Improved Outcomes in Colon and Rectal Surgery part 22 docx

9 improved outcomes in colon and rectal surgery 155. Consten CJ, Siors FJM, Noten HJ et al. Anorectal surgery in human immunodeficiency virus-infected patients. Dis Colon Rectum 1995; 38: 1169–75. 156. Miles AJG, Mellor CH, Gazzard B et al. Surgical management of anorectal disease in HIV-positive homosexuals. Br J Surg 1990; 77: 869–71. 157. Munoz-Villasmil J, Sands L, Hellinger M. Management of perianal sepsis in immunosuppressed patients. Am Surg 2001; 67: 484–6. 158. Onerheim RM. A case of perianal mucinous adenocarcinoma arising in a fistula-in-ano: a clue to the early patho- logic diagnosis. Am J Clin Pathol 1988; 89: 809–12. 159. Seya T, Tanaka N, Shinji S et al. Squamous cell carcinoma arising from recurrent anal fistula. J Nippon Med Sch 2007; 74: 319–24. 160. Korelitz BI. Carcinoma of the intestinal tract in Crohn’s disease: results of a survey conducted by the National Foundation for Ileitis and Colitis. Am J Gastroenterol 1983; 78: 44–6. 161. Smith R, Hicks D, Tomljanovich PI et al. Adenocarcinoma arising from chronic perianal Crohn’s disease: case report and review of the literature. Am Surg 2008; 74: 59–61. 162. Sarani B, Orkin BA. Squamous cell carcinoma arising in an unhealed wound in Crohn’s disease. South Med J 1997; 90: 940–2.  20 Surgery and nonoperative therapy of anal fissure Jaime L Bohl and Alan J Herline CHALLENGING CASE A 35-year-old woman presents with a recurrent posterior anal fissure. She had a left lateral anal sphincterotomy 4 years ago for an unresponsive anal fissure. Her fissure healed until 6 months ago. She has had two previously vaginal deliveries. Exam reveals a posterior anal fissure with exposed sphincter muscle and a sentinel skin tag. Anal manometry revealed mildly decreased resting pressure and a hypertonic squeeze pressure. The patient’s symptoms have not responded to stool softners and topical medication. CASE MANAGEMENT A repeat sphincterotomy is relatively contraindicated due to the decreased sphincter function. An acceptable surgical option is an advancement flap. INTRODUCTION An anal fissure is a longitudinal tear or ulcer in the anal canal from the dentate line to the anal verge. Fissures affect both genders equally, across age groups with young and middle aged adults con- stituting the majority of patients.(1) Although the true incidence is not known, anal fissure is common. In a survey of Italian proc- tology clinics, 10% of 15,000 consecutive referrals were diagnosed with anal fissure.(2) Fissures can be classified by etiology, location, and chronicity. It is hypothesized that most fissures are caused by trauma to the anal canal, usually from passage of hard stool. Anal fissures are commonly located in the posterior midline (75%), although a smaller percentage can be found in the anterior midline (13%) and an anterior and posterior location may be seen simultaneously (11%). Anterior fissures are seen more commonly in women (19%).(1) Fissures may be associated with other chronic medical conditions such as Crohn’s disease, HIV/AIDS, tuberculosis, syphilis, or anal carcinoma. Fissures in patient with these conditions typically occur off the midline and may be multiple or irregular (Figure 20.1). These fissures are best treated according to the underlying disease state. Early or acute fissures are a simple linear tear in the anoderm. Fissures that have been present for >4 weeks show signs of chronicity: the base of the fissure reveals internal sphincter fibers with indurated edges, and a sentinel pile (cranial) or hypertrophied apical papilla (distal). The chronicity of a fissure is important to discern from patient history and clinical exam as this will affect treatment recommendations. PATHPHYSIOLOGY The exact mechanisms leading to acute anal fissure and the factors that encourage fissure chronicity have been the subject of debate. However, anatomic and physiologic studies suggest an ischemic etiology to anal fissure chronicity. In 1986 Gibbons and Read confirmed that patients with anal fissures had elevated anal resting pressures and they hypothesized that elevated anal resting pressures led to tissue ischemia and ulceration within the anal canal.(3) This hypothesis was further supported by anatomic studies performed by Klosterhalfen and colleagues who showed that the posterior anal canal has a limited blood supply compared to the rest of the anal canal.(4) The decreased blood supply to the posterior anal canal was evident through the lack of inferior rectal artery branches to the posterior anal commissure in 85% of postmortem specimens, and the decreased capillary density in histologic specimens.(4) Schouten and colleagues put these findings together when they demonstrated an inverse relationship between anal resting pressure and anodermal blood flow.(5) Therefore, patients with anal fissure have less blood flow to their posterior midline secondary to anal hypertonia. The ischemia in the posterior midline allows per- sistence of anal fissures and poor healing. Treatments for anal fissure are therefore aimed at decreasing anal hypertonia and increasing anodermal blood flow. Anal fissures can be exquisitely painful despite the small size of the lesion. Patients complain of sharp, persistent pain dur- ing and after defecation, which may lead patients to avoid bowel movements. Patients may also notice blood on the toilet tissue or coating the stool with limited bleeding or perianal swelling. POSTERIOR ANTERIOR Acute and Chronic anal fissure Acute and Chronic anal fissure Crohn’s disease Ulcerative colitis Syphilis Tuberculosis Leukemia Cancer HIV Crohn’s disease Ulcerative colitis Syphilis Tuberculosis Leukemia Cancer HIV Figure 20.1 Fissure location related to etiology. 200 improved outcomes in colon and rectal surgery DIAGNOSIS The clinician should inquire about known risk factors for fissure including alteration in bowel habits (constipation or diarrhea), childbirth, previous anorectal surgery, or associated medical conditions. The clinician should also inquire to previous episodes of the presenting symptom complex. The natural history of anal fissure is one that waxes and wanes, sometimes with healing between recurrences. Anal fissure can be diagnosed by inspection of the anus. Patients are usually too symptomatic to allow for digital examination or anoscopy at the initial visit. If the clinician suspects another diagnosis because of an atypical location, the presence of multiple or chronic fissures, or a fissure cannot be diagnosed by inspection, then exam under anesthesia may be necessary. Suspicion of an alternative diagnosis may warrant biopsy and culture of the anal lesions. TREATMENT Anal fissures have been treated with a variety of medical and surgical therapies. A growing body of randomized controlled trials has helped to guide current treatment recommendations for anal fissure. Currently available treatments include conservative therapy, nitrates, calcium