Article, Forensic Medicine

Optimal initial anticoagulant therapy in pulmonary thromboembolism: randomized trial suggested


instantaneous rigor or something else?B,BB

To the Editor,

Lee and Jung [1] had interpreted jaw muscle stiffness (masseter spasm) as instantaneous rigor. “Cadaveric spasm” or “instantaneous rigor” is a rare form of virtually rapid rigor that develops at the time of death with no period of post-mortem primary ftaccidity of muscles [2]. It often crystallizes the last activity of the victim prior to death, and hence, it becomes an important one in forensic investiga- tions. It rarely involves the whole body but typically involves only a group of muscles, such as the hands or arms. This phenomenon occurs when ATP supply of the body is exhausted at the time of death, for example, in a man who was shot dead after struggle.

Chakravarthy [3] reported antemortem muscle stiffness in the form of rigor mortis in a live patient and it was criticized. Masseter spasm is a common feature of hypoxia and is not an unheard phenomenon in patients with cardiac arrest, which is often known as hypoxic clenching or jaw clenching. Unfortunately, it is less or never discussed in the life support training programs. In the present context, we would like to highlight the mechanism and implications of this entity.

Muscle stiffness may happen owing to interplay of several brain stem structures and neurochemicals released during hypoxia affecting modulation of muscle tone. Kranjc et al.

[4] reported the occurrence of maximal neurotransmitter changes after hypoxic insult. Probably, oxygen and/or glucose deprivation disturb electrical transmission in the brain, alter cerebral energy mechanisms and contribute to accumulation of free radicals, all of which enhance resting muscle tension with a more pronounced effect on the masseter, thus resulting in hypoxic jaw clenching [5].

The rigidity/spasm is usually transient and resolves spontaneously but may be prolonged as reported [1]. This stresses the importance of pre-oxygenation in rapid sequence intubation and a contingency plan in failed airway. Proper bag mask ventilation and blind Nasotracheal intubation with or without lighted stylet are viable options if masseter spasm is prolonged.

Before embarking non-responsiveness to succinylcholine, one has to exclude improper technique of drug administra- tion, ineffective chest compression or malfunction of the intravenous line rather than patient’s physiology. The succinylcholine per se can produce transient masseter spasm [6] but resolves while fasciculation stops. However, other differential diagnoses for masseter spasm are pseudo- cholinesterase deficiency, myotonia and trismus of masseter as seen in malignant hyperthermia. The entity of masseter spasm or hypoxic jaw clenching has to be included in the educational programs on resuscitation.

? Financial support-Nil.

?? Conftict of interest-Nil.


Subramanian Senthilkumaran

Sri Gokulam Hospitals & Research Institute

Salem, TamilNadu, India E-mail address: [email protected]

Ritesh G. Menezes

Srinivas Institute of Medical sciences & Research Centre

Mangalore, India

Savita Lasrado

Father Muller Medical College

Mangalore, India

Ponniah Thirumalaikolundusubramanian

Chennai Medical College Hospital & Research Center

Irungalur, Trichy, India


  1. Lee JH, Jung KY. Emergency cricothyrotomy for trismus caused by instantaneous rigor in cardiac arrest patients. Am J Emerg Med 2012;30: 1014.e1-2.
  2. Knight B. Forensic pathology. 2nd ed. London: Arnold; 1996.
  3. Chakravarthy M. “Rigor mortis” in a live patient. Am J Forensic Med Pathol 2010;31:87-8.
  4. Krajnc D, Wemlinger TA, Neff NH, Hadjiconstantinou M. Neonatal hypoxia: early neurotransmitter responses and the consequences of treatment with GM1 ganglioside. J Pharmacol Exp Ther 1994;271: 1299-305.
  5. Pedersen JZ, Bernardi G, Centonze D, Pisani A, Rossi L, Rotilio G, et al. Hypoglycemia, hypoxia, and ischemia in a corticostriatal slice preparation: electrophysiologic changes and ascorbyl radical formation. J Cereb Blood Flow Metab 1998;18:868-75.
  6. Roman CS, Rosin A. Succinylcholine-induced masseter muscle rigidity associated with rapid sequence intubation. Am J Emerg Med 2007;25: 102-4.

Optimal initial anticoagulant therapy in pulmonary thromboembolism: randomized trial suggested

To the Editor,

Numerous lines of evidence suggest a need for an improvement in pulmonary thromboembolism (PTE) therapy:

  1. According to relevant US data (Heart Disease and Stroke Statistics-2012 Update), 30-day mortality of PTE is no less than 40.9%, which is clearly not acceptable [1].
  2. Moreover, residual thrombosis in pulmonary arteries can be found in 50% of PTE patients despite adequate antic- oagulation at 1 year [2]. Sometimes, residual thrombosis is diagnosed in as many as 70.9% of PTE patients, months after the index episode, which is much higher than we usually think [3]. American Heart Association Guidelines have recognized that the amount of residual thrombus after

408 Correspondence

anticoagulant therapy correlated strongly with the risk of recurrent venous thromboembolism [2]. Further- more, if the acute PTE has not resolved in 1 to 4 weeks, the embolic material becomes incorporated into the pulmonary arterial wall [2].

