The Role of Pharmacotherapy in Perioperative Management of Patients with Acromegaly

Anat Ben-Shlomo and Shlomo Melmed

Cedars-Sinai Research Institute, University of California Los Angeles School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Academic Affairs, Room 2015, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail: melmed{at}csmc.edu.

The major complications of acromegaly, including cardio- and cerebrovascular disease and respiratory and metabolic dysfunction, are associated with a significant increase in morbidity and mortality (1, 2, 3). These complications are well known to be major risk factors in perioperative patients, especially the elderly (4, 5, 6, 7, 8). Therefore, controlling cardio- and cerebrovascular disease, pulmonary dysfunction, and hyperglycemia is important in patients undergoing anesthesia and surgery. This review evaluates the rationale for administering somatostatin analog treatment before either transsphenoidal resection of a GH-secreting pituitary adenoma or any other surgical procedure requiring general anesthesia in the patient with uncontrolled acromegaly.

Preoperative pharmacotherapy and remission rates

Does treatment with somatostatin analogs before surgery improve surgical outcome?

In the hands of an experienced surgeon and if rigorous criteria are used to interpret surgical results [GH <= 1 ng/ml after oral glucose tolerance test (OGTT) and normalized IGF-I levels], approximately 90% of patients with microadenomas and 50% of those with macroadenomas are controlled by surgery in the most experienced centers (9). In a recent study, 70% of 57 surgically treated patients (67% of whom harbored macroadenomas) exhibited normalized IGF-I, and 61% exhibited nadir GH less than 1 µg/liter 12 months after surgery (10). Summarizing 14 studies (Table 1Go), 55–89% of patients harboring mostly macroadenomas experience disease control if short-term treatment with somatostatin analogs is administered before surgery, and 23–100% exhibit more than 20% tumor shrinkage. If tight control is achieved with sc octreotide (GH <= 1 ng/ml after OGTT and normal IGF-I levels; Ref.1), 55–75% of patients have controlled hormone levels, and 36–50% exhibit tumor shrinkage. Insufficient studies have been conducted using octreotide LAR (long-acting release) or lanreotide SR (slow release), but remission rates may well be higher because patient compliance is improved and control of serum hormone levels by slow-release drugs is readily attainable. The statistical estimation of disease control rose from 68% success rate for patients with macroadenomas treated with primary pharmacotherapy to 81% (and even 87% for noninvasive macroadenomas) for patients undergoing surgery followed by postoperative somatostatin analogs (11). The question of whether shrinkage of tumors before surgery may facilitate their complete resection has not been examined in a controlled, randomized, blinded manner and therefore cannot be rigorously answered.


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Table 1. Outcomes of somatostatin analog perioperative treatment

 
Is the response to primary treatment with somatostatin analog more favorable than when these drugs are administered after surgery or irradiation?

Baldelli et al. (12) addressed this question by comparing serum GH responses to lanreotide in 3 groups of patients (71 who underwent surgery, 24 who were irradiated, and 23 newly diagnosed and not yet treated; Fig. 1Go). After 6 months, the response to lanreotide in naive patients was more favorable than that observed in previously irradiated patients, and after 12 months it was also improved over previously operated patients. No such observed difference was reported for IGF-I levels. The authors concluded that prior radiotherapy probably caused partial somatostatin resistance. In contrast, another study found no differences in GH or IGF-I levels in 15 naive patients and in operated patients receiving long-term octreotide LAR for up to 24 months (13). Seventy-three percent of newly diagnosed patients had GH levels of 2.5 ng/ml or less, and 53% had normal IGF-I levels after octreotide LAR treatment. In patients who underwent surgery before medical treatment, 76% had GH of 2.5 ng/ml or less, and 71% had normal IGF-I levels (13).



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Figure 1. GH levels during long-term lanreotide treatment in operated, irradiated, and newly diagnosed patients. Number of patients is shown in parentheses. a, P < 0.05 vs. irradiated; b, P < 0.05 vs. operated; c, P < 0.0005 vs. irradiated; d, P < 005 vs. irradiated. Figure was compiled from data derived from Ref.12 .