channel blockers, botulinum toxin, anal dilation, open or closed lateral sphincterotomy, and anal advancement flap. Conservative therapy comprises increased dietary fluid and fiber, sitz baths, and stool softeners. Nitrates may include ointments of nitroglycerin (NTG) or glyceryl trinitrate (GTN), nitroglycerin transdermal patch, or other nitrate analogs such as isosorbide dinitrate (IDN) or isosorbide mononitrate (IMN). Calcium channel blockers have been used in ointment or tablet form (diltiazem or nifedipine). Finally, botulinum toxin (BT) has been used in the treatment of anal fissure. It is sold in two commercially available preparations, Dysport (Speywood Biopharm Ltd, Wrexham, UK) and Botox (Allergan, Irvine, CA, USA). Both preparations of BT have been shown to have equal efficacy in the treatment of chronic anal fissure (6) with 100 units of Dysport toxin having the bioequivalence of 20 units of Botox. All of these medical and surgical treatments have been used in randomized controlled trials to assess the effect on fissure healing rates, anal resting pressure, pain, and fissure recurrence. Other treatment effects which are important to consider are complications such as incontinence to flatus or stool, headache, hypotension, and allergic reactions. Importantly, two recent meta-analyses of all medical and surgical treatments used for anal fissure are available.(7–10) This has lead to improved decision making regarding the treatment of anal fissure. Conservative therapy is often used as a comparison to other medical or surgical treatment. The effect of conservative therapy on healing rate for anal fissure has been 50% for acute (11) and 34% for chronic anal fissures.(7) Therefore, other medical and surgical treatments should be tested with this therapy in mind. The effect of conservative therapy on anal fissure healing rate, reduction in symptoms, and safety profile has lead to the recommendation by the American Society of Colon and Rectal Surgeons for conservative therapy to be the first line treatment of anal fissure.(12) ACUTE ANAL FISSURE Clinical experience dictates that over half of acute anal fissures will heal within several weeks. Therefore, most clinicians recommend conservative therapy for acute anal fissure. Conservative therapy consists of fiber supplements and sitz baths with or without the use of topical anesthetics. However, few randomized controlled trials have evaluated acute anal fissure healing with conservative therapy as compared to no therapy. One trial compared warm sitz baths and 10 g of unprocessed bran to 2% lignocaine ointment or 2% hydrocortisone ointment applied in the anal canal twice per day. (13) After 3 weeks of treatment, patients treated with bran and sitz baths had significantly more healed fissures (88%) than patients treated with lignocaine ointment (60%). Unfortunately, patients with healed fissures were not followed long-term and rates of fissure recurrence were not measured. One randomized controlled trial does suggest the ability of long-term conservative therapy to prevent fissure recurrence.(14) Ninety patients with recently healed posterior anal fissures were randomized and blinded to three different treatments groups for 1 year. Patients received either 5 g unprocessed bran three times a day, 2.5 g unprocessed bran plus 2.5 g placebo, or 5 g placebo. Patients receiving 5 g of unprocessed bran over 1 year had significantly fewer recurrences of anal fissure (16%) as compared to patients who received the lower bran dose (60%) or placebo (60%). In addition, within 6 months of discontinuing treatment, the recurrence rate between the three groups was similar. Finally, one study evaluated the role of sitz baths in symptom relief and acute anal fissure healing while also providing psyllium supplementation over 4 weeks.(15) Although there was a trend toward improved pain scores after defecation and overall intensity of pain, there were no significant differences in fissure healing between groups (85%). The authors hypothesize that sitz baths provide transient pain relief via a thermosphincteric reflex which allows for decrease in sphincter tone and temporary pain relief. However, sitz baths do not lead to long-term reduction in anal tone that allows for fissure healing. Overall, these studies show that fiber therapy is more effective in preventing acute anal fissure recurrence, but only suggest that fiber therapy can improve acute fissure healing. In an effort to improve acute anal fissure healing rates and maintain healing, some investigators have added anal dilation or pharmacologic agents to conservative treatment. One study shows no additional therapeutic benefit of twice daily anal dilation in combination with stool softener and lignocaine jelly.(16) Another small randomized study that included patients with both acute and chronic fissures compared topical nitroglycerin to topical xylocaine.(17) In patients who had acute fissures, those receiving topical nitroglycerin had fissure healing rates of 92% compared to 0% of the control arm after 14 days of therapy. This treatment effect persisted, with the same number of patients in the nitroglycerin group maintaining healing at 28 days compared to 50% of patients who received xylocaine ointment. No long-term follow-up data was provided and all treatment failures were referred for lateral sphincterotomy. A larger randomized trial examined the healing rate of acute anal fissure after treatment with 0.2% nifedipine ointment twice daily compared to conservative therapy. (18) Patients who received nifedipine treatment had higher fissure healing rates compared to conservative therapy (98 vs. 60%) after 4 weeks of treatment. One novel approach to achieve acute anal fissure healing has been to compare the efficacy of gonyautoxin, a paralyzing phytotoxin, to normal saline placebo which are both 20 surgery and nonoperative therapy of anal fissure injected into the internal anal sphincter.(19) This study included 17 patients with acute anal fissure and was eventually unblinded secondary to a large treatment effect of the toxin. Patients with acute anal fissures had a healing rate of 100% at 15 days as compared to 0% of the 3 patients who received placebo. All patients who were injected with the toxin showed a significant decrease in anal resting pressure from baseline. Complications included minor bleeding but did not result in any cases of incontinence to stool or flatus. After 14 months of follow-up this treatment effect has been maintained. In all, these studies show that the addition of a pharmacologic agent can increase the healing rates of acute anal fissure; however, larger trials are needed to replicate these results. CHRONIC ANAL FISSURE Medical Therapy Anal fissure chronicity is attributed to sphincter hypertonia and decreased anodermal blood flow in the posterior anal canal. Pharma- cologic manipulation of the hypertonic internal anal sphincter has been sought, given the permanent changes that can occur with surgical intervention. Medical treatments that result in temporary relaxation of the internal anal sphincter or chemical sphincterotomy have been used in the treatment of chronic anal fissure. Nitrates Nitrates have been shown to have a relaxing effect on the human internal anal sphincter (IAS). Ex vivo studies on the human IAS show that nitric oxide (NO) mediates sphincter relaxation through enteric inhibitory neurons which are found within the muscle fibers.