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Acute Appendicitis: Influence of Early Pain Relief on the Accuracy of Clinical and US Findings in the Decision to Operate—A Randomized Trial

¹ Emergency Department (B.V., P.F.U.)
² Clinical Epidemiology Division (A.M., C. Goehring)
³ Radiology Department (C. Grangier, I.S., F.T.), Hôpitaux Universitaires de Genève, Rue Micheli-de-Crest 24, CH-1211 Genève 14, Switzerland.

	Abstract

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PURPOSE: To determine the influence of early pain relief on the diagnostic performance of ultrasonography (US) and on the appropriateness of the surgical decision.

MATERIALS AND METHODS: A prospective randomized, double-blind placebo-controlled trial with morphine was conducted. A visual analog scale was used to evaluate pain in 340 patients aged 16 years or older. US was performed with a standardized protocol. Diagnosis was confirmed at histologic analysis or, in the patients released without surgery, at follow-up.

RESULTS: One hundred seventy-five patients were injected with morphine, and 165 were injected with the placebo. Pain relief was stronger in the morphine group. In the morphine group, US had lower (71.1%) sensitivity (difference, -9.5%; 95% CI, -18.5%, -0.5%) and higher (65.2%) specificity (difference, 11.4%; 95% CI, 1.0%, 21.8%). This group had also a higher positive predictive value (64.6%) and a lower negative predictive value (71.4%), but the differences between this group and the placebo group were not statistically significant. Among female patients, the decision to operate was appropriate more often in the morphine group (75.8%), but the difference between this group and the placebo group was not statistically significant (5.1%; 95% CI, -7.4%, 17.6%). In male patients and overall, opiate analgesia did not influence the appropriateness of the decision. The appropriateness to discharge patients without surgery was 100% in all groups.

CONCLUSION: Morphine does not improve US-based diagnosis of appendicitis.

Index terms: Anesthesia • Appendicitis, 751.291, 752.291 • Appendix, US, 751.1298, 752.1298 • Ultrasound (US), utilization, 751.1298, 752.1298

	Introduction

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Surgeons are reluctant to use opiate analgesia while investigating pain in the right lower part of the abdomen that they suspect is due to appendicitis. They fear that the analgesia will mask the symptomatology and delay the diagnosis. However, in 1979, an editorial in the British Medical Journal (1) suggested the use of opiate analgesia for abdominal pain. Then, the results of the studies by Zoltie and Cust in 1986 (2), Attard et al in 1992 (3), and Pace and Burke in 1996 (4) showed that the use of opiate analgesia for acute abdominal pain did not cause either a delay in diagnosis or drug-related adverse effects.

Pain relief may have beneficial aspects in the diagnosis of appendicitis. Ultrasonography (US) has become a major tool for investigating and diagnosing many abdominal pathologic entities. The reported accuracy of US in diagnosing appendicitis varies between 75% and 90% in sensitivity and between 95% and 100% in specificity (5–8). Technically, the examination of the cecum requires a graded compression of the right lower region of the abdomen, as described by Puylaert (9) or others (10,11). It is reasonable to expect that localized peritonitis may hamper the compression and therefore lower the quality and interpretation of US images. On the other hand, it can also be argued that the presence of pain tends to indicate a positive diagnosis of acute appendicitis and that morphine could mask and therefore decrease the sensitivity of this technique. The problem is that, to our knowledge, no scientific evidence of whether pain can alter the accuracy of US in the right lower region of the abdomen has been reported yet.

We therefore conducted a prospective randomized, double-blind, and placebo-controlled trial on early pain relief with intravenous administration of morphine in patients admitted to an emergency department for pain in the right lower part of the abdomen. The objectives of the trial were to determine the influence of opiate analgesia on the diagnostic performance of US and on the appropriateness of the decision of whether to operate.

	MATERIALS AND METHODS

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Eligible patients were male and female patients aged 16 years or older who consulted the emergency department of a university hospital for pain in the right lower part of the abdomen between April 1993 and October 1995. The hospital ethical committee approved the protocol. Exclusion criteria were a previous appendectomy; a clinical presentation highly suggestive of a nonappendicular pathologic condition (eg, renal colic or extrauterine pregnancy); the presence of renal, hepatic, or respiratory insufficiency; and the use of psychotropic medication. Patients who were admitted several times during the study were eligible to participate only once. Of the 488 eligible patients, 350 (72%) participated in the study. They all gave written informed consent.

The medical history was taken and a clinical examination was performed by the emergency department resident who checked the inclusion criteria. All patients were asked to assess their pain by using a 10-cm visual analog scale, or VAS, during the first examination (pain score 1). After providing signed informed consent, the patients were then randomized to receive one of 440 vials specially prepared by the hospital pharmacy for the study. These vials contained either 10 mg of morphine (1 mg/mL) or a placebo (sodium chloride 0.9%). The dose of morphine administered for analgesia was 0.1 mg per kilogram of body weight, which was administered intravenously (50% in 3 minutes, then 50% in 2 minutes). About 45 minutes after the administration of either substance—the morphine or the placebo—the patients were asked to give a second assessment of their level of pain by using the visual analog scale (pain score 2).