 
Therefore, currently available results indicate that primary therapy does not seem beneficial for the already excellent outcomes achieved with microadenoma resections. As for macroadenomas, preoperative biochemical control may improve cure rates.

Perioperative morbidity

Does pharmacotherapy alter the frequency of perioperative morbidity in patients undergoing surgery?

Although morbidity and mortality during and immediately after transsphenoidal excision of a GH-secreting tumor is low (11, 14, 15), in the hands of experienced neurosurgeons the extent and magnitude of perioperative complications should be assessed. Large variability in surgical expertise influences cure rates after surgery (whether reported or not). With improved medical care, life expectancy of patients with acromegaly is now longer, compared with previous decades, and the longer the duration of the disease, the more likely the occurrence of complications such as diabetes, cardio- and cerebrovascular disease, and respiratory problems. The frailty of older age renders these patients more prone to complications of acromegaly compared with younger patients, and their ability to undergo surgery safely is compromised. Thus, it is important to determine whether primary pharmacotherapy before surgery prevents or ameliorates perioperative complications.

Overall, patients with acromegaly experience anesthetic morbidity (16). Cardiovascular, pulmonary, and metabolic parameters were examined retrospectively in 28 patients with acromegaly compared with 28 sex- and age-matched controls undergoing general anesthesia. Although no significant major hemodynamic changes or differences in response to vasoactive drugs during anesthesia were noted, 12 of 28 patients (>20%) had anesthetic-associated hemodynamic changes, compared with only 5 in the control group. Gas exchange abnormalities in some patients did not significantly impact anesthesia. Blood glucose levels were higher, and urine output was lower in patients with acromegaly during anesthesia compared with controls. Twelve of 28 patients with acromegaly had a difficult intubation (vs. 1 of 28 controls), and 3 required fiberoptic intubation (vs. none of the controls). Therefore, lessening soft tissue swelling and improving hemodynamic function before surgery may ameliorate some of these complications.

In addition to these direct effects on the anesthetic procedure, several unique clinical factors of acromegaly also contribute to perioperative morbidity. These complications are largely caused by the deleterious impact of high GH or IGF-I levels; all require careful clinical evaluation and management.

Cardiovascular disease is the most important determinant of morbidity and mortality in acromegaly, responsible for approximately 60% of deaths (3, 17, 18), and is therefore of concern for preoperative assessment. Even patients with shorter disease duration and younger patients exhibit impaired cardiac structure and function (19).

Before surgery, both overt and underlying cardiovascular disease should be evaluated. Early manifestations include left ventricular hypertrophy (LVH) with increased wall thickness and cavity dimension, increased stroke volume and cardiac index (19, 20, 21), and ultimately development of concentric biventricular cardiomyopathy with diastolic (21, 22, 23) and eventually systolic dysfunction, reduced left ventricular ejection fraction (LVEF) on effort and rest, and finally cardiac failure (17). A recent study found that 10 of 102 newly diagnosed patients (90% males) with acromegaly had overt high output heart failure (20). Moreover, other acromegaly complications including dyslipidemia, insulin resistance, or overt diabetes mellitus may also contribute to ischemic heart disease, further compromise cardiovascular function, and lead to deleterious effects during and after surgery.

To date, there is insufficient data regarding cardiovascular morbidity and mortality during and after surgery in acromegaly. It is reasonable to assume that the longer the duration of the active disease (24) and the older the patient (25), the more severe and prevalent the cardiac disease, and more cardiovascular complications during and after surgery are expected. Hence, improving cardiac performance before surgery should be beneficial. Improved cardiac function has been reported with octreotide, octreotide LAR, and lanreotide (24, 25, 26, 27, 28, 29). In patients who achieved disease control, there was a reduction in left ventricular mass and septal and posterior wall mass after 1 wk to 10 yr of therapy (24, 25, 27, 28, 29). Although improved LVEF at rest, during, and after exercise was observed in controlled patients after 6 months to 5 yr of octreotide LAR (27), and 1 yr and 5 yr of sc octreotide (25, 30), other reports did not show improved LVEF even after 18 months treatment with lanreotide (29). Diastolic dysfunction did not improve after therapy (25). Surprisingly, even 1 d of octreotide infusion to 10 patients with LVH improved systolic and diastolic functional indexes at rest, anaerobic threshold, and workload and oxygen consumption at maximal exercise, as assessed by echocardiography and bicycle ergometry (31). Similar results were reported after a single lanreotide injection (32). Insufficient data exist regarding the relationship between suppression of GH/IGF-I levels with pharmacotherapy and subsequent cardiac effects in patients with established severe cardiomyopathy. This would suggest a beneficial impact of preoperative octreotide administration on cardiac indices.

