2 Minute Medicine Rewind April 24, 2023

Efficacy and Safety of Esketamine for Supplemental Analgesia During Elective Cesarean Delivery

1. In women undergoing cesarean delivery under epidural anesthesia, the administration of esketamine produced transient sedation and clinically insignificant analgesia, with no significant effect on neonatal depression.

Evidence Rating Level: 1 (Excellent)

Epidural anesthesia is commonly used during cesarean delivery. However, some patients still experience pain and discomfort during the surgery due to an incomplete block of the splanchnic nerve. Therefore, additional analgesics like opioids and dexmedetomidine are often administered. Given the adverse effects of these analgesics that limit their widespread use, alternative drugs are being explored. Esketamine is an isomer of ketamine that is two times more potent than its counterpart and less likely to cause adverse psychiatric reactions. This double-blinded, placebo-controlled randomized clinical trial aimed to investigate the safety and efficacy of intravenous esketamine before childbirth during cesarean delivery with epidural anesthesia.  The trial assessed the eligibility of parturients from 5 medical centers and enrolled 600 women aged 18 or older who had a full-term single pregnancy. Patients were randomly assigned to receive either 0.25 mg/kg of esketamine, or the control, the same volume of normal saline, administered intravenously 2 minutes before incision. Pain intensity immediately after fetal delivery, as measured by the NRS pain score, was found to be lower in the esketamine group than in the placebo group (P = .001). However, this difference was not clinically meaningful. This is likely because of excellent analgesia in the control group, thereby not allowing for further improvement in analgesia. Patients in the esketamine group had clinically important, deeper levels of sedation compared to the placebo group (P<0.001). While Eskatamine reduced the incidence of hypotension (4.7% compared with 8.7%  in the placebo group, p=0.047), it was associated with neurologic or mental symptoms like somnolence, nystagmus, and vertigo, along with higher incidences of hypertension, tachycardia, and postoperative nausea or vomiting. Finally, despite esketamine easily crossing the placental barrier with an umbilical vein to maternal artery ratio of 0.83 (0.09), the neonatal Apgar score was not affected. Overall, the study found that for women undergoing cesarean delivery with epidural anesthesia, esketamine did not have a meaningful effect on analgesia.

Comparison of Propylthiouracil vs Methimazole for Thyroid Storm in Critically Ill Patients

1. In this multi-centre cohort study, there were no significant differences in mortality or adverse effects between methimazole and propylthiouracil in the management of thyroid storm.

Evidence Rating Level: 2 (Good)

Thyroid storm is a medical emergency characterized by severe thyrotoxicosis that results in potentially fatal acute end-organ damage and is therefore associated with a high mortality rate of 8-25%. Management of thyroid storm includes thioamides (propylthiouracil, methimazole, or carbimazole), but there is global variation in the recommendations for first-line thioamide therapy. The Premier Healthcare Database was used to identify and evaluate a cohort of 1383 patients admitted to US intensive or intermediate care units with a diagnosis of thyroid storm between January 2016 to December 2020, to compare the efficacy of propylthiouracil and methimazole as treatments. The primary composite outcome of in-hospital death or hospice discharge occurred in 8.5% (95% CI, 6.4%-10.7%) of patients in the propylthiouracil group and 7.4% (95% CI, 4.6%-8.1%)  of patients in the methimazole group. This difference was not statistically significant according to the adjusted risk difference of 0.6% (95% CI, −1.8% to 3.0%, P = .64). Similarly, no differences were found in the outcomes of in-hospital mortality alone, hospice discharge alone, duration of organ support, or total hospitalization costs. There was a small decrease in thioamide-specific costs when using methimazole compared to propylthiouracil (adjusted mean difference, $72 [95% CI, $48 to $97]; P < .001). Despite this, these results suggest that propylthiouracil and methimazole can be used interchangeably in the management of thyroid storm.

The effect of intradialytic exercise on dialysis patient survival: a randomized controlled trial

1. Intradialytic exercise for a minimum of 60 minutes during thrice weekly dialysis sessions improved survival rates in adult patients who are receiving hemodialysis (HD).

Evidence Rating Level:1 (Excellent)