(20) Nitrates which are NO donors are readily available pharmacologic agents. Loder et al. demonstrated that GTN ointment causes a decrease in anal resting pressure in normal and anal fissure patients which was comparable to sphincterotomy. (21) Schouten and colleagues then showed that anal resting pressure decreased and anodermal blood flow increased after chronic anal fissure patients were treated with isosorbide dinitrate.(22) They concluded that the reduction in anal sphincter pressure and increased blood would contribute to early pain relief, while fissure healing would require more time. More recent studies have shown conflicting data on the ability of nitrates to significantly decrease anal resting pressure in chronic anal fissure patients. Thornton et al. clarified these conflicting results with a regression analysis which showed that patients who were mostly likely to heal their fissure in response to nitrate therapy were those with higher pretreatment anal resting pressures and a greater percent reduction in posttreatment anal resting pressures.(23) Based on these physiologic studies, nitrates have become an obvious choice for the pharmacologic treatment of chronic anal fissure. Nitrates versus Placebo There are ten randomized controlled trials in the English literature which compare nitrate therapy to placebo or conservative therapy in adults with chronic anal fissure. (Table 20.1) There have been a variety nitrate preparations, ointment strengths, Table 20.1 Randomized Controlled Trials of Nitrate Therapy versus Placebo for the Treatment of Chronic Anal Fissure. Author/Year Number Patients Treatment Groups (%) Length Treatment (weeks) Fissure Healing Rates (%) Side Effects (%) Follow-up (months) Recurrence (%) Lund 1997 (24) 80 P vs. 0.2 GTN BID 8 8 vs. 68 (p < 0.0001) HA: 18 vs. 58 (p < 0.05) 4 11.5% GTN Kennedy 1999 (27) 43 P vs. 0.2 GTN TID 4 16 vs. 46 (p = 0.001) HA: 21 vs. 29 Discontinued treatment: 13 29 NR Altomere 2000 (26) 132 P vs. 0.2 GTN BID 4 52 vs. 49 (p = ns) HA: 8 vs. 34 (p = 0.001) Orthostatic hypotension: 6 3 19% GTN Chaudhuri 2001 (25) 19 P vs. 0.2 GTN BID 6 22 vs. 70 (p < 0.05) Not reported 3 None Maan 2004 (28) 64 P / 5 xylocaine / proctosedyl / 0.2 GTN BID 6 25 vs. 94 (p < 0.0001) HA: 0 vs. 19 None NR Carapeti 1999 (29) 70 P / 0.2 / 0.2+0.1qwk GTN TID 8 32 vs. 67 all GTN (p = 0.008) HA: 27 vs. 72 all GTN (p < 0.001) 9 43 vs. 29 (p = 0.7) Bailey 2002 (30) 304 P / 0.1 / 0.2 / 0.4 NTG BID or TID 8 50- all groups (p < 0.62) Discontinued treatment: 3.3 None NR Scholfield 2003 (31) 200 P / 0.1 / 0.2 / 0.4 GTN BID 8 38 vs. 47 all GTN (p = 0.3) HA: 13 vs. 31 all GTN (p < 0.01) None NR Wierre 2001 (31) 37 P vs. 1 IDN 5x/day 10 35 vs. 85 (p < 0.003) HA:18 vs. 45 10 33 vs. 12 Tankova 2002 (32) 19 P vs. 0.2 IMN BID 3 22 vs. 80 HA: 0 vs. 20 3 None Note: P = placebo; GTN = glyceryl trinitrate; BID = twice per day; HA = headache; TID = three times per day; NR = not recorded; NS = not statistically significant; NTG = nitroglycerin; IDN = isosorbide dinitrate; IMN = isosorbide 5-mononitrate. 202 improved outcomes in colon and rectal surgery schedules, treatment length, and instructions for nitrate administration that have been utilized in these studies. Five randomized controlled trials have measured the effect of 0.2% GTN ointment in comparison to placebo.(24–28) In these studies a total of 338 patients were instructed to apply an active versus inert ointment to their anal canal either twice or three time daily for a period of 4 to 8 weeks. Outcome measures included fissure healing, pain, mean anal resting pressure (MARP), fissure recurrence, and ointment side effects. Four of these studies were able to measure an increase in anal fissure healing rates with nitroglycerin ointment compared to placebo.(24, 25, 27, 28) However, there was a wide range of GTN treatment effect (8–52% placebo vs. 46–94% GTN). The fifth and largest study included 132 patients and did not measure a difference in healing rates between the placebo and GTN ointment (52% vs. 49%).(26) In four studies, pain was reported as a secondary outcome. In three studies pain was significantly decreased after treatment compared to pain at time of trial entry in both GTN and placebo groups.(24, 26, 27) However, only one study measured a significant difference in pain scores between GTN and placebo treatment groups.(28) All five studies measured treatment effect on MARP. Two studies measured a decrease in MARP after treatment compared to time at trial entry for both placebo and GTN groups.(25, 26) In the other three studies, only the GTN treatment group had a significant decrease in MARP.(24, 27, 28) One trial reported loss of decreased MARP 48 hours after discontinuing GTN therapy.(27) The most significant side effect of nitrate therapy was headache. In four trials, there was a higher rate of headaches in GTN patients (19–58%) compared to placebo treated patients (0–21%).(24, 25, 27, 28) There was also a difference in the severity of headache reported between these two groups.(27) Ultimately, headaches lead to sub- sequent decreases in dose or discontinuation of GTN for several patients in each trial. In two studies there was an attempt to follow patients long-term.(24, 26) The rate of fissure recurrence in the GTN treated group was 11.5–19% after 3–4 months of follow-up. Overall, these five trials suggest a slightly increased rate of anal fissure healing with GTN ointment compared to placebo. However, there is an increased incidence and severity of headache with GTN treatment which may require a decreased dose for continued patient compliance. Despite healing, there may be a high rate of fissure recurrence within several months of follow-up. Three additional trials have tested the effect of increasing doses of GTN ointment on anal fissure healing rate, MARP, pain scores, headache, and anal fissure recurrence.(29–31) Two trials compared placebo with 0.1%, 0.2% and 0.4% GTN ointment (B,S). The third trial compared placebo with 0.2% GTN ointment and an increasing dose of GTN ointment which started at 0.2% and was increased by 0.1% every week to a dose of 0.6% GTN.(28) All treatment was administered for 8 weeks and applied either BID or TID. In these trials there was only one that measured a difference in fissure healing rate of the GTN treatment group compared to placebo.