Although beneficial in acute and chronic pain management, the use of local anaesthetics is limited by its duration of action and the dose dependent adverse effects on the cardiac and central nervous system. Adjuvants or additives are often used with local anaesthetics for its synergistic effect by prolonging the duration of sensory-motor block and limiting the cumulative dose requirement of local anaesthetics. The armamentarium of local anesthetic adjuvants have evolved over time from classical opioids to a wide array of drugs spanning several groups and varying mechanisms of action. A large array of opioids ranging from morphine, fentanyl and sufentanyl to hydromorphone, buprenorphine and tramadol has been used with varying success. However, their use has been limited by their adverse effect like respiratory depression, nausea, vomiting and pruritus, especially with its neuraxial use. Epinephrine potentiates the local anesthetics by its antinociceptive properties mediated by alpha-2 adrenoreceptor activation along with its vasoconstrictive properties limiting the systemic absorption of local anesthetics. Alpha 2 adrenoreceptor antagonists like clonidine and dexmedetomidine are one of the most widely used class of local anesthetic adjuvants. Other drugs like steroids (dexamethasone), anti-inflammatory agents (parecoxib and lornoxicam), midazolam, ketamine, magnesium sulfate and neostigmine have also been used with mixed success. The concern regarding the safety profile of these adjuvants is due to its potential neurotoxicity and neurological complications which necessitate further research in this direction. Current research is directed towards a search for agents and techniques which would prolong local anaesthetic action without its deleterious effects. This includes novel approaches like use of charged molecules to produce local anaesthetic action (tonicaine and n butyl tetracaine), new age delivery mechanisms for prolonged bioavailability (liposomal, microspheres and cyclodextrin systems) and further studies with other drugs (adenosine, neuromuscular blockers, dextrans).

Adjuvants to local anesthetics: Current understanding and future trends

Stress ulcer prophylaxis (SUP) is commonly prescribed in the intensive care unit. However, data from systematic reviews and conventional meta-analyses are limited by imprecision and restricted to direct comparisons. We conducted a network meta-analysis of randomized clinical trials (RCTs) to examine the safety and efficacy of drugs available for SUP in critically ill patients. We searched MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials through April 2017 for randomized controlled trials that examined the efficacy and safety of proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), and sucralfate for SUP in critically ill patients. No date or language restrictions were applied. Data on study characteristics, methods, outcomes, and risk of bias were abstracted by two reviewers. Of 96 potentially eligible studies, we included 57 trials enrolling 7293 patients. The results showed that PPIs are probably more effective for preventing clinically important gastrointestinal bleeding (CIB) than H2RAs [odds ratio (OR) 0.38; 95% confidence interval (95% CI) 0.20, 0.73], sucralfate (OR 0.30; 95% CI 0.13, 0.69), and placebo (OR 0.24; 95% CI 0.10, 0.60) (all moderate quality evidence). There were no convincing differences among H2RA, sucralfate, and placebo. PPIs probably increase the risk of developing pneumonia compared with H2RAs (OR 1.27; 95% CI 0.96, 1.68), sucralfate (OR 1.65; 95% CI 1.20, 2.27), and placebo (OR 1.52; 95% CI 0.95, 2.42) (all moderate quality). Mortality is probably similar across interventions (moderate quality). Estimates of baseline risks of bleeding varied significantly across studies, and only one study reported on Clostridium difficile infection. Definitions of pneumonia varied considerably. Most studies on sucralfate predate pneumonia prevention strategies. Our results provide moderate quality evidence that PPIs are the most effective agents in preventing CIB, but they may increase the risk of pneumonia. The balance of benefits and harms leaves the routine use of SUP open to question.

