Continuous infusion of dual analgesic and sedative agents (analgosedatives) with or without an additional sedative agent are a fundamental core in mechanically ventillated critically ill patient’s daily care. Analgosedatives are widely used in all world ICU units to achieve the target Richmond Agitation Sedative Scale (RASS) in the range of -1 to -4 [1]. Although commonly used morphine and other related opioids are effective, they cause an undesirable adverse effect, including but not excluded to; delirium, hypotension, elevating gastric residual volume (GRV), lowering ventilation free days, increasing emerging of multi-drug resistant bacteria of Acinetobacter.Baumannii, Pseudomonas.Aeruginosa, and Enterobacteriaceae.spp, and increasing overall mortality rate [2-4].

Unfortunately, Morphine has the tendency to cause hypotension resulting from histamine release, in addition to opioid-induced constipation which many patients develop during their ICU stay. [5-7] Also, there are limited data on the safety and efficacy of Morphine to support its use as a continuous infusion for sedation in septic shock mechanically     ventilated   ICU      patients.       This     study the continuous Morphine infusion in septic or non-septic mechanically ventilated critically ill patients in terms of the total vasopressors requirement (NErate), the hemodynamic parameters of MAP, systolic blood pressure (SBP), and diastolic blood pressure (DBP), the risk of opioid-induced constipation (OIC), the incidence of convulsion, the ICU and overall hospital length of stay (LOS), and the overall 28-day ICU mortality.            

This was a single-center observational retrospective study conducted in the departments of King Hussein Medical Center (KHMC) at Royal Medical Services (RMS) in Jordan between Apr 2018 and Sep 2020. This study was approved by our Institutional Review Board (IRB), and a requirement for consent was waived owing to its retrospective design. This study included a 78 septic and non-septic mechanically ventilated critically ill patients. Our sample was stratified into two groups: Group I (Septic critically ill patients who were on Morphine infusion) and Group II (Non-Septic critically ill patients who were on Morphine infusion. Analysis values were compared among the two tested groups by using Independent T-Test for continuous variables and Chi Square test for nominal data in which the continuous variables of all patients were expressed as Mean±SD and nominal data were expressed as numbers with percentages. Statistical analyses were performed using IBM SPSS ver. 25 (IBM Corp., Armonk, NY, USA) and p-values ≤0.05 were considered statistically significant.

The mean age of our studied critically ill patients was 58.94±10.37. 56 patients of the eligible sample were male while 22 were female. There were insignificant differences between the two groups regarding anthropometrics of body weight (BW) and body mass index (BMI), nutritional indices of total calorie input (TCI) and protein density (PD), acute phase reactants of c-reactive protein (CRP) and CRP to ALB ratio (CRP: ALB), laboratories of blood glucose level (BG) and blood urea nitrogen (BUN), liver functionality, admission length of stay (LOS) days, and overall 28-day ICU mortality. The analgosedative infusion rate of Morphine was significantly higher in Group I versus Group II which was accompanied by a significantly higher NErate. (4.16±0.32 ml/hr vs 4.12±0.34 ml/hr) and NErate of (11.22±1.70 mcg/min, 6.17±0.76 mcg/min).

The incidence of convulsive seizure was significantly lower in Group II vs Group I with number (%) 14 (35.9%), and 19 (48.7%), respectively. Regarding consumption rate of prokinetic (PROK) of either erythromycin or metoclopramide, the PROK rate was significantly lower in Group II compared with Group I with number (%) of 37 (94.9%), and 39 (100.0%), respectively. Demographics, anthropometrics, nutritional indices, laboratory data, hemodynamics, analgosedative and vasopressor infusion rate, and other primary and major clinical outcomes of GRV, convulsive incidence, LOS, and overall 28-day ICU mortality are fully described in Table 1-2.

A total of 78 patients were included in this study divided into two different groups as septic or non-septic and the type of analgosedative administered, Group I vs II with 39 vs 39 patients in each group, respectively. The anthropometric data for the patients included in the study is illustrated in Table 1, with a mean age of 58.94±10.37 years and BMI of 25.90±3.97 Kg/m2 for the total number of patients and no significant difference in age or BMI between the two groups. Some clinical data that may affect the interpretation of the results were taken into consideration and recorded, such as the Total fluid input, BG, CRP, and CRP: ALB. The differences in these measurements between the different groups were statistically insignificant (P-value > 0.05), as shown in Table 1. 

In our study, one group of the two studied groups was already off vasopressor infusion (Group II), while the other group was on Norepinephrine as a vasopressor (Group I). By comparing the results, the patients were on Morphine continuous infusion recorded a noticeable increase in hemodynamic parameters compared to baseline measurements, but at cost of increasing vasopressor requirements in Septic mechanically ventilated critically ill patients compared with non-Septic. These findings are consistent with findings from previous studies that demonstrated that Morphine does negatively affect hemodynamics and may actually increase vasopressor requirements when used as a continuous infusion in mechanically ventilated ICU patients especially if the patients have a sign of sepsis [8].

Other clinical outcomes were measured such as GRV which was increased in all groups but variably with magnitude increase the lowest among non-septic patients. This conclusion was further confirmed by the percent of patients administered Prokinetics within Group I and II. Interestingly, the incidence of convulsion seizure, the requirement of Morphine to maintain the target RASS, and the requirement of vasopressor to maintain the target MAP were lower in non-septic mechanically ventilated critically ill patients compared with septic cohort. Overall hospital/ICU length of stay and survival were not significantly different among the two groups [9].

This study is limited by its retrospective design, using single-center data, and the lack of multiple comparisons of various significant variables between Group I and II. Nonetheless, our center is an experienced and high-volume unit, so our data may be useful in other centers. A larger, multisite, and prospective study is needed to control for multiple confounders.

Table 1: Demographics, Anthropometrics, Laboratory Values, Nutritional Indices, and Admission Days

Group I: Septic critically ill patients who were on Morphine infusion. Group II: Non-Septic critically ill patients who were on Morphine infusion. N: Number of Patients.SD: Standard Deviation. S: Significant. NS: Non-Significant. 0: Baseline at admission. BW: Body Weight. BMI: Body Mass Index. CRP: C-reactive protein. g: Magnesium. BG: Blood glucose. K: Potassium. Temp: Temperature. M: Male. F: Female.               ALB: Albumin. CRP: ALB: CRP to ALB Ratio. TCI: Total Calorie Input. PD: Protein density input. BUN: Blood Urea Nitrogen. ICU: Intensive care unit. ∑FLUD I: Total fluid input.

Table 2:  Hemodynamics, Analgosedative and Vasopressor Infusion Rate, Prokinetic and Convulsive Rate, and Overall ICU Mortality

Group I: Septic critically ill patients who were on Morphine infusion. Group II: Non-Septic critically ill patients who were on Morphine infusion. N: Number of Patients. SD: Standard Deviation. S: Significant. NS: Non-Significant. 0: Baseline at admission. NE: Norepinephrine. SBP: Systolic Blood Pressure. DBP: Diastolic Blood Pressure. MAP: Mean Arterial Pressure. HR: Heart Rate. ICU: Intensive care unit. GRV: Gastric residual volume. CSP: Child Pugh Score. PROK: Prokinetic.

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