Michael Tryba

Long-term oral opioid therapy in patients with chronic nonmalignant pain

In contrast to the use of opioids for the treatment of acute and chronic cancer pain, the administration of chronic opioid therapy for pain not due to malignancy remains controversial. We describe 100 patients who were chronically given opioids for treatment of nonmalignant pain. Most patients experienced neuropathic pain or back pain. We used sustained-release dihydrocodeine, buprenorphine, and sustained-release morphine. Pain reduction was measured with visual analogue scales (VAS), and the Karnofsky Performance Status Scale was used to assess the patients function. Good pain relief was obtained in 51 patients and partial pain relief was reported by 28 patients. Only 21 patients had no beneficial effect from opioid therapy. There was a close correlation between the sum and the peak VAS values (r = 0.983; p less than 0.0001) and pain reduction was associated with an increase in performance (p less than 0.0001). The most common side effects were constipation and nausea. There were no cases of respiratory depression or addiction to opioids. Our results indicate that opioids can be effective in chronic nonmalignant pain, with side effects that are comparable to those that complicate the treatment of cancer pain.

Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain

&NA; Direct conversion from oral morphine to transdermal fentanyl with a ratio of oral morphine/transdermal fentanyl (100:1 mg) daily was examined in patients with cancer pain. Patients with a ‘stable and low level of cancer pain’ receiving a constant dosage of sustained release morphine during a pre‐study phase of 6 days were included in the study. Initial fentanyl dosage was calculated by a conversion table. The transdermal system was changed every 72 h and the dosage was adjusted to the needs of the patients according to the VAS scores and the requirement of liquid morphine, which was allowed to achieve sufficient pain relief. Regression analysis at the end of the study revealed a mean morphine/transdermal fentanyl ratio of 70:1. Pain relief during treatment with transdermal fentanyl was identical to sustained release morphine. However, significantly more patients took: supplemental medication with liquid morphine during transdermal fentanyl therapy. The number of patients suffering from pain attacks did not increase with transdermal fentanyl. Constipation and medication with laxatives decreased significantly during fentanyl therapy. Other side effects and vital signs were identical. Three patients suffered from a morphine withdrawal syndrom beginning within the first 24 h of transdermal fentanyl therapy. Cutaneous reactions to the patch were rare, mild and transient. Patients and physicians reported satisfaction with the transdermal therapy. 94.7% of the patients chose to continue the transdermal fentanyl therapy at the end of the study due to better performance in comparison to oral morphine. Due to these results an initial conversion from oral morphine to transdermal fentanyl with the ratio of 100:1 is safe and effective.

Risk of acute stress bleeding and nosocomial pneumonia in ventilated intensive care unit patients: Sucralfate versus antacids☆

In a prospective, controlled, randomized study of the prophylaxis of stress bleeding, 100 ventilated high-risk patients in a surgical intensive care unit received, on a daily basis, 1 g of sucralfate suspension (n = 50) every four hours, or an antacid (n = 50) every two hours. The mean duration of the treatment was about six days in both of the groups. Gastric pH was determined every eight hours. Bleeding was defined as macroscopically visible bleeding. The intragastric pH was less than 4 significantly more often in patients treated with sucralfate. In each group, one case of macroscopically visible bleeding occurred. Both of the patients had a very high risk of bleeding. None of the bleedings influenced the outcome of the patients. When patients with primary thoracic trauma or pneumonia were excluded, nosocomial pneumonia developed in significantly fewer (p less than 0.05) patients in the sucralfate group (three of 29) than in the antacid group (11 of 32). In four of the latter patients, pneumonia influenced the outcome of the patients. Sucralfate provides adequate protection against stress bleeding while also minimizing the danger of pneumonia caused by infection via the gastropulmonary route.

Preoperative alpha2-adrenergic receptor agonists prevent the deterioration of renal function after cardiac surgery: results of a randomized, controlled trial.

