Evaluation of the effects of dexmedetomidine infusion on oxygenation and lung mechanics in morbidly obese patients with restrictive lung disease

Dexmedetomidine is a selective α − 2 agonist with various clinical uses in both anesthesia and intensive care unit. In addition to its sedative and cardiovascular effects, dexmedetomidine has favourable respiratory effects in animals [1, 2], and in selected patient groups in humans. The effects of dexmedetomidine on oxygenation and lung mechanics had been investigated in obstructive lung disease. Dexmedetomidine decreased dead space and improved both lung compliance and oxygenation in chronic obstructive pulmonary disease (COPD) patients undergoing lung cancer surgery [3].

In restrictive lung disease, the possible effect of dexmedetomidine was not well investigated in humans. In an animal model of experimental obesity, dexmedetomidine administration showed better morphological and functional lung characteristics compared to propofol [4]; thus, we hypothesized that a similar effect could be present in humans. Morbidly obese patients are characterized by the high prevalence of restrictive lung disease [5]; thus, we investigated the effects of dexmedetomidine infusion on oxygenation (P/F ratio) as well as lung mechanics (compliance and dead space) in a selected group of morbidly obese patients with restrictive lung disease, to find out the possible benefits of this drug on this population.

A randomized controlled double-blinded study was conducted in Cairo university hospital after institutional board review approval (N − 12-2016) on 24 December 2016. The study was registered at clinical.trials.​gov registry system on 20 July 2016 (NCT02843698). A written informed consent was obtained from participants before recruitment. Patients were randomized according to an online random number generator. Concealment was achieved using sealed opaque envelopes.

The study included 42 morbidly obese patients {with body mass index (BMI) above 40 Kg/m²} with restrictive lung disease {diagnosed by pulmonary function tests: forced vital capacity (FVC) < 70%}, scheduled for laparoscopic sleeve gastrectomy. Exclusion criteria were: heart failure, arrhythmias, severe liver or kidney impairment. Patients with forced expiratory volume in 1 sec (FEV1)/FVC < 70% were also excluded.

Upon arrival at the operating room, patients were pre-medicated with metoclopramide (10 mg) and ranitidine (50 mg). Basic monitors were applied {electrocardiogram (ECG), non-invasive blood pressure monitor, capnography and pulse oximetry}. Drug dosing was calculated using lean body weight for all drugs except neostigmine (Total body weight was used) [6]. LBW was calculated using James equation {Men: (1.10 weight) - (128 (weight/height)²}, {Women: (1.07 weight) - (148 (weight/height)²} [6]. Anesthesia was induced by propofol (2 mg/Kg LBW) and fentanyl (2 μg/Kg LBW). After induction of anesthesia, endotracheal tube was inserted aided by rocuronium (0.5 mg/Kg LBW). Anesthesia was maintained by isoflurane (1–1.5%) and rocuronium (0.1 mg/Kg/40 min) at FiO₂ of 40%. Intravenous paracetamol (2 g) and Ketorolac (40 mg) was administered before the end of surgery.

Patients were mechanically ventilated using Maquet (Flow-i) anesthesia machine. Our ventilatory management included: volume controlled ventilation, low tidal volume (6-8 ml/Kg LBW), positive end expiratory pressure (PEEP) 8–10 mmH₂O, and respiratory rate adopted to maintain end-tidal CO₂ between 30 and 35 mmHg [7]. No recruitment manoeuvres were used in our patients.

Patients were randomly allocated into our double-blinded study using computer generated sequence into two groups: 1- Dexmedetomidine group (n = 21): received dexmedetomidine (Precedex, Hospira, Lake forest, IL, USA) in a dose of (1μg/Kg LBW) bolus 15-min after endotracheal intubation, followed by 0.5μg/Kg/hour continuous infusion for 90 min. 2- Control group (n = 21): received 1 mL normal saline followed by continuous normal saline infusion for 90 min. The study drug was prepared and the infusion rate was calculated by a research assistant to ensure blinding of the investigator.

At the end of the operation, isoflurane was discontinued, residual neuromuscular block was reversed using neostigmine (0.05 mg/Kg) and atropine (0.02 mg/Kg), then patient was extubated. In the post anesthesia care unit (PACU), patient was monitored by basic monitors (pulse oximetry, non-invasive blood pressure monitor, and ECG). Patients with oxygen saturation less than 88% on 6-l oxygen mask were admitted to the intensive care unit.

Dynamic lung compliance was calculated using Maquet anesthesia machine as: tidal volume/ (peak airway pressure - PEEP). Static lung compliance was calculated as: Tidal volume/ (plateau pressure - PEEP). Plateau pressure was calculated by increasing the end-inspiratory pause to 30–40%. Physiological dead space was calculated by Hardman & Aitkenhead equation [8]: Vd/Vt = 1.14 (PaCO₂–EtCO₂)/PaCO₂–0.005.

Forty-two patients were available for final analysis (Fig. 1). Demographic data and baseline characteristics were comparable between both study groups (Table 1). Pre-operative pulmonary functions were also comparable between the two study groups (Table 1). At 90 min, there was significant improvement in both P/F ratio and lung compliance within dexmedetomidine group compared to the baseline reading. Δ P/F ratio was significantly higher in dexmedetomidine group compared to control group {32 (43) mmHg versus − 2 (60) mmHg, P = 0.046) (Table 2).

