Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 7  |  Issue : 3  |  Page : 406-411

Influence of choice of analgesic agent on the course and outcome of sickle cell patients presented to ICU with acute chest syndrome


Department of Anesthesiology, Intensive Care, and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission03-Jan-2014
Date of Acceptance12-Feb-2014
Date of Web Publication27-Aug-2014

Correspondence Address:
Hatem Said Abdel Hamid
Department of Anesthesiology, Intensive Care, and Pain Management, Faculty of Medicine, Ain Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.139581

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  Abstract 

Background
Sickle cell anemia is an inherited disease in which red blood cells become crescent shaped, resulting in abnormal function causing small blood clots that give rise to recurrent painful episodes called sickle cell pain crises. Acute chest syndrome (ACS) is the leading cause of death among patients with sickle cell disease. The purpose of the study was to compare tramadol versus dexmedetomidine as a painkiller and a morphine-sparing drug, besides its role in improvement of the respiratory parameters and improving prognosis in patients with ACS.
Patients and methods
Over a period of 1 year, this prospective study was conducted on 60 sickle cell disease patients admitted to the ICU with ACS. Patients were randomly allocated into two groups, each containing 30 patients. Group A (n = 30) received morphine (10-20 mcg/kg/h) + tramadol (0.2 mg/kg/h) intravenous infusion. Group B (n = 30) received morphine (10-20 mcg/kg/h) + dexmedetomidine (0.5 mcg/kg/h) intravenous infusion. The efficacy of the study medications were compared in this study between the two groups in terms of pain relief assessment using a visual analogue scale. At the same time, the degree of sedation was monitored according to a four-point scale and bispectral index. Lung performance was assessed between the two groups through arterial blood gases, oxygenation index, and rapid shallow breathing index monitoring; hemodynamic parameters were also measured. All these variables were monitored for the first 4 days of admission to the ICU. The outcome prognosis was also compared between the two groups in terms of the average length of ICU stay, and survival or death was assessed during a follow-up of as long as 20 days.
Results
Significant difference was found with regard to pain relief among the study groups, with significantly lower (visual analogue scale) parameters in group A (n = 30) (morphine/tramadol) compared with group B (n = 30) (morphine/dexmedetomidine). No significant difference was discovered regarding degree of awareness, lung performance, and hemodynamic parameters among the two study groups. With regard to outcome prognosis, in terms of average length of ICU stay and mortality, comparable results were obtained in the two groups.
Conclusion
Adequate pain control is one of the cornerstones in the management of ACS; yet no influence on the outcome prognosis was detected in the choice of study medications.

Keywords: acute chest syndrome, dexmedetomidine, morphine, outcome prognosis, sickle cell disease, Tramal


How to cite this article:
Hamid HA, Sobhi A. Influence of choice of analgesic agent on the course and outcome of sickle cell patients presented to ICU with acute chest syndrome. Ain-Shams J Anaesthesiol 2014;7:406-11

How to cite this URL:
Hamid HA, Sobhi A. Influence of choice of analgesic agent on the course and outcome of sickle cell patients presented to ICU with acute chest syndrome. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2019 Sep 19];7:406-11. Available from: http://www.asja.eg.net/text.asp?2014/7/3/406/139581


  Introduction Top


Sickle cell disease (SCD) results from the substitution of a valine residue for glutamic acid at position 6 in the β-subunit of hemoglobin. Upon deoxygenation, hemoglobin S undergoes conformational changes, resulting in deforming erythrocytes, as they release their oxygen in the capillaries and are trapped in the microcirculation. The blockade of blood flow produces areas of tissue ischemia [1].

Vaso-occlusive crises are the most frequent and debilitating problems encountered by patients with SCD. The cooperative study of the natural history of SCD showed that about 5% of patients accounted for one-third of hospital days devoted to pain control [2].

Epidural analgesia has been used for pain control in some patients with SCD; this approach is most effective when the major discomfort is below the level of the chest. Although some patients receive good relief with epidural analgesia alone, others continue to require systemic analgesics [3].

Acute chest syndrome (ACS) is difficult to diagnose because its etiology and manifestations are variable. Diagnostic criteria include a new infiltrate on chest radiography associated with one or more new symptoms: fever, cough, sputum production, dyspnea, or hypoxia [4].

Pulmonary infiltrates can have a lobar distribution such as simple pneumonia, but are often bilateral, diffuse, and hazy opacities that resemble adult respiratory distress syndrome [5].

The arterial blood oxygen saturation commonly falls with ACS to a greater degree than it occurs with simple pneumonia of same magnitude.

Although bone marrow transplant can be curative, this therapy is indicated in only a minority of patients, predominantly owing to high risk of the procedure and difficulty in finding suitable donors. Gene therapy (replacing the hemoglobin S with hemoglobin A) may be an ideal treatment, but it is proven to be difficult in humans.