US was performed at the latest within the 4 hours after the intravenous injection of morphine or the placebo by the radiologist in the emergency department, who was a second- or third-year resident. A US scanning unit (Acuson, Mountain View, Calif) with 3.5- (convex sectorial for the entire abdomen) and 7.5-MHz (linear for local examination of the appendix) probes was used. The examination was performed by using a standard protocol established by the radiology department. The radiologist had to answer specific questions about the position, diameter, length, and deformability of the appendix and more general questions about the bladder, cecum, distal ileum, pericecal fat, presence of pericecal liquid, and influence of pain on the examination. He or she then had to classify the diagnosis of appendicitis as sure, probable, or absent.

After US, all patients presented to a surgeon for clinical examination, analysis of the radiologic and laboratory results, and therapeutic decision. The decision of the surgeon was not analyzed. Laparoscopic surgery was performed if no major contraindication was present within 24 hours after admission. A histologic diagnosis was obtained in all patients who underwent surgery. Patients who were not operated on and stayed in the ward 24 hours or more for observation were examined again by a surgeon before leaving the hospital. All of these patients were contacted after 30 days for follow-up. The randomization code was broken and communicated to the authors only after all of the data had been collected.

The Student t test for paired and unpaired data was used to compute differences in pain score within the groups (ie, morphine group and placebo group) and between the groups. The heterogeneity of proportions between the two groups was assessed by using probability differences and 95% CIs (12). The analyses were performed with SAS, version 6 software (SAS Institute, Cary, NC). The sensitivity of US was the proportion of histologically confirmed cases of appendicitis that were classified as sure or probable by the radiologist. The specificity of US was the proportion of all patients who were discharged without undergoing surgery, who were not readmitted during the following month, and in whom appendicitis was ruled out by the radiologist. The positive predictive value of US was the proportion of histologically confirmed cases of appendicitis in patients whose US findings were classified as sure or probable for the presence of appendicitis by the radiologist. The negative predictive value was the proportion of non–histologically confirmed cases of appendicitis in patients in whom appendicitis had been ruled out by the radiologist.

Reasons for refusal to participate in the study were no consent from the parents of patients younger than 20 years (n = 22) and communication problems due to foreign language (n = 5).

As shown in the Figure, 350 patients were able to participate in the study, and the medical files of 340 patients could be analyzed. Ten files could not be used because clinical or radiologic information was missing (seven patients), there was no follow-up at 1 month (two patients), or the operation took place before the protocol procedure was completed (one patient).

View larger version (15K): [in this window] [in a new window]   Figure 1. There were 340 patients in the study. *App + = number of patients with appendicitis and other diagnoses (eg, gynecologic pathologic entities, appendicular carcinoids, peritoneal carcinosis, spontaneous adhesion, and appendicular cancer) in which surgery was required, **App - = number of patients with a normal appendix at surgery, App + = number of patients who had a reconsultation and eventually underwent surgery in our emergency department or at another facility for suspicion of appendicitis or another diagnosis within 30 days of leaving the emergency department, App - = number of patients who did not have a new consultation for abdominal pain at any facility within 30 days after leaving the emergency department.

	RESULTS

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Overall, 205 patients underwent surgery; in 181 (88%) of these patients, the surgery was laparoscopy. One hundred thirteen (65%) patients in the morphine group and 92 (56%) patients in the placebo group were operated on. Overall, appendicitis (acute, phlegmonous, or perforated) was confirmed histologically in 155 (76%) patients. The corresponding frequencies were 83 (73%) patients in the morphine group who underwent surgery and 72 (78%) patients in the placebo group who underwent surgery. None of the 135 patients who did not undergo surgery and left the hospital after 24 hours of observation was readmitted or operated on at another local hospital.

A normal appendix was diagnosed in 34 patients who underwent surgery (28 [26%] of 107 female patients and six [6%] of 98 male patients). Sixteen patients (13 [12%] of 107 female patients and three [3%] of 98 male patients) had other diagnoses, which included gynecologic pathologic conditions, appendicular carcinoids, peritoneal carcinosis, spontaneous adhesion, appendicular cancer, Crohn disease, or omental infarcts. No adverse effects after the morphine or placebo injection that necessitated the use of naloxone were reported.

The data in Table 1 show that in all the groups the pain score diminished significantly (P = .001) after the injection of morphine or the placebo. The pain relief was, however, stronger in the morphine group (minus about 2 points) than in the placebo group (minus about 1 point). The numbers of patients with positive and with negative diagnoses, as determined at US and at final diagnosis, are shown in Table 2. These numbers were used to compute the statistics presented in Tables 3 and 4.