OBJECTIVE To evaluate the influence of the alpha2-adrenergic receptor agonist clonidine on creatinine clearance as a measure of renal function. DESIGN Prospective, double-blind, randomized, placebo-controlled clinical trial. SETTING University hospital. PATIENTS Patients undergoing coronary artery bypass graft surgery (n = 48) with normal risk. INTERVENTIONS Administration of clonidine (4 micrograms/kg iv)) or placebo 1 hr before induction of anesthesia. MEASUREMENTS AND MAIN RESULTS Induction and maintenance of anesthesia (etomidate, midazolam, and fentanyl) and cardiopulmonary bypass technique (nonpulsatile, normothermic, intermittent cold blood cardioplegia) were standardized in all patients. The night before surgery and the first and third night after surgery, creatinine clearance was calculated from a 12-hr urine collection period. Venous blood samples for determination of plasma antidiuretic hormone (ADH) concentrations were taken the evening before surgery, immediately before induction of anesthesia and the evening after surgery (n = 16). Arterial catecholamine plasma concentrations were determined (high-performance liquid chromatography) before induction, 15 mins after induction of anesthesia, immediately after sternotomy, before initiation of cardiopulmonary bypass, as well as 5, 15, and 30 mins after initiation of cardiopulmonary bypass (n = 16). The total amount of anesthetics, infusions, transfusions, diuresis, and blood loss was not different between the groups. Creatinine clearance decreased over the first postoperative night from 98 +/- 18 (preoperatively) to 68 +/- 19 mL/min (p < .05) in placebo-treated patients. Creatinine clearance remained unchanged in clonidine-treated patients (90 +/- 19 [preoperatively] to 92 +/- 17 mL/min). There was a significant difference in creatinine clearance between the groups during the first postoperative night (p < .05; Mann-Whitney U test). In the third postoperative night, mean creatinine clearance of both groups was not different (75 +/- 31 vs. 86 +/- 28 mL/min). ADH concentrations were not different between the groups at any time, while plasma catecholamine concentrations were always significantly lower in clonidine-treated patients. CONCLUSIONS Preoperative treatment with clonidine (4 microgram/kilogram) prevents the deterioration of renal function after cardiac surgery. This effect might be due to clonidine-induced reduction in the sympathetic nervous system response to coronary artery bypass graft surgery.

Current Guidelines on Stress Ulcer Prophylaxis

SummaryAcute upper gastrointestinal bleeding in intensive care unit (ICU) patients may occur due to peptic ulcer disease, adverse drug effects, gastric tube lesions, acute renal failure, liver failure or stress-induced gastric mucosal lesions. Gastric acid hypersecretion can be observed in patients with head trauma or neurosurgical procedures. Gastric mucosal ischaemia due to hypotension and shock is the most important risk factor for stress ulcer bleeding.Preventive strategies aim to reduce gastric acidity (histamine H2 receptor antagonists, antacids), strengthen mucosal defensive mechanisms (sucralfate, antacids, pirenzepine) and normalise gastric mucosal microcirculation (sucralfate, pirenzepine). However, the most important prophylactic measure is an optimised resuscitation and ICU regime aiming to improve oxygenation and microcirculation.All drugs approved for stress ulcer prophylaxis in Europe (H2 antagonists, antacids, pirenzepine, sucralfate) have been shown to be effective in prospective controlled randomised trials. However, due to insufficient clinical data, prostaglandins and omeprazole cannot be recommended for this use. Stress ulcer prophylaxis is indicated only in patients at risk, and not in every ICU patient.The selection of drugs today depends not only on efficacy but also on possible adverse effects and on costs. In this regard, the most cost-effective drug is sucralfate. The clinical relevance of nosocomial pneumonia due to gastric bacterial overgrowth has decreased during the past decade due to several changes in the management of critically ill patients.

DOSE-RESPONSE EFFECTS OF INTRAVENOUS CLONIDINE ON STRESS RESPONSE DURING INDUCTION OF ANESTHESIA IN CORONARY ARTERY BYPASS GRAFT PATIENTS

This study was designed to evaluate the dose-response effects of different doses of clonidine on the stress response to laryngoscopy and endotracheal intubation. In a randomized, double-blind study, 48 coronary artery bypass grafting (CABG) patients received 0, 2, 4, or 6 micro gram/kg clonidine as an intravenous (IV) infusion during a 15-min period 30 min prior to induction of anesthesia with etomidate (0.3 mg/kg), fentanyl (5-7 micro gram/kg), and pancuronium (0.1 mg/kg). Sedation was assessed prior to induction of anesthesia. Cardiovascular variables and catecholamine plasma levels were measured at predefined intervals. Additional bolus doses of etomidate and fentanyl for suppression of stress-induced reactions were administered if predefined limits of heart rate and blood pressure were exceeded. Clonidine 4 and 6 micro gram/kg significantly attenuated hemodynamic and adrenergic reactions to stress, reduced pharmacologic interventions, and increased sedation. However, clonidine 6 micro gram/kg was not more effective than 4 micro gram/kg, and clonidine 2 micro gram/kg was equally effective as placebo. We conclude that clonidine 4 micro gram/kg IV is the appropriate dose to attenuate the stress response to laryngoscopy in CABG patients. Side effects limiting the use of IV clonidine were not observed. (Anesth Analg 1995;80:263-8)

Antibacterial activity of sucralfate in human gastric juice

A series of experiments was conducted to determine the rate of bacterial growth in human gastric juice at various pH values in relation to the addition of sucralfate and antacid. Whereas the addition of antacid resulted in bacterial growth in gastric juice, sucralfate showed an antibacterial effect. This may account for the decreased rate of pneumonia among intensive-care patients who are receiving artificial ventilation and being treated with sucralfate for the prevention of stress-induced gastrointestinal bleeding compared with the rate in patients receiving conventional prophylaxis with histamine (H2)-antagonists or antacids.