Therefore, the purpose of therapy is to manage and control symptoms resulting from crises and to try to limit the frequency of crises.

Exchange transfusion is the treatment of choice for ACS aiming to reduce the percentage of hemoglobin S cells to under 30%. The indications for exchange transfusion include poor pulmonary function as evidenced by arterial oxygen saturation (SaO 2 ) persistently less than 80%, despite aggressive ventilator support, unstable or worsening vital signs, and persistent respiratory rate greater than 30/min [6].

Hydroxyurea (Hydrea) was found to help some patients by reducing the frequency of painful crises and episodes of ACS, and decreasing the need for blood transfusions [7].

Treatment of pain with adequate analgesics is critical; non-narcotic medications may be effective, but some patients will require narcotics.

Tramadol (Tramal, 100 mg/2 ml ampoule) is a synthetic analgesic with a weak μ-opioid agonist; it also has important nonopioid spinal effect through the norepinephrine and serotonergic pathways. It undergoes slow metabolism; main biotransformation pathways are O-demethylation and N-demethylation. O-demethyl tramadol metabolite has shown to be one to five times more potent than the parent drug. Relatively high amounts of unchanged drug are excreted renally. Plasma elimination half-life is in the range of 5-7 h [8].

Dexmedetomidine (Precedex, 100 mcg/ml, available in 2 ml vial) is a highly selective α2 -adrenoreceptor agonist; it is the dextroenantiomer of medetomidine. Spectrum of activities is unique in that it has been shown to produce sedative/hypnotic, anesthetic-sparing, and sympatholytic effects. An interesting property of dexmedetomidine is its ability to induce minimal respiratory depression when compared with narcotics. The terminal elimination half-life of dexmedetomidine is approximately 2 h [9].

Morphine (10 mg/ml ampoule) is a highly potent opiate analgesic acting directly on the central nervous system, and at the synapses of the nucleus accumbens. It is a phenanthrene opioid receptor agonist, its main effect is binding to the μ-opioid receptors, resulting in analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is also a k-opioid receptor agonist resulting in spinal analgesia and miosis, and α-opioid receptor agonist plays a role in analgesia. The elimination half-life of morphine is ˜120 min [10].

The purpose of the study was to compare tramadol versus dexmedetomidine as a painkiller and a morphine-sparing drug, besides its role in improving the respiratory parameters and prognosis in patients with ACS.


  Patients and methods Top


Over a 2-year period, this prospective study was conducted in a combined medical and surgical ICU in a private hospital in KSA after approval of the study protocol by the hospital authority on 60 patients aged 35 ± 15, 33 male and 27 female, who originated either from the emergency room or the general ward.

Inclusion criteria

SCD patients admitted to the ICU with ACS diagnosed by a new infiltrate on chest radiograph, associated with one or more new symptoms such as fever, cough, sputum production, or hypoxia [4].

Patients were not enrolled in case of early discharge or death or patients, necessitating invasive mechanical ventilation (within 24 h of admission). On arrival to the ICU, patients were randomly allocated - using computer generated random numbers and sealed envelopes - into two groups, each containing 30 patients. Group A (n = 30) received morphine (10-20 mcg/kg/h) + tramadol (0.2 mg/kg/h) intravenous infusion. Group B (n = 30) received morphine (10-20 mcg/kg/h) + dexmedetomidine (0.5 mcg/kg/h) intravenous infusion. The efficacy of the medications were compared in this study between the two groups in terms of pain relief assessment using a 100-mm visual analogue scale (VAS), with end-points labeled no pain and (100) worst possible pain [11]. At the same time, the degree of sedation was monitored according to a four-point scale [Table 1] [12] and bispectral index (BIS) (Datex-Ohmeda, CS/3) [Table 2] [13].

Both visual analogue and sedation scores were recorded every 6 h (before the next dosage of Tramal or dexmedetomidine).
Table 1 Degree of sedation scoring [12]

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Table 2 Bispectral index readings and corresponding clinical state [13]

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Hemodynamic parameters including systolic blood pressure, diastolic blood pressure, and heart rate were recorded every hour noninvasively, using HPv570 monitor.

Lung performance was assessed every 6 h among the two groups through arterial blood gases measurements, using radiometer (Bayer rapid lab 855), oxygenation index monitoring (arterial/inspired oxygen ratio), and rapid shallow breathing index monitoring (respiratory frequency/tidal volume); tidal volume is measured using a Wrights respirometer (Wright Mark 8) attached to a one-way valve mouth piece connection and by using nasal clips [14].

All these variables were monitored for the first 4 days of admission to the ICU; the average length of ICU stay was compared among the two study groups, as well. Survival or death was assessed during a follow-up of as long as 20 days. Survival was defined as leaving the hospital alive and being able to resume all previous daily activities.