(29) There were no differences found in fissure healing rate with changes in GTN dose. One trial reported a 21% reduction in pain when treated with 0.4% GTN compared to placebo. (30) There was no difference in pain scores between placebo and GTN or between GTN doses in the other studies.(29, 31) Across these three trials, MARP was not uniformly decreased in the nitrate treated group compared to baseline. All three studies reported a high incidence of headache in the GTN group (31–72%) compared to placebo (13–27%). Headaches were more frequent and severe with increasing dose of GTN ointment. Follow-up was performed in one study. One third of anal fissures that initially healed recurred within 9 months.(29) These trials demonstrate that increasing doses of GTN do not increase the rate of fissure healing or improve fissure related pain, but do result in more severe and frequent headaches. Again, recurrence when reported, occurs in up to one-third of patients. Two additional studies have used alternative nitrate preparations for the treatment of chronic anal fissure for comparison with placebo. Wierre et al. used 1% isosorbide dinitrate ointment five times per day for 10 weeks.(32) There was a significant difference in fissure healing rate between placebo and active ointments (35 vs. 85%). However there was no significant change in MARP throughout the trial period. There was also a significant incidence of headache in the treatment group (45%) compared to placebo (18%) with 10% of patients in the active treatment discontinuing therapy. Thirty-three percent of patients in the active treatment arm had fissure recurrence and requested alternative therapy. Tankova et al. used 0.2% isosorbide mononitrate on chronic anal fissures compared to placebo administered BID over a 3 week treatment course.(33) Eighty percent in the active treatment arm healed their fissures compared to 20% in the placebo group. Twenty percent in the active group had headaches which were treated with mild analgesics. No recurrences were seen in 3 months of follow-up. The authors of both these studies agree that different nitrate preparations can be used to treat chronic anal fissure but that more studies are required to determine the optimal preparation, dose, and schedule of nitrate therapy. Two studies have compared 0.2% GTN ointment to a transdermal nitroglycerin patch for either 6 or 8 weeks of treatment.(34, 35) In both studies the transdermal patch was a 10 mg dose that was applied for either 12 or 24 hours. These studies found that both preparations resulted in equivalent fissure healing rates at 6 weeks (65–73%), 8 weeks (63–67%) and 12 weeks (79–81%). One trial reported a decrease in pain from baseline by 50% in both the ointment and patch patients.(35) The rate of headache was substantially lower in one study (16–19%) (34) compared to another (63–72%) (35) but both studies reported the headache to be responsive to mild analgesics and equal in occurrence between the two treatment groups. Six percent of patients in one study reported transient incontinence to flatus which had resolved by the time of trial resolu- tion.(35) Recurrence at 3 months for one trial occurred in 9–15% (34) patients and 25% in the other.(35) In all, 0.2% GTN ointment seems equivalent to transdermal patch in the rate of anal fissure healing, pain relief, side effects, and recurrence. Overall, chronic anal fissure healing rates after treatment with nitrates (49%) may be slightly improved compared to placebo (37%).(7) Nitrate therapy may decrease pain associated with anal fissure but with a concomitant increase in headaches (27%) that can lead to noncompliance. Given the side effect profile and high recurrence rates after nitrate therapy (33%), the patient may request alternative therapeutic interventions. Nitrate therapy remains a treatment alternative for patients wanting to avoid surgery and does not exclude the patient from other therapies in the future. 20 surgery and nonoperative therapy of anal fissure Nitrates versus Sphincterotomy Nitrate therapy has been compared to internal sphincterotomy for the treatment of chronic anal fissure. Six studies have compared these two treatments in a randomized controlled fashion.(36–41) (Table 20.2) Four studies found internal sphincterotomy to be superior to nitrate therapy for fissure healing after 6–8 weeks. (36–39) The two studies which showed no difference in fissure healing between treatment groups, were smaller and measured a larger nitrate treatment effect than is traditionally seen (83–90%). Richard and colleagues found nitrate therapy to help fissure related pain despite poor fissure healing (36). Parellada and colleagues found a posttreatment decrease in MARP from baseline in both treatment groups (30%) without a significant difference between groups.(39) Four studies found a significant rate of headaches in nitrate treated patients.(36–38, 41) These headaches caused significant problems with patient compliance and 20–30% of patients discontinued ointment application. In comparison, there were relatively few and minor side effects in patients undergoing sphincterotomy. While one study measured a high rate of postoperative incontinence to flatus (44%), this decreased to 15% after 2 years follow-up.(39) Initially, Richards et al. did not find any difference in immediate postoperative continence scores between patients treated with nitrates or sphincterotomy.(36) After 5 years, the investigators contacted 62% of the study patients. With the use of a sensitive incontinence scale, there were still no differences in continence scores between the two groups. However, 2/3 of patients reported some degree of incontinence. Finally, fissure recurrence occurred rarely in patients undergoing sphincterotomy (0–4%) compared to high rates of recurrence among patients treated with nitrates (13–45%). In all, nitrates are significantly less effective than sphincterotomy for fissure healing, acute relief of pain, fissure recurrence, and number of treatment side-effects when administered for treatment of chronic anal fissure. Calcium Channel Antagonists Given the frequency of adverse side effects with nitrate therapy, other medical treatments have been sought for patients with chronic anal fissure. Calcium channel antagonists have been used as alternative agents for temporary chemical sphincterotomy. Calcium is necessary for tonic contraction and spontaneous activ- ity in the IAS smooth muscle.(42) When IAS muscle is subjected to a calcium channel antagonist, nifedipine, tone and spontaneous contraction of the muscle is inhibited. Therefore, a calcium channel antagonist may reduce the IAS hypertonia that is observed in chronic anal fissure. Indeed, nifedipine has been shown to decrease anal resting pressure in normal controls and patients with anal fissure or hemorrhoids.(43) Nifedipine decreased anal resting pressure by approximately 30% in all groups. Decreased anal pressure is thought to cause increased anodermal blood flow and allow for fissure healing. Carapeti and colleagues showed that diltiazem ointment significantly reduced anal resting pressure and allowed for 67% of patients with chronic anal fissure to heal over 8 weeks. However, they were unable to measure a significant difference in anodermal blood flow using laser Doppler before and after diltiazem administration.