding the C1 esterase inhibitor protein. Hereditary AE presents with either low levels of C1 esterase inhibitor protein or with a dysfunctional enzyme. Acquired C1 esterase inhibitor deficiency can be differentiated from HAE by complement studies measuring C4, C1 esterase inhibitor antigenic protein levels [25]. In AAE, C1 esterase inhibitor levels are normal, whereas its activity is diminished, probably by the presence of neutralizing autoantibodies [26]. Acquired forms of AE may be associated with an underlying Hematologic malignancy [27] or immune complex disease, causing activation of complement factor C1Q [28].

Bowen et al [25] recently published a diagnostic algorithm for the analysis of different types of AE. In this algorithm, drug-induced AE is one of the last explanations for AE, to be considered after C1 esterase inhibitor protein function and C4 and C1 esterase inhibitor Protein Serum level have been proven to be normal. However, because early withdrawal of the medication causing AE can prevent further complications and, in some cases, needless surgery, we propose an altered algorithm in which ACE-i- and NSAID- induced AE is excluded at an early stage (Fig. 3).

Without intervention, AE attacks typically last from 1 to 5 days, depending on the underlying cause. Although rare, fatal ACE-i-induced AE has been reported. Life-threatening acute attacks of AE generally do not respond to epinephrine, antihistamines, or steroids [29]. Therapy is, therefore, mainly supportive and consists of analgesics, intravenous fluids, and airway management. Fresh frozen plasma is an alternative therapy, which is generally effective [30], but it can temporarily worsen the symptoms due to a transient increase in C2 and C4 levels [31].

For treating acute attacks of HAE, new medication has become available recently, such as the bradykinin-2

Table 1 Causes of angioedema Form Mechanism

  1. Hereditary AE Type 1: Genetic mutations in the C1

INH gene result in low levels of C1 esterase inhibitor. Removal of its inhibitory actions results in complement activation and elevated BK levels

Type 2: Genetic mutations in the C1 INH gene result in normal levels of C1 esterase inhibitor, but the protein is dysfunctional, which leads to BK accumulation as in HAE type 1

  1. HAE with normal C1 Missense mutation in the factor XII esterase inhibitor levels gene causes an increase in the

protease activity of activated factor XII, increasing BK generation.

Decreased activity of enzymes such as ACE and aminopeptidase P, which metabolizes BK when ACE activity is inhibited

  1. AAE Type 1: IC formation associated with rheumatologic, lymphoproliferative and neoplastic disorders continuously activate C1, causing C1 esterase inhibitor depletion and BK accumulation Type 2: Autoantibodies inactivate C1 esterase inhibitor, leading to BK accumulation
  2. Food and inhaled Allergens react with IgE antibodies allergens on the surface of mast cells, causing

degranulation and release of histamine

  1. Various other drugs and Allergic: allergens react with IgE agents a antibodies on the surface of mast

cells, causing degranulation and release of histamine Nonallergic: direct increase in histamine release

  1. NSAIDs Inhibition of COX-1 leads to overproduction of a variety of vasoactive substances, including cysteinyl leukotrienes
  2. ACE-i ACE-i prevents the conversion of bradykinin to inactive metabolites, leading to BK accumulation

Table adapted from Hoefnagel et al [23] and Nzeako et al [24]. BK indicates bradykinin, C1 INH, the gene encoding the C1 esterase inhibitor protein; IC, immune complex; COX-1, cyclooxygenase 1.

a Antibiotics, Muscle relaxants, opiates, Contrast agents, and volume expanders.

receptor antagonist Icatibant, the kallikrein inhibitor Ecallantide [32-34], and C1 esterase inhibitor derived from human plasma, recently reviewed by Nzeako [24]. Prophylactic maintenance therapies for HAE and AAE include the fibrinolysis inhibitors epsilon amino caproic

Fig. 3 Diagnostic algorithm for the analysis of AE (adapted from Bowen et al [25]). *As well as statins, proton pump inhibitors, Selective serotonin reuptake inhibitors, and tacrolimus.

acid and Tranexamic acid, which inhibit plasmin activation. Androgen hormone therapy may also be useful, due to an increased hepatic synthesis of C1 esterase inhibitor [35].

However, in the case of drug-induced AE, the most important intervention is discontinuation of the medication. Therefore, awareness of the association between AE and commonly prescribed drugs such as ACE-i is essential.

In summary, we present a case of unnecessary abdominal surgery in a patient with acute abdominal pain caused by AE

due to ACE-i use. Laparotomy (and that of other patients) could have been prevented by a detailed medical history and by the awareness of the existence of ACE-i-induced intestinal AE. Clinicians (surgeons, internists, ED physi- cians) should, therefore, always consider ACE-i in the first differential diagnosis of unexplained abdominal pain. Because early withdrawal of the medication causing AE can prevent further complications and, in some cases, needless surgery, we propose an altered version of the

known diagnostic algorithm in which ACE-i- and NSAID- induced AE is excluded at an early stage.

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