Chronic kidney disease is becoming increasingly prevalent worldwide, leading to an exponential increase in the number of individuals experiencing kidney failure requiring kidney-replacement therapy (KRT), which is primarily achieved through hemodialysis. Patients undergoing HD experience high rates of morbidity, and a mortality rate 10-30 times higher than those with normal kidney function. Low physical activity resulting from comorbidities, reduced physical function, decreased aerobic capacity, inactivity during HD sessions, and post-dialysis fatigue, plays a major role in the poor outcomes experienced by HD patients. Therefore, this study aimed to evaluate the effects of intradialytic exercises on HD patient survival and clinical outcomes associated with survival. 74 patients aged ≥ 18 years, receiving regular HD 3 times a week and HD for at least 1 year, were randomized to either the intervention, concurrent 60 minutes of intradialytic exercise during the 2nd hour of dialysis for 6 months, or the control that received usual care. 2 participants in the intervention group and 9 participants in the control group died. The cumulative survival rate in the control group was significantly lower than that in the intervention group (Log rank statistics = 6.5, P = 0.01). In terms of secondary outcomes, the intervention group demonstrated increased serum albumin, hemoglobin, red blood cell count, serum calcium, physical function (6MWT), and nutritional status (GNRI), while the control group’s levels remained mostly unchanged. Overall, the study showed that intradialytic exercise for 6 months improved the survival and certain laboratory parameters of adult patients receiving HD for 12 months. Though further studies are warranted, intradialytic exercise may be a promising adjunctive lifestyle modification for patients with end stage renal disease.

Relationship between mean blood pressure during hospitalization and clinical outcome after acute ischemic stroke

1. This retrospective cohort study found a U-shaped relationship between mean SBP and 3-month functional outcome after acute ischemic stroke, with an optimal mean SBP of 135-150 mmHg.

Evidence Rating Level: 2 (Good)

Elevated blood pressure (BP) is frequently observed in acute ischemic stroke (AIS), possibly as a compensatory mechanism to increase perfusion to ischemic brain areas. Excessive control of blood pressure in the acute stage of AIS is generally avoided because it may cause ischemic tissue hypoperfusion due to lowered blood flow. However, increased BP during AIS may exacerbate edema and hemorrhagic transformation of ischemic tissue. Therefore, controlling BP to an appropriate range is an important factor in AIS patients’ clinical outcomes. The objective of this retrospective cohort study was to analyze the relationship between mean BP and admission BP with clinical outcomes in patients with AIS. A cohort of 649 patients with ischemic stroke (median age 69, IQR 60-77) was identified using data from the stroke center of Jiangsu Province Hospital of Chinese Medicine between December 2020 and July 2021. The primary outcome was patient functional outcomes at 3 months post-stroke as measured by the modified Rankin Scale (mRS), with scores ≥3 defined as poor outcomes. The study found that in patients with AIS, admission SBP and mean SBP followed a U-curved relationship between functional prognosis. In other words, both extremes of BP were associated with poor outcomes. In a subgroup analysis, this relationship was equally present in both the acute (days 1-4) and subacute (>4 days) phases. Furthermore, when performing a logistical regression to control for antihypertensive treatment, the study conclusions remained unchanged. Overall, the optimal range of mean SBP was found to be 135 mmHg and 150 mmHg, with pressures above or below this range having higher median mRS scores and more deaths at 90 days as compared to patients within the range. Although this study is limited by its retrospective, single-center design, these findings suggest that early initiation of treatment for high BP may be more beneficial than conservatively delaying therapy until a specific time point after symptoms appear.

Denosumab and incidence of type 2 diabetes among adults with osteoporosis: population-based cohort study

1. In a cohort of adults with osteoporosis, the use of denosumab was linked to a reduced risk of developing type 2 diabetes when compared to the use of oral bisphosphonates.

Evidence Rating Level: 2 (Good)

Antiresorptive drugs are the most prevalent treatment for osteoporosis. One such potent antiresorptive drug is denosumab, a monoclonal antibody against the receptor activator of nuclear factor κ B (RNAK) ligand (RANKL). Recent studies suggest that higher RANKL levels were correlated with an increased risk of developing type 2 diabetes (T2D), while inhibiting RANKL/RANK signaling has been associated with improved glucose homeostasis in T2D or prediabetes patients. Given that the literature surrounding the incidence of T2D among denosumab users is limited, and that approximately 80% of denosumab users had previously used other anti-osteoporosis drugs like oral bisphosphonates, this study aimed to examine the effect of switching to denosumab versus continuing oral bisphosphonate on the risk of incident T2D over a 5-year follow-up period. Using the IQVIA Medical Research Data (IMRD) UK primary care database, 4301 eligible individuals (mean age 69 years, 94% women) who switched to or initiated denosumab were matched on propensity scores to 21 038 users (mean age 72 years, 81% women) of oral bisphosphonates. Those in the denosumab cohort had a T2D incidence of 5.7 per 1000 person-years compared to 8.3 per 1000 person-years in the matched oral bisphosphonate cohort. In other words, initiation of denosumab reduced the risk of incident T2D (hazard ratio 0.68, 95% CI 0.52 to 0.89). Participants at a higher risk of T2D – those with prediabetes or obesity – seemed to benefit more from denosumab initiation compared with oral bisphosphonate use with a hazard ratio of 0.54 (95% Cl 0.35 to 0.82) and 0.65 (95% Cl 0.40 to 1.06) respectively. Overall, this study provides evidence that treating osteoporosis with denosumab may simultaneously reduce the risk of T2D, which raises important considerations when treating patients with osteoporosis.

Image: PD

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