  1. In PTE patients, 6 months after the initial PTE episode, a 19.8% persistent echocardiographic right ventricle (RV) dysfunction or high pressure in pulmonary artery was found and related closely to residual thrombosis. As studied patients were hemodynamically stable, the figure might be even higher if we analyze all PTE patients [4]. Additionally, RV dysfunction persistence at the time of discharge was an independent predictor of long-term mortality and pulmonary embolism recurrence [5,6].
  2. Prospective studies suggest that chronic thromboembolic pulmonary hypertension (CTPH) occurs in ?3% of PTE patients [7]. After PTE initiates CTPH, pulmonary vascular remodeling may cause severe pulmonary hyper- tension out of proportion with pulmonary vascular thrombosis [7].

Therefore, our current protocol for PTE therapy is not optimal [8]. One of the ways to improve it is to select carefully additional PTE patients, who are not hypotensive, but who are likely to benefit from thrombolysis, which was the aim of the Pulmonary Embolism Thrombolysis Study trial.

The other possible approach to improve PTE treatment as a whole is to optimize anticoagulant therapy, because each PTE patient should receive it, unless contraindicated. Moreover, 90% of early deaths attributable to PTE, occur in patients without massive form [9]. The anticoagulant therapy is usually all what such patients get (of the Antithrombotic treatment) and, thus, the most important tool to prevent majority of early deaths.

One new avenue just opened. This year brought (for the first time) guidelines (American College of Chest Physicians 9), suggesting an oral drug rivaroxaban as a possibility for the initial (as well as prolonged) PTE treatment [7]. This recommendation is based upon the good results in the Oral Rivaroxaban Alone for Symptomatic Pulmonary Embolism (The EINSTEIN PE Study), a randomized, open-label, event- driven trial, involving 4832 PTE patients, which showed that rivaroxaban (15 mg twice daily for 3 weeks, and then 20 mg once daily) was noninferior (P=.003) to Standard therapy, enoxaparin, followed by an adjusted-dose vitamin K antagonist for 3, 6 or 12 for the primary efficacy outcome (symptomatic recurrent VTE): 2.1% events in the rivaroxaban group versus 1.8% in the standard-therapy group. The principal safety outcome (major or clinically relevant nonmajor bleeding) was found in 10.3% in the rivaroxaban group and in 11.4% of the standard-therapy group (P=NS). Major bleeding was observed in 1.1% in the rivaroxaban group and in 2.2% patients in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31-0.79; P=0.003) [10].
  • Moreover, individualized approach has been pro-
  • posed for the evaluation recently [11]. Namely, all relevant

    PTE guidelines recommend for all non-cancer patients that warfarin should be introduced on the first day and parenteral anticoagulants should be abandoned when international normalized ratio is over 2 in 2 consecutive days [2,7,12]. The main idea of individualized approach is not to start with warfarin form the first day, but individually. It is logical to decrease the intensity of anticoagulant therapy for PTE [by switching from stronger (parenteral) to weaker (oral drug, e.g., warfarin)], only after most of the following gets under control: symptoms, O2 saturation, electrocardiographic, echocardiographic, and/or Computed tomography pulmonary angiography findings of acute PTE, brain natriuretic peptide, D-dimer, and troponin [11].

    All in all, it is probably the right time to perform a randomized clinical trial to see if the two new therapeutic modalities for initial anticoagulation in PTE (rivaroxaban or individualized approach) have advantages over the current one. Such trial could have 3 arms:

    1. Standard care (ie, enoxaparin, fondaparinux or unfractio- nated heparin [UFH]);
    2. rivaroxaban arm; and
    3. individualized protocol (ie, fondaparinux, enoxaparin or UFH).

    As the individualized approach might expose a PTE patient to somewhat longer use of a parenteral anticoag- ulant, chances for Heparin-induced thrombocytopenia (HIT) will raise with enoxaparin and much more with UFH. Thus, as fondaparinux has very low probability to lead to HIT (and even may be used to treat HIT) [13], it may have the advantage over the other parenteral drugs in this context.

    To conclude, proposed randomized clinical trial may bring the answer to the burning and the most important question in PTE therapy today: Which is the optimal approach for the initial anticoagulant therapy in PTE? This answer is badly needed for most PTE patients.

    This work has been supported by the Serbian Ministry of Education and Science, grant No.175092.

    Goran P. Koracevic MD, PhD

    Department of Cardiology Clinical Centre and Medical Faculty University of Nis, Nis, Serbia

    E-mail address: [email protected]


    1. Writing Group MembersRoger VL, Go AS, Lloyd-Jones DM, et al. Executive summary: Heart Disease and Stroke Statistics–2012 update: a report from the American Heart Association. Circulation 2012;125:188-97.