Statistical analysis

Statistical analysis was carried out using Epicalc 2000 software with the following inputs:

(1) Study power of 90% (power of test) with type II error of 10% (β).

(2) Significance level of 0.05 (type I error) (α). The sample size of 60 patients was found to be sufficient to conduct the study.

Statistical analysis was performed using computer software 'SPSS' (Statistical Package of Social Science) version 17.0; all data were expressed as mean ± SD, or number of patients (%). Data were analyzed by analysis of variance of non-normalized values for repeated measures on two factors (group and time). Pairwise multiple comparisons were tested using the Student-Newman-Keuls method. Significance was accepted at P-value of less than 0.05.


  Results Top


A total of 60 adult ICU patients, 33 male and 27 female, were enrolled in the study, meeting the diagnostic criteria of ACS [4].

Demographic baseline characteristics of the study population are presented in [Table 3], the mean age was 35 years (range 20-50 years), the mean body weight was 89 kg (range 75-103 kg), and the mean height was 1.68 m (range 1.57-1.79 m). Male patients constituted 55%, and female patients 45%.
Table 3 General characteristics of the study population

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Analgesic efficacy of the study medications were compared in [Table 4], in terms of pain relief assessment using a 100-mm VAS.

Significant difference was found with regard to pain relief among the two groups, with significantly lower VAS parameters in group A compared with group B (P < 0.05).

None of the patients had experienced more than moderate sedation (grade 3), according to the four-point scale [Table 5]. BIS readings ranged between 70 and 100 among the whole study population, as shown in [Table 6].
Table 4 Visual analogue scale parameters

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Table 5 Bispectral index readings, hemodynamic parameters, and four-point sedation score parameters

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Table 6 Arterial blood gases measurements

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No significant difference was discovered regarding the degree of awareness between patients in group A and group B in terms of four-point sedation score and BIS reading parameters (P > 0.05).

Lung performance was assessed among the two groups through arterial blood gases analysis [Table 7], oxygenation index, and rapid shallow breathing index monitoring [Table 8], showing comparable results among the two study groups.
Table 7 Oxygenation index and rapid shallow breathing index parameters

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No significant difference was discovered regarding hemodynamic parameters between patients in group A and group B as shown in [Table 9] (P > 0.05).

With regard to outcome prognosis, in terms of average length of stay, no significant difference was found between the two groups (P > 0.05). In addition, regarding mortality, comparable results were obtained in the two groups: group A survivors constituted 16.6% of the total study population, whereas group B constituted 20% of the total study population, as shown in [Table 10] (P > 0.05).
Table 8 Outcome prognosis parameters

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{Table 9}{Table 10}


  Discussion Top


Sickle cell anemia is one of the most prevalent diseases worldwide. The term ACS broadly describes a disease that is the leading cause of death and the second most common cause of hospitalization in patients with SCD [15]. The approach to diagnosis, monitoring, and treatment requires recognition of complication, correction - if possible - of inciting factors, maintenance of euvolemia, pain control, use of transfusions, and administration of oxygen if needed [16].

In the current study, we determined the influence of using two analgesic agents (tramadol and dexmedetomidine) infused. In addition to morphine intermittent dosage in the two groups of patients, fulfilling diagnostic criteria of ACS, we traced the efficacy of the study medications among the two groups in terms of pain relief assessment, using a VAS. At the same time, the degree of sedation was monitored according to a four-point scale and BIS. Lung performance was assessed among the two groups through arterial blood gas analysis, oxygenation index, and rapid shallow breathing index monitoring. Hemodynamic parameters were also measured. All these variables were monitored for the first 4 days of admission to the ICU. The outcome prognosis was also compared between the two groups in terms of the average length of ICU stay, and survival or death was assessed during a follow-up of as long as 20 days.

In a 30-center study conducted by Elliot and colleagues who analyzed 671 episodes of the ACS in 538 patients with SCD to determine the cause, outcome, and response to the therapy, nearly half the patients were initially admitted for another reason, mainly pain. When the ACS was diagnosed, patients had hypoxia, decreasing hemoglobin values, and progressive multilobar pneumonia. The mean length of hospital stay was 10.5 days. Of the patients, 13% required mechanical ventilation, and 3% died. Patients who were 20 or more years of age had a more severe course than those who were younger [6].

Another study by Ernest et al. [17] concluded that the risk of ACS is significantly associated with high systemic exposure to morphine and its active metabolite morphine-6-glucoronide after oral administration of slow-release morphine.

