Abstract: We included 72 RCTs. The included trials studied the effects of 32 drugs belonging to different pharmacological groups. Only two trials mentioned the primary outcome of morbidity and mortality related to the haemodynamic response to tracheal intubation. Of the secondary outcomes, 40 of the included trials observed arrhythmia only, 11 observed myocardial ischaemia only and 20 observed both arrhythmias and myocardial ischaemia. Arrhythmias were observed in 2932 participants and myocardial ischaemia in 1616 participants. Arrhythmias were observed in 134 out of 993 patients in the control group compared to 80 out of 1939 in the intervention group. The risk of arrhythmias was significantly reduced with pharmacological interventions in the pooled data (Peto odds ratio (OR) 0.19, 95% CI 0.14 to 0.26, P < 0.00001, I2= 47%). Local anaesthetics, calcium channel blockers, beta blockers and narcotics reduced the risk of arrhythmia in the intervention group compared to the control group. Myocardial ischaemia was observed in 21 out of 604 patients in the control group compared to 10 out of 1012 in the treatment group; the result was statistically significant (Peto OR 0.45, 95% CI 0.22 to 0.92, P = 0.03, I2 = 19%). However, in subgroup analysis only local anaesthetics significantly reduced the ECG changes indicating ischaemia, but this evidence came from one study. The majority of the studies had a negative outcome. Hypotension and bradycardia were reported with 40 µg kg-1 intravenous alfentanil, chest rigidity with 75 ug kg-1 alfentanil, and increased bronchomotor tone with sympathetic blockers. There were 17 studies which included high risk patients. Pharmacological treatment in this group resulted in the reduction of arrhythmias when the data from nine trials looking at arrhythmias were pooled (Peto OR 0.18, 95% CI 0.05 to 0.59, P = 0.005, I2 = 80%). The analysis from four studies was not included. Three of these trials looked at the effect of sympathetic blockers but arrhythmias or myocardial ischaemia was observed throughout the perioperative period in two studies and some patients had arrhythmias due to atropine premedication in the third study. In the fourth study the authors mentioned myocardial ischaemia in the objectives section but did not report it in the results. The risk of arrhythmias associated with tracheal intubation was significantly reduced with pre-induction administration of local anaesthetics, calcium channel blockers, beta blockers and narcotics compared to placebo. Pharmacological intervention also reduced the risk of ECG evidence of myocardial ischaemia in the pooled data. Lignocaine pretreatment showed a significant effect but evidence came from one study only. The data suggested that there may be a reduction in ECG evidence of myocardial ischaemia with beta blocker pretreatment but this difference was not statistically significant. There is a need to focus on outcomes rather than haemodynamic measurements alone when studying this response in future trials.

Plain-language summary: We included adult patients aged 18 years and above undergoing elective surgery in the operating room setting. We found that the effects of drugs on the stress response was the subject of 72 studies. The investigators used 32 drugs. Promising results were seen in the reduction of arrhythmias with intravenous injections of beta blockers (drugs that decrease the heart rate), narcotics (drug used to treat pain), local anaesthetics, and calcium channel blockers (drugs that block movement of calcium). Serious side effects were only reported with high doses of narcotics and an increase in airway pressure was seen in some patients with beta blockers. Only local anaesthetic drugs clearly reduced the risk of myocardial ischaemia but this evidence came from only one trial. There was some difficulty in comparing and interpreting the results of these different trials. Patients at a high risk of complications were investigated in 17 trials. A reduction in arrhythmias with treatment was seen in this high risk group but the number of studies was too small to reach a conclusion. Doctors need to further research the effects of drugs used for blunting the haemodynamic response and their effect on outcomes in terms of morbidity, in a standardized manner.