(44) Due to the ability of calcium channel antagonists to reduce anal resting pressure, they have been used as alternatives to nitrates for chemical sphincterotomy in patients with chronic anal fissure. Calcium Channel Antagonists versus Placebo One study has compared the efficacy of a calcium channel antagonist, nifedipine to a treatment consisting of lidocaine, and hydrocortisone ointment for the treatment of chronic anal fissure.(45) (Table 20.3). One hundred and ten patients were given either 0.3% nifedipine ointment or 1.5% lidocaine plus 1.0% hydrocortisone ointment for twice daily application over 6 weeks. Patients who were given nifedipine ointment had a significant reduction in anal resting pressure (11%) from baseline after 3 weeks of treatment. In addition, 95% of these patients had a healed fissure after 6 weeks. Positive treatment effects were not seen in the placebo treatment arm with manometric studies measuring a 4.4% increase in anal resting pressure, and only 16% of patients experienced fissure healing. The patients did not report any side effects. Six percent of patients treated with nifedipine had fissure recurrence, 66% were Table 20.2 Randomized Controlled Trials of Nitrates versus Surgical Sphincterotomy for the Treatment of Chronic Anal Fissure. Author/ Year Number Patients Treatment Groups (% ointment) Length of Treatment (weeks) Fissure Healing (%) Overall Side-effects (%) HA % IC Flatus (%) Follow-up (months) Recurrence (%) Oettle 1997 (40) 24 NTG/ LIS TID 4 83 vs. 100 (p = NS) NR NR NR 1 NR Richard 2000 (36) 82 0.25/0.5 GTN/LIS TID 6 30 vs. 90 (p = 0.00) 84 vs. 29 (p < 0.0001) 21 None 6 38 vs. 3 Evans 2001 (37) 60 0.2 GTN/LIS TID 8 61 vs. 97 (p < 0.001) NR 33 7.4 5 45 vs. 4 Libertiny 2002 (38) 70 0.2 GTN/LIS TID 8 54 vs. 100 (p = 0.02) NR 20 2.8 24 16 vs. 2.8 Parellada 2004 (39) 54 0.2 IDN/LIS TID 6 67 vs. 96 (p < 0.001) 30 vs. 44 (p = NR) NR 44 @ 5 wk 15 @ 24 wk 24 13 vs. 0 Mishra 2005 (41) 40 0.2 GTN/LIS BID 6 90 vs. 85 (p = 0.347) 40 vs. 70 (p = NR) 15 15 4 NR Note: NTG = nitroglycerin; LIS = lateral internal sphincterotomy; TID = three times per day; NS = not statistically significant; NR = not recorded; GTN = glyceryl trinitrate; IDN = isosorbide dinitrate. 20 improved outcomes in colon and rectal surgery retreated and, once again, their fissure healed. This is in comparison to 55% recurrence in the placebo arm. Of the 47 patients who did not achieve fissure healing or who suffered a recurrence after placebo treatment, 45 elected to have nifedipine treatment at the study conclusion with a 95% healing rate. While this study is prom- ising for the use of nifedipine as an alternative to nitrate therapy for chronic anal fissure, the extent of treatment effect is questionable given the low fissure healing rate in the placebo arm. Calcium Channel antagonists versus Nitrates Five studies have compared calcium channel antagonists to nitrate therapy in patients with chronic anal fissure. (Table 20.3) Three of these studies have used 2% diltiazem ointment in comparison to 0.2% or 0.5% GTN administered over 6–8 weeks.(46–48) All three studies report no difference in anal fissure healing between the GTN or diltiazem treated groups. In all three studies, there were more overall side effects and headaches in the nitrate treated patients compared to the diltiazem treated patients. In the largest of the three studies, recurrence occurred sooner and more frequently among patient receiving GTN compared to diltiazem. (48) Overall, diltiazem ointment has equal efficacy to GTN ointment for anal fissure healing with fewer side effects, and possibly a lower rate and longer interval to recurrence. Two studies used nifedipine preparations for comparison with GTN for the treatment of chronic anal fissure.(49, 50) In one study, a 0.2% nifedipine ointment (49) was used while oral nifedipine was used in the other.(50) Ezri et al. found the nifedipine ointment to be superior to the GTN ointment in healing anal fissure. They also found a higher rate of overall side effects in the GTN treated group. However, both treatment arms were found to have a high recurrence rate over 12 months (31–42%). In contrast, the oral nifedipine was equivalent to GTN ointment in fissure healing, recurrence, and side effects. These two studies demonstrate that multiple preparations of calcium channel antagonists may be used for the treatment of chronic anal fissure with equal healing efficacy and fewer side effects than GTN ointment. Calcium Antagonists versus Sphincterotomy Two studies have compared calcium channel blockade (oral and ointment preparations) to lateral internal sphincterotomy in the treatment of chronic anal fissure.(49, 50) (Table 20.3) While both studies measure a high rate of fissure healing in patients undergoing sphincterotomy (95–100%), there is a wide range in the fissure healing rate for patients receiving nifedipine treatment (16–97%). In one study, oral nifedipine was used.(51) The authors report a significant problem with patient compliance in this treatment arm secondary to side effects, slow fissure healing, and minimal symptomatic improvement. Overall 41% of patients in the oral nifedipine group experienced these problems, and 70% withdrew from the study. While these patients were analyzed on an inten- tion to treat basis, the effect of oral nifedipine on fissure healing may have been substantially decreased. In contrast, Katsinelos and colleagues measured a high rate of fissure healing after treatment with nifedipine ointment (97%) that was not significantly different from fissure healing after sphincterotomy (100%, p = 0.49). (52) The increased treatment effect of nifedipine ointment may be secondary to a higher dose that was used in this study compared to others (0.5% vs. 0.2%). In addition, topical calcium channel antagonists have been proven more effective than oral preparations in fissure healing and side effect profile.