/pdf/efficacy-and-safety-of-stress-ulcer-prophylaxis-in-40x6cnd3qs.pdf

Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials

10.4103/0970-2113.99248 A. K. Janmeja, Chandigarh; Abhishek Goyal, Chandigarh; Aditya Jindal, Chandigarh; Ajay Handa, Bangalore; Aloke G. Ghoshal, Kolkata; Ashish Bhalla, Chandigarh; Bharat Gopal, Delhi; D. Behera, Delhi; D. Dadhwal, Chandigarh; D. J. Christopher, Vellore; Deepak Talwar, Noida; Dhruva Chaudhry, Rohtak; Dipesh Maskey, Chandigarh; George D’Souza, Bangalore; Honey Sawhney, Chandigarh; Inderpal Singh, Chandigarh; Jai Kishan, Chandigarh; K. B. Gupta, Rohtak; Mandeep Garg, Chandigarh; Navneet Sharma, Chandigarh; Nirmal K. Jain, Jaipur; Nusrat Shafiq, Chandigarh; P. Sarat, Chandigarh; Pranab Baruwa, Guwahati; R. S. Bedi, Patiala; Rajendra Prasad, Etawa; Randeep Guleria, Delhi; S. K. Chhabra, Delhi; S. K. Sharma, Delhi; Sabir Mohammed, Bikaner; Sahajal Dhooria, Chandigarh; Samir Malhotra, Chandigarh; Sanjay Jain, Chandigarh; Subhash Varma, Chandigarh; Sunil Sharma, Shimla; Surender Kashyap, Karnal; Surya Kant, Lucknow; U. P. S. Sidhu, Ludhiana; V. Nagarjun Mataru, Chandigarh; Vikas Gautam, Chandigarh; Vikram K. Jain, Jaipur; Vishal Chopra, Patiala; Vishwanath Gella, Chandigarh

Guidelines for diagnosis and management of community- and hospital-acquired pneumonia in adults: Joint ICS/NCCP(I) recommendations.

BACKGROUND:
Nausea and vomiting are distressing symptoms which are experienced commonly during caesarean section under regional anaesthesia and can also occur in the period following the procedure. 
OBJECTIVES:
To assess the efficacy of pharmacological and non-pharmacological interventions given prophylactically to prevent nausea and vomiting in women undergoing regional anaesthesia for caesarean section.
SEARCH METHODS:
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (27 February 2012) and reference lists of identified studies.
SELECTION CRITERIA:
We included randomised controlled trials (RCTs) and excluded quasi-RCTs and cross-over studies.
DATA COLLECTION AND ANALYSIS:
Review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. Data entry was checked. 
MAIN RESULTS:
Fifty-two studies met the inclusion criteria but only 41 studies, involving 5046 women, provided useable data for the review involving women having caesareans under regional anaesthesia. The majority of the studies involved women undergoing elective caesarean section. Only two studies included emergency surgery, however, they did not stratify data according to type of surgery. The studies covered numerous comparisons, but the majority of studies involved 5-HT(3) receptor antagonists, dopamine receptor antagonists, corticosteroids or acupressure. Studies were mainly small and of unclear quality.Three classes of intervention were found to be effective in at least three out of four of our primary outcomes (intraoperative nausea, intraoperative vomiting, postoperative nausea and postoperative vomiting). These interventions were 5-HT(3) antagonists, dopamine antagonists and sedatives. Other classes of intervention were effective for fewer than three of our primary outcomes.With 5-HT antagonists, we found a reduction in intraoperative nausea (average risk ratio (RR) 0.64, 95% confidence interval (CI) 0.46 to 0.88, eight studies, 720 women). There were also reductions in postoperative nausea (average RR 0.40, 95% CI 0.25 to 0.64, four studies, 405 women) and vomiting (average RR 0.50, 95% CI 0.32 to 0.77, five studies, 565 women). We did not detect a significant reduction in intraoperative vomiting (average RR 0.56, 95% CI 0.31 to 1.00, seven studies, 668 women).Dopamine antagonists demonstrated a reduction in intraoperative nausea (average RR 0.38, 95% CI 0.25 to 0.57, nine studies, 636 women) and intraoperative vomiting (average 0.39, 95% CI 0.24 to 0.64, eight studies, 536 women), with similar reductions in postoperative nausea (average RR 0.60, 95% CI 0.40 to 0.91, five studies, 412 women) and vomiting (average RR 0.57, 95% CI 0.36 to 0.91, six studies, 472 women). These differences were observed with both metoclopramide and droperidol.Sedatives (most commonly propofol) demonstrated a reduction in intraoperative nausea (average RR 0.71, 95% CI 0.52 to 0.96, four studies, 285 women) and intraoperative vomiting (average RR 0.42, 95% CI 0.26 to 0.68, four studies, 285 women), also with a reduction in postoperative nausea (average RR 0.25, 95% CI 0.09 to 0.71, two studies 145 women) and vomiting (average RR 0.09, 95% CI 0.03 to 0.28, two studies, 145 women).Acupressure was found to be effective for intraoperative nausea (average RR 0.59, 95% CI 0.38 to 0.90, six studies, 649 women) but not postoperative nausea (average RR 0.83, 95% CI 0.68 to 1.00, three studies, 429 women). Acupressure was not effective at reducing vomiting either intraoperatively (average RR 0.74, 95% CI 0.46 to 1.18, six studies, 649 women) or postoperatively (average RR 0.69, 95% CI 0.45 to 1.06, three studies, 429 women).Other effective intervention classes included corticosteroids, antihistamines, and anticholinergics.There were insufficient data to demonstrate any class of intervention was superior to another. There were no significant differences observed in the comparison of combined versus single interventions.Few studies assessed our secondary outcomes or the incidence of adverse effects. However, one study showed an increase in respiratory depression with sedation (midazolam) compared with dopamine antagonists.
AUTHORS' CONCLUSIONS:
This review indicates that many different interventions have efficacy in preventing nausea and vomiting in women undergoing regional anaesthesia for caesarean section. There is little evidence that combinations of treatment are better than single agents.