Increased prevalence of simple to life-threatening arrhythmias may complicate perioperative outcomes. The frequency of late potentials, a predictor of ventricular dysrhythmias (including severe ventricular dysrhythmias with sudden death), is significantly higher in patients with active acromegaly compared with healthy control subjects (prevalence of 23% vs. 0%, respectively). Only 2 of 36 controlled patients (GH <=1 ng/ml after OGTT and normal IGF-I) had late potentials (33). Ninety-two percent of daily ventricular premature complexes disappeared after 4 wk of treatment with octreotide before transsphenoidal surgery (34). Heart rate decreased in patients with LVH who were treated with somatostatin analogs (28, 32) and only if GH/IGF-I levels were controlled (25, 30). Three to 6 months of octreotide treatment normalized electrocardiogram recordings in 7 of 11 patients, and sinus arrhythmia, supraventricular, and ventricular tachycardia improved in 6 of 11 patients (26).

Hypertension occurs in 20–51% of patients with active acromegaly (17, 35) and aggravates acromegalic cardiomyopathy, atherosclerosis, and cardio- and cerebrovascular disease (36). Preoperative blood pressure control may not correlate with GH or IGF-I levels. Effects of somatostatin analogs on blood pressure in patients with acromegaly are unclear. A decrease in systolic blood pressure occurred in 10 patients with LVH treated with octreotide (28), and decreased systolic and diastolic pressure were reported in 5 of 8 patients treated with octreotide for 6 months (26). In contrast, no differences in blood pressure were demonstrated in more prolonged studies with octreotide (25, 30), octreotide LAR (27), or lanreotide (29). However, systolic blood pressure was reduced in 10 patients after a single lanreotide injection (32). It is therefore unclear whether or not treatment with somatostatin analogs is beneficial for short- or long-term blood pressure control in these patients.

Integrity of the respiratory system is a critical preoperative clinical concern because a 2-fold increase in mortality due to respiratory disorders was reported in patients with acromegaly. Importantly, duration of disease did not correlate with respiratory mortality (3). Respiratory disorders occur commonly in acromegaly and are mainly attributed to tissue swelling and thickening of the upper respiratory tract, including macroglossia, hypertrophied nasal structures, and enlargement and distortion of glottic structures with additional folds. Laryngeal and pharyngeal soft tissue hypertrophy and vocal cord swelling may result in vocal cord fixation with laryngeal stenosis, which makes intubation difficult and necessitates preoperative fiberoptic intubation or tracheostomy (37, 38). Between 10 and 30% of anesthetic intubations for surgery in acromegaly are reported as difficult (38). Vocal cord edema, mass, length, elasticity, and voice changes improve within 10–14 d of lowering GH levels by surgical tumor excision (39) or octreotide treatment (40) and imply that lowering GH levels using somatostatin analog before surgery may enable easier anesthetic intubation.

Increased lung volumes and lung distensibility with normal diffusion capacity were demonstrated in patients with acromegaly, presumably due to an increase in alveolar size (41). The impact of these changes on lung function during anesthesia and surgery has not been evaluated. Normalization of lung distensibility and volume was partly achieved as GH levels were suppressed by surgery or somatostatin analogs to under 2 ng/ml after OGTT (41).