Brookoff and Polmano formally abandoned the use of short-acting opioid injections for sickle cell crises. Instead, under a new protocol, patients initially receive a continuous intravenous infusion of morphine. Once pain is substantially relieved, they are switched to oral controlled-release morphine, which is continued for 1 or 2 weeks after discharge from the hospital. Patients also receive a limited supply of immediate-release morphine tablets to take for pain exacerbations. As this new protocol was initiated, these authors reported a 44% decrease in hospital admission for sickle cell pain, a 23% reduction in length of stay, and a 67% decrease in the number of emergency department visits for painful crises [18].

Lewing et al. [19], in a retrospective study, documented in 988 admissions that, when nalbuphine is used alone as the single parenteral opioid agent to treat painful episodes in patients with SCD, the incidence of ACS is less than when compared with other opioids used to treat pain. Similar data were obtained by Buchanan et al. [20] who mentioned that opioid selection during sickle cell pain crisis may have an impact on the development of ACS. In a study conducted by William et al. [21], they observed a profound analgesic effect on patients with acute sickle cell pain crisis from the α2-agonist dexmedetomidine. Uzun and colleagues compared meperidine and tramadol with respect to their effects on the hemodynamics and pain relief in patients with SCD, who were admitted to the emergency department with painful crisis. Pain intensity and relief were documented by VAS and pain relief scale, respectively. Sedation level was defined according to the Ramsay sedation scale. The administration of both meperidine and tramadol resulted in a significant reduction in systolic and diastolic blood pressure after 2 h. Efficacy in pain relief between the analgesics was more rapid and better in the meperidine group, although the degree of relief was significantly improved compared with baseline levels in both groups. Sedation was more commonly seen in the meperidine group [22] ([Figure 1] and [Figure 2]).
Figure 1: Pain measurement by visual analogue scale. Data are presented as mean ± SD. Group T, tramadol group; group D, dexmedetomidine gr oup

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Figure 2: Hemodynamic measurement and bispectral index. Group T, tramadol group; group D, dexmedetomidine gr oup.

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  Conclusion Top


Tramadol is a good choice as a painkiller and a morphine-sparing drug in improving respiratory function and decreasing length of ICU stay, even better than dexmedetomidine. However, there was influence on mortality rates.


  Acknowledgements Top


 
  References Top

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4. Hayns JJr, Kirkpatric MB. The acute chest syndrome of sickle cell disease. Am J Med Sci 1993; 305:326-330.  Back to cited text no. 4
    
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7. Silva-Pinto AC, Angulo IL, Brunetta DM, Neves FI, Bassi, SC, Santis GC, et al. Clinical and hematological effects of hydroxyurea therapy in sickle cell patients: a single-center experience in Brazil. Sao Paulo Med J 2013; 131:238-243.  Back to cited text no. 7
    
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10.New T, Venable C, Fraser L, Rosenberg E, Schmidt J, James-Herry A, et al. Management of refractory pain in hospitalized adolescents with sickle cell disease: changing from intravenous opioids to continuous infusion epidural analgesia. J Pediatr Hematol Oncol 2013; 20:35-44.  Back to cited text no. 10
    
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14.Yang KL, Tobin MJ. A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N Engl J Med 1991; 23:1445-1450.  Back to cited text no. 14
    
15.Golden C, Styles L, Vichinsky E. Acute chest syndrome and sickle cell disease. Curr Opin Hematol 1998; 5:89-92.  Back to cited text no. 15
    
16.Leong CS, Stark P. Thoracic manifestations of sickle cell disease. J Thorac Imaging 1998; 13:128-134.  Back to cited text no. 16
    
17.Ernest A, Kopecky P, Sheila J, Prashant J, Gideon K. Systemic exposure to morphine and the risk of acute chest syndrome in sickle cell disease. Clin Pharmacol Ther 2004; 75:140-146.  Back to cited text no. 17
    
18.Brookoff D, Polmano R. Treating sickle cell pain like cancer pain. Ann Intern Med 1992; 116:364-368.  Back to cited text no. 18
    
19.Lewing K, Britton K, DeBaun M, Woods G. The impact of parenteral narcotic choice in the development of acute chest syndrome in sickle cell disease. J Pediatr Hematol Oncol 2011; 33:255-260.  Back to cited text no. 19
    
20.Buchanan ID, Woodward M, Reed GW. Opioid selection during sickle cell pain crisis and its impact on the development of acute chest syndrome. Pediatr Blood Cancer 2005; 45:716-724.  Back to cited text no. 20
    
21.William JP, Silpa G, Sharon D, Robert G. Dexmedetomidine relieves pain associated with acute sickle cell crisis. J Pain Symptom Manage 2007; 34:346-349.  Back to cited text no. 21
    
22.Uzun B, Kekec Z, Gurkan E. Efficacy of tramadol vs meperidine in vasoocclusive sickle cell crisis. Am J Emerg Med 2010; 28:445-449.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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