    Correspondence 409

    1. Jaff MR, McMurtry MS, Archer SL, et al. American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arterio- sclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein throm- bosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011;123:1788-830.
    2. Kaczynska A, Kostrubiec M, Pacho R, et al. Elevated D-dimer concentration identifies patients with incomplete recanalization of pulmonary artery thromboemboli despite 6 months anticoagulation after the first episode of acute pulmonary embolism. Thromb Res 2008;122:21-5.
    3. Golpe R, Perez-de-Llano LA, Castro-Anon O, et al. Right ventricle dysfunction and pulmonary hypertension in hemodynamically stable pulmonary embolism. Respir Med 2010;104:1370-6.
    4. Ribeiro A, Lindmarker P, Johnsson H, et al. Pulmonary embolism: one-year follow-up with echocardiography Doppler and five-year survival analysis. Circulation 1999;99:1325-30.
    5. Grifoni S, Vanni S, Magazzini S, et al. Association of persistent right ventricular dysfunction at hospital discharge after acute pulmonary embolism with recurrent Thromboembolic events. Arch Intern Med 2006;166:2151-6.
    6. Kearon C, Akl EA, Comerota AJ, et al. antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e419S-94S.
    7. Koracevic GP. Current protocol for initial anticoagulants in pulmonary embolism: one size fits all? Am J Emerg Med 2011;29:460-2.
    8. Baglin T. What happens after venous thromboembolism? J Thromb Haemost 2009;7(Suppl. 1):287-90 [Review].
    9. EINSTEIN-PE Investigators, Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97.
    10. Koracevic GP. Time to individualize duration of parenteral antic- oagulation in pulmonary thromboembolism? Am J Emerg Med 2012;30: 1004-6.
    11. Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;29:2276-315.
    12. Warkentin TE. How I diagnose and manage HIT. Hematology Am Soc Hematol Educ Program 2011;2011:143-9.

    What is the real incidence of oral Tramadol-induced apnea? Is there any association between this type of apnea and mortality?B

    To the Editor,

    I would like to address the article recently published online in your journal titled “Tramadol-induced apnea” [1]. This is an interesting study aiming to determine the incidence and Predisposing factors of tramadol-related apnea. The authors reviewed the medical charts of the patients with their principle diagnostic code to be pure tramadol intoxication within a 14-month period. They determined an incidence rate

    ? Conftict of interest statement: None to declare.

    of 3.6% of Oral tramadol-induced apnea. They, then, divided the patients into 2 groups of those who had and had not developed apnea and compared some variables between these 2 groups finding no predisposing factors for oral tramadol-induced apnea. It seems that there are some serious weaknesses and limitations in the methodology of this study that prevents the reader from withdrawing definite conclu- sions. Of them, is, for instance, the lack of clarity on exactly how the diagnosis of “pure/isolated/alone” tramadol intox- ication was retrospectively made? Was the inclusion or exclusion of the cases based on urine drug screening test or other means including simple history (similar to other studies [2-5])? What confirmatory urine Drug test was used: immunoassay (with many false-positive results) or gas chromatography-mass spectrometry.

    As you know, apnea has so far been only reported in intravenous administration of tramadol (with or without Renal impairment) [6,7]. Respiratory depression due to tramadol intoxication has previously been explained in mixed drug overdose with tramadol [4]. Is it not possible that the authors could not have completely excluded mixed Drug overdoses? In addition, despite what the authors suggest several times throughout the article and is the basic hypothesis of the present study, it does not seem that there is an association between apnea and mortality due to the oral consumption of tramadol. As the studies have shown, death due to the consumption of oral tramadol is due to the coingestion of other central nervous system depressants [8-13]. Moreover, it is not clear what logic relationship exists between other parameters of the study– including the history of drug or substance abuse or history of suicidal attempts or self-poisoning and apnea–for which the authors have compared them between the 2 groups of “the patients with tramadol alone-induced apnea and the others.” Maybe, it was better if they compared parameters including concomitant abnormal signs and symptoms (if any) with apnea such as the changes in the level of consciousness, size of the pupils, and/or vital signs on presentation between these 2 groups (as the probable predisposing factors). Interestingly, two-thirds of the “Discussion” section is about the ultra-rapid metabolizers and suggestion of the high susceptibility of people in the Middle East to the opioid effects of tramadol, possible mechanisms of tramadol-induced seizure, and proconvulsant effects of naloxone in tramadol-Intoxicated patients that do not seem to be related to the tramadol-induced apnea. Of note, they have concluded that apnea is not preceded by prominent central nervous system depression even without evaluating the patients’ level of consciousness!

    Hossein Sanaei-Zadeh MD Medical School, Shiraz University of Medical Sciences Emergency Room/Division of Medical Toxicology

    Hazrat Ali-Asghar (p) Hospital 7143918796 Shiraz- Iran

    E-mail address: [email protected]