Sleep apnea was reported in 20–81% of patients with acromegaly (42, 43, 44, 45, 46) especially in men over 50 yr old (46). Intermittent upper airway obstruction with collapse of both the tongue base and soft palate edges as a result of macroglossia and soft-tissue swelling with pharyngeal hypertrophy (42, 44, 47, 48) and/or the existence of central sleep apnea (46) may hamper both pre- and postoperative status of the patient with acromegaly. Sleep apnea is also associated with increased risk for and mortality from coronary heart disease (49, 50), myocardial infarction (51), cerebral infarction (52), and hypertension (50). Although the correlation between GH/IGF-I serum levels and severity of sleep apnea is controversial (42, 46), controlled serum GH levels by sc octreotide were shown to revert the condition within a few days (43, 53, 54), and complete resolution of the disorder is apparent after 6 months of octreotide treatment (54). The number of apneic events per hour, total apnea time, and oxygen saturation improved by approximately 50% in 19 patients with acromegaly treated with octreotide for 6 months (45). Serum GH levels and total sleep apnea time did not correlate (45). Sleep apnea may complicate postoperative extubation in an already swollen hypertrophied larynx (55). Therefore, correction of sleep apnea before anesthesia and surgery may be beneficial for patients with acromegaly, mainly by preventing hypertension and cardio- and cerebrovascular complications.

Preoperative control of blood sugar levels may be efficiently achieved by standard therapy. However, GH is a potent insulin antagonist, and carbohydrate intolerance and diabetes mellitus are encountered in up to 30% of patients with acromegaly (26). Hyperglycemia and hyperinsulinemia may complicate the perioperative period, especially during surgical recovery. Reducing GH and IGF-I levels is expected to improve carbohydrate intolerance. However, the effect of somatostatin analogs on glucose tolerance varies, because octreotide reduces GH levels but also may inhibit insulin secretion. Twenty-two of 90 (23%) patients treated with octreotide developed impaired glucose tolerance or became overtly diabetic, but 3 of 11 diabetic patients became euglycemic during treatment (56). Six months of octreotide treatment resulted in normalized blood glucose levels in three of four patients treated with oral glucose-lowering drugs. Two of four diabetic patients who required insulin were switched to oral glucose-lowering drugs during octreotide treatment (26). Although the net long-term effect of somatostatin analogs on glucose tolerance is yet unclear, the ability to control diabetes before surgery is appealing because diabetic patients are at increased risk for adverse surgical outcomes related to complications of the disease (atherosclerosis, nephropathy, and neuropathy), poor wound healing, and increased susceptibility to infection (57).

In summary, the benefits of using somatostatin analogs before surgery should be carefully considered because optimization of cardiovascular, respiratory, and metabolic functions is important for perioperative morbidity. Somatostatin analogs do not significantly shrink GH-secreting pituitary tumors, compared with the shrinkage of prolactinomas under treatment with dopamine receptor agonists, although there seems to be an improvement in remission rates in patients treated pharmacologically before surgery. The need for preoperative pharmacotherapy should be evaluated in patients with active acromegaly facing surgery. A prospective, controlled study is required to assess the beneficial impact of preoperative somatostatin treatment on perioperative morbidity.

Footnotes

Abbreviations: LAR, Long-acting release; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; OGTT, oral glucose tolerance test; SR, slow release.

Received January 22, 2002.

Accepted November 20, 2002.