Compared to control group, dexmedetomidine group showed higher dynamic lung compliance at both 45 min {41.3 (8) mL cmH₂O^− 1 Vs 34.6 (5) mL cmH₂O^− 1, P = 0.004}, and 90 min {44.5 (9) mL cmH₂O^− 1 Vs 34.5 (6) mL cmH₂O^− 1, P < 0.001}, in addition to higher Δ dynamic lung compliance {4 (4) mL cmH₂O^− 1 versus − 1 (4) mL cmH₂O^− 1, P = 0 < 0.001} (Table 2). Static lung compliance was higher in dexmedetomidine group compared to control group at 90 min {54 (13) mL cmH₂O^− 1 Vs 45 (11) mL cmH₂O^− 1, P = 0.01}; whilst, both groups showed comparable static lung compliance at other time points (Table 2).

Dead space significantly increased in the control group at 45 min and 90 min compared to the baseline; whilst, dead space decreased in dexmedetomidine group at 90 min compared to the baseline measurement and to the control group (Table 2). Δ dead space (%) was significantly lower in Dexmedetomidine group compared to control group {− 1.6(− 8, 1.5) % Vs 3.4(0.3, 6.5) %, P = 0.01} (Table 2). Plateau pressure was lower in dexmedetomidine group compared to the control group at most measurements (Fig. 2).

Both SBP and DBP were lower in dexmedetomidine group compared to control group and compared to the baseline in most measurements (Fig. 3). Heart rate was also lower in Dexmedetomidine group compared to control group at 15 min, and to the baseline at 60, 75, 90, and 105 min (Fig. 4).

Dexmedetomidine infusion improved oxygenation and lung mechanics in morbidly obese patients with restrictive lung disease. Dexmedetomidine group showed higher P/F ratio, higher compliance, lower dead space, and lower plateau pressure compared to control group.

The evidence on the possible mechanism of the favourable respiratory effects of dexmedetomidine is not clear; however various mechanisms might contribute in these effects. Animal studies reported that dexmedetomidine has a bronchodilator effect in histamine-mediated bronchospasm [1]. Dexmedetomidine was reported to preserve the hypoxic pulmonary vasoconstriction from the inhibitory effect of inhalational anesthetic agents [10], increase the perfusion of ventilated lungs [10], reduce the oxidative stress [11], and increase nitric oxide (NO) [11, 12] during OLV. Dexmedetomidine enhances hypoxic pulmonary vasoconstriction through stimulation of alpha-2B receptors in vascular smooth muscles; thus, it would improve ventilation/perfusion ratio and consequently improve oxygenation [12]. As it increases the NO level in blood, dexmedetomidine reduces intrapulmonary shunt [12]. Down regulation of various inflammatory mediators might contribute to the protective respiratory effects of dexmedetomidine [13, 14]; however, this assumption needs further evaluation in more studies because we did not measure these mediators in our patients. The potential better sedation state with dexmedetomidine administration might also contribute for improvement of lung mechanics due to better relaxation of the chest wall.

When used as a sedative agent, dexmedetomidine resulted in better patient-ventilator synchrony [15] and more ventilator free hours [16] in critically ill adults. Dexmedetomidine had shortened the weaning process in critically ill children [17]. Dexmedetomidine improved oxygenation and lung mechanics during OLV in thoracic surgery [10, 12] and in COPD patients undergoing lung cancer surgery [3]. Dexmedetomidine had a protective effect against independent lung injury during OLV [13]. Dexmedetomidine improved alveolar oxygenation when used for induction of anesthesia in children with tetralogy of Fallot [18]. In restrictive lung diseases, the available data were extracted from animal studies. Compared to Propofol, dexmedetomidine administration resulted in better lung characteristics in rats with experimental obesity [4]. Dexmedetomidine had a protective effect lipopolysaccharide-induced lung injury rats [14, 19]. To the best of our knowledge, this study is the first to investigate the effect of dexmedetomidine on oxygenation and lung mechanics in patients with restrictive lung disease.

According to the baseline characteristics, all our patients showed isolated pattern of restrictive lung disease without the evidence of obstructive pattern. Thus, our findings declare a relatively novel effect of dexmedetomidine infusion on respiratory mechanics in the population of morbidly obese patients with restrictive lung disease. This effect was not previously reported in humans. The favourable effects for dexmedetomidine on oxygenation and lung mechanics in our patients were moderate; we reported an improvement of nearly 10% in the P/F ratio after 90-min dexmedetomidine infusion. Lee et al. had reported similar improvement in oxygenation and lung mechanics in COPD patients undergoing lung cancer surgery [3]. Longer duration (and/or higher doses) might result in more significant results. Moreover, this moderate improvement might be of higher value in patients with compromised respiratory status in operating room and intensive care unit. However, this assumption need to be confirmed by randomized controlled trials.

Only five of our patients (12%) experienced postoperative hypoxia in the PACU that needed ICU admission. Although there was no significant difference between both study groups regarding postoperative ICU need, we could not generalize this finding because our study was not powered enough to judge it.

A 90-min dexmedetomidine infusion resulted in moderate improvement in oxygenation and lung mechanics in morbidly obese patients with restrictive lung disease.