The data in Table 4 show that the prevalence of appendicitis was lower in the female patients (40.2% in the morphine group and 27.2% in the placebo group) than in the male patients (57.5% in the morphine group and 64.4% in the placebo group). Because of the higher prevalence of appendicitis in the male patients, the positive predictive value of US was substantially better in these patients than in the female patients; in both the morphine and the placebo groups, the negative predictive value tended to be higher in the female patients (not statistically significant in the morphine group). In the female patients, morphine injection resulted in a lower negative predictive value (72.6%) than that in the placebo group (89.7%) (difference, -17.1%; 95% CI, -27.8%, -6.4%); this suggests that morphine had masked the US-based diagnosis. On the other hand, the positive predictive value was better in the morphine group (52.9%) than in the placebo group (39.6%), but the difference was not statistically significant. In male patients, both the positive and the negative predictive values were better in the morphine group, but the differences did not reach statistical significance.

The proportion of surgical findings and the appropriateness of the decision of whether to undergo surgery, based on the data in the Figure, are presented in Table 5. Surgical findings included the histopathologic diagnosis of appendicitis or of another pathologic entity. The surgical findings were more frequent in the male patients than in the female patients. The decision to operate was considered to be appropriate when it resulted in surgical findings. The highest probability of an appropriate decision was observed among the male patients in the morphine group (93.6%; 95% CI, 86.6%, 100%). The lowest probability of an appropriate decision was observed among the female patients in the placebo group (70.7%; 95% CI, 56.8%, 84.7%). Among the female patients, the decision to operate was more often appropriate in the morphine group (75.8%), but the difference between this group and the placebo group was not statistically significant (5.1%; 95% CI, -7.4%, 17.6%). In the male patients and overall, opiate analgesia did not influence the appropriateness of the decision to operate.

	DISCUSSION

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
The results of our study show that use of a major analgesic substantially reduces pain in patients. This result is comparable to that of Pace and Burke (4), who, with the same doses of morphine, observed a substantial reduction in pain as measured on a visual analog scale for all types of abdominal pain.

The diagnostic accuracy of US was more contrasted. Morphine tended to decrease sensitivity but increase specificity. This is consistent with the surgeon's concern that analgesia may mask the symptomatology of appendicitis. This was paradoxical; we expected morphine to improve sensitivity because it facilitated the maneuvers of the radiologist and reduced the proportion of false-negative findings. The explanation may be that pain also influences radiologic diagnosis (11,13–15). On the other hand, analgesia appears to be beneficial for specificity, that is, for reducing the proportion of false-positive US-based diagnoses of appendicitis.

As a result, analgesia tended to improve the positive predictive value but worsen the negative predictive value of US. It is of note, however, that the overall differences between the morphine group and the placebo group were not statistically significant. The results of this study could then be interpreted as being basically negative for the influence of morphine on the accuracy of US in the diagnosis of right lower abdominal pain.

But these results confirm those of three other studies (2–4) that showed that the use of a major analgesic (ie, morphine) for abdominal pain does not hinder the diagnostic process. This may be because morphine influences the perception of pain and the affective reaction to it more than it confers complete analgesia.

The most important finding of the present study is that pain relief does not modify the appropriateness of the decision of whether to operate on or discharge the patient. The decision not to operate on a patient with pain in the right lower part of the abdomen has always been appropriate for patients who received morphine as well as for those who did not. The appropriateness of the decision to perform surgery, which is essentially laparoscopy (16), has not been as good, probably because this procedure is relatively noninvasive and because clinicians want a visual diagnosis and thus accept a large proportion of null explorations. With 26% of null laparoscopic explorations in women and 9% in men reported, our results do not differ from those reported in the current literature (17–19).

In conclusion, the results of our study do not demonstrate that the use of analgesia improves the diagnostic performance of US. However, they do not indicate that major analgesia used with a strictly applied protocol for pain in the right lower part of the abdomen has a deleterious effect on the diagnosis of appendicitis or on the decision to perform laparoscopy. Thus, surgeon fear that analgesia will bias the decision is not warranted. This conclusion, however, may not be generalized to other abdominal pathologic entities such as pancreatitis or toxic megacolon, in which opiate analgesia is usually not recommended.

	Acknowledgments

 
We thank Mr. Ba-Lau Luong for the management of the data and the nurses and physicians of the Emergency Department at Hôpitaux Universitaires de Genève for participating in the study.

	Footnotes

 
Address reprint requests to B.V.

From the 1997 RSNA scientific assembly.

Author contributions: Guarantors of integrity of entire study, P.F.U., F.T.; study concept, B.V.; study design, B.V., A.M., C. Grangier; clinical studies, B.V.; data acquisition, B.V., C. Grangier, I.S.; data analysis, A.M., C. Goehring; statistical analysis, A.M., C. Goehring; manuscript preparation, B.V., A.M., C. Goehring, C. Grangier; manuscript review, B.V.

Received March 19, 1998; revision requested June 17, 1998; revision received July 16, 1998; accepted September 8, 1998.

	References

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