References

  1. Melmed S 1998 Tight control of growth hormone: an attainable outcome for acromegaly treatment. J Clin Endocrinol Metab 83:3409–3410[Free Full Text]
  2. Klibanski A, Ho K, Freda PU, Clemmons DR, Barkan AL, Kleinberg DL, Trainer P, Swearingen B, Molitch ME, Wass JAH, Thorner MO, Melmed S, Strasburger CJ, Frohman LA 2001 State-of the art strategies for the diagnosis and management of acromegaly. The Endocrinologist 11:223–232
  3. Orme SM, McNally RJQ, Cartwright RA, Belchetz PE 1998 Mortality and cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol Metab 83:2730–2734[Abstract/Free Full Text]
  4. Muravchick S 2000 Preoperative assessment of the elderly patient. Anesthesiol Clin North America 18:71–89[Medline]
  5. Belzberg H, Rivkind Ai 1999 Preoperative cardiac preparation. Chest 115(5 Suppl):82S–95S
  6. Bach DS 1998 Management of specific medical conditions in the perioperative period. Prog Cardiovasc Dis 40:469–476[Medline]
  7. Peters A, Kerner W 1995 Perioperative management of the diabetic patient. Exp Clin Endocrinol Diabetes 103:213–218[Medline]
  8. Drain CB 1996 Physiology of respiratory system related to anesthesia. CRNA 7:163–180[Medline]
  9. Melmed S, Casanueva FF, Cavagnini F, Chanson P, Frohman L, Glossman A, Ho K, Kleinberg D, Lamberts S, Laws E, Lombardi G, Vance, ML, von Werder K, Wass J, Giustina A 2002 Consensus: guidelines for acromegaly management. J Clin Endocrinol Metab 87:4054–4058[Free Full Text]
  10. Kreutzer J, Vance ML, Lopes MBS, Laws Jr ER 2001 Surgical management of GH-secreting pituitary adenoma: an outcome study using modern remission criteria. J Clin Endocrinol Metab 86:4072–4077[Abstract/Free Full Text]
  11. Freda PU, Wardlaw SL 1998 Primary medical therapy for acromegaly. J Clin Endocrinol Metab 83:3031–3033[Free Full Text]
  12. Baldelli R, Colao A, Razzore P, Jaffrain-Rea ML, Marzullo P, Ciccarelli E, Ferretti E, Ferone D, Gaia D, Camanni F, Lombardi G, Tamburrano G 2000 Two-year follow-up of acromegalic patients treated with slow release lanreotide (30 mg). J Clin Endocrinol Metab 85:4099–4103[Abstract/Free Full Text]
  13. Colao A, Ferone D, Marzullo P, Cappabianca P, Cirillo S, Boerlin V, Lancranjan I, Lombardi G 2001 Long-term effects of depot long-acting somatostatin analog octreotide on hormone levels and tumor mass in acromegaly. J Clin Endocrinol Metab 86:2779–2786[Abstract/Free Full Text]
  14. Swearingen B, Barker FG, Katznelson L, Biller BMK, Grinspoon S, Klibanski A, Moayeri N, Black PM, Zervas NT 1998 Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly. J Clin Endocrinol Metab 83:3419–3426[Abstract/Free Full Text]
  15. Freda PU, Wardlaw SL, Post KD 1998 Long-term endocrinologic follow-up after transsphenoidal surgery for acromegaly. J Neurosurg 89:353–358[CrossRef][Medline]
  16. Seidman PA, Kofke WA, Policare R, Young M 2000 Anesthetic complications in acromegaly. Br J Anaesth 84:179–182[Abstract/Free Full Text]
  17. Saccà L, Cittadini A, Fazio S 1994 Growth hormone and the heart. Endocr Rev 15:555–573[Abstract]
  18. Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK 1994 Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf) 41:95–102[Medline]
  19. Fazio S, Cittadini A, Biondi B, Palmieri EA, Riccio G, Bonè F, Oliviero U, Saccà L 2000 Cardiovascular effects of short-term growth hormone hypersecretion. J Clin Endocrinol Metab 85:179–182[Abstract/Free Full Text]