Interventions for preventing nausea and vomiting in women undergoing regional anaesthesia for caesarean section

Intrathecal midazolam binds with gamma aminobutyric acid-A receptors in the spinal cord leading to an analgesic effect. Clinical studies suggested that intrathecal midazolam may also reduce nausea ...

Use of intrathecal midazolam to improve perioperative analgesia: a meta-analysis.

Analgesic efficacy of two doses of intrathecal midazolam with bupivacaine in patients undergoing cesarean delivery.

This study was conducted to evaluate the incidence of early- and late-onset nosocomial pneumonia, gastric colonization, and gastrointestinal bleeding in 50 orotracheally intubated, mechanically ventilated patients treated with sucralfate or ranitidine for stress ulcer prophylaxis in the intensive care unit. Patients received either iv ranitidine (50 mg every 6h) in Ranitidine group or nasogastric sucralfate suspension (1 g every 6h) in Sucralfate group. The overall incidence of pneumonia and incidence of early-onset pneumonia was comparable between the two groups (p > 0.05). Late- onset pneumonia was observed in 10 (23.8%) patients in the Ranitidine group and 2 (4.8%) patients in the Sucralfate group (P= 0.001). The mean gastric pH (6.04 ± 1.34 and 3.64 ± 1.55, respectively; P= 0.001)), rate of gastric colonization (92% and 16%, respectively; P=0.000), and gastric source of pneumonia (10 patients and 1 patient, respectively; P= 0.017) was higher in the Ranitidine group as compared to the Sucralfate group. Mortality and gastrointestinal bleeding were comparable between groups. We concluded that stress ulcer prophylaxis with ranitidine increases the risk for late- onset pneumonia in mechanically ventilated critically ill patients by favoring gastric colonization by gram- negative bacilli compared with sucralfate. In patients receiving mechanical ventilation, the use of sucralfate may be preferable to H 2 blockers.

Nosocomial Pneumonia in Mechanically Ventilated Patients Receiving Ranitidine or Sucralfate as Stress Ulcer Prophylaxis

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Analgesic efficacy of two doses of intrathecal midazolam with bupivacaine in patients undergoing cesarean delivery.

Nosocomial Pneumonia in Mechanically Ventilated Patients Receiving Ranitidine or Sucralfate as Stress Ulcer Prophylaxis