Prevention of acute stress bleeding with sucralfate, antacids, or cimetidine: A controlled study with pirenzepine as a basic medication

In a prospective, controlled, randomized study of a prophylaxis for stress bleeding, 100 high-risk patients in an intensive care unit received, on a daily basis, 1 g of sucralfate every four hours, an antacid every two hours, or 2 g of cimetidine intravenously. All patients also received 50 mg of pirenzepine by intravenous infusion each day. Gastric pH was determined every eight hours. Bleeding was defined as macroscopically visible bleeding. The intragastric pH was less than 4 significantly more often in patients treated with sucralfate than in patients treated with the other agents, but stress bleeding occurred only in patients treated with cimetidine (n = 2) or antacids (n = 2). In the latter two treatment groups, the probability of bleeding correlated with the incidence of pH values below 4. No side effects of sucralfate therapy were observed. The results indicate that prophylactic treatment of stress bleeding with pirenzepine and sucralfate is at least as effective as combined treatment with pirenzepine and cimetidine or antacids.

The gastropulmonary route of infection—Fact or fiction?

Published studies relating to whether medicinal stress-bleeding prophylaxis leading to an increase of gastric pH favors the development of bronchopulmonary infections are reviewed. Results from studies in healthy humans, patients with ulcer disease, and patients in the intensive care unit (ICU) clearly show that the risk of gastric bacterial colonization significantly increases relative to increasing gastric pH. Moreover, a drug-induced increase of gastric pH leads directly to gastric bacterial colonization also in patients in the ICU, above all with bacteria typical of the gastrointestinal tract. Comparing the different bacterial spectra of the oropharynx, stomach, and upper small intestine, it becomes clear that the stomach is a reservoir of bacteria independent of the oropharynx and also subject to retrograde colonization due to the duodenogastric reflux. Both by means of microbiological and in particular direct detection procedures, it can be demonstrated that in at least 30-40% of intubated patients a gastropulmonary route of colonization occurs. In patient groups without a medication-induced increase of gastric pH the number of bacteria detected in the tracheal secretion is about 33% less than in the case of conventional stress-bleeding prophylaxis. These findings make it understandable that a highly significant increase in the pneumonia rate is seen in patients receiving pH-increasing stress-bleeding prophylaxis versus control groups without therapy essentially influencing gastric pH. A risk score was developed that allows an easy description of those patients who are at an increased risk of pulmonary infections due to the gastropulmonary route of colonization.

Gastric Alkalinization, Pneumonia, and Systemic Infections: The Controversy

BACKGROUND Gastric alkalinization has been suspected as a cause of pneumonia in critically ill patients. Although meta-analysis of the available data confirms an association between the administration of antacids/H2-antagonists and the risk of pneumonia, controversy remains whether stress ulcer prophylaxis with sucralfate reduces the risk of pneumonia. We hypothesized that the conflicting study results may be due to differences in patient population and general treatment regimens. RISK FACTORS Microbiological studies have shown that a gastric pH > 4 is crucial for overgrowth of gastric gram-negative but not gram-positive bacteria. Sucralfate mainly influences the growth of gram-negative bacteria. Thus, in patient groups with a high frequency of gram-positive pneumonia, preservation of gastric acidity does not influence the pneumonia rate. Since 40-60% of critically ill patients show gastric pH values > 4 even without administration of acid-neutralizing agents, an increased risk of nosocomial pneumonia with antacids/H2-antagonists can only be expected if these agents substantially increase the frequency of patients with gastric pH > 4. No influence of stress ulcer prophylaxis on the pneumonia rate can be expected in patients on enteral nutrition, especially if administered continuously. In non-ventilated patients or in those with a short duration of ventilation no significant influence of stress ulcer prophylaxis on nosocomial pneumonia rate can be expected. The same is true for patient groups where regurgitation of gastric content is prevented, e.g. head-up position in neurosurgical patients. Furthermore, in patient groups with primary lung injury nosocomial pneumonia occurs due to specific pathomechanisms, e.g. lung contusion or inhalation injury. Based on these factors we have developed a scoring system and have performed a regression analysis between the sum of the risk scores and the odds ratio of nosocomial pneumonia of all available stress ulcer studies dealing with nosocomial pneumonia. RESULTS A highly significant correlation (p < 0.0001) could be demonstrated between the sum of the risk score and the odds ratio for pneumonia. An increased risk of nosocomial pneumonia due to stress ulcer prophylaxis with antacids/H2-antagonists occurred in patient groups with a risk score of > or = 2. CONCLUSIONS This analysis supports the hypothesis that gastric alkalinization significantly increases the risk of nosocomial pneumonia in long-term ventilated patients. However, this analysis also shows that only specific subgroups of patients benefit from acid-independent stress ulcer prophylaxis relative to nosocomial pneumonia. Furthermore, recent experimental and clinical studies support the hypothesis that gastric alkalinization may increase the risk of systemic infections and that sucralfate may have significant protective effects.