  20. Damjanovic SS, Neskovic AN, Petakov MS, Popovic V, Vujisic B, Petrovic M, Nikolic-Djurovic M, Simic M, Pekic S, Marinkovic J 2002 High output heart failure in patients with newly diagnosed acromegaly. Am J Med 112:610–616[CrossRef][Medline]
  21. Vianna CB, Vieira ML, Mady C, Lieberman B, Durazzo AE, Knoepfelmacher M, Salgado LR, Ramires JA 2002 Treatment of acromegaly improves myocardial abnormalities. Am Heart J 143:873–876[CrossRef][Medline]
  22. Fazio S, Cittadini A, Sabatini D, Merola B, Colao AM, Biondi B, Lombardi G, Saccà L 1993 Evidence for biventricular involvement in acromegaly: a Doppler echocardiography study. Eur Heart J 14:26–33[Abstract]
  23. Bruch C, Herrmann B, Schmermund A, Bartel T, Mann K, Erbel R 2002 Impact of disease activity on left ventricular performance in patients with acromegaly. Am Heart J 144:538–543[CrossRef][Medline]
  24. Hradec J, Marek J, Kral J, Janota T, Poloniecki J, Malic M 1993 Long-term echocardiographic follow-up of acromegalic heart disease. Am J Cardiol 72:205–210[Medline]
  25. Colao A, Cuocolo A, Marzullo P, Nicolai E, Ferone D, Florimonte L, Salvatore M, Lombardi G 1999 Effects of 1-year treatment with octreotide on cardiac performance in patients with acromegaly. J Clin Endocrinol Metab 84:17–23[Abstract/Free Full Text]
  26. Colao A, Ferone D, Cappabianca P, del Basso De Caro ML, Marzullo P, Monticelli A, Alfieri A, Merola B, Call A, de Divitiis E, Lombardi G 1997 Effect of octreotide pretreatment on surgical outcome in acromegaly. J Clin Endocrinol Metab 82:3308–3314[Abstract/Free Full Text]
  27. Colao A, Marzullo P, Ferone D, Spinelli L, Cuocolo A, Bonaduce D, Salvatore M, Boerlin V, Lancranjan I, Lombardi G 2000 Cardiovascular effects of depot long-acting somatostatin analog sandostatin LAR in acromegaly. J Clin Endocrinol Metab 85:3132–3140[Abstract/Free Full Text]
  28. Lim MJ, Barkan AL, Buda AJ 1992 Rapid reduction of left ventricular hypertrophy in acromegaly after suppression of growth hormone hypersecretion. Ann Intern Med 117:719–726[Medline]
  29. Hradec J, Kral J, Janota T, Krsek M, Hana V, Marek J, Malik N 1999 Regression of acromegalic left ventricular hypertrophy after lanreotide (a slow-release somatostatin analog). Am J Cardiol 83:1506–1509[CrossRef][Medline]
  30. Colao A, Cuocolo A, Marzullo P, Nicolai E, Ferone D, Della Morte AM, Petretta M, Salvatore M, Lombardi G 2001 Is the acromegalic cardiomyopathy reversible? Effect of 5-year normalization of growth hormone and insulin-like growth factor 1 levels on cardiac performance. J Clin Endocrinol Metab 86:1551–1557[Abstract/Free Full Text]
  31. Giustina A, Boni E, Romanelli G, Grassi V, Giustina G 1995 Cardiopulmonary performance during exercise in acromegaly, and the effects of acute suppression of growth hormone hypersecretion with octreotide. Am J Cardiol 75:1042–1047[CrossRef][Medline]
  32. Manelli F, Desenzani P, Boni E, Bugari G, Negrini F, Romanelli G, Grassi G, Giustina A 1999 Cardiovascular effects of a single slow release lanreotide injection in patients with acromegaly and left ventricular hypertrophy. Pituitary 2:205–210[CrossRef][Medline]
  33. Herrmann BL, Bruch C, Saller B, Ferdin S, Dagres N, Ose C, Erbel R, Mann K 2001 Occurrence of ventricular late potentials in patients with active acromegaly. Clin Endocrinol (Oxf) 55:201–207[CrossRef][Medline]
  34. Suyama K, Uchida D, Tanaka T, Saito J, Noguchi Y, Nakamura S, Tatsuno I, Saito Y, Saeki N 2000 Octreotide improved ventricular arrhythmia in an acromegalic patient. Endocr J 47(Suppl):S73–S75