(53) Overall, these studies suggest that oral calcium channel antagonists do not increase fissure healing rates but do increase side effects. However, increases in ointment concentrations may increase treatment efficacy without a change in adverse side effects. Table 20.3 Randomized Controlled Trials of Calcium Channel Blockers for the Treatment of Chronic Anal Fissure. Author/ Year Number of Patients Treatment Groups (% ointment) Length of Treatment (weeks) Fissure Healing (%) Overall Side Effects (%) Follow-up (months) Recurrence (%) Perrotti 2002 (45) 110 1.5 lidocaine + 1.0 hydrocortisone vs. 0.3 N BID 6 16 vs. 95 (p < 0.001) None 18 55 vs. 6 (p = NR) Kocher 2002 (47) 60 0.2 GTN vs. 2 D BID 6–8 86 vs. 77 (p = 0.21) 72 vs. 42 (p = 0.01) 3 2 vs. 0 (p = NR) Bielecki 2003 (46) 43 0.5 GTN vs. 2 D BID 8 86 vs. 86 (p = 0.95) 33 vs. 0 (p = NR) None NR Ezri 2003 (49) 52 0.2 GTN vs. 0.2 N QID 24 58 vs. 89 (p < 0.04) 40 vs. 5 (p < 0.01) 12 31 vs. 42 (p = NR) Mustafa 2005 (50) 20 0.2 GTN vs. 20 mg PO N BID 8 70 vs. 60 (p = NS) 30 vs. 10 (p = NR) 3 0 vs. 10 (p = NR) Shrivastava 2007 (48) 90 P vs. 0.2 GTN vs. 2 D BID 6 33 / 73 / 80 (p = <0.02) 0 / 67 / 0 (p = NR) 12 13 / 32 / 50 (p < 0.015) Ho 2005 (51) 132 LIS vs. TS vs. 20 mg PO N BID 6 96/ 95/ 16 (p < 0.001) No difference in continence 4 0/ 2.4/ 57 (p = 0.003) Katsinelos 2006 (52) 64 LIS vs. 0.5 N TID 8 100 vs. 97 (p = 0.49) 19 vs. 50 (p = NR) 20 0 vs. 7 (p = NR) Jonas 2001 (53) 50 60 mg PO D vs. 2 D BID 8 38 vs. 65 (p = 0.09) 33 vs. 0 (p = 0.001) 6 11 vs. 7 (p = NR) Note: N = nifedipine; BID = two times per day; NR = not recorded; GTN = glyceryl trinitrate; D = diltiazem; QID = four times per day; NS = not statistically significant; LIS = lateral internal sphincterotomy; TS = tailored sphincterotomy; TID = three times per day. 20 surgery and nonoperative therapy of anal fissure In summary, topical calcium channel antagonists may be used in the treatment of chronic anal fissure. They have similar efficacy to nitrates with a lower occurrence of side effects. Topical preparations of nifedipine or diltiazem are preferred over oral preparations due to a higher fissure healing rate and fewer side effects compared with oral administration. Sphincterotomy remains the gold standard for healing of chronic anal fissure, but given the chance for incontinence after surgery, topical calcium channel antagonists are preferred for first line therapy. Botulinum toxin Botulinum toxin (BT) is an exotoxin produced by the bacterium Clostridium botulinum. BT has been used medically in the treatment of multiple diseases in which there is muscular hypertonicity. Chronic anal fissure is characterized by internal anal sphincter (IAS) hypertonia and has been treated with BT since 1993. The exact mechanism of BT on internal anal sphincter relaxation is still unclear. In striated muscle, BT binds to presynaptic nerve terminals and prevents the release of acetylcholine, resulting in paralysis. However, in smooth muscle, BT reduces the release of excitatory neurotransmitters from sympathetic nerves and probably causes IAS relaxation through sympathetic blockade.(54) Manometric studies demonstrate a sustained decrease in mean anal resting pressure (MARP) when BT is injected into the internal anal sphincter. This sustained reduction in MARP is in contrast to the short-lived relaxation seen in response to GTN therapy. This longer period of IAS relaxation after BT injection may lead to higher rates of chronic anal fissure healing secondary to improved blood flow to the posterior commissure. Multiple studies have been performed to determine the optimal dose and method of delivery for BT to the IAS. Most studies have been performed to determine the BT dose with the highest fissure healing rate and the least amount of complications.(55–59) All these studies show that fissure healing rates are improved with increasing BT doses. Botox doses as high as 40–50 units of have been used in a single injection. Increasing doses do not lead to higher complication rates but do lead to more significant decreases in MARP from baseline.(57) This increased efficacy is secondary to a dose dependent diffusion of the toxin through the IAS muscle. Higher BT doses have a direct effect throughout the muscle whereas smaller BT doses demonstrate a gradient of paralysis through the muscle length.(58) Other factors which may lead to variations in clinical response are differences in drug dilution volumes, number of injection sites, presence or absence of antibodies, variations in active drug, and susceptibility of target cells. Maria et al. examined the role of BT injection site on fissure healing.(60) Their hypothesis was that posterior injection of BT leads to impaired diffusion of the toxin secondary to increased fibrosis around posterior fissures. Indeed, they found that 20 units of Botox on either side of the anterior midline resulted in lower mean anal resting pressures as well as higher fissure healing rates compared to 20 units of Botox administered on either side of the posterior midline. Results from these studies show BT is safely administered in high doses (30–40 units Botox) as initial therapy and may be more effective if administered in the anterior rather than posterior midline. Botulinum Toxin versus Placebo Three randomized studies have evaluated BT efficacy in comparison to a “placebo” treatment.(61–63) (Table 20.4). In two studies, normal saline injections of a volume equal to that of the toxin used, were injected into the IAS.(62, 63) In the third Table 20.4 Randomized Controlled Trials of Botulinum Toxin for the Treatment of Chronic Anal Fissure. Author/ Year Number of Patients Treatment Groups Fissure Healing (%) Side Effects (%) Follow-up (months) Recurrence (%) Maria 1998 (57) 30 0.4 ml saline vs. 20 U B 13 vs. 73 (p = 0.003) IC flatus: 3.3 overall 4 None Colak 2002 (61) 62 Lidocaine BID 4 wks vs. 50 U B 21 vs. 71 (p = 0.006) None 2 NR Siproudis 2003 (62) 44 0.4 ml saline vs. 100 U Dysport 32 vs. 32 (p = NS) Perianal thrombosis: 9.1 vs. 18.2 Abscess: 13.6 vs. 4.5 3 9.1 vs. 13.6 (p = NS) Brisinda 1999 (64) 50 0.2%GTN BID 6 wks vs. 20 U B a 60 vs. 96 (p = 0.005) GTN: 20% HA BT: None 15 None DeNardi 2006 (66) 30 0.2% GTN BID 8 wks vs. 20 U B 3 months: 67 vs. 47 (p = 0.51) GTN: 20% HA BT:None 36 33 vs. 33 (p = NS) Fruehauf 2006 (67) 50 0.2% GTN BID 2 wks vs. 30 U B 2 weeks: 52 vs. 24 (p < 0.05) 26% overall GTN: 48% HA 3 NR Brisinda 2007 (65) 100 0.2% GTN TID 8 wks vs. 30 U B a 70 vs. 92 (p = 0.009) GTN: 34% HA BT: 6% IC flatus 21 20 vs. 0 (p = NR) Mentes 2003 (71) 101 LIS vs. 0.3U/kg BT (20U or 30U) B 98 vs. 74 (p < 0.001) IC: 8 vs. 0 12 5 vs. 11 (p = NR) Iswariah 2005 (70) 38 LIS vs. 20 U B 6 weeks: 86 vs. 41 (p = 0.004) IC: no difference 6 10 vs. 53 (p < 0.05) Arroyo 2005 (69) 80 LIS vs. 25 U B 12 months: 93 vs. 45 (p < 0.001) IC: 7.5 vs. 5 (p = NS) 36 7.5 vs. 55 (p < 0.001) Note: B = Botox; IC = incontinence; BID = two times per day; NR = not reported; NS = not statistically significant; GTN = Glyceryl trinitrate; HA = Headache; TID = three times per day; LIS = Lateral Internal sphincterotomy a. Crossover after 2 months treatment. 20 improved outcomes in colon and rectal surgery study, lidocaine ointment was applied twice daily and with bowel movements for a 4 week period.(61) In two studies, there was a significant difference in fissure healing between placebo and BT treated patients (13–21% vs. 71–73%).(61, 63) In the third, there was no measured difference in fissure healing between the two groups (32%).(62) Maria et al. also reported a 25% posttreatment decrease in MARP from baseline in the toxin group but not in the placebo group.