  35. Colao A, Cuocolo A, Marzullo P, Nicolai E, Ferone D, Della Morte AM, Petretta M, Salvatore M, Lombardi G 1999 Impact of patient’s age and disease duration on cardiac performance in acromegaly: a radionuclide angiography study. J Clin Endocrinol Metab 84:1518–1523[Abstract/Free Full Text]
  36. Gorelick PB, Sacco RL, Smith DB, Alberts M, Mustone-Alexander L, Rader D, Ross JL, Raps E, Ozer MN, Brass LM, Malone ME, Goldberg S, Booss J, Hanley DF, Toole JF, Greengold NL, Rhew DC 1999 Prevention of first stroke: a review of guidelines and a multidisciplinary consensus statement from National Stroke Association. JAMA 281:1112–1120[Abstract/Free Full Text]
  37. Ben-Shlomo A, Melmed S 2001 Acromegaly. Endocrinol Metab Clin North Am 30:565–583[Medline]
  38. Schmitt H, Buchfelder M, Radespiel-Tröger M, Fahlbusch R 2000 Difficult intubation in acromegaly patients. Incidence and predictability. Anesthesiology 93:110–114[Medline]
  39. Williams RG, Richards SH, Mills RG, Eccles R 1994 Voice changes in acromegaly. Laryngoscope 104:484–487[Medline]
  40. Ezzat S, Snyder PJ, Young WF, Boyajy LD, Newman C, Klibanski A, Molitch ME, Boyd AE, Sheeler L, Cook DM, Malarkey WB, Jackson I, Vance ML, Thorner MO, Barkan A, Frohman LA, Melmed S 1992 Octreotide treatment of acromegaly. A randomized, multicenter study. Ann Intern Med 117:711–718[Medline]
  41. Garcia-Rio F, Pino JM, Diez JJ, Ruiz A, Villasante C, Villamor J 2001 Reduction of lung distensibility in acromegaly after suppression of growth hormone hypersecretion. Am J Respir Crit Care Med 164:852–857[Abstract/Free Full Text]
  42. Rosenow F, Reuter S, Deuss U, Szelies B, Hilgers RD, Winkelmann W, Heiss WD 1996 Sleep apnoea in treated acromegaly: relative frequency and predisposing factors. Clin Endocrinol (Oxf) 45:563–569[Medline]
  43. Hart TB, Radow SK, Blackard WG, Tucker HS, Cooper KR 1985 Sleep apnea in active acromegaly. Arch Intern Med 145:865–866[Abstract]
  44. Ip MSM, Tan KCB, Peh WCG, Lam KSL 2001 Effect of sandostatin LAR on sleep apnoea in acromegaly: correlation with computerized tomographic cephalometry and hormonal activity. Clin Endocrinol (Oxf) 55:477–483[CrossRef][Medline]
  45. Grunstein RR, Ho KKY, Sullivan CE 1994 Effect of octreotide, a somatostatin analog, on sleep apnea in patients with acromegaly. Ann Intern Med 121:478–483[Abstract/Free Full Text]
  46. Grunstein RR, Ho KY, Sullivan CE 1991 Sleep apnea in acromegaly. Ann Intern Med 115:527–532[Medline]
  47. Cadieux R, Kales A, Santen R, Bixler E, Godon R 1982 Endoscopic findings in sleep apnoea associated with acromegaly. J Clin Endocrinol Metab 55:18–22[Abstract]
  48. Isono S, Saeki N, Tanaka A, Nishino T 1999 Collapsibility of passive pharynx in patients with acromegaly. Am J Respir Crit Care Med 160:64–68[Abstract/Free Full Text]
  49. He J, Kryger MH, Zorich FJ, Conway W, Roth T 1988 Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest 94:9–14[Abstract]
  50. Koskenvup M, Kaprio J, Partinen M, Langinvainio H, Sarna S, Heikkila K 1985 Snoring as a risk factor for hypertension and angina pectoris. Lancet 1:893–896[Medline]
  51. Hung J, Whitford EG, Parsons RW, Hillman DR 1990 Association of sleep apnoea with myocardial infarction in men. Lancet 336:261–264[Medline]
  52. Mohsenin V 2001 Sleep-related breathing disorders and risk of stroke. Stroke 32:1271–1278[Abstract/Free Full Text]
  53. Chanson P, Timsit J, Benoit O, Augendre B, Moulonguet M, Guillausseau PJ, Warnet A, Lubetzki J 1986 Rapid improvement in sleep apnoea of acromegaly after short-term treatment with somatostatin analogue SMS 201–995. Lancet 1:1270–1271[Medline]
  54. Leibowitz G, Shapiro MS, Salameh M, Glaser B 1994 Improvement of sleep apnoea due to acromegaly during short-term treatment with octreotide. J Intern Med 236:231–235[Medline]
  55. Young ML, Hanson CW 1993 An alternative to tracheostomy following transsphenoidal hypophysectomy in a patient with acromegaly and sleep apnea. Anesth Analg 76:446–449[Medline]
  56. Koop BL, Harris AG, Ezzat S 1994 Effects of octreotide on glucose tolerance in acromegaly. Eur J Endocrinol 130:581–586[Medline]
  57. Hoogwerf BJ 2001 postoperative management of the diabetic patient. Med Clin North Am 85:1213–1228[Medline]
  58. Barkan A, Lloyd RV, Chandler WF, Hatfield MK, Gebarski SS, Kelch RP, Beitins IZ 1988 Preoperative treatment of acromegaly with long-acting somatostatin analog SMS 201–995: shrinkage of invasive pituitary macroadenomas and improved surgical remission rate. J Clin Endocrinol Metab 67:1040–1048[Abstract]
  59. Plöckinger U, Reichel M, Fett U, Saeger W, Quabbe HJ 1994 Preoperative octreotide treatment of growth hormone-secreting and clinically nonfunctioning pituitary macroadenomas: effect on tumor volume and lack of correlation with immunohistochemistry and somatostatin receptor scintigraphy. J Clin Endocrinol Metab 79:1416–1423[Abstract]
  60. Lucas-Morante T, García-Uría J, Estrada J, Saucedo G, Cabello A, Alcaniz J, Barceló B 1994 Treatment of invasive growth hormone pituitary adenomas with long-acting somatostatin analog SMS 201–995 before transsphenoidal surgery. J Neurosurg 81:10–14[Medline]
  61. Stevenaert A, Beckers A 1996 Presurgical octreotide: treatment in acromegaly. Metabolism 45(Suppl 1):72–74
  62. Newman CE, Melmed S, George A, Torigian D, Duhaney M, Snyder P, Young W, Klibanski A, Molitch ME, Gagel R, Sheeler L, Cook D, Malarkey W, Jackson I, Vance ML, Barkan A, Frohman L, Kleinberg DL 1998 Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab 83:3034–3040[Abstract/Free Full Text]
  63. Tamura M, Yokoyama N, Abe Y, Sera N, Tominaga T, Ashizawa K, Ejima E, Kiriyama T, Uetani M, Kuwayama A, Nagataki S 1998 Preoperative treatment of growth hormone-producing pituitary adenoma with continuous subcutaneous infusion of octreotide. Endocr J 45:269–275[Medline]
  64. Tachibana E, Saito K, Yoshida J 1999 Preoperative short-term administration of octreotide for facilitating transsphenoidal removal of invasive growth hormone-secreting macroadenomas. Neurol Med Chir (Tokyo) 39:496–499
  65. Kristof RA, Stoffel-Wagner B, Klingmüller D, Schramm J 1999 Does octreotide treatment improve the surgical results of macro-adenomas in acromegaly? A randomized study. Acta Neurochir (Wien) 141:399–405[CrossRef]
  66. Abe T, Lüdecke DK 2001 Effects of preoperative octreotide treatment on different subtypes of 90 GH-secreting pituitary adenomas and outcome in one surgical center. Eur J Endocrinol 145:137–145[Medline]
  67. Amato G, Mazziotti G, Rotondi M, Iorio S, Doga M, Sorvillo F, Manganella G, Di Salle F, Glustina A, Carella C 2002 Long-term effects of lanreotide SR and octreotide LAR on tumour shrinkage and GH hypersecretion in patients with previously untreated acromegaly. Clin Endocrinol (Oxf) 56:65–71[CrossRef][Medline]