(63) Reported side effects in these studies were minimal with incontinence to flatus in one patient, perianal thrombosis in six and perianal abscess in four of 136 total patients. The recurrence rate was not consistent among these studies with reports of no recurrence compared to a high of 13% in the BT treatment group after 4 months. The different findings in these three studies which compare BT to placebo for chronic anal fissure may be explained by methodological differences and baseline differences in the study groups at randomization. In one trial there were more men and higher maximal voluntary anal squeeze pressures in the placebo group as compared to the BT treated group.(63) This may have lead to a difference in treatment effect. Also, one trial was not able to be blinded secondary to the use of ointment in the placebo group and injection in the toxin group.(61) It is unclear whether clinicians who were grading fissure healing were blinded to randomized treatment groups. Finally, the third study was stopped early before reach- ing the intended sample size because of newly published studies demonstrating BT efficacy in fissure healing. Despite these methodological differences and group differences after randomization, these studies suggest that BT is superior to placebo in the healing of chronic anal fissure. Botulinum Toxin versus Nitrates Four randomized trials have compared the efficacy of BT to GTN ointment.(64–67) (Table 20.4) In each trial there were differences in the length of treatment (2–8 weeks) and application frequency (2–3 times per day) of GTN ointment. There were also differences in the dose of BT used with two studies using 20 units of Botox and the other two studies using 30 units. Two studies found a significant improvement in anal fissure healing for patients treated with BT compared to 0.2% GTN ointment (92–96% vs. 60–70%). (64, 65) A third study measured an advantage of GTN treatment administered over 2 weeks compared to BT (52% vs. 24%).(67) These findings are surprising given the previous studies which show 4–8 weeks are needed to achieve fissure healing with GTN treatment. In the fourth study, there was no difference in treatment efficacy between BT and GTN ointment administered over 8 weeks.(66) However, this is the smallest of the four studies and may not have been adequately powered to measure a difference in treatment efficacy. Patients treated with GTN ointment were more likely to suffer adverse side effects (20–34% headache) in comparison to BT treated patients (0–6% temporary incontinence to flatus). Fissure recurrence was more frequent in GTN treated patients in one study (65) but not in another.(66) In a different study, long-term fissure recurrence after BT treatment was 42% after 42 months.(68) Overall, these studies show a benefit of BT compared to GTN in terms of short term fissure healing and adverse medication effects. Frequent fissure recurrence after GTN and BT treatment has been observed. In two studies of GTN versus BT treatment crossover was performed at 2 months.(64, 65) Patients who did not heal with their initial treatment and accepted the alternative treatment were able to achieve fissure healing with the alternative treatment In both studies, patients who failed BT and then received GTN (8 patients), experienced fissure healing within 2 months. Twenty one patients who failed GTN and then received BT achieved fissure healing within 2 months. These studies suggest that patients who fail initial therapy with GTN or BT, can be successfully treated with an alternative medical therapy before surgical treatment is considered. Botulinum Toxin versus Sphincterotomy There are three randomized studies which compare outcomes for patients receiving either BT or internal sphincterotomy (IS). (69–71) (Table 20.4) In these studies, IS was superior to BT for fissure healing (86–98% vs. 41–75%). While sphincterotomy is usually avoided secondary to fears of incontinence, there was no significant difference in continence scores in any of these four studies. Incontinence after fissure treatment with either BT or sphincterotomy was associated with lower mean anal resting pressures after treatment and age >50 years.(69) Fissure recurrence was also more common in BT treated patients compared to IS treated patients.(69, 70) Recurrences were seen 6–12 months after fissure healing.(69) Recurrence was associated with certain clinical and manometric risk factors. These include symptom duration greater than 12 months, presence of a sentinel pile, persistently elevated mean anal resting pressure and amount of time slow wave and ultra slow waves are present on manometric examination. Based on these studies, patients who are at high risk of anal fissure recurrence should undergo IS as a first line therapy. In patients who are at high risk of incontinence after IS, the first line therapy should be BT since healing can be achieved with lower complications even if repeat injection is required. Overall, BT injections can be used for the treatment of chronic anal fissure with improved fissure healing rates compared to placebo and GTN. Fissure healing may take longer after BT treatment when compared to fissure healing after IS, but is associated with few complications. Patients at high risk of incontinence (age> 50 yrs, previous anorectal surgery, multiparous females, diagnosis of inflammatory bowel disease) should be treated with BT before IS. Anal fissure recurrences after BT treatment are common, but can be treated with repeat BT injection without adverse effects. SURGICAL THERAPY While surgical treatment of chronic anal fissure has been employed since the 19th century, improved pathophysiologic understanding in the middle of the 20th century, led to the reintroduction of surgical treatments. In 1964, Watts, Bennett and Goligher described stretch- ing of the anal sphincter with finger dilation, and Eisenhammer recommended sectioning the internal anal sphincter to reduce sphincter resting pressure.(72, 73) Since their initial description, anal dilation and sphincterotomy have been used in numerous randomized controlled trials to determine the ideal surgical treatment for chronic anal fissure. Overall there is a clear benefit of sphincterotomy compared to anal stretch for fissure healing and postoperative incontinence. This has been confirmed in clinical trials as well as manometric evaluations. After sphincterotomy, mean 20 surgery and nonoperative therapy of anal fissure anal resting pressure is permanently reduced in patients with anal fissure who have been shown to have significantly elevated preop- erative resting pressures compared to controls.(74) Yet, the initial surgical techniques of Watt and Eisenhammer have been revised with multiple studies comparing the efficacy of modified surgical interventions on fissure healing, recurrence, anal resting pressure, and treatment complications such as incontinence. Anal Dilatation Anal dilation has been used in three different forms for the treatment of chronic anal fissure. Gentle, graduated anal dilation has been accomplished with standardized anal dilators (20–27 mm) which are increased in size over several weeks of treatment. Anal dilation has also been achieved with a one time pneumatic balloon dilation of the sphincter to 1.4 atmospheres. Finally, anal dilation has been performed using anal stretch with 4–6 finger dilation of the sphincter. All these techniques have been criticized for the poorly controlled sphincter stretch that results in damage to both the internal and external sphincter. The result of uncon- trolled sphincter stretch can lead to high rates of incontinence for both flatus and stool that may be permanent. In reality, each of these forms of anal dilation lead to variable degrees of control over the amount of sphincter stretch and thereby affect fissure healing, recurrence, and incontinence rates differently. The forceful anal stretch procedure has the least amount of standardization on sphincter dilation. It has been compared to the gold standard, internal anal sphincterotomy, in five randomized controlled trials.(75–79) Three of these studies found that internal sphincterotomy was superior to anal stretch secondary to higher fissure healing rates (90–97% vs. 70–71%) with significantly lower rates of incontinence (3.3–20% vs. 20–39%).(75–77) The other two studies found an advantage in fissure healing rates after anal stretch at 4 month follow-up with comparable rates of fissure recurrence and incontinence.(77, 79) However, these two studies have been criticized for high drop out rates, short follow- up, and question of inadequate sphincterotomy. Overall, internal sphincterotomy is superior to forceful anal stretch for the surgical treatment of chronic anal fissure. Given previous criticisms, techniques for controlled anal stretch have been developed. When graduated anal dilators are used over several weeks, the effect on fissure healing is inconsequential and not better than placebo.(80) The addition of heat to anal dilators along with nitroglycerin ointment may lead to improved fissure healing rates (94% at 12 months). (81) However, this was a small study which has not been replicated. Controlled anal stretch with increased dilation effect has been attempted with pneumatic balloon dilation. In a prospective clinical trial, Renzi and colleagues measured the effect of anal balloon dilatation to 1.4 atmospheres over six minutes. In 33 patients, 94% healed within 5 weeks of treatment, 3% recurred over 12 months and 6% of patients had transient incontinence. These treatment effects were achieved with a measureable decrease in anal resting pressure with no visible sphincter defect on endorectal ultrasound.(82) This study was followed by a randomized controlled trial of 36 patients who received either pneumatic sphincter dilatation or nitroglycerin ointment.(83) At 30 days, 95% of patient undergoing pneumatic sphincter dilation had healed fissures compared to 40% of patients who received nitroglycerin ointment. While local wound problems such hemorrhoid thrombosis occurred in the short-term, there were no patients who complained of problems with continence after pneumatic dilation. In all, graduated anal dilation is not more effective than placebo for the treatment of chronic anal fissure, while pneumatic balloon dilation of the sphincter may result in improved fissure recurrence and incontinence rates than those seen with forceful anal dilation. Further studies of pneumatic balloon dilation are needed to see if it is in fact comparable to internal sphincterotomy. Sphincterotomy Internal sphincterotomy has also been subjected to revisions in technique. Initially, Eisenhammer described division of the external sphincter and then modified his technique to that of the internal sphincter at the posterior midline.(73) Overtime, it became apparent that fissurectomy with posterior midline sphincterotomy resulted in a “keyhole deformity” or deep furrow in the excision site which interfered with closure of the anal canal while at rest.(84) This deformity lead to increased rates of incontinence compared to lateral sphincterotomy with longer healing times. (78) Posterior sphincterotomy has subsequently been abandoned in favor of lateral internal sphincterotomy. Lateral internal sphincterotomy has also been performed in an open and closed fashion. The open technique involves a 1–2 cm skin incision over the intersphincteric groove and lateral to the anal canal.(85) The internal anal sphincter is then separated from the external sphincter and mucosa up to the dentate line so that it can be divided under direct vision. Closed internal sphincterotomy was first described by Notaras in 1969.(86) With this technique, an 11 blade scalpel is inserted through the anoderm into the intersphincteric plane. While using a finger for guidance, the surgeon rotates the blade 90 degrees and an internal sphincterotomy is performed upto the dentate line. Given the blind technique of closed internal sphincterotomy, surgeons have questioned the adequacy of sphincter division using this technique. In fact, closed sphincterotomy has been compared to open sphincterotomy in 4 randomized controlled trials with 299 patients.(87–90) All four studies found equivalent rates of fissure healing (90–100%), and recurrence (0–10%). Incontinence occurred infrequently (4.1– 7.5%) and improved with time. Therefore, both open and closed techniques have been shown through randomized controlled trials to have equal outcomes. Surgical treatment of chronic anal fissure can lead to variable rates of incontinence to gas and liquids that can be temporary or permanent. In an effort to reduce rates of incontinence after sphincterotomy, investigators have sought to determine the optimal length of sphincterotomy which allows for fissure healing but minimizes postoperative incontinence. Two randomized studies have examined the role of sphincterotomy length on fissure healing, recurrence, and incontinence. In these studies, limited sphincterotomy to the fissure apex was compared to a full sphincterotomy to the dentate line.(91–92) Fissure healing rates were similar (88–100%) in both studies. In one study there was no fissure recurrence after 24 weeks of follow-up (91), and, in the other, there was a 13.2% treatment failure rate in the limited sphincterotomy group.(92) There were also short-term differences in incontinence between . 9 improved outcomes in colon and rectal surgery 155. Consten CJ, Siors FJM, Noten HJ et al. Anorectal surgery in human immunodeficiency virus-infected patients. Dis Colon Rectum. related to etiology. 200 improved outcomes in colon and rectal surgery DIAGNOSIS The clinician should inquire about known risk factors for fissure including alteration in bowel habits (constipation. nitroglycerin; IDN = isosorbide dinitrate; IMN = isosorbide 5-mononitrate. 202 improved outcomes in colon and rectal surgery schedules, treatment length, and instructions for nitrate administration

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